RxPG News : Alzheimer's

Simple lifestyle changes can prevent Alzheimer's

Wed, 20 Jul 2011 16:57:28 PST

( from http://www.rxpgnews.com ) Over half of all Alzheimer's disease cases can be prevented through lifestyle changes and treatment or prevention of chronic medical conditions.

The biggest risk factors for Alzheimer's disease are physical inactivity, depression, mid-life hypertension, low education, smoking, diabetes and mid-life obesity.

The findings are based on studies involving hundreds of thousands of participants worldwide, by Deborah Barnes, researcher at San Francisco Veterans Affairs Medical Centre and professor of psychiatry at the University of California, San Francisco.

Together, these risk factors are associated with up to 51 percent of Alzheimer's cases globally - and up to 54 percent cases in the US -, according to Barnes, reports journal Lancet Neurology.

'This suggests that some very simple lifestyle changes, such as increasing physical activity and quitting smoking, could have a tremendous impact on preventing Alzheimer's and other dementias in the US and worldwide,' said Barnes, according to Medical Centre statement.

The study results were presented at the 2011 meeting of the Alzheimer's Association International Conference in Paris, France.

Alzheimer's disease is the most common form of dementia among older people. Dementia is a brain disorder that seriously affects a person's ability to carry out daily activities.

--Indo-Asian News service

st/rah/tb

Falls- an early sign of Alzheimer's Disease

Tue, 19 Jul 2011 17:33:11 PST

( from http://www.rxpgnews.com ) Falls and balance problems may be early indicators of Alzheimer’s disease, researchers at Washington University School of Medicine in St. Louis report July 17, 2011, at the Alzheimer’s Association International Conference on Alzheimer’s Disease in Paris.

Scientists found that study participants with brain changes suggestive of early Alzheimer’s disease were more likely to fall than those whose brains did not show the same changes. Until now, falls had only been associated with Alzheimer’s in the late stages of dementia.

“If you meet these people on the street, they appear healthy and have no obvious cognitive problems,” says lead author Susan Stark, PhD, assistant professor of occupational therapy and neurology. “But they have changes in their brain that look similar to Alzheimer’s disease, and they have twice the typical annual rate of falls for their age group.”

Stark and her colleagues recruited 119 volunteers from studies of aging and health at Washington University’s Knight Alzheimer’s Disease Research Center. All the participants were 65 or older and cognitively normal.

Brain scans showed that 18 participants had high levels of amyloid plaques, a hallmark of Alzheimer’s. The two major findings in the brain of patients with Alzheimer's are amyloid plaques and neurofibrillary tangles. Amyloid plaques are found outside the neurons, neurofibrillary plaques are found inside the neurons. Amyloid plaques are mostly made up of a protein called B-amyloid protein. The other 101 volunteers had normal amyloid levels in the brain.

Participants in the study were asked to make a note of any falls. Then, the researchers followed up with a questionnaire and a phone interview about the falls. This follow-up allowed researchers to gather information for future analyses that will compare and contrast the nature of the falls.

About one in three adults age 65 or older typically fall each year. But in the 18 participants with high amyloid levels in the brain, two-thirds fell within the first eight months of the study. High levels of amyloid in the brain were the best predictor of an increased risk of falls.

“Falls are a serious health concern for older adults,” Stark says. “Our study points to the notion that we may need to consider preclinical Alzheimer’s disease as a potential cause.”

Excess copper, iron linked with Alzheimer's

Sun, 22 May 2011 11:49:40 PST

( from http://www.rxpgnews.com ) Washington, May 22 - The exact causes of neuro-degenerative disorders like Alzheimer's and Parkinson's disease are unknown, but scientists say excess of copper and iron in the human brain may be one of the influencing factors.

Another is DNA damage by reactive oxygen species, highly destructive molecules usually formed as a byproduct of cellular respiration.

Researchers from the University of Texas Medical Branch at Galveston have discovered how these two pieces of the neuro-degenerative disease puzzle fit together, the Journal of Alzheimer's Disease reports.

'Reactive oxygen species cause the majority of the brain cell DNA damage that we see in Alzheimer's and Parkinson's disease, as well as most other neuro-degenerative disorders,' said post-doctoral fellow Muralidhar Hegde, who led the study.

Alzheimer's sufferers may repeat statements and questions over and over, forget chats, appointments or events, routinely misplace possessions, often putting them in illogical locations. Eventually they forget the names of family members and everyday objects.

Humans ordinarily have small amounts of iron and copper in their bodies - in fact, the elements are essential to health, according to a Texas statement.

But some people's tissues contain much larger quantities of iron or copper, which overwhelm the proteins that normally bind the metals and sequester them for safe storage.

The result -- so-called 'free' iron or copper ions circulating in the blood are able to initiate chemical reactions that produce reactive oxygen species.

A high level of copper or iron, they say, can function as a 'double whammy' in the brain by both helping generate a large numbers of the DNA-attacking reactive oxygen species and interfering with the machinery of DNA repair that prevents the deleterious consequences of genome damage.

Depression increases risk of Alzheimer's disease

Tue, 08 Apr 2008 09:38:07 PST

( from http://www.rxpgnews.com ) Washington, April 8 - Depressed people are more likely to develop Alzheimer's disease than those with a more positive outlook to life, says a new study.

The finding is based on a six-year survey of 486 healthy people aged 60 to 90. Of those, 134 people had experienced depression once, prompting them to seek medical advice - 33 of them developed Alzheimer's.

People who experienced depression were 2.5 times more likely to develop Alzheimer's disease than normal people, the study found.

The risk was four times greater for those who were depressed before 60, according to the study, which has been published in the latest issue of the journal Neurology.

'We don't know yet whether depression contributes to the development of Alzheimer's disease or whether another unknown factor causes both depression and dementia,' said the study's author Monique MBreteler of Erasmus University Medical Centre in Rotterdam.

'We'll need to do more studies to understand the relationship between depression and dementia.'

One theory is that depression leads to loss of brain cells, which contributes to Alzheimer's disease.

One third of risk for dementia attributable to small vessel disease, autopsy study shows

Sun, 06 Apr 2008 04:00:00 PST

( from http://www.rxpgnews.com ) Alzheimer's disease may be what most people fear as they grow older, but autopsy data from a long-range study of 3,400 men and women in the Seattle region found that the brains of a third of those who had become demented before death showed evidence of small vessel damage: the type of small, cumulative injury that can come from hypertension or diabetes.

Dr. Thomas Montine, University of Washington, presented the study results at Experimental Biology 2008 in San Diego on April 6. His presentation was part of the scientific program of the American Society for Biochemistry and Molecular Biology (ASBMB).

In the autopsied brains of people who had experienced cognitive decline and dementia, 45 percent of the risk for dementia was associated with pathologic changes of Alzheimer's disease. Another 10 percent of dementia risk was associated with Lewy bodies, neocortical structural changes that indicate a degenerative brain disease known as Lewy Body Dementia, believed by some clinicians to be a variant of Alzheimer's and/or Parkinson's disease. But a third of the risk for dementia (33 percent) was associated with damage to the brain from small vessel disease.

Dr. Montine and his colleagues believe that, and are now studying in more detail, this small vessel damage is the cumulative effect of multiple small strokes caused by hypertension and diabetes, strokes so small that the person experiences no sensation or problems until the cumulative effect reaches a tipping point. This may be good news, says Dr. Montine. At a time when prevention and treatment for Alzheimer's remain investigational, methods for preventing complications of hypertension and diabetes are currently available.

These findings are very different from both conventional wisdom and from those of most autopsy studies of brain aging and dementia, says Dr. Montine.

Why such different results? Perhaps because of the broad reach of the population on which the autopsy study was based, says Dr. Montine. Most studies looking at the structural changes on autopsy in brains of persons with dementia have focused on participants in Alzheimer's disease center studies or in populations limited to one gender, ethnic or professional group. Individuals in this study were part of the Group Health Cooperative, one of the oldest and largest managed care programs in the United States.

Members in the group who reach 65 with normal cognitive ability are eligible to volunteer for an Adult Changes in Thought (ACT) study, established by Dr. Eric Larson, director of Research at the Group Health Cooperative. ACT participants undergo cognitive, neurological and psychological tests every two years until their death.

Between 1994 and 2006, the period covered by this study, 3,400 men and women entered the ACT study. They were representative of the Seattle urban and suburban area: white, Asian, African American and Hispanic, with a range of educational and professional levels. During this 12-year period, some participants suffered cognitive impairment and dementia, while others did not. Roughly a third of all participants died, and autopsies were performed on the 221 who had given permission for this to be done.

With 55 percent of the risk for dementia attributable to Alzheimer's and Lewy Body Dementia, these findings underscore the therapeutic imperative for developing new pharmacologic and other means of preventing or delaying the onset of Alzheimer's and Lewy Body disease, says Dr. Montine. But the unexpected finding that a third of the risk for dementia is related to small vessel disease also provides an additional reason to control hypertension and diabetes: not only to protect cardiovascular and renal health but also to protect the health of the brain.

Omega-3 supplements affect Alzheimer's symptoms

Fri, 22 Jun 2007 16:00:00 PST

( from http://www.rxpgnews.com ) Omega-3 supplements can, in certain cases, help combat the depression and agitation symptoms associated with Alzheimer's disease, according to a clinical study conducted at the Swedish medical university Karolinska Institutet.

A number of epidemiological studies have shown that eating fatty fish provides a certain degree of protection against Alzheimer's and other dementia diseases - an effect often thought attributable to the omega-3 fatty acids it contains. Some studies also suggest that omega-3 can have a therapeutic effect on some psychiatric conditions.

Researchers at Karolinska Institutet and Uppsala University have now examined whether omega-3 supplementation has any effect on the psychiatric symptoms associated with Alzheimer's disease. Just under 200 patients with mild Alzheimer's were divided into two groups, one of which received omega-3, and one a placebo. The study lasted for one year.

There was no observable difference in therapeutic effect between the patients receiving the omega-3 and the placebo group. However, when the researchers took into account which of the patients carried the susceptibility gene APOE 4 and which did not, an appreciable difference appeared. Carriers of the gene who had received active treatment responded positively to the omega-3 as regards agitation symptoms, while non-bearers of the gene showed an improvement in depressive symptoms.

The team points out that no general therapeutic recommendations can be made from the results until larger studies on individuals with more pronounced neuropsychiatric symptoms are conducted.

Beta-secretase (BACE) can Disrupt Brain's Neural Activity in the Alzheimer's

Tue, 19 Jun 2007 16:00:00 PST

( from http://www.rxpgnews.com ) An enzyme involved in the formation of the amyloid-beta protein associated with Alzheimer's disease can also alter the mechanism by which signals are transmitted between brain cells, the disruption of which can cause seizures. These findings from researchers at the MassGeneral Institute for Neurodegenerative Disorders (MGH-MIND) may explain the increased incidence of seizures in Alzheimer's patients and suggest that potential treatments that block this enzyme - called beta-secretase or BACE - may alleviate their occurrence.

"We have found a molecular pathway by which BACE can modulate the activity of sodium channels on neuronal cell membranes," says study leader Dora Kovacs, PhD, director of the Neurobiology of Disease Laboratory in the Genetics and Aging Research Unit at MGH-MIND. "That implies that elevated BACE activity may be responsible for the seizures frequently observed in Alzheimer's patients."

Alzheimer's disease is characterized by plaques within the brain of the toxic amyloid-beta protein. Amyloid-beta is formed when the larger amyloid precursor protein (APP) is clipped by two enzymes ' BACE and gamma-secretase which releases the amyloid-beta fragment.

Signaling impulses in nerve cells are transmitted via voltage-gated sodium channels, structures on the cell membrane that transmit electrochemical signal by admitting charged sodium particles into the cell's interior. Sodium channels consist of an alpha subunit, which makes up the body of the channel, and one or two beta subunits that help to regulate the channels' activity.

Previous studies from Kovacs' team and others showed that the BACE and gamma-secretase enzymes that release amyloid-beta from APP also act on the beta2 subunit of neuronal sodium channels. The current study was designed to examine how this processing of the beta2 subunit may alter neuronal function.

Lead author Doo Yeon Kim, PhD, and colleagues first confirmed that the beta2 subunit, similar to APP, can be acted on by BACE and gamma-secretase, releasing a portion of the beta2 molecule from the cell membrane. A series of experiments using brain tissue from animal models and from Alzheimer's patients revealed the following series of cellular events: Elevated levels of the free beta2 segment within the cell appear to increase production of the alpha subunits, but those molecules are not incorporated into new sodium channels on the cell surface. The resulting deficit of membrane sodium channels inhibits the passage of neuronal signals into and through the cells.

Neuronal sodium-channel dysfunction is known to cause seizures in both mice and humans. In a supplement to the current paper the investigators present evidence that sodium channel metabolism is altered in the brains of Alzheimer's patients compared with non-demented individuals of similar age.

"Our study suggests that the BACE inhibitors currently being developed to reduce amyloid-beta generation in Alzheimer's disease patients may also help prevent seizures by alleviating disrupted neural activity," Kovacs explains. "However, complete inhibition of BACE activity could interfere with the enzyme's normal regulation of sodium channels, so therapeutic strategies using those inhibitors will need to be carefully designed." Kovacs is an associate professor of Neurology at Harvard Medical School.

Nursing home placement associated with accelerated cognitive decline in Alzheimer's disease

Mon, 04 Jun 2007 16:00:00 PST

( from http://www.rxpgnews.com ) People with Alzheimer's disease experience an acceleration in the rate of cognitive decline after being placed in a nursing home according to a new study by Rush University Medical Center. The study, published in the June issue of the American Journal of Psychiatry, finds that prior experience in adult day care may lessen this association.

The observational study involved 432 older persons with Alzheimer's disease who were recruited from health care settings in the Chicago area. At baseline, they lived in the community and 196 participants were using day care services from 2 to 6 days a week for an overall mean of 1.7 days a week. At six month intervals for up to four years, they completed nine cognitive tests from which a composite measure of global cognition was derived.

On average, cognition declined at a gradually increasing rate for all participants. During the study period, 155 persons were placed in a nursing home, and placement was associated with a lower level of cognition and more rapid cognitive decline.

Study participants who had previous adult day care experience fared better. As level of day care use at study onset increased, the association of nursing home placement with accelerated cognitive decline substantially decreased. Thus, people using day care 3 to 4 days a week at the beginning of the study showed no increase in cognitive decline upon nursing home placement.

The findings suggest that experience in day care may help individuals with Alzheimer's disease make the transition from the community to institutional residence, said study author Robert S. Wilson, Ph.D., a neuropsychologist at the Rush Alzheimer's Disease Center.

The study also found that a higher level of education was associated with accelerated cognitive decline upon nursing home placement. Yet, day care use markedly reduced the association of education with accelerated cognitive decline in the nursing home; further evidence that there is a robust association between day care experience and cognition during the transition to a nursing home.

The authors considered the possibility that nursing home placement is simply a sign of increased severity of Alzheimer's disease. Yet, the nursing-home-related increase in cognitive decline was observed even after simultaneous control for cognitive and noncognitive indicators of dementia severity at the time of nursing home entry.

Alternatively, the increased cognitive decline upon placement may reflect difficulty adapting to an unfamiliar environment, consistent with clinical reports of increased confusion and behavior problems in those with dementia during acute hospitalization or trips away from home. Patients who had prior adult day care services may be better able to adjust to the unfamiliar environment.

Alzheimer's weight gain initiative also improved patients' intellectual abilities

Tue, 15 May 2007 19:10:55 PST

( from http://www.rxpgnews.com ) Swedish researchers have found a way to increase the weight of people with Alzheimer's, by improving communication and patient involvement, altering meal routines and providing a more homely eating environment

During the three-month study, published in the May issue of Journal of Clinical Nursing, 13 of the 18 patients in the intervention group put on weight, compared with just two of the 15 patients in the control group.

Patients who gained weight also displayed improved intellectual abilities.

"Weight loss is a common issue among people with dementia and in particular Alzheimer's" explains lead researcher Anna-Greta Mamhidir from the Karolinska Institutet in Stockholm, Sweden.

"Meal environment, communication difficulties, loss of independence and confusion are just some of the factors that appear to contribute to this problem.

"Malnutrition can also lead to other serious issues, such as increased infection rates, delayed wound healing and increased risk of hip fractures."

The aim of the study was to measure weight changes in patients with moderate and severe dementia and analyse whether providing staff training and a more supportive environment could lead to weight gain.

Two nursing home wards with similar staffing profiles and numbers of patients were selected. Both received meals from the same central kitchen.

The medical profiles of the two groups of patients were similar and drug regimes were unaltered during the study. Most of the patients had communication problems and memory loss and were physically dependent on staff.

Patients in the intervention group weighed between 31.5kg and 76kg at the start of the study, with an average weight of 55.9kg. By the end of the study this average had risen to 56.4kg.

When the team looked at individual patients they found that the largest weight gain in the intervention group was 7kg (15.4 pounds) and the smallest was 0.6kg (1.3 pounds).

Patients in the control group weighed between 45kg and 76.3kg at the start of the study, with an average weight of 62.5kg. This average fell to 58.4kg over course of the study.

Staff in the intervention group attended a one-week training course run by a psychologist and professor of nursing science. It comprised 20 hours of lectures and 18 hours of group discussion covering three key themes: delivering care in a way that promotes the patient's integrity, how to communicate more effectively with patients with dementia and how to create a calmer and more homely environment.

During the study, the staff who had received training were asked to keep diary notes of any changes and they effect they had on patients. They also received support and encouragement from a research assistant, who spent most days on the ward, and a nurse researcher who visited the ward three to four times a week.

"We felt that this level of involvement in the project would make it easier for staff to accept and implement these new ideas" says Anna-Greta Mamhidir.

New pictures were placed on the dining room walls and staff worked with patients to print new patterns on curtains and tablecloths.

Patients' rooms were given name plates, they were encouraged to have more private items in their rooms and staff wore brightly coloured clothes.

The prepared trays sent by the kitchen were replaced with serving bowls and patients were encouraged to help themselves.

No changes were made to the control ward.

Staff on the intervention ward noted in their diaries that the changes increased the contact between patients and staff and created a more pleasant atmosphere.

"Patients took part in activities, sat at the table together during mealtimes and served themselves food from bowls, encouraging them to be more independent and interact more with other patients" says Anna-Greta Mamhidir.

"The initiative was so successful that staff on the control ward were given the same training at the end of the study so that they could make the same improvements on their ward."

Roger Watson, editor of Journal of Clinical Nursing, says that the research carried out by Mamhidir and colleagues makes a significant contribution to the field of food and dementia and has congratulated them for delving into what is a complex and difficult area.

"Societies are ageing and debates about food and old people and food and dementia â which are regular topics in the Journal â can only increase" he says.

"The current study shows a marked difference in weight change between the intervention and control groups and a strong link between weight gain and improved intellectual ability.

"I hope that it will stimulate further lines of enquiry as there is a vital need to improve nutrition among elderly patients, particularly those with Alzheimer's and other forms of dementia."

New therapeutic targets for neurodegenerative diseases

Thu, 10 May 2007 08:22:23 PST

( from http://www.rxpgnews.com ) The focus of work in the Neurosciences Departmentâs Neurobiology Laboratory at the University of the Basque Countryâs Faculty of Medicine and Odontology is the investigation of the molecular and cellular bases of neurodegenerative illnesses â those that affect the brain and the spinal cord. Some of these neurodegenerative illnesses are well known and affect a significant part of the population, such as Alzheimerâs disease and multiple sclerosis.

Researchers at the University of the Basque Country (UPV-EHU) are studying the signals in the central nervous system - the brain and the spinal cord - that do not function well, in particular, those signals that cause the death of nerve cells. There are basically two types of cells in the central nervous system: neurones and the glial cells. Both types are sensitive to these functioning errors and both can die. In the case of Alzheimerâs disease, it is the neurones, above all, that die. However, in the case of multiple sclerosis, it is a class of glial cells â known as oligodendrocytes â that perish.

From in vitro cells to biological samples of human origin

The researchers at the Neurobiology Laboratory are investigating cells in cultures - neurones, oligodendrocytes or other cells of the nervous system -, and are trying to reproduce in vitro circumstances that are thought to be relevant in these ailments. That is to say, they are creating the conditions that cause the death of these cells, in order to determine what molecules intervene in the process â from the moment of the lethal signal to the point where the cells collapse. In this type of experimental work a series of molecules involved in the death process are identified, the aim being to come up with pharmaceutical medicines that will improve treatment.

Apart from working with in vitro cells, they are also experimenting with animals that reproduce some of the elements involved in neurodegenerative illnesses under certain conditions, i.e. sensory symptoms, motor symptoms, etc. and that can be induced in these animals. And they are examining if these substances that have proved to be interesting with the in vitro cells are also efficacious in these experimental models of the diseases.

Moreover, over the past few years they have had the opportunity to study samples of brains of patients who have died of some neurodegenerative illness, such as, for example, multiple sclerosis. The illnesses leaves a mark in these samples and, although the brain has been at a terminal stage of the illness, they can investigate to see if there are signs of alterations to the molecules similar to those observed in the experiments, both with cells and with the animals. In this way it can be determined if the molecular targets discovered experimentally are relevant or not to the neurodegenerative processes and, if they are, develop pharmaceutical medicines that can neutralise these processes or the elements that enable them to progress, the goal being to halt the process of death.

In collaboration with neurologists they have also been able to access biological samples of patients who have given their consent and donated them to research. Biological samples such as, fundamentally, blood, given that changes in blood plasma that may indicate alterations at the brain level can be identified.

In search of biological samples

All this is a dynamic process that enables clues to be found and which are, in some cases, relevant for developing pharmaceutical drugs that can halt, or at least slow down, the course of a neurodegenerative illness. Apart from finding these molecules or targets that interact with pharmaceutical medicines, in order to stop the process of progressive deterioration, substances that favour the survival of the neurones and oligodendrocytes are also sought; substances such as, for example, antioxidants, given that, in many of the neurodegenerative illnesses the cells die because oxidative stress is produced. In recent years the Neurobiology Laboratory researchers have found a number of antioxidants that put a brake on the dying process and can act as a neuroprotector. Antioxidants of natural origin that are in our diet â fruit, vegetables, and so on â and which, in some way appear to alleviate the damage cause by these illnesses.

In short, the goal is to gain more knowledge about the molecular bases of these pathologies, define therapeutic targets (molecules of the cell that recognise a pharmaceutical drug and thus respond to it) and, in the last analysis, to come up with pharmaceutical medicines that improve treatment.

Mayo Clinic Research Suggests Patterns of Brain Tissue Loss in Early Alzheimer's Disease May Predict Course of Disease

Tue, 01 May 2007 09:35:06 PST

( from http://www.rxpgnews.com ) Magnetic resonance imaging (MRI) that shows patterns of brain tissue loss may help physicians predict which patients with amnestic mild cognitive impairment (early Alzheimer's disease) will develop full-blown Alzheimer's, according to findings of a Mayo Clinic study presented in Boston today at the annual meeting of the American Academy of Neurology.

By comparing patterns of brain tissue loss in 89 patients with amnestic mild cognitive impairment symptoms, Mayo Clinic researchers found that the 52 patients who developed Alzheimer's lost more tissue in areas of the brain involved in thinking, planning and remembering than did the 37 patients who remained stable and did not progress to Alzheimer's. Amnestic mild cognitive impairment is a transition stage between the cognitive changes of normal aging, specifically memory loss, and the more serious problems caused by Alzheimer's disease.

In the future, these findings may improve physicians' ability to predict the course of the disease and may help identify mechanisms that drive the progression of Alzheimer's -- or protect against it.

"The regions of tissue loss in the brain that the patients with Alzheimer's disease experienced fit the known anatomic progression pattern of Alzheimer's disease," explains Clifford Jack, M.D., the senior author on the study. "But the lack of grey matter tissue loss in the clinically stable patients (patients who didn't progress to full-blown Alzheimer's disease) was unexpected. Why there are these differing patterns of brain atrophy between the two groups is not known, and is a topic of ongoing research."

"Grey matter" refers to brain tissue made up of nerve cell bodies -- the kinds of cells that are destroyed by Alzheimer's disease. Jennifer Whitwell, Ph.D., the study's lead author who presented the findings, says "The fact that there is this difference in tissue atrophy and it is clearly visible on MRI suggests the differential patterns of brain atrophy may be clinically useful in predicting the likely course of Alzheimer's disease. It also may help patients and families prepare for a specific kind of future. This ability alone would be an advance, because one of the most devastating things about Alzheimer's disease is the loss of control and the inability to plan."

Significance of the Mayo Clinic Study

Using MRI images to identify which cognitively impaired patients are likely to progress to Alzheimer's disease and which are likely to remain stable would be an important advance in terms of characterizing the disease and its likely clinical course. Physicians have no way of doing this now. Use of MRI imaging for this identification is still experimental and is not yet available for patient care.

About the Study

In the study, 89 patients who had mild cognitive impairment that included amnesia were given an initial MRI scan and monitored by physicians for 3.5 to 4.5 years. During this time they had clinical exams and additional MRIs to document changes in brain tissue, behavior and cognitive abilities. Each test subject was matched to a healthy person of the same age and gender so physicians could compare changes in the early Alzheimer's disease group two ways: with each other and with a healthy person.

Results

Compared to the control group:

-- patients who developed Alzheimer's disease showed a pattern of loss on both sides of the brain affecting the mesial and inferior temporal lobes, and to a lesser extent, the temporoparietal association neocortex and frontal lobes.

-- stable patients who did not progress to Alzheimer's disease showed no regions of grey matter loss compared to normal elderly control subjects.

Compared to each other, patients who developed Alzheimer's disease showed greater loss in the mesial and inferior temporal lobes, the temporoparietal association neocortex, posterior cingulate and frontal lobes than the stable patients who did not progress to Alzheimer's disease.

Inhaled anesthetics may accelerate the onset of Alzheimer's Disease

Sat, 10 Mar 2007 11:48:51 PST

( from http://www.rxpgnews.com )

It is important to remember that this effect is likely to be subtle, especially with brief surgical procedures, so the risk of not having needed surgery may exceed any potential risk from this still unproven effect. But this latest study adds a little urgency to the effort to find out.

Researchers at the University of Pennsylvania's School of Medicine have discovered that common inhaled anesthetics increase the number of amyloid plaques in the brains of animals, which might accelerate the onset of neurodegenerative diseases like Alzheimer's. Roderic Eckenhoff, MD, Vice Chair of Research in the University of Pennsylvania's Department of Anesthesia and Critical Care, and his co-authors, report their findings in the March 7th online edition of Neurobiology of Aging.

Every year over 100 million people undergo surgery worldwide, most under general anesthesia with an inhaled drug. These drugs clearly affect cognitive ability at least in the short term, but the growing concern is that inhaled anesthetics may affect a person well beyond the perioperative period, even permanently. Several factors appear to play a role in this subtle loss of cognitive ability, most notably age.

A specific effect of these drugs on dementias like Alzheimer's disease, though suspected for many years, has only been recently supported by data. In 2003, Eckenhoff's group showed that the inhaled anesthetics enhance the aggregation and cytotoxicity of the amyloid beta peptide. Just last month, a study reported that these drugs also enhance the production of amyloid beta in isolated cells. But these protein and cell culture studies are a long way from showing that an effect occurs in vivo. This new study provides the first evidence that the predicted effect occurs in animals.

"This animal study data suggests that we have to at least consider the possibility that anesthetics accelerate certain neurodegenerative disorders," said Eckenhoff. "In the field of Alzheimer's research, most effort is focused on delaying, not curing the disease. A delay in the onset of Alzheimer's disease of only three to five years would be considered a success. Therefore, if commonly used drugs, like anesthetics, are accelerating this disorder, even by a few years, then a similar success might follow even small changes in the care of the operative patient."

Mice don't naturally get Alzheimer's, so the animals in this study were genetically engineered to express the human protein responsible, called amyloid beta. "These mice develop a syndrome with many features of the human disease," explains Eckenhoff. Post-doctoral fellow and first author Shannon Bianchi, MD, exposed "middle-aged" Alzheimer mice to anesthetics at low to moderate concentrations for two hours a day over a total of five days, not unusual for a clinical scenario. The cognitive abilities of the mice were then analyzed using standard behavioral tests, and their brains were examined for plaque and cell death.

"Compared to controls, the anesthesia did not appear to worsen cognitive ability, which was already considerably compromised at this age, but it did accelerate amyloid beta aggregation and plaque appearance," said corresponding author Maryellen Eckenhoff, PhD. "We need to test whether anesthetic at earlier, presymptomatic stages, might accelerate both cognitive loss and plaque." This is the main cause of concern because a large fraction of clinical patients receiving inhaled anesthetics during surgery are older, but presymptomatic individuals.

Are there anesthetics that do not accelerate plaque? "We think so, but far more research is necessary to show this with any confidence. We have to take this one step at a time – a problem has still not been demonstrated in humans". It is important to remember that this effect is likely to be subtle, especially with brief surgical procedures, so the risk of not having needed surgery may exceed any potential risk from this still unproven effect. But this latest study adds a little urgency to the effort to find out. "If inhaled anesthetics are contributing to the rise and early onset of this devastating disease then we need to know, and soon," concludes Eckenhoff.

Amyloid plaques and neurofibrillary tangles are mere markers, not cause of Alzheimers disease

Thu, 15 Feb 2007 03:20:03 PST

( from http://www.rxpgnews.com ) A completely new approach to the study of Alzheimers disease, initiated by a professor at the University of California, Santa Barbara, may solve a critical piece in the puzzle of the disease. This tragic neurological illness progressively erases memory in its millions of victims. The key to the new approach is understanding the way certain proteins in the brain fold, or rather misfold.

Michael Bowers, a professor in the Department of Chemistry and Biochemistry, developed this project, which is being funded by the National Institutes of Health. Bowerss laboratory will receive $1.3 million of the total $9 million project grant, plus biological samples worth an additional $500,000. The grant covers a five-year period. Four institutions are involved.

Bowers is using specialized chemical research methods and applying them to biology. His research will depend upon the study of rare peptides, or strings of amino acids, that are difficult to produce. These will be provided by co-investigator David Teplow, a professor at UCLAs David Geffen School of Medicine, who has been involved in Alzheimers research for over 10 years. Joan-Emma Shea, also a professor in UCSBs Department of Chemistry and Biochemistry, heads the theoretical modeling aspect of the project.

Until about five or six years ago, everyone assumed that the large amyloid plaques, or neurofibrillary tangles, that were found in the brains of Alzheimers victims were the cause of the disease, said Bowers. However, recent scientific discoveries indicate that these large, insoluble aggregates might merely be markers of the disease they do not cause the disease. Rather, smaller soluble oligomers, or peptide complexes, are now felt to be the causative agents, and I find that very interesting.

He explained that now the hunt is on for the small stuff. Because of their expertise in certain chemical methodologies, Bowers and his research group are able to track down the molecular level changes that lead to development of the disease.

The process of aggregation of proteins that cause the plaque begins in a way that Bowers has begun to clarify. The goal is to find non-toxic drugs that will interrupt the aggregation process. If we can do that, we can stop the disease, said Bowers. However, once you start losing neurons, things become very difficult, because the body doesnt readily replace them due to their very large size. If we could find a marker, early on, to indicate when the patient first has the disease, then the new drug or drugs that we hope to develop could prevent further damage.

Bowers described his approach as a whole new way to determine the structure and composition of the Abeta 42 peptide and its oligomers that are primarily responsible for Alzheimers disease. The research team is analyzing the way this peptide folds, causing it to aggregate and disrupt neuronal function.

In biology, structure and function are tightly coupled, said Bowers. When it became clear that small soluble oligomers were most probably the toxic agents, I realized our ion mobility methods could contribute, since we could measure the oligomer distribution and shapes of these peptides for the first time.

Three years of preliminary work convinced the National Institutes of Health to provide funding. In the last several months, I believe we have uncovered the identity and shape of the primary toxic oligomer, said Bowers. Our results are consistent with findings on transgenic mice, recently published in the journal Nature, indicating that soluble oligomers with masses matching those we have identified have been extracted from the brains of the diseased animals.

The transgenic mice that Bowers refers to are laboratory mice that have had the gene that creates the Abeta 42 precursor protein spliced into their genome. This process has been shown experimentally to produce memory loss in the animals.

The key aspect of ion mobility is its ability to measure accurate cross sections of complex aggregations of proteins and obtain information on their three-dimensional shape. When coupled with mass spectrometry, electrospray ionization, and high-level molecular modeling, it becomes a very powerful technique.

The experiment starts with electrospray ionization, a method of spraying the solution containing the peptides of interest into fine droplets and then letting the droplets evaporate. Following evaporation, mass spectrometry is employed to determine the mass or weight of the species that were in the solution, and from that to determine the composition. Finally ion mobility is used to show the shape of the Abeta 42 peptide and its oligomers.

Our experimental and theoretical methods allow us to investigate structure, aggregation, and energetics in a variety of protein systems, said Bowers. In addition, we are able to explore correlations between solution and gas phase protein structures, learning that in many critical cases, these structures are very similar.

The experimental methodology for the Alzheimers study was developed at UCSB 15 years ago, in studies involving buckyballs. Buckyball is the nickname for the versatile carbon molecule known as C60, which scientists named buckminsterfullerene after American architect R. Buckminster Fuller, who designed geodesic domes in a soccer-ball shape. Our ion mobility and mass spectrometry methods provide a new way to attack the molecular basis of neurological diseases that has not been explored until now, said Bowers.

Bowers and his group are currently investigating proteins involved in the study of several neurological diseases. Besides Alzheimers disease, they are studying Parkinsons disease and the various transmissible spongiform encephalopathies or prion diseases. In this latter case Bowers is receiving funding from the British government to find an ante-mortem test for the bovine prion disease usually called mad cow disease. The same test, if successful, should also work on deer and elk; an epidemic in the Midwestern United States now affects these animals.

Isoflurane may produce Alzheimer's-like changes in the brain

Thu, 08 Feb 2007 03:56:30 PST

( from http://www.rxpgnews.com )

It is known that a small but significant number of surgical patients experience a form of dementia in the postoperative period, but there is insufficient evidence of a direct connection between anesthesia and the risk of dementia.

A new study has found how one of the most commonly used anesthetics may produce Alzheimer's-like changes in the brain. Previous studies have shown that applying the anesthetic isoflurane to cultured neural cells can lead to generation of amyloid-beta protein -- the key component of senile plaques seen in the brains of Alzheimer's patients -- and to the cell-death process known as apoptosis. In the Feb. 7 Journal of Neuroscience, researchers from Massachusetts General Hospital (MGH) and colleagues describe how isoflurane may set off a process in which A-beta generation and apoptosis interact with and magnify each other. Since this work was done in cell cultures, it is unknown whether the findings reflect a possible effect of the anesthetic on human brains.

"Our studies have shown that isoflurane may induce a vicious cycle of apoptosis, amyloid-beta generation, and further rounds of apoptosis leading to cell death," says Zhongcong Xie, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), the study's lead author. "If future studies support these findings, they suggest that caution be used in choosing this anesthetic for elderly patients, who already are at increased risk for Alzheimer's and for postoperative cognitive dysfunction." Xie is also associated with the MGH Department of Anesthesia and Critical Care.

Alzheimer's disease is characterized by plaques within the brain of amyloid-beta protein (A-beta), which is toxic to brain cells. A-beta is formed when the larger amyloid precursor protein (APP) is clipped by two enzymes -- beta-secretase, also known as BACE, and gamma-secretase -- to release the A-beta fragment. Normal processing of APP by an enzyme called alpha-secretase produces an alternative, non-toxic protein.

Some studies have indicated that general anesthesia may increase the risk of developing Alzheimer's disease. It also is known that a small but significant number of surgical patients experience a form of dementia in the postoperative period, but there is insufficient evidence of a direct connection between anesthesia and the risk of dementia. Previous articles -- including a recent report from the same research team -- have shown that isoflurane increases both A-beta generation and apoptosis in several types of cultured cells. The current study was designed to investigate the relationship between isoflurane-induced apoptosis and A-beta generation.

In a series of experiments, the researchers first found that applying isoflurane to cultured neural cells increased the activation of the enzyme caspase -- a key player in a pathway leading to apoptosis -- with no change in A-beta generation or APP processing. When they applied isoflurane to neural cells that express APP and had been treated with a caspase inhibitor, the expected changes in APP processing and A-beta generation were significantly reduced, indicating that caspase activation is essential to the pathway leading to A-beta generation and aggregation.

The researchers also found that isoflurane appears to raise levels of the A-beta-releasing enzymes BACE and gamma secretase and that generation of A-beta plaques further increases isoflurane-induced caspase activation. In addition, adding A-beta to neuronal cells that do not express APP also increased caspase activation in response to isoflurane. Overall, the study's results define molecular pathways by which isoflurane induces deposition of A-beta, both directly and via caspase activation, and by which A-beta deposits lead to further caspase activation and apoptosis.

"Even though our findings and those from other studies suggest that isoflurane may affect Alzheimer's pathogenesis, these experiments were performed in cultured cells only," says Rudolph Tanzi, PhD, director of the MGH-MIND Genetics and Aging Research Unit and senior author of the current paper. "We need to conduct in vivo studies before we can determine whether these results might be relevant to the development of delirium or Alzheimer's disease in human patients." Tanzi is a professor of Neurology at Harvard Medical School, where Xie is an assistant professor of Anesthesia. The researchers also plan to investigate whether other anesthetic agents may produce the same results seen with isoflurane, which is the only anesthetic tested in previous studies.

Researchers find missing link between amyloid and tau in Alzheimers disease

Thu, 08 Feb 2007 03:13:37 PST

( from http://www.rxpgnews.com )

The paper defines one of the earliest events that causes neurons to die in both early-onset familial Alzheimer%u2019s and late-onset Alzheimer%u2019s disease. This is the first evidence for the long elusive %u2018missing link%u2019 between amyloid and tau in Alzheimer%u2019s disease.

Scientists at the University of Virginia have identified what appears to be a major missing link in the process that destroys nerve cells in Alzheimers disease, an incurable disease that slowly destroys memory and cognitive abilities. The findings are reported in the Nov. 20, 2006, issue of the Journal of Cell Biology and could eventually lead to new drugs that target and disrupt specific proteins that conspire in the brain to cause Alzheimers.

In Alzheimers disease, two kinds of abnormal structures accumulate in the brain: amyloid plaques and neurofibrillary tangles. The plaques contain fibrils that are made from protein fragments called beta-amyloid peptides. The tangles also are fibrous, but they are made from a different substance, a protein called tau. In the new U.Va. study, the researchers found a deadly connection between beta-amyloid and tau, one that occurs before they form plaques and tangles, respectively.

According to George Bloom, the senior author of the study and a professor of biology and cell biology at U.Va., this connection causes the swiftest, most sensitive and most dramatic toxic effect of beta-amyloid found so far. What makes it most remarkable, though, is that it requires a form of amyloid that represents the building blocks of plaques, so called pre-fibrillar beta-amyloid, and it only happens in cells that contain tau. Even though they account for just ~10 percent of the cells in the brain, nerve cells are the major source of tau, which likely explains why they are specifically attacked in Alzheimers disease.

The researchers used cultured mammalian cells that either did or did not make tau to study how cells respond to beta-amyloid. They found that pre-fibrillar, but not fibrillar beta-amyloid works together with tau to break apart microtubules highways along which synapse replacement parts move rapidly in the nerve cell from where they are made to where they are needed. Synapses are connections between nerve cells, and in the brain they are the structural basis of memory and cognition. When nerve cells in the brain lose their microtubules they also lose the ability to replace worn out synapse parts, and synapses therefore disappear. The loss of synapses, and consequent loss of memories and cognitive skills, cannot be reversed, and can lead directly to nerve cell death.

We think weve found one of the seminal cell biological events in the pathogenesis of Alzheimers and if we can figure out all of the steps in the process and understand each player at every step, it will represent many potential new drug targets for Alzheimers therapy, Bloom said. Our paper defines one of the earliest events that causes neurons to die in both early-onset familial Alzheimers and late-onset Alzheimers disease. We believe this is the first evidence for the long elusive missing link between amyloid and tau in Alzheimers disease.

This is a very significant finding that greatly improves our understanding of the mechanisms within the cell that ultimately lead to Alzheimers disease, said Lester Binder, professor of cell and molecular biology at Northwestern University and a leading researcher on Alzheimers. Binder said he has already incorporated the U.Va. study into classes he teaches on the pathogenesis of Alzheimers disease and dementia.

The studys first author and lead investigator is Michelle King, a U.Va. research assistant professor of biology. Other investigators include Bloom, Ho-Man Kan and Alev Erisir of U.Va., Peter W. Baas of Drexel University and Charles G. Glabe of the University of California at Irvine.

Apolipoprotein E (APOE) gene raises newborns' cerebral palsy risk

Sun, 04 Feb 2007 23:25:34 PST

( from http://www.rxpgnews.com ) Apolipoprotein E (APOE), a gene associated with heightened risk for Alzheimer's disease in adults, can also increase the likelihood that brain-injured newborns will develop cerebral palsy, researchers at Children's Memorial Research Center have discovered.

This is the first identification of a gene that increases susceptibility to cerebral palsy. Results of the study, published in the February issue of the journal Pediatrics, may enable early identification of children who are at risk for poor neuro-developmental outcome after brain injury as newborns and thus target those children for early therapeutic intervention.

The lead scientist on the study was Mark S. Wainwright, M.D., Ph.D., assistant professor of pediatrics (neurology) and molecular pharmacology and biological chemistry at Northwestern University's Feinberg School of Medicine and the Children's Memorial Research Center. Wainwright is also a researcher in the Center for Drug Discovery and Chemical Biology at Feinberg.

Wainwright and his laboratory group compared APOE genotypes in 209 children with cerebral palsy and a matched control group of children in good health. They found that children who carry the E4 or the E2 form (or allele) of the APOE gene are not only more likely to develop cerebral palsy but also to have more severe neurologic impairment following perinatal brain injury, just as adults who carry the E4 form of the APOE gene may be more susceptible to developing Alzheimer's disease and have worse outcome after brain injury, including stroke and head injury.

Overall findings from the study showed that carrying the E4 allele was associated with greater than a threefold-elevated risk for cerebral palsy. The risk was higher for children with quadriplegia/triplegia and was associated with more severe motor impairment in this group.

Cerebral palsy affects two in every 1,000 school-aged children in the United States, has an annual economic toll on society estimated at $5 billion and is the most costly of the clinically significant birth defects in the United States.

Cerebral palsy encompasses a diverse group of disorders characterized by non-progressive impairment of motor function resulting from injury to the developing brain. Cerebral palsy is often associated with impaired intellectual function, sensory deficits, behavioral disorders and seizures. In the majority of cases, a specific cause for cerebral palsy cannot be identified.

The protein apoE that is coded by the APOE gene is produced in the brain, where it plays multiple roles, including protecting against injury. Wainwright said that the contribution of the APOE gene to susceptibility to neurologic injury might vary with age and the nature of the brain injury.

"People who carry the E4 allele may not be able to recover as effectively from a brain injury, making these newborns at greater risk for developing cerebral palsy," he said.

Wainwright hopes to conduct additional studies to confirm these findings in other populations and to evaluate the role of the apoE protein in specific biochemical pathways in the brain for development of cerebral palsy after perinatal brain injury.

Role of inhaled anesthetics in Alzheimer's disease

Thu, 25 Jan 2007 07:16:44 PST

( from http://www.rxpgnews.com ) Inhaled anesthetics commonly used in surgery are more likely to cause the aggregation of Alzheimer's disease-related plaques in the brain than intravenous anesthetics say University of Pittsburgh School of Medicine researchers in a journal article published in the Jan. 23 issue of Biochemistry. This is the first report using state-of-the-art nuclear magnetic resonance (NMR) spectroscopic technique to explain the detailed molecular mechanism behind the aggregation of amyloid beta peptide due to various anesthetics.

amyloid beta plaques are found in the brains of people with Alzheimer's disease. Many believe that the uncontrolled clumping of amyloid beta is the cause of Alzheimer's disease and that the similar aggregation of peptides and proteins play a role in the development of other neurodegenerative diseases such as Parkinson's disease.

"Many people know of or have heard of an elderly person who went into surgery where they received anesthesia and when they woke up they had noticeable memory loss or cognitive dysfunction," said Pravat K. Mandal, Ph.D., assistant professor of psychiatry, University of Pittsburgh School of Medicine and lead author of the study. Previous studies by the Pittsburgh researchers found that the inhaled anesthetics halothane and isoflurane and the intravenous anesthetic propofol encouraged the growth and clumping of Aβ in a test tube experiment.

"Our prior research had shown in molecular models that anesthetics may play a role by causing amyloid peptides to clump together—something that is thought to signal the advancement of Alzheimer's disease. In this study, we set out to see why this was happening and to determine if any one form of anesthesia might be a safer option than another," said Dr. Mandal.

In this study the researchers used NMR spectroscopy to determine how the inhaled anesthetics halothane and isoflurane and the intravenous anesthetics propofol and thiopental interact with Aβ influencing the aggregation of amyloid beta in forms commonly found in the brains of people with Alzheimer's disease. The results were strikingly different between the inhaled and injected anesthetics. The inhaled halothane and isoflurane had the most potent interaction with amyloid beta peptides causing the highest levels of amyloid beta aggregation. The injected anesthetic propofol only interacted and caused aggregation at high concentrations—interaction was not evident at lower concentrations. The intravenous thiopental did not cause the clustering of amyloid beta peptides even at high concentrations. Additionally, the molecular details for the interaction of these anesthetics with amyloid beta peptide were revealed.

Dr. Mandal noted that if the same thing occurs in humans, anesthetics could lead to more amyloid plaques which may lead to earlier memory problems, warranting further studies of anesthetics with Aβ both in laboratory and clinical settings.

Active mind may delay onset of Alzheimer's

Wed, 24 Jan 2007 11:43:25 PST

( from http://www.rxpgnews.com ) New York, Jan 24 - The elderly can delay the onset of Alzheimer's disease by keeping their mind active, says a new study.

Frank LaFerla, a professor of neurobiology and behaviour at the University of California at Irvine, studied hundreds of mice between two and 18 months of age that were bred to develop the plaques and tangles characteristic of the disease, reported health portal News Medical.

Mice in one group were made to swim in a round tank of water until they found a submerged platform on which to stand. The mice were trained four times a day for one week at two, six, nine, 12, 15 and 18 months of age, and were evaluated at each session for learning and memory abilities.

Other groups of untrained mice were allowed to swim in the tank for just one session before their learning and memory skills were tested and their brains examined for plaques and tangles.

Mice up to 12 months of age that learned on previous occasions had fewer plaques and tangles in their brains, and they learned and remembered the location of the escape platform much better than mice not previously allowed to learn.

At the 12-month point, the mice that had learned developed levels of beta amyloid and hyperphosphorylated-tau that were 60 percent less than the mice that had not learned.

But by 15 months of age, the mice that had learned deteriorated and were identical both physically and cognitively to the mice that had not learned.

'We were surprised this mild learning had such big effect at reducing Alzheimer's disease pathology and cognitive decline, but the effects were not strong enough to overcome later and more severe pathology,' a researcher said.

The study with genetically modified mice is the first to show that short but repeated learning sessions can slow a process known for causing the protein beta amyloid to clump in the brain and form plaques, which disrupt communication between cells and lead to symptoms of Alzheimer's disease.

The researchers are now investigating if more frequent and vigorous learning will have bigger and longer benefits to Alzheimer's disease.

Common anaesthetic isoflurane can kill brain cells

Wed, 17 Jan 2007 13:19:33 PST

( from http://www.rxpgnews.com ) New York, Jan 17 - The commonly used anaesthetic isoflurane could kill brain cells and raise the risk of Alzheimer's, suggests a new study questioning the safety of the drug.

Isoflurane is an anaesthetic, which is inhaled and used when general anaesthesia is required.

Many people, especially the elderly, suffer from postoperative cognitive dysfunction after anaesthesia as well as scrambling and delirium that can last six hours or two weeks or months, reported the health portal HealthCentral.

'To me, a big dose of isoflurane mimics a stroke or a bang to the head, and you don't want that as a risk factor for Alzheimer's disease at any age,' said Rudolph Tanzi of the Massachusetts General Institute for Neurodegenerative Disease who led the study.

Tanzi's team exposed cells that had an amyloid-beta protein, a protein that restores brain function, to isoflurane for six hours.

The researchers found that isoflurane caused these cells to die. 'It also caused the cell to overproduce the toxic molecule responsible for the pathology of Alzheimer's disease, particularly amyloid-beta,' Tanzi said.

This is a warning, he said. 'Isoflurane may be one reason why the elderly are more prone to cognitive dysfunction following anaesthesia.'

The researcher believes that isoflurane should be avoided when possible. 'We don't have enough data yet to ban isoflurane... But I'm convinced enough that I won't let my mother have it. I would advise any family or friends to stay away from isoflurane.'

US House backs wider stem-cell research, defies Bush

Fri, 12 Jan 2007 09:53:38 PST

( from http://www.rxpgnews.com ) Washington, Jan 12 - Lawmakers in the Democratic-led US lower house approved plans to expand government funding for human embryonic stem-cell research, defying a threatened veto by President George W. Bush.

The bill, which requires Senate approval before it could land on Bush's desk, signalled the first major clash between the Republican president and the centre-left Democrats who won control of Congress in November elections.

The proposal passed the House of Representatives by a 253-174 vote Thursday and was also expected to clear the Senate. It would open the door for further government funding of the research, but specific details about money would be determined later. Cutting across party lines, 37 Republicans joined Democrats in backing the expansion.

But the House vote fell short of the two-thirds majority that would be needed to override a Bush veto.

Bush, a born-again Christian who draws critical support from socially conservative Republicans, rejected a virtually identical bill in July that was passed by a Republican-led Congress. He said it 'crossed a moral boundary'.

Many scientists believe stem-cell research holds the promise of cures for wasting diseases such as Alzheimer's. But a restrictive US policy adopted by Bush in 2001 limits research to some 20 lines of human embryonic stem cells that existed at the time.

Bush opposes opening up federally funded research to new stem-cell lines because it would allow 'intentional destruction of living human embryos for the derivation of their cells' under US law for the first time, a White House statement said.

'Destroying nascent human life for research raises serious ethical problems, and millions of Americans consider the practice immoral,' the White House said.

Bush would veto the bill in its present form, the statement said.

'Researchers are now developing promising new techniques to produce stem cells similar in nature to those derived from human embryos, but not requiring the use of embryos,' the statement said.

Physical exercise fights mental woes

Sun, 07 Jan 2007 12:26:05 PST

( from http://www.rxpgnews.com ) New York, Jan 7 - Physical activities improve blood flow to the brain, helps the bodies detoxify and could ward off addiction, depression, stress and even Alzheimer's, say researchers.

'Exercise improves thinking and mental function and decreases your tendency toward addiction,' Marc Siegel, associate professor of medicine at the New York University of Medicine, was quoted as saying by health portal Health Central.

'Studies have shown that it works better than some drugs. It's also a great anti-anxiety intervention,' said James Maddux, professor of psychology at George Mason University in Fairfax, and an expert on the mind-body health connection.

Aerobic exercises like running or swimming can lead to a healthy release of the body's natural opiates, neurochemicals called endorphins. According to Siegel, these are natural stress-busters, but exercise's impact on stress goes 'way beyond endorphins'.

'Exercise is a ritualistic activity that redirects your energy,' said Siegel, who is also the author of a book on worry and stress called 'False Alarm: The Truth About the Epidemic of Fear'.

'Stress is a build-up of inactivity, of over-thinking without release,' he said. 'But exercise gives you a physical release that diminishes that psychic frustration.'

For many people, exercise also provides a valuable sense of control over their physical health. 'It's that sense of a loss of control that can lead to stress,' Siegel said.

And physical activity - especially when individuals join sports clubs, teams or have workout partners - also increases socialisation, which has been proven to boost mental and physical health and increase lifespan, he said.

Researchers say that regular workouts could even help smokers beat their addiction.

New scan technique could spot early Alzheimer's

Wed, 27 Dec 2006 17:34:07 PST

( from http://www.rxpgnews.com ) New York, Dec 27 - Scientists in the US claim to have developed an advanced scan technique that can spot early symptoms of Alzheimer's disease.

According to researchers, Alzheimer's disease is strongly linked to the appearance of abnormal areas called 'amyloid plaques' and 'tangles' in the brain although the precise role of these is not fully understood.

These areas do not show up using conventional Magnetic reasoning imaging - or Computed Tomography - scanning and are visible only during autopsy.

Alzheimer's disease is a progressive brain disorder that gradually destroys a person's memory and ability to learn reason and make judgments.

Although the disease can be diagnosed by assessing mental decline, physical changes within the brain can usually be confirmed only by a post-mortem.

A team at the University of California claims to have invented a chemical that not only shows up on scans but will bind to plaques and tangles, reported the online edition of BBC News. Using another scanner called Positron Emitting Tomography -, the damaged areas show up clearly.

The researchers studied over 80 people - some of them healthy, some with mild cognitive impairments such as memory loss and 25 who were diagnosed with Alzheimer's because their symptoms were more advanced.

After being injected with the chemical, they were scanned to see if there were any differences between the groups.

The levels of the chemical appearing on the scans were much higher among the Alzheimer's patients compared with the others. The technique also highlighted more subtle differences between the healthy volunteers and those with mild symptoms.

Said Gary Small, who led the study: 'This suggests that we may now have a new diagnostic tool for detecting pre-Alzheimer's conditions to help us identify those at risk, perhaps years before symptoms become obvious.

'This imaging technology may also allow us to test novel drug therapies and manage disease progression over time, possibly protecting the brain before damage occurs.'

Scientists create antibody to prevent Alzheimer's

Fri, 22 Dec 2006 22:44:32 PST

( from http://www.rxpgnews.com ) London, Dec 22 - Scientists in Britain claim to have created an antibody that can be used as preventive treatment for people with a family history of Alzheimer's.

Alzheimer's is a progressive brain disorder that gradually destroys a person's memory and ability to learn reason and make judgments.

The researchers led by Dr Emma Kidd at Cardiff University said they created an antibody which could block the production of brain chemicals 'amyloid' that are linked to the debilitating disease, reported the online edition of BBC News.

Deposits of amyloid build up in the brain, preventing it from functioning properly. The antibody will reduce this build-up, improving the patient's memory and quality of life, the researchers claim.

'We believe that our approach could lead in time to a new therapy for this distressing and debilitating disease as it should prevent or reduce the irreversible deterioration of a patient's memory and other brain functions,' they said.

A final treatment could take several years to develop and the team are now seeking more money for the next stage of the work.

There is no known cure for Alzheimer's, which causes irreversible loss of brain function and memory. The disease affects one in 20 people aged over 65 and a fifth of all people aged over 80 in Britain.

Yeast model shows promise as Alzheimer's test

Sun, 19 Nov 2006 04:25:15 PST

( from http://www.rxpgnews.com ) A century ago this month, German psychiatrist Alois Alzheimer formally described characteristics of the neurodegenerative disease which ultimately came to bear his name. While international efforts to learn about Alzheimer's disease and develop treatments have progressed significantly in recent years, a cure remains an elusive goal.

A new research tool developed by Susan Liebman, distinguished university professor of biological sciences at the University of Illinois at Chicago, may ultimately provide a means for treating the earliest stage of Alzheimer's, thereby stemming its progression.

Alzheimer's disease is characterized by the formation of plaques in the brain largely composed of fibers made from a peptide called beta-amyloid, or A-beta, for short. There is abundant evidence to support the hypothesis that accumulation of A-beta peptide triggers the appearance of Alzheimer's. But while earlier research suggested the A-beta fiber caused Alzheimer's, recent research points at much smaller aggregates of the peptide as the culprit.

"We've developed a yeast model system in which A-beta small aggregate formation can be detected," said Liebman. "The system employs a fusion of the human A-beta peptide to a functional yeast protein, called a reporter protein, which is only active in allowing cells to grow on test media if the fusion does not form aggregates."

Liebman said the yeast model system can be used to develop a high throughput assay to screen small molecules to find those that inhibit the A-beta dependent aggregation. "We'll screen a library of drugs and compounds, looking for ones that allow our yeast with the reporter protein to grow."

She said after the assay conditions are perfected, the screen will be ready for an automated process that will allow for fast testing of many compounds. Medicinal chemists would then study the structures of compounds that pass the screen and design compounds that enhance the activity without being toxic. Animal and human trials would follow.

"One promising, emerging approach for treatment of Alzheimer's disease is to prevent these smaller aggregates from forming," said Liebman. "Disruption of these small aggregates rather than the larger fibers seems prudent since inhibition of A-beta fiber formation might cause the smaller aggregate species to accumulate, and since inhibiting smaller aggregate formation should also prevent the initial formation of the fibers."

Hope remains for Alzheimer's sufferers

Tue, 31 Oct 2006 16:08:00 PST

( from http://www.rxpgnews.com ) The National Institute of Clinical Excellence (NICE), who last week rejected appeals to allow patients with mild Alzheimer's to receive the life-changing medication donepezil (Aricept®), will hopefully re-appraise their decision in three-years time, according to neurologist Professor Robert Kerwin in an article published in the November issue of the medical journal Future Neurology.

Kerwin evaluated recent research published in the Lancet that may not have been taken into account by the NICE committee. In this study, nursing home patients with severe Alzheimer's disease were administered with donepezil, or a placebo drug, and were observed for 6-months. Those patients receiving donepezil treatment showed significantly improved cognitive function, compared with those patients not receiving the drug, despite recommendations by NICE not to prescribe donepezil to this patient group.

Kerwin also evaluates recent data suggesting that the drugs are effective in patients with milder forms of Alzheimer's disease. The recent 2005 NICE revised guidelines for cholinesterase inhibitors, the class of drug that donepezil and other Alzheimer drugs rivastigmine(Exelon®/Prometax®) and galantamine (Reminyl®) belong to, state that these drugs can only be administered to patients with moderate Alzheimer's, for whom NICE believe the evidence is strongest. At the same time NICE withdrew its recommendations for the use of these drugs for patients with mild-to-moderate Alzheimer's. Memantime (Exiba®), belonging to another class of drugs, is not recommended to Alzheimer's sufferers, but is restricted to ongoing clinical trials and may be possible treatment in the future.

"NICE's decisions are based upon the economic health calculations that they do, which are balanced against clinical benefit. Even though the drugs do work in the long-term, patients do progress to requirements of alternative care that do not necessarily lead to savings within the NHS." Commented Kerwin, who is a Professor of Clinical Neuropharmacology at the Institute of Psychiatry, London.

750,000 people are estimated to suffer from Alzheimer's disease in the UK alone, with 78,000 of these receiving rivastigmine, galantamine and memantine; a further 2-thirds of sufferers take donepezil. Since NICE's original 2001 guidelines that this family of drugs should be made broadly available within the UK NHS for mild-to-moderate Alzheimer's disease, prescriptions have risen sharply and many sufferers have experienced a welcome relief from the debilitating symptoms of memory loss and cognitive decline. In 2005, NICE reviewed their previous decision based on the cost effectiveness and clinical benefit of such drugs in mild- and severe-Alzheimer's sufferers, and ruled that the drugs should be limited only to patients with moderate forms of the disease. This is only applicable to newly diagnosed patients. Despite uproar from patient groups appealing this decision, NICE stuck by their guidelines and last week issued a statement over-ruling the appeal.

"It is a bizarre decision," continued Kerwin, "the economists in the appraisal may well have had sway over the clinicians in the appraisal, and the clinicians may, on the other hand, have said that the drugs do help mild patients to quite a significant degree. I personally think NICE would have made a mistake over this decision if it is dominated by health economists rather than clinicians, however I have no knowledge of the final deliberations of the NICE committee." Kerwin, who once sat on the NICE committee appraising these drugs, points out that they would only have analysed current data in their review and that more recent data, published in the gap between the final draft of the appraisal and the appeal, would possibly not have been taken into account. NICE would only have evaluated their process and the methods used to reach such a decision.

"These drugs work in ways that are not predictable for severe Alzheimer's disease patients, which suggests there is an added mechanism. Mild patients will always do better, everybody knows that, but the economic sums don't quite fully add up in terms of cost. I believe that progression, when measured economically rather than clinically, may not be very impressive."

Despite the recent uproar, Kerwin remains hopeful that with new data, such as those analysed in his article on severe Alzheimer's disease patients, NICE could potentially reverse their decision due to their working principal of 'positive review' on a 3-yearly cycle. Future Neurology is published by Future Medicine an imprint of the Future Science Group.

CATIE Study: Antipsychotics in Alzheimer's No Better Than Placebo

Fri, 13 Oct 2006 11:08:00 PST

( from http://www.rxpgnews.com ) Most Alzheimers patients prescribed antipsychotic drugs for delusions, agitation or aggression do no better than those who take a placebo because so many discontinue the drugs due to significant side effects, according to a new nationwide study led by Lon Schneider, professor of psychiatry, neurology and gerontology at the Keck School of Medicine of USC.

The study is highly anticipated because it provides the first long-term comparative look at the three major antipsychotic drugs now used off label to treat difficult symptoms of Alzheimers disease.

We thought overall the drugs would show their effectiveness, Schneider said. The answer is yes, they are somewhat effective, but overall the efficacy is offset by adverse events that resulted in discontinuing the medication. It was a surprise, in that the expert opinion which drove this study was that these drugs are particularly useful in treating these difficult symptoms.

Almost all Alzheimers patients suffer delusions or aggression, Schneider said, which makes their care particularly difficult. The studys 421 participants at 42 nationwide sites all had Alzheimers disease and were experiencing delusions, hallucinations, aggression or agitation that disrupted their daily functioning.

The findings here look at the time to discontinuation for the antipsychotics versus the placebo, and that time difference reflects the overall effectiveness of the medication, Schneider explained. By that measure, the medications were not better than placebo. Patients on the medications were more likely to discontinue because of the side effects, offsetting the efficacy.

Side effects from the three antipsychotic medications olanzapine, quetiapine and risperidone ranged from sedation, weight gain and confusion to worsening psychosis.

Almost a quarter of those taking olanzapine quit because of adverse events, as did 18 percent on risperidone and 16 percent on quetiapine. Those on all three medications were significantly more likely to discontinue treatment than those who received a placebo.

Ultimately between 77 to 85 percent of study participants discontinued their medication, either because of adverse side effects or no improvement.

The results suggest antipsychotic drugs should be prescribed only with some deliberation, Schneider said.

Mediterranean diet associated with a lower risk for Alzheimers disease

Wed, 11 Oct 2006 04:51:00 PST

( from http://www.rxpgnews.com ) Eating a Mediterranean diet, which emphasizes fruits, vegetables and olive oil and includes little red meat, is associated with a lower risk for Alzheimers disease, according to an article posted online today that will appear in the December 2006 print issue of Archives of Neurology, one of the JAMA/Archives journals. This association persisted even when researchers considered whether individuals had vascular diseasesdiseases of the blood vessels, such as stroke, heart disease and diabetessuggesting that the diet may work through different pathways to reduce Alzheimers disease risk.

The Mediterranean diet consists of high amounts of fruits, vegetables, legumes, cereals and fish, mild to moderate amounts of alcohol and low amounts of red meat and dairy products, according to background information in the article. This diet has been associated with a lower risk for several diseases and risk factors, including cancer, obesity, high cholesterol, high blood pressure, problems with processing glucose that may lead to diabetes, coronary heart disease and overall death.

Nikolaos Scarmeas, M.D., and colleagues at Columbia University, New York, studied whether the Mediterranean diet could also help prevent Alzheimers diseasea debilitating neurodegenerative diseasein a group of 1,984 adults with an average age of 76.3. The participants, 194 of whom already had Alzheimers disease and 1,790 of whom did not, were given complete physical and neurological examinations and a series of tests of brain function. Their diet over the previous year was analyzed and scored based on how closely it adhered to the principles of the Mediterranean dietscores ranged from zero to nine, with higher scores indicating eating patterns that aligned closely with the Mediterranean diet. The researchers obtained information about vascular disease diagnoses from the exams, participants or relatives reports and medical records.

Eating a diet that closely followed the Mediterranean model was associated with a significantly lower risk for Alzheimers disease. For each additional unit on the diet score, risk for Alzheimers disease decreased by 19 to 24 percent. After the researchers considered other factors that could influence Alzheimers disease risk, including age and body mass index, those who were in the top one-third of the diet scores had 68 percent lower odds of having Alzheimers disease than those in the bottom one-third, and those in the middle-one third had 53 percent lower odds.

Growing evidence links the Mediterranean diet to a reduced risk for vascular disease and suggests that vascular risk factors may contribute to the risk for Alzheimers disease, the authors write. Thus, vascular variables are likely to be in the causal pathway between the Mediterranean diet and Alzheimers disease and should be considered as possible mediators, they continue. However, when we considered vascular risk factors in our models, the association between the Mediterranean diet and Alzheimers disease did not change. This was the case despite our attempt to capture vascular comorbidity in the most complete possible way by simultaneously considering both a long list and alternative definitions of vascular variables.

This could be the result of either other biological mechanisms (oxidative or inflammatory) being implicated or measurement error of the vascular variables, the authors conclude.

Omega-3 fatty acid supplements may slow cognitive decline

Wed, 11 Oct 2006 04:48:00 PST

( from http://www.rxpgnews.com ) Omega-3 fatty acid supplements may slow cognitive decline in some patients with very mild Alzheimers disease, but do not appear to affect those with more advanced cases, according to results of a clinical trial published in the October issue of Archives of Neurology, one of the JAMA/Archives journals.

Alzheimers disease is a severely debilitating condition that affects thinking, learning and memory, beginning with declines in episodic memory (including memory about events in ones own life), according to background information in the article. Medications are available to treat the symptoms, but these drugs do not affect the underlying cause and progression of the disease. Several studies have shown that eating fish, which is high in omega-3 fatty acids, may protect against Alzheimers disease, leading researchers to question whether supplements could have similar effects.

Yvonne Freund-Levi, M.D., Karolinska Institutet, Stockholm, Sweden, and colleagues compared the effects of supplements containing two omega-3 fatty acids with placebo in 204 patients with Alzheimers disease, 174 of whom completed the entire study. For six months, 89 patients (51 women and 38 men) took 1.7 grams of docosahexaenoic acid (DHA) and .6 grams of eicosapentaenoic acid (EPA), while 85 patients (39 women and 46 men) took placebo. For an additional six months, both groups took the omega-3 fatty acids. Patients had physical examinations, which included blood tests and blood pressure measurement, and took cognitive tests at the beginning of the study and at the six- and 12-month marks.

After six months, there was no difference in the rate of cognitive decline between the two groups. However, among a subgroup of 32 patients with very mild cognitive impairment at the beginning of the study, those who took the fatty acids experienced less decline in six months compared with those who took placebo. Among those who took placebo during the first six months, decline decreased during the second six months, when they also began taking the omega-3 supplements. The supplements appeared safe and well-tolerated, with no change in blood pressure or blood test results other than a higher ratio of fatty acids in the blood.

The mechanisms by which omega-3 fatty acids could interfere in Alzheimers disease pathophysiologic features are not clear, but since anti-inflammatory effects are an important part of the profile of fish oils, they are conceivable also for Alzheimers disease, the authors write. This could potentially explain why effects were seen only in those with very early-stage diseaserecent evidence suggests that there is a critical period two or more years before patients develop dementia when levels of chemicals that signal the presence of inflammation are elevated. It is possible that when the disease is clinically apparent, the neuropathologic involvement is too advanced to be substantially attenuated by anti-inflammatory treatment.

The authors also point out that these findings cannot serve as a basis for general recommendations for treatment of Alzheimers disease with dietary DHA-rich fish oil preparations. However, studies in larger cohorts with mild cognitive impairment, including those at risk for Alzheimers disease, are needed to further explore the possibility that omega-3 fatty acids might be beneficial in halting initial progression of the disease.

Microscopic brain damage detected in early Alzheimer's disease

Tue, 26 Sep 2006 23:08:00 PST

( from http://www.rxpgnews.com ) Researchers have developed a new computer-aided analysis technique to identify early cellular damage in Alzheimer's disease (AD).

"With increasing longevity among the population, the incidence of AD is expected to rise rapidly, creating a great burden not only for patients and their families, but also for society," said Min-Ying Su, Ph.D., author and associate professor in the Department of Radiological Sciences & the Tu and Yuen Center for Functional Onco-Imaging at the University of California at Irvine. "Our methods may enable earlier diagnosis of AD, allowing earlier intervention to slow down disease progression," she added.

As AD progresses, cell membranes in the brain may be damaged, allowing water molecules to move throughout the brain more freely. This phenomenon can disrupt neural processes and cause neuron cells to die, leading to brain atrophy. This process of cellular damage causes an increase in the "apparent diffusion coefficient," or ADC, which is a measurement used to study the distribution of water in the brain.

Thirteen elderly patients with mild cognitive impairment (MCI) were enrolled in Dr. Su's study. Patients with MCI are at high risk for developing AD. These 13 patients and 13 elderly control subjects underwent magnetic resonance imaging (MRI) of the brain and performed recall tasks. On MRI images, ADC values were measured in gray- and white-matter regions by using the computer-aided analysis program. Findings were compared between patients and healthy controls.

The computerized mapping technique allowed researchers to evaluate ADC values in large regions of the brain. In patients with MCI, researchers identified regions of brain atrophy and increased water content in white-matter areas. Additionally, high ADC values were found in the hippocampus, temporal lobe gray matter and the corpus callosum, which connects the two cerebral hemispheres. The ADC values in the hippocampus were significantly correlated with worse memory performance scores.

"The results have supported our objective to develop a computer-based analysis technique that can analyze different regions in the entire brain, to provide a comprehensive evaluation of cellular changes," Dr. Su said.

Until now, ADC values from gray matter in various lobes of the brain have not been reported, due to the difficulty of obtaining measurements in these regions. This new technology may allow researchers to learn more about how AD develops in the brain and to cultivate better treatment strategies for patients based on their individual cognitive needs.

"Patients with MCI who are very likely to progress to AD may start early treatment interventions, while patients who may remain stable with MCI can be spared from treatment and the associated side effects," added Dr. Su. "The diagnostic accuracy in identifying AD needs to be greatly improved."

AD is the most common form of dementia, affecting more than 4.5 million Americans. Patients diagnosed with AD have an average life expectancy of eight years after initial symptoms appear.

Novel technique can identify early cellular damage in Alzheimer's disease

Tue, 26 Sep 2006 16:33:00 PST

( from http://www.rxpgnews.com ) Researchers have developed a new computer-aided analysis technique to identify early cellular damage in Alzheimer's disease (AD). The study is featured in the October issue of Radiology.

"With increasing longevity among the population, the incidence of AD is expected to rise rapidly, creating a great burden not only for patients and their families, but also for society," said Min-Ying Su, Ph.D., author and associate professor in the Department of Radiological Sciences & the Tu and Yuen Center for Functional Onco-Imaging at the University of California at Irvine. "Our methods may enable earlier diagnosis of AD, allowing earlier intervention to slow down disease progression," she added.

As AD progresses, cell membranes in the brain may be damaged, allowing water molecules to move throughout the brain more freely. This phenomenon can disrupt neural processes and cause neuron cells to die, leading to brain atrophy. This process of cellular damage causes an increase in the "apparent diffusion coefficient," or ADC, which is a measurement used to study the distribution of water in the brain.

Thirteen elderly patients with mild cognitive impairment (MCI) were enrolled in Dr. Su's study. Patients with MCI are at high risk for developing AD. These 13 patients and 13 elderly control subjects underwent magnetic resonance imaging (MRI) of the brain and performed recall tasks. On MRI images, ADC values were measured in gray- and white-matter regions by using the computer-aided analysis program. Findings were compared between patients and healthy controls.

The computerized mapping technique allowed researchers to evaluate ADC values in large regions of the brain. In patients with MCI, researchers identified regions of brain atrophy and increased water content in white-matter areas. Additionally, high ADC values were found in the hippocampus, temporal lobe gray matter and the corpus callosum, which connects the two cerebral hemispheres. The ADC values in the hippocampus were significantly correlated with worse memory performance scores.

"The results have supported our objective to develop a computer-based analysis technique that can analyze different regions in the entire brain, to provide a comprehensive evaluation of cellular changes," Dr. Su said.

Until now, ADC values from gray matter in various lobes of the brain have not been reported, due to the difficulty of obtaining measurements in these regions. This new technology may allow researchers to learn more about how AD develops in the brain and to cultivate better treatment strategies for patients based on their individual cognitive needs.

"Patients with MCI who are very likely to progress to AD may start early treatment interventions, while patients who may remain stable with MCI can be spared from treatment and the associated side effects," added Dr. Su. "The diagnostic accuracy in identifying AD needs to be greatly improved."

AD is the most common form of dementia, affecting more than 4.5 million Americans. Patients diagnosed with AD have an average life expectancy of eight years after initial symptoms appear.

Cathepsin B - Part of protective mechanism against Alzheimer's

Thu, 21 Sep 2006 00:02:00 PST

( from http://www.rxpgnews.com ) An enzyme found naturally in the brain snips apart the protein that forms the sludge called amyloid plaque that is one of the hallmarks of Alzheimer's disease (AD), researchers have found. They said their findings in mice suggest that the protein, called Cathepsin B (CatB), is a key part of a protective mechanism that may fail in some forms of AD. Also, they said their findings suggest that drugs to enhance CatB activity could break down amyloid deposits, counteracting one of the central pathologies of AD.

Li Gan and colleagues published their findings in the September 21, 2006, issue of the journal Neuron, published by Cell Press.

Their experiments were prompted by previous studies showing that the cysteine protease CatB--an enzyme that snips apart proteins--closely associated with the amyloid-ß (Aß) protein that forms the amyloid plaques, a hallmark of AD. However, those studies had not determined whether CatB was "good" or "bad"--that is, whether it acted to produce Aß from a longer protein, called amyloid precursor protein (APP), or whether it broke down Aß.

In their experiments, Gan and colleagues determined that CatB was the latter--breaking down Aß, apparently to enable other enzymes to further degrade the protein for the cell's protein "garbage deposal" system.

They found that knocking out the CatB gene increased plaque deposition in a mouse model of AD in which mice expressed the human form of APP. They also found that CatB tended to accumulate within amyloid plaques and that it acted to reduce Aß levels in neurons. And they found that introducing a pathological form of Aß, called Aß1-42, into neurons increased CatB in young and middle-aged mice with human APP, but not old mice. "Thus, upregulation of CatB may represent a protective mechanism that fails with aging," wrote the researchers, and such failure may play a role in late-onset sporadic AD.

Their test tube studies showed that CatB biochemically degrades Aß by snipping one end of the protein, called the C-terminal end. What's more, the enzyme also degrades the long strings of Aß that form amyloid plaque, they found.

Finally, they found that increasing levels of CatB in aging mice with human APP markedly reduced plaque deposits in the animals' brains.

Gan and colleagues concluded that "our findings suggest that inhibition or loss of CatB function could interfere with its protective function and promote the development of AD, whereas overexpression of CatB could counteract Aß accumulation and aggregation. Thus, pharmacological activation of CatB could downregulate Aß1-42 assemblies through C-terminal truncation, offering an approach to the treatment of AD."

Boosting ubiquitin C-terminal hydrolase L1 (Uch-L1) restores lost memory

Fri, 25 Aug 2006 19:29:00 PST

( from http://www.rxpgnews.com ) Researchers at Columbia University Medical Center have successfully restored normal memory and synaptic function in mice suffering from Alzheimer's disease.

Scientists at Columbia's Taub Institute for Research on Alzheimer's Disease and the Aging Brain have identified an enzyme that is required for normal cognition but that is impaired in a mouse model of Alzheimer's. They discovered that mice regained the ability to form new memories when the enzyme's function was elevated.

The research suggests that boosting the function of this enzyme, known as ubiquitin C-terminal hydrolase L1 (Uch-L1), may provide a promising strategy for battling Alzheimer's disease, and perhaps reversing its effects.

In the new study, the Columbia researchers discovered that the enzyme Uch-L1 is part of a molecular network that controls a memory molecule called CREB, which is inhibited by amyloid beta proteins in people with Alzheimer's. By increasing Uch-L1 levels in mice that had Alzheimer's, they were able to improve the animals' ability to create new memories.

"Because the amyloid beta proteins that cause Alzheimer's may play a normal, important physiological role in the body, we can't destroy them as a therapy," explained Ottavio Arancio, M.D., Ph.D., Assistant Professor of Pathology at Columbia University Medical Center and co-principal investigator of the study with Michael Shelanski, MD, Ph.D., Chairman of the Department of Pathology at the Columbia University College of Physicians and Surgeons. "What makes this newly discovered enzyme exciting as a potentially effective therapy is that it restores memory without destroying amyloid beta proteins."

The researchers tested the memory of the mice by putting them in a cage where they were exposed to a mild stimulus when they touched the cage floor. Mice with normal memory remain still the second time they're placed in the cage, as they recognize the place where they were initially exposed to the stimulus. But mice with Alzheimer's-like changes do not remember the place, and continue moving within the cage. When the Alzheimer's mice were treated with Uch-L1, they acted like normal mice, and remained still.

"While this discovery is very promising, its proven effectiveness is limited to animal models and it will take some time before it could lead to therapies in humans," said Dr. Shelanski. "We continue to work towards that crucial goal." The work was supported by the National Institutes of Neurological Disease and Stroke and the Alzheimer's Center Program of the National Institute of Aging.

New research points toward mechanism of age-onset toxicity of Alzheimer's protein

Fri, 11 Aug 2006 13:40:00 PST

( from http://www.rxpgnews.com ) Like most neurodegenerative diseases, Alzheimer's disease usually appears late in life, raising the question of whether it is a disastrous consequence of aging or if the toxic protein aggregates that cause the disease simply take a long time to form.

Now, a collaboration between researchers at the Salk Institute for Biological Studies and the Scripps Research Institute shows that aging is what's critical. Harmful beta amyloid aggregates accumulate when aging impedes two molecular clean-up crews from getting rid of these toxic species.

This finding opens the door for development of drugs preventing build-up of toxic protein aggregates in the brain. The study appears in the Aug. 10 issue of Science Express, the advanced online edition of the journal Science.

"Aging is the most important risk factor for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease," says senior author Andrew Dillin, Ph.D., an assistant professor in the Salk Molecular and Cell Biology Laboratory. "Our study revealed that the age onset of these diseases is not simply a matter of time but that the aging process plays an active role in controlling the onset of toxicity," he explains.

Beta amyloid production occurs in all brains, but healthy cells clear away excess amounts. Brains of people with Alzheimer's disease, on the other hand, are unable to control beta amyloid accumulation. For years, scientists have scrambled to find out why.

To answer this vexing question, Dillin analyzed protein aggregation in the roundworm, a streamlined organism that, like mammals, uses the insulin/IGF-1 pathway to control lifespan but can be rapidly manipulated genetically. Dillin used roundworms that produce human beta amyloid peptide in body wall muscles. As the worms aged, the protein formed toxic aggregates causing paralysis.

Then researchers experimentally decelerated aging in engineered worms by lowering activity of the insulin/IGF-1 pathway and asked whether it was simply the passage of time--not aging per se--that favored protein aggregation. It wasn't: chronologically "old" worms crawled around happily, while counterparts whose insulin/IGF-1 pathway was normal could only helplessly wriggle their heads.

However, close inspection of the data revealed a surprise: "Worms with reduced insulin signaling seemed perfectly fine although they had high molecular weight aggregates, while worms with an accelerated aging program were extremely sensitive to the toxic effects of beta amyloid but we couldn't detect any large fibrils," explains postdoctoral researcher and co-lead author Ehud Cohen, Ph.D.

Intrigued, Dillin turned to an expert on beta amyloid biochemistry, Jeffery Kelly, Ph.D., a professor of chemistry at Scripps and a member of its Skaggs Institute of Chemical Biology.

Together they found that cells use an unexpected two-pronged strategy to rid themselves of harmful aggregates. Kelly explains, "One pathway disaggregated beta amyloid fibrils, while the other actively packed them into high molecular weight aggregates. But the latter only kicks in when the cell is left with no other options."

The surprise was that very high molecular weight species were actually less toxic than smaller aggregates. "For a long time large protein aggregates were considered the toxic species," explains Cohen. "The fact that cells protect themselves by temporarily storing small fibrils as high molecular weight aggregates marks a clear paradigm shift."

Two proteins controlled by insulin/IGF-1 signaling orchestrate detoxification--HSF-1, which takes care of aggregate break-down, and DAF-16, which mediates formation of safer, super-sized aggregates as debris accumulates. "We assumed that DAF-16 and HSF-1 would do the same job, but they don't. This is extremely exciting because it gives us two unique opportunities to attenuate beta amyloid-mediated toxicity by manipulating the activity of these factors," says Dillin.

Half of all people who reach age 85 will likely be affected by Alzheimer's disease, and the onset age usually around 75 is almost the same for all sporadic neurodegenerative aggregation diseases. Thus, Salk researchers have developed a model that explains why these disorders diseases occur late in life.

Throughout life, brain cells produce aggregation-prone beta-amyloid fragments that must be cleared. "This process is very efficient when we are young but as we get older it gets progressively less efficient," says Cohen. As the affected individual reaches the seventh decade of life the clearance machineries fail to degrade the continually forming toxic aggregates and the disease emerges. In individuals who carry early onset Alzheimer's-linked mutation, an increased "aggregation challenge" leads to clearance failure and the emergence of Alzheimer's much earlier usually during their fifth decade.

"It was very satisfying when the biochemical data from Jeffery's lab and genetic results from our lab came together," recalls Dillin. Both scientists are continuing the collaboration by searching for small molecules that delay the aging program and boost protective mechanisms.

Structure of calbindin-D28K Protein Involved in Preventing Alzheimers, Huntingtons Diseases Characterised

Wed, 26 Jul 2006 12:22:00 PST

( from http://www.rxpgnews.com ) Scientists at North Carolina State University have effectively lifted the veil from an important protein that is linked to the prevention of neurodegenerative diseases like Alzheimers and Huntingtons.

Dr. John Cavanagh, professor of molecular and structural biochemistry, teamed with colleagues from the Mayo Clinic and Duke University to describe the shape of the protein, calbindin-D28K. Understanding a proteins structure allows researchers to learn more about how it functions and interacts with other proteins, which, in this case, may provide clues to developing drugs to halt the diseases.

Calbindin-D28K is a protein that either grabs calcium from areas that have too much or serves as an on/off switch for further chemical reactions. It is known for its flexibility; it is found in the kidneys, pancreas, ocular nerve and in abundant quantities in the brain. Recent studies show, Cavanagh says, that it acts as a bodyguard in the brain, binding to and inhibiting caspase-3, a protein that stimulates plaque formation and tangle formation, which are hallmark characteristics of neurodegenerative disease. Until now, however, the structure of calbindin-D28K remained a mystery.

If you dont know the shape of the protein, you cant figure out how it works, Cavanagh says. It took a long time about five years but weve characterized the structure of this protein and found where it binds caspase-3. Insight into how it binds to caspase-3 might lead to a way of exploiting those interactions to develop therapeutics.

It took a long time to characterize calbindin-D28K, Cavanagh says, because it was initially a challenge to force cells to make enough protein in order to do the requisite studies. Additionally, many parts of the protein are very similar and so are extremely difficult to distinguish from each other.

The research team used nuclear magnetic resonance to get a high-resolution picture of what the protein looks like. In this painstaking technique occurring inside machines that have magnetic fields several hundred times greater than the Earths magnetic pull radio waves are bounced off the approximately 5,000 nuclei in the protein.

When you hit a nucleus with a radiofrequency pulse, it resonates, sort of making its own little noise, like a tuning fork, Cavanagh says. The frequency at which the nuclei resonate after being hit with a pulse is very specific to their specific position in the protein. So after we hit all of them with a pulse, its like hitting all the keys of a piano at the same time and its just an awful mess. And remember, were doing this for 5,000 separate keys. Yet, were able to untangle this mess to find the specific frequency of each nucleus and relate that to where it lies in the protein.

Cavanagh isnt satisfied with this knowledge, however. He says the shape-shifting protein sometimes contains no calcium. When it grabs calcium, it changes its shape.

This could be why the protein plays so many different roles, Cavanagh says. Proteins that change shape usually serve as on/off switches, but this protein also grabs calcium and takes it elsewhere. Now were working to determine the structure of this protein when it has no calcium.

Enhanced mental and physical activity slows neurological decline

Mon, 24 Jul 2006 18:54:00 PST

( from http://www.rxpgnews.com ) Researchers have uncovered the pathways behind the protection offered by environmental stimulation in Alzheimer's disease, further confirming that enhanced mental and physical activity slows neurological decline. The paper by Ambrée et al., "Reduction of amyloid angiopathy and A-Beta plaque burden after enriched housing in TgCRND8 mice: involvement of multiple pathways," appears in the August issue of The American Journal of Pathology.

Alzheimer's disease, the leading cause of senile dementia, presents with cognitive and behavioral deficiencies resulting in part from accumulation of ?-amyloid (A-Beta) deposits within the brain (A-Beta plaques) and its blood vessels (amyloid angiopathy). Although previous studies have shown that increased mental and physical activity can slow the progression of the disease, how such deceleration occurs has been unclear until now.

Dr. Kathy Keyvani's group at University Hospital Muenster examined the effects of environmental stimulation on the brain pathology of TgCRND8 mice. These mice, which express a mutant form of A-Beta found in some Alzheimer's patients, develop Alzheimer-like features including A-Beta plaques and cognitive deficits. To study the effects of enrichment, mice were housed in either standard cages or enriched cages, similar to the standard but with access to a stimulus cage containing permanent fixtures (rope and gnawing wood) as well as removable items (tunnels, balls, ladders, ramps, and exercise wheels) that were changed on a rotating basis.

Following five months of standard versus enriched housing, mouse brains were examined for signs of disease. Mice housed in the enriched environment had fewer A-Beta plaques, smaller plaque size, and reduced amyloid angiopathy compared to mice housed in standard cages. Interestingly, there were no differences in the levels of soluble A-Beta peptide or the transcriptional/translational expression levels of its precursor protein (APP) or the processing of APP between the two groups. So how did environmental stimulation prevent disease?

To answer this question, Ambrée et al. performed DNA microarray analysis to determine which genes were differentially regulated in mice housed in the enriched environment compared to standard cages. Enriched mice exhibited down-regulation of pro-inflammatory genes but up-regulation of genes related to anti-inflammatory processes, protein degradation and cholesterol binding. These results were confirmed by specifically analyzing gene expression for examples in each category. Together these data suggest that an enriched environment elicits protection via pathways that prevent A-Beta accumulation and enhance its clearance.

The authors speculate that the altered expression of inflammatory genes may shift the immune response from one that is neurotoxic to one that is phagocytic, i.e., able to clear unwanted debris, such as A-Beta. In accordance with this, a significant enhancement of microglial activity was found by Western blot and morphometric analyses of microglia, which often surround and infiltrate A-Beta plaques. In addition, activating cellular protein degradation pathways provides another means of removing excess A-Beta. Finally, changes in cholesterol homeostasis, elements of which have been shown to correlate with A-Beta deposition, may exert beneficial effects by preventing plaque formation in the first place.

These data provide strong evidence that an environment rich in mental and physical stimulation slows the progression of Alzheimer-like brain pathology. Further investigation of the pathways and individual elements involved in such protection may provide novel treatment strategies for Alzheimer's disease. Until that time, keep your running shoes and crossword puzzles handy.

Measuring Proteins In Spinal Fluid May Provide Early Clue To Alzheimer's Disease

Wed, 12 Jul 2006 05:37:00 PST

( from http://www.rxpgnews.com ) Early signs of the development of Alzheimer's disease can be seen in the cerebrospinal fluid of middle-aged adults who are genetically predisposed to the neurologic condition, according to a report in the July issue of the Archives of Neurology, one of the JAMA/Archives journals.

The two strongest risk factors for Alzheimer's disease are aging and the presence of an allele (type of gene) known as apolipoprotein E*4 (APOE*4), according to background information in the article. Those with the APOE*4 allele develop clinical dementia about 10 to 15 years earlier than those who do not have the APOE*4 allele. Previous studies have shown that the plaques that form in the brain during Alzheimer's disease, which are made of proteins known as beta-amyloids, begin forming years before affected individuals experience any symptoms of the disease. As beta-amyloid proteins, predominately of a type known as Abeta42, clump together, fewer are available to circulate through the nervous system. Therefore, lower levels of the Abeta42 in the cerebrospinal fluid surrounding the brain and spinal cord serve as biomarkers or chemical indicators of the development of Alzheimer's disease.

Elaine R. Peskind, M.D., VA Puget Sound Health Care System and University of Washington School of Medicine, Seattle, and colleagues estimated the combined effect of aging and the APOE*4 allele on levels of Abeta42 and another beta-amyloid, Abeta40, in 184 adults (94 men and 90 women, average age 50 years). The participants underwent clinical and laboratory screening and were found to be cognitively normal-that is, they had no difficulties with thinking, learning or memory. Researchers took samples of cerebrospinal fluid in the morning after an overnight fast and measured participants' Abeta42 and Abeta40 levels in addition to determining whether each individual had the APOE*4 allele.

Those who were older and who had the APOE*4 allele were more likely to have lower levels of Abeta42. For those who did not have the APOE*4 allele, Abeta42 levels rose slightly until about age 50 years then begin to decline slowly. On the other hand, those with the APOE*4 allele experienced a slight decline in Abeta42 in their younger years and then a dramatic drop between ages 50 and 60 years. Levels of Abeta42 were not associated with scores on any cognitive or memory tests. "In persons with the APOE*4 allele, decline in cerebrospinal fluid Abeta42 concentration possibly begins in young adulthood, followed by marked acceleration of this decline beginning in midlife-decades before clinical manifestations of Alzheimer's disease," the authors write. The same relationship did not hold true for Abeta40, which, although it is also found in amyloid plaques, is less prevalent there than Abeta42; levels of Abeta40 did not change with age in those with the APOE*4 allele and decreased with age in those without the APOE*4 allele.

"These findings have implications for the preclinical diagnosis of Alzheimer's disease, as well as for treatment," the authors conclude. "Therapeutic strategies aimed at prevention of Alzheimer's disease may need to be applied in early midlife or even younger ages to have maximal effect on amyloid deposition. Primary prevention trials for Alzheimer's disease targeting elderly persons may be too late to affect the early stages of disease pathology."

Teddies May Improve Quality of Life in Alzheimers

Mon, 10 Jul 2006 20:49:00 PST

( from http://www.rxpgnews.com ) Dolls and teddy bears can help Alzheimer's patients interact and communicate with others, finds a new study.

A team of doctors at Newcastle General Hospital studied the benefits of dolls after seeing how a patient bonded with a teddy bear from her son, reported the online edition of BBC News.

They found that Alzheimer's disease patients can lose their intellectual, social and emotional abilities over time. The patients also started interacted better with staff and other residents.

In the small-scale study, they gave 14 patients of a Newcastle nursing home a doll or a teddy bear each. They were then assessed over a 12-week period.

Dolls appear to alleviate agitation or distress, help overcome communication difficulties, and reduce withdrawal, the research presented to a British Psychological Society Conference said.

Using toys to help people with dementia has been looked at before as it is an important, non-drug based approach to behaviour disturbances in dementia residents, the study noted.

'What we have done with this study is to look at their use over a longer time period and to investigate whether patients chose to have a doll or teddy bear, said Ian James, a doctor at the hospital.

'Clearly, using a doll doesn't reverse dementia, but it did seem to improve quality of life,' he added.

'The findings will, we hope, help advise other clinical teams in their use of this technique.'

Alzheimer's pathology related to episodic memory

Fri, 30 Jun 2006 02:34:00 PST

( from http://www.rxpgnews.com ) Alzheimer's pathology can appear in the brains of older men and women without dementia or mild cognitive impairment. The pathology is related to loss of episodic memory, according to a new study published in the June 27, 2006, issue of Neurology, the scientific journal of the American Academy of Neurology.

The study evaluated 134 older men and women who didn't have cognitive impairment at the time of their death. Participants came from the Religious Orders Study and the Memory and Aging Project. Both are longitudinal, clinical-pathologic studies of older persons without dementia who underwent annual clinical evaluations and several cognitive performance tests. After they died, their brains were examined at autopsy for evidence of pathology.

More than a third of the participants (50) met criteria for a pathologic diagnosis of Alzheimer's disease. Criteria included lesions of brain tissue on the autopsy. This group also scored significantly lower than the other participants on tests for episodic memory, such as recalling stories and word lists.

"The results provide evidence in support of the idea that some type of neural reserve can allow a large number of older persons to tolerate a significant amount of Alzheimer's pathology without manifesting obvious dementia," said study author David A. Bennett, MD, of the Rush Alzheimer's Disease Center in Chicago.

Scores on the Mini Mental State Examination, a mental status screening test of cognitive functions, were nearly identical for participants with and without a pathologic diagnosis of Alzheimer's disease.

"This study questions the acceptability of minor episodic memory loss in older adults as 'normal'," said Carol F. Lippa, MD, who wrote an editorial in the same issue of Neurology. "Maybe this early decline in episodic memory precedes mild cognitive impairment and should be the target of research efforts in the early detection of Alzheimer's disease."

Alzheimer's Memory loss affects more of the brain

Tue, 27 Jun 2006 19:09:00 PST

( from http://www.rxpgnews.com ) Memory loss associated with early Alzheimer's disease (AD) may be linked to altered activity in several areas of the brain, according to a study in the July issue of Radiology.

For the first time, researchers at Duke University Medical Center in Durham, N.C., used a special, high-field- strength, functional magnetic resonance imaging (fMRI) scanner to study the brain activity of people with amnestic mild cognitive impairment (MCI), a precursor to AD, and found altered functionality in both the frontal and temporal lobes of the brain. Previous studies looking at structural changes alone have shown evidence that brain atrophy in the earliest stages of AD tends to be restricted to the temporal lobe, a region critical to long-term memory formation.

"Involvement of both the frontal and temporal lobes in the earliest stages of AD suggests the possibility of a breakdown in the communication pathway between these two regions, which house short-term and long-term memory, respectively," said lead author Jeffrey R. Petrella, M.D., associate professor of radiology and director of Alzheimer's Disease Imaging Research Laboratory at Duke. "So in many ways the AD brain may be like a computer that is having problems with both its temporary files and its hard-drive files."

MCI affects an estimated 15 percent of the elderly population in the United States. Ten to 15 percent of people with MCI develop AD every year compared to one percent of the normal elderly population. Amnestic MCI is characterized by mild memory impairment and is often confused with ordinary age-related forgetfulness.

The researchers used 4-Tesla fMRI, which has a very strong magnetic field, to observe the brain activity of 20 elderly patients with amnestic MCI and 20 age-matched controls with no memory impairment during a memory task that tested memory formation and retrieval.

"It's like doing a treadmill test for heart patients, except this test puts your brain on a treadmill," Dr. Petrella said.

The test required 40 patients to recall names of familiar faces and to learn and recall unfamiliar face-name associations. All patients showed brain activation in several brain regions during the task, but, compared with the controls, the patients with MCI showed a lower level of activation in the prefrontal cortex (during formation and retrieval), left hippocampus (during retrieval) and left cerebellum (during formation) and an increased level of activation in the posterior frontal lobes (during retrieval).

"These findings suggest that we should be paying closer attention to frontal lobe function in detecting people at risk for AD and may also point to new preventive strategies," said co-principal investigator P. Murali Doraiswamy, M.D., chief of the Division of Biological Psychiatry in the Department of Psychiatry at Duke.

Both researchers caution that their findings are preliminary. They are in the process of completing a larger study to confirm these results and to examine their value as a diagnostic or predictive test. There have also been a number of previous fMRI studies in people with MCI, and researchers are working to put these findings together to develop a synergistic combination of memory testing, genetic and imaging studies that together can best predict early onset and monitor progression of AD.

"If memory problems are beginning to impact the day-to-day life of you and your family, you should undergo comprehensive testing by a physician, as memory loss can be caused by many underlying factors such as depression, thyroid problems and stress, and doesn't necessarily indicate early AD," Dr. Petrella said.

Production of amyloid beta peptide (Abeta) monitored for first time in humans

Tue, 27 Jun 2006 02:45:00 PST

( from http://www.rxpgnews.com ) Science is now poised to answer an important and longstanding question about the origins of Alzheimer's disease: Do Alzheimer's patients have high levels of a brain protein because they make too much of it or because they can't clear it from their brains quickly enough?

Researchers from the Alzheimer's Disease Research Center (ADRC) at Washington University School of Medicine in St. Louis have developed the first safe and sensitive way to monitor the production and clearance rates of amyloid beta peptide (Abeta) in the human central nervous system. According to the authors, the new testing process opens a valuable window into the genesis of Alzheimer's disease that, in addition to helping scientists better understand the origins of the condition, will likely help them improve its diagnosis and treatment.

High levels of Abeta in the brain are a hallmark of Alzheimer's disease and believed to be a pivotal cause of the condition. Tests that measure Abeta levels in the cerebrospinal fluid have been available for some time. However, those fixed assessments of Abeta gave no indication of whether the flood of Abeta in patient's brains came from an increase in the mechanisms that make the protein or a reduction in the processes that regularly clear it from the brain.

Because Alzheimer's symptoms take many years to develop, some researchers had assumed that the creation and clearance rates for Abeta were very slow. But the initial test of the new technique, applied to six healthy volunteers, suggests the opposite.

"Abeta has the second-fastest production rate of any protein whose production rate has been measured so far," says lead author Randall Bateman, M.D., assistant professor of neurology. "In a time span of about six or seven hours, you make half the amyloid beta found in your central nervous system."

Ideally, the production and clearance rates stay balanced, causing the overall amount of Abeta in the central nervous system to remain constant. In the healthy volunteers who were the first test subjects, Bateman found the production and clearance rates were the same. He is now applying the technique to individuals with Alzheimer's disease.

Researchers are developing Alzheimer's drugs that either decrease Abeta production or increase its clearance, Bateman notes, and the new test could be very important in determining which approach is most effective.

Prior to the new test, the only way to assess the effectiveness of a new Alzheimer's drug was to follow the mental performance of patients receiving the treatment over many months or years.

"This new test could let us directly monitor patients in clinical trials to see if the drug is really doing what we want it to do in terms of Abeta metabolism," Bateman says. "If further study confirms the validity of our test, it could be very valuable for determining which drugs go forward in clinical trials and at what doses."

The test also may be useful in diagnosis of Alzheimer's prior to the onset of clinical symptoms, which occurs after Alzheimer's has inflicted widespread and largely irreversible damage to the brain.

"We hope to study whether we can develop ways to identify potential Alzheimer's patients on the basis of a metabolic imbalance between Abeta synthesis and clearance rates," Bateman says.

The test combines technologies that have been available for some time but only through recent technical and procedural advances has become sufficiently sensitive. Via an intravenous drip, scientists give test subjects a form of the amino acid leucine that has been very slightly altered to label it. Inside the leucine are carbon atoms with 13 neutrons and protons in their nucleus instead of the more common 12 neutrons and protons--in scientific parlance, carbon 13 instead of carbon 12.

"Normally only about 1.1 percent of the carbon atoms in our bodies are carbon 13--the vast majority is carbon 12," Bateman notes. "Physiologically and biochemically, carbon 13 acts just like carbon 12, meaning it won't alter the normal Abeta production and clearance processes and is very safe to use."

Over the course of hours, cells in the brain pick up the labeled leucine and incorporate it into the new copies they make of Abeta and other proteins. Scientists take periodic samples of the subjects' cerebrospinal fluid through a lumbar catheter, purify the Abeta from the samples and then use a device known as a mass spectrometer to determine how much of the Abeta includes carbon-13-labeled leucine.

Tracking the rise of the percentage of Abeta with labeled leucine over time gives scientists the subject's Abeta production rate. When the percentage of Abeta containing labeled leucine plateaus, scientists remove the IV drip supplying the labeled leucine. Periodic sampling of the patients' CSF continues, allowing scientists to get a measurement of how quickly the nervous system clears out the labeled Abeta. In the first test subjects, the test procedure lasted for 36 hours.

Other research groups have expressed an interest in applying the new test to Alzheimer's research and to other neurological disorders such as Huntington's disease.

How restricting caloric intake may prevent Alzheimer

Thu, 15 Jun 2006 17:54:00 PST

( from http://www.rxpgnews.com ) A recent study directed by Mount Sinai School of Medicine suggests that experimental dietary regimens might calm or even reverse symptoms of Alzheimer's Disease (AD). The study, which appears in the July 2006 issue of the Journal of Biological Chemistry, is the first to show that restricting caloric intake, specifically carbohydrates, may prevent AD by triggering activity in the brain associated with longevity.

"Both clinical and epidemiological evidence suggests that modification of lifestyle factors such as nutrition may prove crucial to Alzheimer's Disease management," says Giulio Maria Pasinetti, M.D., Ph.D., Professor of Psychiatry and Neuroscience, Director of the Neuroinflammation Research Center at Mount Sinai School of Medicine and lead author of the study. "This research, however, is the first to show a connection between nutrition and Alzheimer's Disease neuropathy by defining mechanistic pathways in the brain and scrutinizing biochemical functions. We hope these findings further unlock the mystery of Alzheimer's and bring hope to the millions of Americans suffering from this disease."

Alzheimer's Disease is a rapidly growing public health concern with potentially devastating effects. An estimated 4.5 million Americans have Alzheimer's Disease and the number of Americans with Alzheimer's has more than doubled since 1980. Presently, there are no known cures or effective preventive strategies. While genetic factors are relevant in early-onset cases, they appear to play less of a role in late-onset-sporadic AD cases, the most common form of AD.

People with AD exhibit elevated levels of beta-amyloid peptides that cause plaque buildup in the brain (the main characteristic of AD). Beta-amyloid peptides activate SIRT1, a member of a broad family of proteins known as sirtuins which influence a variety of functions including metabolism and aging.

Dr. Pasinetti and colleagues used an experimental mouse model to demonstrate that beta-amyloid peptides in the brain can be reduced by subjecting the mice to dietary caloric restriction, primarily based on low carbohydrate food. Conversely, a high caloric intake based on saturated fat was shown to increase levels of beta-amyloid peptides.

This study is the first to suggest that caloric restriction through promotion of SIRT1 (a molecule associated with brain longevity) may initiate a cascade of events like the activation of alpha-secretase which can prevent AD amyloid neuropathology. Since alpha-secretase is known also to inhibit the generation of beta-amyloid peptides in the AD affected brain, the study demonstrates a mechanism by which dietary caloric restriction might benefit AD. Most remarkably, the study finds that a high caloric intake based on saturated fat promotes AD type beta-amyloidosis, while caloric restriction based on reduced carbohydrate intake is able to prevent it.

Among lifestyle factors influencing AD, recent studies strongly support the evidence that caloric intake may play a role in the relative risk for AD clinical dementia. Most importantly, as mechanistic pathways are defined and their biochemical functions scrutinized, the evidence supporting a direct link between nutrition and AD neuropathology continues to grow.

Mild Cognitive Impairment (MCI) Increases Risk for Alzheimer

Thu, 15 Jun 2006 17:15:00 PST

( from http://www.rxpgnews.com ) Research at the University of Navarra has concluded that some patients with mild cognitive impairment (MCI) will develop Alzheimer in the future. The investigation of the detection of early signals of alteration was based on a multidisciplinary analysis of data from a sample of 300 individuals and undertaken at the University Hospital.

This PhD work, carried out by Lluís Samaranch, supports the theory that the majority of patients with MCI are at an intermediate stage which will end up in an acute condition. However, not all cases with mild impairment evolve to this condition.

This conclusion was arrived at after the Memory Disorder Unit at the University Hospital searched for early indicators of the ailment. Besides neuropsychological markers involved, the most significant find was the discovery of PET (Positron Emission Tomography) as a highly efficacious technique for measuring the risk of evolving MCI.

This multidisciplinary research involved neuropsychologists, nurses and engineers working together.

For more than 17 months a sample of 299 patients was studied. Of these, 103 suffered some mild cognitive impairment; 80 volunteered subjective complaints regarding memory; and 54 individuals were used as a control group, made up of volunteers from the Navarre Blood Donors Association.

All were tested neuropsychologically and with magnetic resonance and were subjected to various analyses and a genetic risk markers examination, amongst other procedures. Thanks to all this, the team came to the conclusion that the illness can be identified at early stages, before irreversible damage occurs, albeit with costly techniques such as the PET.

This is why the team insists on the necessity to find new, more accessible and simpler biochemical markers but with the same predictive capacity. In this manner we can undertake therapeutic intervention in the initial stages of Alzheimer precisely when there are more possibilities of success.

Different forms of amyloid beta in Alzheimer's disease harm neurons in different ways

Thu, 01 Jun 2006 13:06:00 PST

( from http://www.rxpgnews.com ) Researchers at UC Irvine have shown that different forms of amyloid beta lead to neural damage in different ways, leading to an increasingly complex view of amyloid toxicity in the Alzheimer brain. The finding could modify the way therapeutic approaches for the treatment of Alzheimers disease are designed.

The researchers studied the effects of different forms of the amyloid beta peptide on human brain cells. Amyloid beta accumulation is one of two hallmarks of Alzheimers disease and is considered a major target for researchers looking into therapies for the treatment of the disease. After death, most amyloid beta found in the brains of Alzheimers patients is in fibrillar form long, insoluble fibers bound together in deposits called senile plaques; however, there are also soluble forms of amyloid beta, or oligomers, that may decisively contribute to neural degeneration.

The experiments conducted at UCI showed that the soluble forms of amyloid beta are much more toxic and lead to neuronal death in as little as 12 hours. The fibrillar form, meanwhile, does not actually kill the neurons, but slowly, over a period of 10 or more days, renders them useless.

Not known is whether the soluble amyloid beta in the Alzheimer brain eventually turns into the fibrillar kind, or whether the two are completely different.

These findings are quite significant because, although both fibrils and oligomers may contribute to dementia, they do so in very different ways over different time spans, said Jorge Busciglio, an assistant professor of neurobiology and behavior. This complexity of the amyloid beta species will require more sophisticated therapeutic approaches. For example, it might be dangerous to create compounds that target fibrillar amyloid and try to break them up, because if the fibers dissolve into the soluble form, that could actually speed up cell death and the onset of dementia rather than treat it.

Atul Deshpande, a graduate student in Busciglios laboratory, tested one preparation of fibrillar amyloid beta and two soluble ones, which resemble the types found in the brains of Alzheimers patients. In less than 12 hours, the human neurons exposed to one of the two soluble forms started to die. Most of the cells were dead after 24 hours. The cells exposed to the other soluble form took about five times longer to die. In contrast, the brain cells treated with the fibrillar form slowly degenerated. The axons and dendrites in the cells became twisted and rendered the cell functionally useless. For the most part, however, the cells did not die.

According to the scientists, previous research has shown that the brain levels of soluble amyloid beta appear to correlate better with severity of cognitive impairment than the number and density of plaques found in the brain. Then, the more soluble beta amyloid is present, the more severe and rapid the onset of the disease.

Researchers now will have to determine why the soluble form of beta amyloid is so much more toxic. One theory is it binds to neuronal connections, or gateways into the cell, and gives soluble amyloid beta easier, quicker access into the neuron. The UCI research also showed that the soluble form quickly impairs the function of mitochondria, the cells energy generators. Brain cells consume more energy than any other cell in the body. If that energy source dies, the cells die as well.

Alzheimers disease is a progressive neurodegenerative disorder, affecting 4.5 million to 5 million adults in the United States. If no effective therapies are developed, it is estimated that 13 million Americans will be afflicted with the disease by 2050. It is the third-most-expensive disease to treat and the third-leading cause of death, behind cancer and coronary heart disease.

Cocktail of dietary supplements holds promise for the treatment of Alzheimer's disease

Sun, 30 Apr 2006 19:36:00 PST

( from http://www.rxpgnews.com ) MIT brain researchers have developed a "cocktail" of dietary supplements, now in human clinical trials, that holds promise for the treatment of Alzheimer's disease.

For years, doctors have encouraged people to consume foods such as fish that are rich in omega-3 fatty acids because they appear to improve memory and other brain functions.

The MIT research suggests that a cocktail treatment of omega-3 fatty acids and two other compounds normally present in the blood, could delay the cognitive decline seen in Alzheimer's disease, which afflicts an estimated 4 million to 5 million Americans.

"It's been enormously frustrating to have so little to offer people that have (Alzheimer's) disease," said Richard Wurtman, the Cecil H. Green Distinguished Professor of Neuropharmacology at MIT, who led the research team. The study appears in the May 9 issue of Brain Research.

Wurtman will present the research at the International Academy of Nutrition and Aging 2006 Symposium on Nutrition and Alzheimer's Disease/Cognitive Decline in Chicago on Tuesday, May 2.

The three compounds in the treatment cocktail - omega-3 fatty acids, uridine and choline - are all needed by brain neurons to make phospholipids, the primary component of cell membranes.

After adding those supplements to the diets of gerbils, the researchers observed a dramatic increase in the amount of membranes that form brain cell synapses, where messages between cells are relayed. Damage in brain synapses is believed to cause the dementia that characterizes Alzheimer's disease.

If the successful results obtained in gerbils can be duplicated in the ongoing human trials, the new treatment could offer perhaps not a cure but a long-term Alzheimer's treatment similar to what L-dopa, a dopamine precursor, does for Parkinson's patients, said Wurtman, a professor in the Department of Brain and Cognitive Sciences.

"It doesn't cure Parkinson's, but what it does do is to help replace something that's missing. It's not permanent, but it has had an enormous impact on people who have Parkinson's," he said.

The new potential treatment offers a different approach from the traditional tactic of targeting the amyloid plaques and tangles that develop in the brains of Alzheimer's patients. Until recently, most researchers believed these plaques and tangles caused the cognitive decline. But the failure of this hypothesis to lead to an effective treatment for Alzheimer's disease has caused some scientists to theorize that, though the plaques and tangles are always associated with the disease, they may not be the main cause of the dementia, nor the best target for treating it.

Instead, the new research focuses on brain synapses, where neurotransmitters such as dopamine, acetylcholine, serotonin and glutamate carry messages from presynaptic neurons to receptors in the membranes of postsynaptic neurons. In Alzheimer's patients, synapses in the cortex and hippocampus, which are involved in learning and memory, are damaged.

After the dietary supplements were given, the researchers detected a large increase in the levels of specific brain proteins known to be concentrated within synapses, indicating that more synaptic membranes had formed, Wurtman said. Synaptic membrane protein levels rose if the gerbils were given either omega-3 fatty acids or uridine plus choline. However, the most dramatic upsurge was observed in gerbils fed all three compounds.

"To my knowledge, this is the first concrete explanation for the behavioral effects of taking omega-3 fatty acids," said Wurtman.

Choline can be found in meats, nuts and eggs, and omega-3 fatty acids are found in a variety of sources, including fish, eggs, flaxseed and meat from grass-fed animals. Uridine, which is found in RNA and produced by the liver and kidney, is not obtained from the diet. However, uridine is found in human breast milk, which is a good indication that supplementary uridine is safe for humans to consume, Wurtman said.

Recent studies by the researchers at MIT, and by scientists at Cambridge University in England, showed that either uridine or omega-3 fatty acids can promote the growth of neurites, which are small outgrowths of neuronal cell membranes. That further supports the hypothesis that omega-3 fatty acids increase synaptic membrane formation, said Wurtman.

Alzheimer's patients in the clinical trials, which will involve multiple medical centers, are being given a drink that contains the compounds under study, or a taste-matched placebo.

"If it works as well on the brains of people with Alzheimer's disease as it does in laboratory animals, I think there will be a lot of interest," Wurtman said.

Social networks protect against Alzheimer's

Sun, 23 Apr 2006 18:17:00 PST

( from http://www.rxpgnews.com ) Having close friends and staying in contact with family members offers a protective effect against the damaging effects of Alzheimers disease according to research by physicians at Rush University Medical Center in Chicago. The study, which is currently posted online in The Lancet Neurology, will be published in the May print edition of the journal.

While other studies have shown people with more extensive social networks were at reduced risk of cognitive impairment, the study by Dr. David A. Bennett, and his colleagues from the Rush Alzheimer's Disease Center, is the first to examine the relations between social networks and Alzheimers disease pathology.

Researchers studied elderly people without known dementia who are participating in the Rush Memory and Aging Project, an epidemiological and clinicopathological study of aging and Alzheimer's disease that involves over 1,100 volunteers across northeastern Illinois. Brain autopsy was done at the time of death and post mortem data was available for analysis from the first 89 people.

"Many elderly people who have the tangles and plaques associated with Alzheimer's disease don't clinically experience cognitive impairment or dementia," said Bennett. "Our findings suggest that social networks are related to something that offers a 'protective reserve' capacity that spares them the clinical manifestations of Alzheimer's disease."

Participants in the study underwent clinical evaluations and 21 cognitive performance tests each year. To determine social network, participants were asked about the number of children they have and see monthly. They were asked about the number of relatives, excluding spouse and children, and friends to whom they feel close and with whom they felt at ease and could talk to about private matters and could call upon for help. They were asked to specify how many of these people they see monthly. Their social network was the number of these individuals seen at least once per month.

The relationship between the amount of Alzheimers disease pathology and cognitive performance changed with the size of the social network. As the size of the social network increased, the same amount of pathology had less effect on cognitive test scores. In other words, for persons without much pathology, social network size had little effect on cognition. However, as the amount of pathology increased, the apparent protective effect on cognition also increased. Thus, social network size appears to have offered a protective reserve capacity despite the fact that their brains had the tangles and plaques indicative of Alzheimer's disease.

The effect was evident across different kinds of cognitive abilities, but was most evident for semantic memory, which is the repository of knowledge about the world and is fundamentally involved in unique human cognitive processes such as language. The results were unchanged after controlling for cognitive, physical, and social activities, depressive symptoms, or number of chronic diseases.

"Identifying factors associated with the ability to tolerate the pathology of Alzheimer's disease has important implications for disease prevention," said Bennett. "Previous studies suggest one factor is education. Now we know that healthy and frequent interactions with friends and family have a positive impact as well."

Severe cerebral congophilic angiopathy found in Camelford resident

Thu, 20 Apr 2006 16:11:00 PST

( from http://www.rxpgnews.com ) A rare form of Alzheimer's disease has been discovered in a resident of Camelford, the town in south west England which bore the brunt of the accidental discharge of 20 tonnes of aluminium sulphate into the local water supply almost 20 years ago.

The incident occurred In July 1988, resulting in 20,000 residents across a large area of north Cornwall being exposed to levels of aluminium around 500 to 3000 times the acceptable limit, as defined by the European Union. The incident is the subject of an ongoing government inquiry.

The findings, published ahead of print in the Journal of Neurology Neurosurgery and Psychiatry, concern a woman, who was 44 at the time of the incident.

In May 2003, some 15 years after the incident, the woman, then aged 58, was referred to a neurologist for repeated headaches, difficulties in finding words and doing simple sums, and hallucinations, symptoms she had had for several months. Her condition progressively worsened and she died in April 2004.

A post-mortem examination revealed little out of the ordinary. But her brain revealed a rare form of Alzheimer's disease, known as sporadic early onset beta amyloid angiopathy. Other features typical of Alzheimer's disease were also evident.

No other members of the woman's family had been affected by either Alzheimer's disease or psychiatric problems.

Very high levels of aluminium were also found in the affected areas of her brain tissue, which may have resulted from her abnormally high exposure to aluminium following the incident, say the authors. Aluminium has previously been associated with an increased risk of developing Alzheimer's disease.

However, they emphasise that it is impossible to say whether aluminium caused the disease found in the woman's brain tissue. But they suggest that the survivors of the incident should be tested to see if they have sustained any impairment to their intellectual capacity.

An accompanying editorial by Professor Daniel Perl of Mount Sinai School of Medicine, points out that the association between an increased risk of Alzheimer's disease and exposure to aluminium is somewhat controversial, largely because there are few epidemiological data to support the theory.

Relatively little is known about the exact contribution of environmental factors to the development of Alzheimer's disease, he says, and a single case does not clarify that position.

"However," he writes, "if additional similar cases were to appear among the 20,000 exposed individuals then the implications of this incident would become extremely important. Only time will tell."

He continues: "At the very least, increased efforts towards surveillance of individuals exposed in Camelford is certainly warranted."

Amount of Amyloid Protein in Brain Determines Age of Onset for Alzheimer's Disease

Thu, 20 Apr 2006 16:06:00 PST

( from http://www.rxpgnews.com ) Researchers from the Flanders Interuniversity Institute for Biotechnology (VIB) connected to the University of Antwerp are the first to show that the quantity of amyloid protein in brain cells is a major risk factor for Alzheimer's disease. Amyloid protein has already been known to be the primary component of the senile plaques in the brains of patients. The new discovery demonstrates that the greater the quantity of the protein that is produced, the younger the dementia patient is.

Alzheimer's disease is a memory disorder that affects up to 70% of all dementia patients. In Belgium, about 100,000 people suffer from this disease. The disease gradually destroys brain cells in the deep areas of the brain that are responsible for memory and knowledge. Ever since the disease was first reported by Alois Alzheimer − 100 years ago now − scientists have been searching diligently for ways to treat it.

Genetic research has previously shown a direct connection between amyloid protein and the development of senile plaques and loss of cells. Amyloid protein originates when it is cut by enzymes from a larger precursor protein. In very rare cases (fewer than 1 in 1000 patients), mutations appear in that amyloid precursor protein, causing it to change shape and be cut differently. The amyloid protein that is formed now has different characteristics, causing it to begin to stick together and precipitate as amyloid plaques. The development of amyloid plaques in the brain tissue of Alzheimer patients is a central factor in the search for a therapy for Alzheimer's disease.

A lot or not much of the amyloid precursor protein is a risk factor The fact that patients with Down syndrome get Alzheimer's disease shows that the quantity of the amyloid precursor protein contributes to the disease: in fact, patients with Down syndrome have 3 copies of the gene (or hereditary code) for the amyloid precursor protein and therefore produce 150% instead of 100% of the protein.

So, Jessie Theuns and her colleagues, under the direction of Christine Van Broeckhoven, hypothesized that the quantity of amyloid precursor protein might also play a role in Alzheimer's disease. The geneticists from Antwerp systematically studied the hereditary code that is responsible for controlling the expression of the gene (= promoter). Biological processes in our body are strictly regulated, primarily by closely controlling the amount of each protein that is produced. The promoter of a gene has the most important control function in this process.

In younger Belgian and Dutch Alzheimer's patients (younger than 70), the researchers found genetic variations in the promoter that increased the gene expression and thus the formation of the amyloid precursor protein. These variations in the promoter that increase expression occur up to 20 times more frequently (2 per 100 patients) than the mutations in the precursor protein that change the shape. Furthermore, there is a connection with the age at which the symptoms are first detected: the higher the expression (up to 150% as in Down syndrome), the younger the patient (starting between 50 and 60 years of age). Thus, the amount of amyloid precursor protein is a genetic risk factor for Alzheimer's disease in the ageing process.

These new findings lead to a new understanding: namely, that the quantity of the amyloid precursor protein, and thus of the amyloid protein, in brain cells contributes significantly to the risk of contracting Alzheimer's. This discovery will have to be taken into account in diagnostic tests and in the search for new medicines.

Reduced insulin in the brain triggers Alzheimer's degeneration

Thu, 23 Mar 2006 17:38:00 PST

( from http://www.rxpgnews.com ) By depleting insulin and its related proteins in the brain, researchers at Rhode Island Hospital and Brown Medical School have replicated the progression of Alzheimer's disease including plaque deposits, neurofibrillary tangles, impaired cognitive functioning, cell loss and overall brain deterioration in an experimental animal model. The study demonstrates that Alzheimer's is a brain-specific neuroendocrine disorder, distinct from other types of diabetes.

In the study, brain deterioration was not related to the pancreas, which regulates insulin for the body. When pancreatic insulin is deficient or the body fails to respond to it, the result is Type 1 or Type 2 diabetes. Previous work by the researchers with postmortem brain tissue of Alzheimer's patients showed a strong link between insulin depletion in the brain and Alzheimer's disease, raising the possibility that Alzheimer's is a neuroendocrine disorder, or a Type 3 diabetes.

"We have demonstrated that a loss of insulin in the brain triggers the onset of Alzheimer's, probably because as the brain loses insulin, the cells that require insulin to function and survive also eventually die. The consequences are increased oxidative stress, brain deterioration, loss of cognitive function, and a buildup of plaques and tangles in the brain all hallmarks of Alzheimer's, says senior author Suzanne M. de la Monte, MD, MPH, a neuropathologist at Rhode Island Hospital and a professor of pathology and clinical neuroscience at Brown Medical School in Providence, RI.

"We now know that if you specifically target insulin and its actions in the brain, you could develop new treatments for this disease," de la Monte says.

Researchers injected the brains of rats with Streptozotocin (STZ), a compound that when metabolized, destroys beta cells in pancreatic islets and produces diabetes. When injected directly into the brain, the treatment caused neurodegeneration, while the pancreatic islet cells remained intact. That is because insulin depletion produced by STZ was confined to the brain, just like what occurs in most cases of Alzheimer's.

"This study provides definitive evidence that impairments in insulin/IGF signaling and deficiencies in the corresponding growth factors can occur in the central nervous system (CNS) independent of Type 1 or Type 2 diabetes," the authors write.

As a result of the treatment, insulin and its IGF-I receptors were significantly reduced in the brain, triggering a cascade of neurodegeneration. Both insulin and IGF-I activate complex signaling pathways downstream, prompting energy metabolism and growth required for learning and memory, and inhibition of oxidative stress, which unchecked could trigger neurodegeneration. As insulin was depleted, neurons died and the brain dropped to half its size, a result of atrophy which is a prominent feature of Alzheimer's. At the same time, there was an increase in astrocytes and microglial cells, which are responsible for neuroinflammation, another critical and consistent feature of Alzheimer's and probably related to the increased amyloid deposition in the brain, the researchers say.

Also, there was increased activation of a kinase called GSK-3 beta. This kinase is overactive in Alzheimer's and triggers tau phosphorylation, which is known to be at the core of neurofibrillary tangles. The researchers had previously shown that tau is regulated by insulin and insulin-like growth factor (IGF-I). In the current research, they found that as insulin and IGF-I were depleted in the brain, the expression of GSK-3 beta increased, leading to oxidative stress and cell death.

While the link between insulin and tau had been established, researchers also looked at the connection between insulin and amyloid precursor protein gene expression, as increased levels could account for amyloid accumulation, or the buildup of plaques in the brain. They found that amyloid beta deposits in vessels and plaques did build up in the brain, and they suggest that these abnormalities occurred due to increased oxidative stress.

Another feature of Alzheimer's affected by impaired insulin signaling, acetylcholine deficiency, is linked to dementia and has long recognized as an early abnormality in Alzheimer's. The enzyme that makes acetylcholine, choline acetyltransferase (ChAT), was previously found to be regulated by insulin and IGF-1. In brains with Alzheimer's, impairment of insulin and IGF-I signaling mechanisms correlate with deficits in acetylcholine production. In this study, ChAT was markedly reduced in the experimental Alzheimer's model.

"Our previous work has shown that many of the important features of Alzheimer's such as the accumulation of phosphorylated tau and the death of neurons were somehow linked to insulin deficiency in the brain. This study shows that insulin is the controlling factor in all of these features of Alzheimer's disease," de la Monte says.

"The evidence suggests that impaired insulin and IGF signaling must be addressed in order to make significant progress in the treatment and prevention of Alzheimer's disease," she says.

Possible Alzheimer's link to Choroid Plexus in Brain

Wed, 22 Mar 2006 08:19:00 PST

( from http://www.rxpgnews.com ) Researchers have discovered that an organ in the brain called the choroid plexus apparently plays a critical role in preventing the accumulation of a protein associated with Alzheimer's disease.

The researchers found that the choroid plexus acts as a sort of "fishnet" that captures the protein, called beta-amyloid, and prevents it from building up in the cerebrospinal fluid, which surrounds and bathes the brain and spinal cord. Moreover, tissue in the organ is able to soak up large amounts of the protein and may contain enzymes capable of digesting beta-amyloid, said Wei Zheng (pronounced Way Zsheng), an associate professor in the School of Health Sciences at Purdue University.

The findings represent the first time that researchers have identified the potential existence of a natural mechanism in the brain for removing beta-amyloid.

"This newly uncovered pathway may help explain how normal brains balance this protein and how an imbalance caused by aging, genetic or environmental factors may lead to or worsen Alzheimer's disease," Zheng said.

Researchers had already known that the cerebrospinal fluid in the brains of Alzheimer's patients contains abnormally high quantities of beta-amyloid fragments. Beta-amyloid deposits accumulate over a period of years, resulting in abnormal clumps, or plaque, typical of Alzheimer's disease. Scientists do not yet know whether the disease is caused by the plaque formations or beta-amyloids themselves.

The discovery suggests that a malfunctioning choroid plexus could allow too much of the protein to build up in the brain.

Scientists do not know how beta-amyloid is deposited in the brains of Alzheimer's disease victims, but a long-held theory is that the protein is overproduced by aging brain cells, or neurons.

"We are coming from a totally different point of view," Zheng said. "We think that a balance of beta-amyloid is maintained partly by the choroid plexus, which removes beta-amyloid, and that this balance breaks down, leading to a buildup."

The majority of Alzheimer's research has historically concentrated on how the brain produces beta-amyloid protein, but the new findings point to the possibly critical importance of the "garbage-removal" process in the choroid plexus, Zheng said.

"We think the choroid plexus plays a role of removing all the garbage, including the beta-amyloid," Zheng said.

The research focused on how the choroid plexus works to clean beta-amyloid from the cerebrospinal fluid. Studies using rat brains indicated that choroidal cells removed about five times more beta-amyloid from cerebrospinal fluid compared to how much of the protein the cells allowed to pass into the fluid.

"These results appear to tell us that a healthy choroid plexus can remove beta-amyloid from the cerebrospinal fluid, suggesting a novel pathway for the brain to maintain a normal balance," Zheng said. "Of course, much more work needs to be done to verify this theory."

The researchers also found that the choroid plexus possesses an enormous capacity to absorb beta-amyloids. The findings support the theory that the choroid plexus may possess a special enzyme that breaks beta-amyloids into smaller pieces, making it possible to soak up large quantities of the protein.

"The tissue must have a unique mechanism that is different from brain cells, something that enables it to chop up these beta-amyloids," Zheng said.

Future research may focus on efforts to isolate possible enzymes.

Zheng said the findings suggest that aging may degrade the organ's performance, and it is also possible that lead poisoning might increase the risk of Alzheimer's disease by damaging the choroid plexus and reducing its ability to filter beta-amyloids.

Excessive peroxidase of amyloid-beta- understanding Alzheimers

Wed, 15 Mar 2006 00:59:00 PST

( from http://www.rxpgnews.com ) Researchers at Children's Hospital & Research Center at Oakland (CHRCO) have published a new study that is the first to explain how brain cells die in patients with Alzheimer's Disease. This discovery is an important first step to helping researchers devise ways to slow, prevent and eventually cure a disease that affects an estimated 4.5 million Americans.
In a study published in the February 28th issue of the Proceedings of the National Academy of Sciences, lead scientist Hani Atamna, Ph.D., found that alterations in the production of heme (a molecule that contains iron) may be the key to understanding why excessive amyloid-beta is toxic to brain cells. Dr. Atamna had previously discovered that Alzheimer's patients have abnormal amounts of heme in their brains. In new research results, Atamna's team showed that amyloid-beta readily binds with heme to form a compound that can be flushed from cells. When there is insufficient heme or too much amyloid-beta, however, the amyloid-beta forms large toxic "clumps" that the cell cannot dissolve and eliminate.

Though heme binding with amyloid-beta can be beneficial, if too much heme is bound up with amyloid-beta, there may be insufficient heme available for the cell to properly function. When this happens, the cell's mitochondria, which are the tiny structures inside brain cells that produce the energy the cells need to function, begin to decay. Dr. Atamna refers to this phenomenon as a "functional heme deficiency" because the cells are still forming heme, but it is trapped within an amyloid-beta/heme compound.

When they examined the heme/ amyloid-beta compound researchers in the Atamna laboratory were surprised to discover it was a peroxidase--a type of enzyme that reacts harmfully with biological materials essential for proper brain function such as serotonin and L-DOPA. Dr. Atamna believes that the combination of functional heme deficiency, which harms mitochondria needed to produce energy, together with the increase in oxidative damage caused by the peroxidase, is what eventually kills the cell.

"Until now, we didn't understand all the factors that trigger Alzheimer's disease. The discovery of the formation of amyloid-beta peroxidase provides a clear picture of why cells die in the brain of Alzheimer's patients. Our next challenge is to develop drugs that directly and selectively target the excessive peroxidase of amyloid-beta, which could lead to the first significant therapy for Alzheimer's disease."

High levels of education speeds up the progression of Alzheimer's

Thu, 16 Feb 2006 16:48:00 PST

( from http://www.rxpgnews.com ) High levels of education may help ward off Alzheimer's disease, but they also speed up its progression once developed, reveals research in the Journal of Neurology Neurosurgery and Psychiatry.

The findings are based on 312 New Yorkers aged 65 and older, who were diagnosed with Alzheimer's disease and monitored for over 5 years.

All the patients underwent around four neurological assessments, each of which comprised a dozen separate tests of brain function.

Overall mental agility declined every year among all the patients. But each additional year of education equated to an additional 0.3 per cent deterioration.

The level of this drop off was particularly evident in the speed of thought processes and memory.

It was independent of age, mental ability at diagnosis, or other factors likely to affect brain function, such as depression and vascular disease.

One of the possible explanations for this finding is 'cognitive reserve' theory, suggest the authors.

This theory holds that the brain's ability to cope with Alzheimer's disease varies from person to person. But the amount of nerve connections (neurons) and information hubs (synapses) are likely to be more numerous in people who are highly educated.

Alternatively, the theory suggests that even if the quantity of neurons and synapses is no different, the synapses are likely to be more efficient and/or alternative circuitry is likely to be operating in those who are highly educated.

Therefore, higher education (or higher cognitive reserve) means that the brain develops the decreased mental agility of Alzheimer disease later, because it can "tolerate" changes for longer.

But the subsequent impact is likely to be greater than it would be in less educated brains, because of the higher levels of accumulated damage.

Neuronal Receptor Response May Help Explain Alzheimerâs Memory Loss

Sun, 12 Feb 2006 18:31:00 PST

( from http://www.rxpgnews.com ) Based on laboratory research, scientists at Georgetown University Medical Center have a new theory as to why people with Alzheimer's disease have trouble performing even the simplest memory tasks, such as remembering a family memberâs name.

Thatâs because they discovered a physical link between apolipoprotein E (APOE), the transport molecules known to play a role in development of the disease, and glutamate, a brain chemical necessary for establishing human memory.

In a study published in the Journal of Biological Chemistry, the research team specifically found that receptors on the outside of brain nerve cells (neurons) that bind on to APOE and glutamate are connected on the surface of neurons, separated from each other by only a small protein.

While the researchers donât know why these receptors are linked together, they say inefficient or higher-than-average levels of APOE in the brain could possibly be clogging these binding sites, preventing glutamate from activating the processes necessary to form memories.

âWe have found out that two receptors previously thought to have nothing to do with each other do, in fact, interact, leading us to conclude that APOE affects the NMDA glutamate channel that is important in memory,â says the studyâs senior author, G. William Rebeck, PhD, associate professor of neuroscience in Georgetownâs Biomedical Graduate Research Organization.

The researchers also hypothesize that this interaction might have something to do with development of Alzheimerâs disease, although they stress that at this early stage of research, this is impossible to prove.

Rebeck and first author Hyang-Sook Hoe, PhD, also of Georgetown, say that laboratory work now underway is attempting to unravel the relationship between APOE and NMDA receptors.

APOE is a protein that helps shuttle cholesterol and other non-soluble lipid particles around the body, moving these substances to where they are needed. All cells have receptors that bind on to APOE so that they can use lipids as needed, such as for quick energy, to store as fat for later use, or to repair wounds.

But researchers now know that APOE does more than distribute lipids, especially in the brain. About a decade ago, scientists linked APOE4, one of the three common forms of APOE, to development of Alzheimerâs disease, although the biological link between the protein and neurodegenerative diseases such as Alzheimerâs is not clear.

Based on recent research, Rebeck and others suspect that, in the brain, APOE also acts as a transporter, picking up lipids and perhaps other material that result from normal brain tissue wear and tear, or from trauma, and moving it to where it can be used or can be cleared away from the brain. Work in Rebeckâs lab found that APOE receptor 2 (ApoEr2), one of the eight different APOE receptor types, is crucial to both the development and operation of a normal brain.

Glutamate is a substance released at the synapse of neurons â the junction between one nerve cell and the next through which chemical messages are transmitted. Glutamate increases the strength of a synaptic response following stimulation. The NMDA glutamate receptor binds on to the drug NMDA, and also on to glutamate, an excitatory neurotransmitter that also stimulates nerve cell activity. Researchers know that the NMDA receptor is needed to produce the long-lasting synaptic response that is necessary in order to establish, or âlay down,â memory, Rebeck says. âThe molecular basis of memory depends on NMDA receptor.â

In work leading up to this study, Rebeck and the research team found that adding APOE to neurons in laboratory culture blocked NMDA receptors. In this study, they confirmed through a series of experiments that the receptors for APOE and NMDA interacted, and that the protein that linked the two was PSD95, often found in neural synaptic junctions. Together, they form a multiprotein complex that could presumably be activated by either APOE, NMDA or glutamate.

Rebeck suspects that the APOE4 variant â the one linked to Alzheimerâs disease â is less efficient at removing lipid debris in the brain than is APOE2 or APOE3, and because of this, brain cells secrete more of the faulty protein to do the job. If too much APOE ends up binding to the APOE/NMDA receptor, one of two things could possibly happen, Rebeck says. In one scenario, the receptor becomes over-stimulated due to the accumulating presence of APOE, which could trigger a process called excitotoxicity that results in death of the neruons. Or, in the presence of damage and secreted APOE, the receptor âturns downâ its activity â thus, hampering memory formation â until the brain is repaired. âHaving damage around tells the brain not to think too much for awhile,â Rebeck says. But if APOE4 cannot clear up accumulating damage, the ability to make new memories, and use old ones, may be increasingly lost.

âThis is, of course, speculation, but now we have new avenues in which we can explore the molecular basis of memory and possibly Alzheimerâs disease,â Rebeck says.

Increasing NogoReceptor Protein Can Treat Alzheimer's Deficits

Fri, 03 Feb 2006 16:12:00 PST

( from http://www.rxpgnews.com ) Increasing the level of a protein that plays a key role in traumatic spinal cord injuries and multiple sclerosis reduces the concentration of disease-causing plaque in Alzheimer's disease, Yale School of Medicine researchers report in the Journal of Neuroscience.

"Our new findings indicate that pharmacological methods to increase the protein, NogoReceptor, may be a way to treat the deficits associated with Alzheimer's disease," said Stephen Strittmatter, M.D., senior author of the study and co-director of the new program in Cellular Neuroscience, Neurodegeneration and Repair at Yale.

It is well known that the clinical dementia of Alzheimer's disease is associated with specific pathological changes in the brain. One such change is deposits of the peptide beta-amyloid in brain plaques, a hallmark of the disease. Nerve fibers also play a crucial role in the neurodegenerative process of Alzheimer's disease. "We asked whether those mechanisms that regulate nerve fiber growth might lessen the Alzheimer's disease process," said Strittmatter, professor in the Departments of Neurology and Neurobiology.

In brain sections from Alzheimer's patients, the protein NogoReceptor is distributed in an unusual pattern in conjunction with beta-amyloid peptide, which is the primary component of plaque that forms in the brains of patients with Alzheimer's disease, he said.

"Using genetic mouse models, we show that the NogoReceptor and beta-amyloid bind to one another," Strittmatter said. "Therefore, we investigated whether the NogoReceptor might alter the Alzheimer's process."

"Using an Alzheimer's model in mice, we demonstrated that decreasing the level of NogoReceptor causes more of the Alzheimer's beta-amyloid to build up in the brain," he said. "Conversely, higher levels of NogoReceptor reduced the concentration of the disease-causing beta-amyloid in the brain."

Strittmatter's laboratory previously determined that a molecular pathway involving the NogoReceptor protein played a crucial role in determining whether nerve fibers grow or remain stationary in the adult brain. The protein inhibits the regeneration of axonal nerve fibers in injured spinal cords and in neurodegenerative diseases such as multiple sclerosis.

MCI-A and MCI-MCD - two transitional states that lead to Alzheimer's disease

Sun, 22 Jan 2006 16:33:00 PST

( from http://www.rxpgnews.com ) Mild cognitive impairment (MCI), a transitional stage between normal cognition and Alzheimer's disease, exists in two different forms, according to a study published today by researchers from the University of Pittsburgh School of Medicine and the University of California, Los Angeles in the Archives of Neurology.

Using a new imaging procedure that creates 3-D maps of the brain, researchers determined specific areas that had degenerated in people with MCI. Depending on the person's symptoms, more tissue was lost in the hippocampus, a brain area critical for memory and one of the earliest to change in Alzheimer's disease, indicating two different paths of progression to Alzheimer's disease. The finding could lead to better diagnosis and treatment of patients with MCI, perhaps delaying or preventing the onset of dementia.

MCI is categorized into two sub-types currently distinguished based solely on symptoms. Those with MCI, amnesic subtype (MCI-A) have memory impairments only, while those with MCI, multiple cognitive domain subtype (MCI-MCD) have other types of mild impairments, such as in judgment or language, but also have either mild or no memory loss. Both sub-types progress to Alzheimer's disease at the same rate. Until now it was not known if the pathologies of the two types of MCI were different, or if MCI-MCD was just a more advanced form of MCI-A.

Researchers found that the hippocampus of the patients with MCI-A was 14 percent smaller than that of the healthy subjects, nearly as great as the 23 percent shrinkage seen in Alzheimer's disease. But, the hippocampus of those with MCI-MCD most resembled that of the controls, showing only 5 percent shrinkage.

Using highly accurate Magnetic Resonance Imaging (MRI) data from six patients with MCI-A, 20 with MCI-MCD and 20 with Alzheimer's disease who were seen at the University of Pittsburgh's Alzheimer Disease Research Center and 20 healthy controls, researchers created 3-D mesh reconstructions of each participant's hippocampus that allowed them to see where the hippocampus had deteriorated. This study is the first to use such modeling technology to visualize changes in the brains of people with MCI. Prior studies have only been able to measure the volume of the hippocampus and estimate atrophy through noticeable volume loss.

"These vibrant images produced by 3-D modeling have proven what we suspected there are at least two transitional states that lead to Alzheimer's disease," said James T. Becker, Ph.D., a neuropsychologist and professor of psychiatry, neurology and psychology, at the University of Pittsburgh School of Medicine and lead author of the study. "Now we can investigate these pathways and develop treatments that, we hope, may slow or stop the progression of Alzheimer's."

Alzheimer's disease affects as many as 10 percent of people older than 65, and delaying or preventing the onset of dementia is an important medical priority. "We can now see the pattern of brain damage in people with MCI and we can use these new types of images to monitor how different therapies may be working," said Paul M. Thompson, Ph.D., associate professor of neurology, at the University of California, Los Angeles. "By imaging the brain like this, we can explore the progression of diseases, and see if therapies are protecting the brain."

Memantine effective and safe in Alzheimer's disease

Sun, 22 Jan 2006 16:31:00 PST

( from http://www.rxpgnews.com ) Memantine, a drug approved for the treatment of Alzheimer disease, appears safe and effective in patients with moderate to severe cases of the condition, according to a study in the January issue of Archives of Neurology, one of the JAMA/Archives journals.

Millions of people worldwide have Alzheimer disease (AD), a progressive neurodegenerative disorder, according to background information in the article. Various chemical and other processes in the brain may contribute to the development of the condition. Memantine appears to act on one of those pathways, which involves the neurotransmitter glutamate, the authors report. The drug was approved in the United States in 2003 and also is available in the European Union and Australia.

Barry Reisberg, M.D., from the New York University School of Medicine, and colleagues conducted a 24-week open-label extension trial. In this type of trial, participants who had previously been part of a double-blind study--where some were taking an active drug and some were taking a placebo--were all given the same amount of the active drug. For this study, 175 patients with moderate to severe AD who completed the previous 28-week study received 20 mg of memantine daily for an additional 24 weeks.

The authors report that during the study, cognitive tests, reports from caregivers and observations by clinicians all indicated that memantine was beneficial to AD patients. "The benefits of memantine seen in the double-blind phase were again observed when patients treated with placebo were switched to memantine treatment in the open extension," they write. "For the patients who were randomized to memantine treatment during the double-blind phase, these clinically relevant benefits also appeared to be maintained in sum." The completion rate for the extension phase was high (78 percent) and the adverse event profile for memantine was similar to that observed in the double-blind study.

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(Arch Neurol. 2006;63:49-54. Available pre-embargo to the media at www.jamamedia.org)

Editor's Note: This study was funded by Merz Pharmaceuticals GmbH, Frankfurt, Germany. Development of measurements used in this study was supported by grants from the National Institute of Aging and the U.S. National Institutes of Health. Please see Archives of Neurology study for authors' financial disclosures.

Editorial: What Researchers Have Learned about Memantine

In an accompanying editorial, Jeffrey L. Cummings, M.D., of the David Geffen School of Medicine at the University of California, Los Angeles, comments on the current study on memantine and the overall benefits of this type of trial.

"Previous studies support the use of memantine to improve cognitive function or delay its decline, reduce the rate of loss of activities of daily living and reduce or decrease the emergence of new behavioral symptoms in patients with AD," Dr. Cummings writes. "These new data from Reisberg and coworkers provide additional reassurance to prescribing physicians that long-term use of memantine is safe, continues to have a low rate of adverse effects and may have continuing beneficial clinical effects."

Blood flow in brain takes a twist in Alzheimer's understanding

Sun, 22 Jan 2006 16:26:00 PST

( from http://www.rxpgnews.com ) New findings that long-overlooked brain cells play an important role in regulating blood flow in the brain call into question one of the basic assumptions underlying today's most sophisticated brain imaging techniques and could open a new frontier when it comes to understanding Alzheimer's disease.

In a paper to appear in the February issue of Nature Neuroscience and now available on-line, scientists at the University of Rochester Medical Center demonstrate that star-shaped brain cells known as astrocytes play a direct role in controlling blood flow in the brain, a crucial process that allows parts of the brain to burst into activity when needed. The finding is intriguing for a disease like Alzheimer's, which has long been considered a disease of brain cells known as neurons, and certainly not astrocytes.

"For many years, astrocytes have been considered mainly as housekeeping cells that help nourish and maintain a healthy environment for neurons. But it's turning out that astrocytes may play a central role in many human diseases," said neuroscientist Maiken Nedergaard, M.D., Ph.D., who has produced a string of publications fingering astrocytes in diseases like epilepsy and spinal cord injury.

"In a disease like Alzheimer's, for instance, perhaps it's the astrocytes themselves that are damaged first," she said. "It may be that for whatever reason, astrocytes are not doing their job properly, and then blood flow decreases. This could lead to the death of the neurons, which would starve from a lack of nutrients, since the neurons depend on the astrocytes for their survival."

The new research focuses on a process critical to the health of people with Alzheimer's and everyone else: the moment-to-moment allocation of vital resources like oxygen that goes on within our bodies. It's a supply problem familiar to anyone who worried over the availability of gasoline immediately after hurricane Katrina. In our bodies the process is particularly crucial in the brain, which is the body's most voracious guzzler of "fuel," with a constant need for oxygen. When part of the brain becomes more active, more blood is shunted to that region to bring extra nutrients like oxygen, making the increased activity possible.

Most scientists have assumed that the more blood that flows to a particular part of the brain, the more activity on the part of neurons, the nerve cells that send electrical signals that are widely considered to be "brain activity." The assumption that more blood flow equals more active neurons forms the basis for interpretation of sophisticated brain imaging techniques such as PET scans and functional MRI scans.

Now the group led by Nedergaard, professor in the Department of Neurosurgery and a member of the Center for Aging and Developmental Biology, and post-doctoral associate Takahiro Takano, Ph.D., the first author of the paper, has thrown doubt on the assumption by showing that astrocytes are important players in the process too. Studies by the team in mice show that signaling from astrocytes causes arteries in the brain to expand, bringing about an increase in blood flow.

"When we measure blood flow," said Nedergaard, "it may be that we are not measuring the activity of neurons so much as that of astrocytes."

The idea creates a "chicken or egg" type question in patients with conditions like Alzheimer's or traumatic brain injury where blood flow to parts of the brain plummets. In Alzheimer's it's known that neurons sicken and die over a period of years. To diagnose the disease, doctors often order a brain scan. When the test shows lessened blood flow, doctors assume that there must be less of a demand for blood, and so significant numbers of neurons in that brain region must have died. While that still may be true, Nedergaard said, the new results muddy the picture, calling into question any straightforward link between the health of neurons and blood flow.

Nedergaard said that while it is new to find that astrocytes can regulate blood flow, the finding shouldn't be entirely surprising. She said that astrocytes physically touch both synapses the spaces between neurons that are crucial to brain activity and blood vessels. In fact, "footprints" of astrocytes are literally all over blood vessels in the brain: Portions of astrocytes known as "astrocytic endfeet" wrap around nearly all the blood vessels in the brain.

Previously a few scientists have looked at slices of brain tissue and come up with hints that astrocytes might regulate blood flow in brain tissue. The current research, funded by the National Institute of Neurological Disorders and Stroke, relies on a sophisticated laser system developed by Nedergaard to study the activity of astrocytes in living organisms. The team used a fluorescent dye to light up the blood vessels, then put a special form of the chemical calcium into astrocytes. They used one laser to activate the calcium, and another laser to monitor how astrocytes processed the chemical. They found that astrocytes caused blood vessels to dilate.

Region of chromosome 10 strongly associated with Alzheimer's disease

Sun, 22 Jan 2006 16:07:00 PST

( from http://www.rxpgnews.com ) An international team of researchers, led by investigators at Washington University School of Medicine in St. Louis, are zeroing in on a gene that increases risk for Alzheimer's disease. They have identified a region of chromosome 10 that appears to be involved in risk for the disease that currently affects an estimated 4.5 million Americans.

"There are a few genes that have been implicated in the development of early-onset Alzheimer's disease, but other than APOE, no genes have been found that increase risk for the more common, late-onset form of the disease," says principal investigator Alison M. Goate, D. Phil., the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry at Washington University. "The region of DNA identified in our study showed evidence of replication in four independent series of experiments. I haven't seen a putative risk factor show such consistent results since the e4 variant of the APOE gene was identified as a risk factor for late-onset Alzheimer's disease more than 10 years ago."

In the January issue of the American Journal of Human Genetics, Goate's team of researchers reports results of a scan of more than 1,400 single-nucleotide polymorphisms (SNPs) on chromosome 10 to home in on susceptibility genes for late-onset Alzheimer's disease.

A SNP is an area of DNA where a change has occurred. A strand of DNA consists of four chemical bases, or nucleotides, represented by the letters A, C, G and T. When several regions of DNA from a population are compared, sites where variations exist may be found. Some individuals will have the original base, and others will have a variant. That site where a difference can be identified is called a single nucleotide polymorphism, or SNP.

Since most DNA does not make proteins, the majority of SNPs have no effect on DNA function or on health and disease. However, some SNP variants can cause major health problems. An example is APOE4, a common SNP in the apolipoprotein E gene that increases risk for Alzheimer's disease.

Goate and colleagues have not yet isolated a gene on chromosome 10, but in studying the 1,400 SNPs on chromosome 10 in DNA from three series, each with approximately 400 people with late-onset Alzheimer's disease and 400 healthy, age-matched controls, her team found only one SNP that consistently showed evidence of risk for Alzheimer's disease in all three series.

"The region of DNA implicated in our study contains six genes," Goate says. "We don't know which of those genes is most likely to harbor this particular risk factor for Alzheimer's disease, but we're getting closer. We're now trying to nail down which one of these six genes is the most likely to be involved."

Goate expects between five and 10 genes eventually will be implicated as possible risk factors for late-onset Alzheimer's disease, and she says it's possible that more than one of those genes is located on chromosome 10.

"One thing we're trying to do at a functional level is to see whether any of the six genes that we've identified might be involved in pathways that we already know are related to Alzheimer's disease," she says. "For example, we know amyloid-beta peptide plays a role, so we want to see whether any of these genes might have a role in amyloid-beta metabolism.

"We don't really know the nature of this risk factor yet. What we can say is that we believe we know where it's located, and we know there are six genes in that region. But there also could be other regulatory elements within that strand of DNA that don't directly produce a protein but may somehow affect proteins produced elsewhere in the genome. At this point, we can say that there is a variant in this region of DNA that is increasing risk for Alzheimer's disease, but we can't yet say how," Goate says.

MW01-5-188WH stops brain cell degeneration in Alzheimer's disease

Fri, 20 Jan 2006 13:39:00 PST

( from http://www.rxpgnews.com ) Drug discovery researchers at Northwestern University have developed a novel orally administered compound specifically targeted to suppress brain cell inflammation and neuron loss associated with Alzheimer's disease.

The compound is also rapidly absorbed by the brain and is non-toxic important considerations for a central nervous system drug that might need to be taken for extended periods.

As described in the Jan. 11 issue of the Journal of Neuroscience, the compound, called MW01-5-188WH, selectively inhibits production of pro-inflammatory proteins called cytokines by glia, important cells of the central nervous system that normally help the body mount a response, but are overactivated in certain neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, stroke and traumatic brain injury.

The compound was designed and synthesized in the laboratory of D. Martin Watterson at Northwestern University Feinberg School of Medicine, using a synthetic chemistry platform developed in his lab by researchers at the Northwestern University Center for Drug Discovery and Chemical Biology (CDDCB) for the rapid discovery of new potential therapeutic compounds.

Watterson is co-director of the CDDCB, the J.G. Searle Professor of Molecular Biology and Biochemistry and professor of molecular pharmacology and biological chemistry at the Feinberg School.

The efficacy and safety of the compound in an animal model of Alzheimer's disease was evaluated in collaboration with Linda J. Van Eldik, co-director of the CDDCB and professor of cell and molecular biology at Feinberg.

Besides providing a lead compound for drug development, the study has important implications for drug discovery in neurodegenerative diseases in general because it provides proof of concept that targeting over-production of cytokines by activated glia is a viable approach that has the potential to modulate disease onset and progression, the researchers said.

Decline of cognitive functions linked to the part of the brain called the hippocampus is a clinical hallmark of Alzheimer's disease. The report demonstrates that targeting excessive glial activation can suppress brain inflammation and neuron dysfunction in the hippocampus and protect against cognitive decline in an animal model.

Neuron dysfunction can lead to further glia activation and contribute to further exacerbation of the disease process. The Northwestern researchers found that 188WH and related compounds slowed or reversed the progression of the neuroinflammatory cascade and reduced human amyloid beta-induced glia activation in a mouse specially designed to develop many of the signs of Alzheimer's disease, including neuroinflammation, neuronal and synaptic degeneration and behavioral deficits.

The compound also restored normal levels of markers of synaptic dysfunction in the hippocampus, the area of the brain that helps regulate memory and is gradually destroyed in neurodegenerative diseases such as Alzheimer's. Treatment with the compound also attenuated Alzheimer's-like behavioral deficits in the mice that are due to injury to the hippocampus.

While previous research by the authors and many other investigators in the field has linked plaques, tangles and neuronal injury to synaptic dysfunction and cognitive decline, the direct linkage of glia to these processes and their potential as a selective target for new therapies has not previously been implicated so directly.

There are three key aspects of the report, Watterson said.

"First, a novel compound for development into a new class of Alzheimer's disease therapeutics that target disease has been described. Second, an innovative approach was used for the rapid and cost-effective discovery of orally bioavailable, safe and efficacious compounds, and this approach can be extended to other disease areas," Watterson said.

"Third, the design, synthesis and in vivo analyses were carried out by a new generation of young scientists trained in our educational program to instruct the next generation of interdisciplinary scientists," Watterson said.

Northwestern University patented the compound designated 188WH and has exclusively licensed the patent rights to NeuroMedix, Inc., for clinical development.

Workouts reduce risk of Alzheimer's disease

Thu, 19 Jan 2006 13:12:00 PST

( from http://www.rxpgnews.com ) Regular exercise reduces the risk of memory disorders such as dementia and Alzheimer's disease, say scientists. Workouts may also help to delay progression of the condition in people who begin to develop these symptoms.

Researchers led by Eric Larson at the University of Washington studied the effect of exercise on the people suffering from such disorders and found it reduces risk by 40 percent, reported the online edition of BBC News.

The study followed 1,740 people aged 65 and older over a six-year period. At the start of the study none showed signs of dementia. After six years, 158 participants had developed dementia, of which 107 had been diagnosed with Alzheimer's disease.

People who exercised three or more times a week had a 30 percent to 40 percent lower risk of developing dementia compared with those who exercised fewer than three times per week, it found.

Larson believes exercise may improve brain function by boosting blood flow to areas of the brain used for memory. The frailer a person, the more likely that exercise would help.

A regular gentle workout was enough to produce a positive effect - even for people aged over 65. Even if you're 75 and have never exercised before, you can still benefit by starting to exercise now, the study said.

Larson said walking for 15 minutes three times a week was enough to cut the risk.

Astrocytes are not just housekeepers

Fri, 06 Jan 2006 22:33:00 PST

Mechanism Tying Obesity to Alzheimers Disease Uncovered

Fri, 30 Dec 2005 15:58:00 PST

( from http://www.rxpgnews.com ) If heart disease and diabetes arent bad enough, now comes another reason to watch your weight. According to a study just released, packing on too many pounds can increase the risk of developing Alzheimers disease.

A team led by researchers at the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia and Edith Cowan University in Joondalup, Western Australia has shown that being extremely overweight or obese increases the likelihood of developing Alzheimers. They found a strong correlation between body mass index and high levels of beta-amyloid, the sticky protein substance that builds up in the Alzheimers brain and is thought to play a major role in destroying nerve cells and in cognitive and behavioral problems associated with the disease.

We looked at the levels of beta-amyloid and found a relationship between obesity and circulating amyloid, says Sam E. Gandy, M.D., Ph.D., director of the Farber Institute for Neurosciences. Thats almost certainly why the risk for Alzheimers is increased, says Dr. Gandy, who is also professor of neurology, and biochemistry and molecular biology at Jefferson Medical College of Thomas Jefferson University. Heightened levels of amyloid in the blood vessels and the brain indicate the start of the Alzheimers process. The scientists reported their findings this month in the Journal of Alzheimers Disease.

According to, Dr. Gandy, evidence has emerged over the last five years that many of the conditions that raise the risk for heart disease such as obesity, uncontrolled diabetes, hypertension and hypercholesterolemia also increase the risk for Alzheimers. Yet exactly how such factors made an individual more likely to develop Alzheimers remained a mystery.

Dr. Gandy, Ralph Martins, Ph.D., of Edith Cowan University and their colleagues measured body mass index and beta-amyloid levels in the blood. They also looked at several other factors associated with heart disease and diabetes, such as the inflammatory marker C-reactive protein, insulin, and high density lipoprotein in 18 healthy adults who were either extremely overweight or obese. They found a statistically significant correlation between body mass index and beta-amyloid.

Ours is one of the first attempts to try to find out on both the pathological and the molecular levels how obesity was increasing the risk of Alzheimers, says Dr. Gandy, who serves as chairman of the Alzheimer's Associations Medical and Scientific Advisory Council.

One implication of these findings could be that by losing excess weight and maintaining normal body weight, an individual might reduce the risk of developing Alzheimers. However, this has not been proven, notes Dr. Gandy.

Whats especially interesting about this is that several studies are showing that even medical conditions in midlife may predispose to Alzheimers later on, he says. The baby boomers today should pay attention to this. Their medical risk factors today will play a role 30 years later. Think about weight, cholesterol, blood pressure, which could affect you long-term. In terms of Alzheimers, another risk factor is maintaining an active mental lifestyle.

The next step is to follow such patients over the long term to see how many do indeed develop Alzheimers. We need to first develop a medicine that is effective in humans in lowering amyloid accumulation or generation, says Dr. Gandy. We have those now in mice and we are testing them in humans. If we can develop such a medicine, then the question will be, if we can lower amyloid, will that in fact prevent Alzheimers?

Cyanobacteria Nostoc can be natural drug source for Alzheimer's

Fri, 30 Dec 2005 15:53:00 PST

( from http://www.rxpgnews.com ) A compound isolated from a cyanobacterium, a type of blue-green algae known as Nostoc, shows promise of becoming a natural drug candidate for fighting Alzheimer's and other neurodegenerative diseases, according to an in vitro study by researchers in Switzerland. It is believed to be the first time that a potent agent against Alzheimer's has been isolated from cyanobacteria, commonly known as 'pond scum.' The study was published in the Dec. 26 issue of the Journal of Natural Products, a monthly peer-reviewed joint publication of the American Chemical Society and the American Society of Pharmacognosy.

Cyanobacteria and other marine natural products have been increasingly found to be a promising source of drug candidates for fighting a variety of human diseases, including cancer and bacterial infections, but their chemistry has been largely unexplored, experts say. Now, a common marine organism could lead to yet another potential health benefit, says study leader Karl Gademann, Ph.D., an organic chemist at the Swiss Federal Institute of Technology (ETH) in Zürich. Gademann's lab specializes in identifying, synthesizing and studying new bioactive compounds from natural sources.

There is no cure for Alzheimer's at present, although cholinesterase inhibitors have shown promise for delaying or preventing the symptoms of mild to moderate forms of the disease, experts say. The newly isolated compound, nostocarboline, was shown to be a potent inhibitor of cholinesterase -- a brain chemical thought to be important for memory and thinking -- whose breakdown has been associated with the disease's progression. The natural compound's potency is comparable to galanthamine, a cholinesterase inhibitor already approved for the treatment of Alzheimer's, the researchers say.

As with any promising structure, it could be many years before the new compound is tested as a drug candidate in humans, the scientists caution. In addition to Gademann, others involved in this study include Friedrich Jüttner and Paul Becher of the University of Zürich and Julien Beuchat, currently with the Université de Lausanne in Switzerland.

Synthetic Melatonin Metabolites Appear to Prevent Brain Cell Death

Thu, 22 Dec 2005 16:32:00 PST

( from http://www.rxpgnews.com ) Spanish chemists have developed a promising set of synthetic compounds that one day could help slow or perhaps halt the progression of Alzheimer's disease and other neurological disorders. The preliminary finding, based on test tube studies by researchers at the Universidad de Granada and others, appears in the Dec. 29 issue of the American Chemical Society's Journal of Medicinal Chemistry.

The compounds, particularly a synthesized metabolite of the hormone melatonin, all inhibit an enzyme called inducible nitric oxide synthase (iNOS), which is needed to produce nitric oxide (NO). NO, a signaling molecule that can activate the immune system, plays an important role in the brain, according to the researchers. But too much NO can trigger the death of brain cells and some scientists theorize the compound is involved in the development of Alzheimer's and Parkinson's diseases.

Like melatonin, the new synthetic compounds apparently can cross biological barriers, suppress iNOS production, and, in turn, prevent NO-induced brain damage, the researchers say. However, they caution that additional research will be needed to verify these results.

Research sheds light on creatine's presence in brain

Thu, 22 Dec 2005 05:15:00 PST

( from http://www.rxpgnews.com ) Alzheimer's disease is one of the most hauntingly destructive maladies to wreak havoc on humans. It robs children of parents and spouses of each other-with lifetimes of memories lost forever behind blank stares.

But researchers are working toward answers to the many questions that have made Alzheimer's a complex and unsolved degenerative disease and, in some cases, a death sentence.

In an article in the November Journal of Biological Chemistry, a team of Canadian and American scientists reports the first-ever finding of elevated levels of creatine-the newly discovered agent of Alzheimer's-in brain tissue. The article is available pre-press at the Journal of Biological Chemistry's Web site.

"It is the first time anyone has succeeded in detecting creatine directly in situ, in any tissue. The usual methods are to grind up a large amount of tissue and extract it in bulk," explains one of the paper's authors, Kathleen Gough, professor of chemistry at the University of Manitoba.

Gough and her colleagues, along with many others in the field, are searching tenaciously for the molecular answers that might someday lead to the end of Alzheimer's disease. Of particular note regarding the current study was the use of infrared spectroscopy as another tool that has contributed to the body of knowledge regarding Alzheimer's.

"It's the first time that we've discovered creatine in Alzheimer's disease samples that didn't appear in control samples. Nobody has ever seen this before," explains Robert Julian, an expert in infrared spectroscopy at the University of Wisconsin-Madison Synchrotron Radiation Center (SRC), the light source utilized for this project.

The key to using infrared, the researchers explain, is that it is relatively unobtrusive as compared to normal laboratory protocols used to study brain tissues, thus keeping the samples closer to being "pristine."

"Due to its small size and great solubility, creatine dissolves and would be washed away under normal tissue preparation protocols for staining. Step one in any staining process is to soak a tissue sample in an aqueous solution of formaldehyde, called formalin. This 'fixes' the proteins in place, but also washes out the small, soluble metabolites like creatine," explains Gough. "What we do is prepare the tissue without any treatment, and we look at unfixed, flash frozen tissue-nothing added or removed, except water."

Thus while the use of synchrotron radiation, a traditionally physics-focused tool for discovery, to study Alzheimer's has surprised some, it may be this application that could one day turn the tide on Alzheimer's Disease. "That's where all of this is going ultimately-is to try and find a cure," explains Julian.

Yet researchers stress that while this information sheds more light on a troubling disease and might possibly lead to improved treatment, the term "cure" simply cannot be used yet.

"It could be really important," concludes Gough. "It seems that there is an overlooked aspect of energy disturbance in Alzheimer's disease, and maybe in other diseases. But as to the detailed explanation of why (the disturbance) is there - the jury is still out."

Advances in biomarkers search to detect Alzheimer's disease (AD)

Thu, 22 Dec 2005 03:52:00 PST

( from http://www.rxpgnews.com ) The search for new measures, or "biomarkers," to detect Alzheimer's disease (AD) before signs of memory loss appear has advanced an important step in a study by researchers at Washington University in St. Louis, MO, and the University of Pittsburgh.

The researchers combined high-tech brain imaging with measurement of beta-amyloid protein fragments in cerebrospinal fluid (CSF). They found that greater amounts of beta-amyloid containing plaques in the brain were associated with lower levels of a specific protein fragment, amyloid-beta 1-42, in CSF. Prior research indicates that amyloid-beta 1-42 is central to AD development. The fragment is a major component of amyloid plaques in the brain, which are believed to influence cell-to-cell communication and are considered a hallmark of the Alzheimer's brain.

The study, published online December 21, 2005, by the Annals of Neurology, is the first to examine the relationship between levels of amyloid plaque deposits in the brain and different forms of beta-amyloid in CSF in living humans. It was supported by the National Institute on Aging (NIA), a component of the National Institutes of Health (NIH) at the U.S. Department of Health and Human Services, and by the Washington University General Clinical Research Center, funded by the NIH.

The method studied might one day help to more accurately diagnose AD, even before the appearance of cognitive symptoms, and to monitor disease progression. In the near term, the findings could be useful in a research context, allowing scientists to track the effects of potential beta-amyloid lowering treatments in clinical trials.

"We presently don't have fully validated imaging or biomarker measures that can help us monitor the development or progression of Alzheimer's in living people," explains Neil Buckholtz, Ph.D., chief of the Dementias of Aging Branch at the NIA. "This study represents one step in the progress being made toward identifying clinically useful biological measures for AD."

The research was conducted by Anne M. Fagan, Ph.D., and colleagues David M. Holtzman, M.D., Mark A. Mintun, M.D., and John C. Morris, M.D., of the Alzheimer's Disease Research Center (ADRC) at Washington University School of Medicine and used a newly developed imaging tracer for beta-amyloid from investigators at the ADRC at the University of Pittsburgh. Both ADRCs are funded by the NIA.

The study included 24 people ages 48 to 83 years who were cognitively normal or had very mild, mild, or moderate dementia. The researchers used positron emission tomography (PET), a brain imaging technique, with a tracing substance called Pittsburgh Compound B (PIB), to determine the amount of plaques in the participants' brains. PIB travels through the bloodstream into the brain and then binds to beta-amyloid containing plaques in the brain. PIB makes it possible to see on PET images any areas of the brain with high concentrations of plaques.

The researchers also analyzed samples of study participants' CSF and blood plasma for levels of specific protein fragments, including two forms of beta-amyloid and the protein tau.

The seven participants whose PET scans showed PIB binding -- and therefore deposits of beta-amyloid containing plaques in the brain -- had the lowest levels of amyloid-beta 1-42 in their CSF. Those without PIB binding had the highest levels of CSF amyloid-beta 1-42. No relationship was seen between PIB binding and the other CSF or blood-plasma biomarkers studied, including plasma amyloid-beta 1-42. As shown in previous studies of mice, decreases in CSF beta-amyloid may result from plaques acting as a "sink," hindering movement of soluble beta-amyloid between the brain and CSF, the researchers hypothesize.

Importantly, three of the participants had normal cognitive evaluations but had high PIB binding and low CSF amyloid-beta 1-42, suggesting the possibility that this combination of methods may be useful as "antecedent" biomarkers of AD, identifying the presence of AD amyloid pathology before the development of cognitive impairments. Alternatively, if these subjects never develop cognitive decline, it is possible that plaque number is not always a predictor of the disease.

"Although this study involved a very small sample, the findings suggest that amyloid imaging and CSF beta-amyloid measures together may have utility as biomarkers of AD before symptoms develop and as the disease progresses," says Fagan. "These measures hold potential for identifying individuals with AD pathology before cognitive symptoms, improving the accuracy of clinical diagnosis of AD and facilitating the testing of future therapies."

However, she cautions, "It is important to recognize that this is still a research study and the findings must be carefully validated before this approach can be considered for clinical use."

The search for biomarkers to detect AD and to monitor disease progression was accelerated recently when the NIA, in conjunction with more than a dozen other Federal Government and private-sector organizations, launched the 5-year, $60 million Alzheimer's Disease Neuroimaging Initiative. The initiative is the most comprehensive effort to date to study and correlate neuroimaging and fluid biomarkers with the changes associated with mild cognitive impairment and AD. It will examine whether serial magnetic resonance imaging (MRI), PET, other biomarkers, and clinical and neuropsychological assessment can be combined to assess mild cognitive impairment and early AD progression.

The Neuroimaging Initiative has begun recruiting people ages 55 to 90 to participate in the study. Participants may be cognitively normal or have MCI or early AD. Further information about the study and a list of the 58 local study sites in the U.S. and Canada may be obtained by calling the NIA's Alzheimer's Disease Education and Referral (ADEAR) Center toll free at 1-800-438-4380 or visiting the ADNI section of the ADEAR website at www.alzheimers.org/imagine. Anyone interested in learning more about enrollment in the project may contact the study site closest to them. Spanish-language capabilities are available at some of the study sites.

Testosterone therapy may improve life quality in some Alzheimer patients

Wed, 14 Dec 2005 17:10:00 PST

( from http://www.rxpgnews.com ) Testosterone replacement therapy may help improve the quality of life for elderly men with mild cases of Alzheimer's disease, according to a study posted online today that will appear in the February 2006 print issue of the Archives of Neurology, one of the JAMA/Archives journals.

"There is a compelling need for therapies that prevent, defer the onset, slow the progression, or improve the symptoms of Alzheimer disease (AD)," the authors provide as background information in the article. They note that hormonal therapies have been the focus of research attention in recent years since male aging is associated with a gradual progressive decline in testosterone levels. "The gradual decline in testosterone level is associated with decreased muscle mass and strength, osteoporosis, decreased libido, mood alterations, and changes in cognition, conditions that may be reversed with testosterone replacement." The authors add that the age-related decline in testosterone is potentially relevant to AD as previous studies have found significantly lower concentrations of the hormone in middle-aged and elderly men who developed AD.

Po H. Lu, Psy.D., from the David Geffen School of Medicine, University of California, Los Angeles, and colleagues conducted a 24-week, randomized study to evaluate the effects of testosterone therapy on cognition, neuropsychiatric symptoms, and quality of life in 16 male patients with mild AD and 22 healthy elderly men who served as controls. The study participants were randomized to receive packets of gel to apply on their skin that either contained testosterone or a placebo. Standardized tests were administered at least twice (baseline and end) during the study for the assessment of cognitive functions and quality of life.

"For the patients with AD, the testosterone-treated group had significantly greater improvements in the scores on the caregiver version of the quality-of-life scale," the researchers report. "No significant treatment group differences were detected in the cognitive scores at end of study, although numerically greater improvement or less decline on measures of visuospatial functions was demonstrated with testosterone treatment compared with placebo. In the healthy control group, a nonsignificant trend toward greater improvement in self-rated quality of life was observed in the testosterone-treated group compared with placebo treatment. No difference between the treatment groups was detected in the remaining outcome measures."

"In conclusion, the present results should be considered preliminary and do not warrant routine treatment of AD and healthy control men with testosterone. Future studies with larger sample sizes are needed before clinical decisions regarding testosterone therapy can be rationally based. For men with compromised quality of life, as reflected on the type of measure employed in this study, and who suffer from low serum T [testosterone] levels, testosterone therapy may be a reasonable consideration."

Alzheimer's plaque precursor characterized

Wed, 23 Nov 2005 17:49:00 PST

( from http://www.rxpgnews.com ) Using a nuclear magnetic resonance technique, University of Illinois at Chicago chemists have obtained the first molecular-level images of precursors of bundled fibrils that form the brain plaques seen in Alzheimer's disease.

Untangling the molecular structure of these pre-fibril forms, which may be the key neurotoxins in Alzheimer's, may help identify targets for new drugs to combat many neurodegenerative diseases.

Microscopic bundled fibrils made of proteins called amyloid-beta are presumed to be the toxic culprits in the senile plaques found in the brain with Alzheimer's. But there is increasing evidence that even smaller assemblies of amyloid-beta found prior to formation of pre-fibrils are the real nerve-killers. Scientists have been frustrated that electron microscope images of these nanometer-scale spherical assemblies have failed to reveal any distinct molecular structure.

Yoshitaka Ishii, assistant professor of chemistry at UIC, and graduate student Sandra Chimon have now determined this structure using a methodology developed with high-resolution solid-state nuclear magnetic resonance, or SSNMR. Details were reported in a Communication article last month in JACS, the Journal of the American Chemical Society.

"This is the first case showing that these intermediate species, the smaller assemblies, have a well-defined structure," said Ishii, who conducted a two-year search to map the structure of the pre-fibril assemblies, then spent another year confirming his findings.

Ishii's technique uses what is called time-resolution SSNMR to view nanoscale spectral images of this chemical formation.

Thioflavin, a dye commonly used to stain amyloid senile plaques, is applied to detect formation of the intermediate assemblies in florescence. The intermediate sample is then frozen to capture quickly changing spectral images of the molecules before they can self-assemble into fibril-forming sheets.

The resulting SSNMR "snapshots" provide a structural diagram for finding molecular binding targets that may stop proteins from misfolding, which may stop Alzheimer's disease from developing.

"We're interested in how the molecules assemble in this shape, and eventually into fibrils," Ishii said. "We wanted to find out what kind of structure each amino acid takes in a certain site of a protein at the atomic level. It gives us an idea of how these molecules interact with each other to make this structure."

Ishii said the SSNMR technique may be used to study small chemical subunits involved in diseases such as Parkinson's and prion diseases like mad cow or Creutzfeld-Jacob, to name just some of the 20 or so neurodegenerative diseases characterized by misfolding proteins.

"You want to design molecules that will interact and prevent this," said Ishii. "That's been difficult. Now we have a new clue to learn how."

Early Anti-amyloid Treatments in Alzheimer's are most effective

Tue, 15 Nov 2005 19:34:00 PST

( from http://www.rxpgnews.com ) Dementia is a common condition in the elderly; around 6% of people over 65 and up to 50% over 90 have some form of dementia, about half of which are due to Alzheimer disease (AD). The dementia caused by AD has an insidious onset and a progressive course with slow deterioration in cerebral function, initially affecting short-term memory and cognitive skills, and later speech, motor functions, and personality. Death usually occurs within four to eight years after diagnosis.

The aim of treatment is to reverse cognitive decline and improve behavioral and psychological functions. Key questions in Alzheimer research are how best to halt the progression of disease to maintain and if possible restore cognitive skills, and when to initiate such interventions in order to be effective.

AD is identified at autopsy by the presence of hallmark lesions in key regions of the brain. These lesions, known as amyloid plaques, are formed by the aggregation of small peptides, called amyloid Î² peptide (AÎ²), that are produced when amyloid precursor protein (APP) is cleaved by the action of two enzymes, Î²-APP cleaving enzyme and Î³-secretase. One approach to the treatment of Alzheimer is, therefore, limiting the production of AÎ² from its precursor by inhibiting one or both of these enzymes. However, it is not yet clear whether this approach will prevent the brain lesions and cognitive symptoms from getting worse, and if it will then promote the removal of preexisting plaques and reverse cognitive decline.

To answer such questions, Joanna Jankowsky and colleagues have developed mice that produce AÎ² at levels sufficient to induce severe amyloid burden by six months of age. The animals carry an additional transgene that acts as a switch to control when AÎ² is produced. Commonly known as the tet-off system, the switch is turned off when the mice are fed tetracycline or its analog, doxycycline. Once given the drug, AÎ² production in the brains of these mice diminishes by more than 95% of pretreatment levels within two weeks. This system, thus, mimics the effect of shutting down AÎ² production with enzyme inhibitors that are being developed for use in human patients.

In the study, the researchers used doxycycline to switch off production of AÎ², and examined what happened to the amyloid pathology. Not surprisingly, the increase in number and size of amyloid lesions that normally occurs as the mice get older was completely prevented by suppressing AÎ² production. However, the researchers also found no substantial clearance of preexisitng plaques, even after six months of treatment (one-quarter of the normal mouse lifespan).

What do these findings mean for human Alzheimer research? First, the study provides evidence that the lesions found in AD may be more difficult for the brain to repair than protein aggregates found in other diseases such as Huntington or prion disease. Second, the findings suggest that the removal of plaques, once formed, may require more than simply halting the production of the AÎ² peptide. However, as with all animal models, there are differences in comparison to the human disease, leading to both over- and underestimation of the relative importance of an effect in humans. The researchers do not yet know whether the plaques formed in mice may be more resistant to clearance than those seen in human disease. Conversely, the human brain, unlike the murine one, may have a more efficient way of clearing amyloid plaques. What this study makes clear is that treatments directed at reducing AÎ² peptide production in AD will likely be most effective when started as early as possible.

Resveratrol found in red wine can protect against Alzheimer's

Sun, 06 Nov 2005 15:02:00 PST

( from http://www.rxpgnews.com ) A study published in the November 11 issue of the Journal of Biological Chemistry shows that resveratrol, a compound found in grapes and red wine, lowers the levels of the amyloid-beta peptides which cause the telltale senile plaques of Alzheimer's disease.

"Resveratrol is a natural polyphenol occurring in abundance in several plants, including grapes, berries and peanuts," explains study author Philippe Marambaud. "The polyphenol is found in high concentrations in red wines. The highest concentration of resveratrol has been reported in wines prepared from Pinot Noir grapes. Generally, white wines contain 1% to 5% of the resveratrol content present in most red wines."

One of the characteristic features of Alzheimer's disease is the deposition of amyloid-beta peptides in the brain. Philippe Marambaud and his colleagues at the Litwin-Zucker Research Center for the Study of Alzheimer's Disease and Memory Disorders in Manhasset, New York, administered resveratrol to cells which produce human amyloid-beta and tested the compound's effectiveness by monitoring amyloid-beta levels inside and outside the cells. They found that levels of amyloid-beta in the treated cells were much lower than those in untreated cells.

The researchers believe the compound acts by stimulating the degradation of amyloid-beta peptides by the proteasome, a barrel-shaped multi-protein complex that can specifically digest proteins into short polypeptides and amino acids.

However, eating grapes may not be a cure for Alzheimer's disease. "It is difficult to know whether the anti-amyloidogenic effect of resveratrol observed in cell culture systems can support the beneficial effect of specific diets such as eating grapes," cautions Marambaud. "Resveratrol in grapes may never reach the concentrations required to obtain the effect observed in our studies. Grapes and wine however contain more than 600 different components, including well-characterized antioxidant molecules. Therefore, we cannot exclude the possibility that several compounds work in synergy with small amounts of resveratrol to slow down the progression of the neurodegenerative process in humans."

Following up on their studies, Marambaud and his colleagues are trying to figure out how resveratrol exerts its effects in order to develop similar compounds to use in fighting Alzheimer's disease. "Our long-term goal is now to elucidate the exact molecular mechanisms involved in the beneficial properties of resveratrol as a necessary prerequisite to the identification of novel molecular targets and therapeutic approaches," says Marambaud. "The observation that resveratrol has a strong anti-amyloidogenic activity is a powerful starting point for screening analogues of resveratrol for more active and more stable compounds, a task in which our laboratory is actively involved. We have already obtained analogues of resveratrol that are 20 times more potent than the original natural compound. We are now aiming to find more stable analogues and to test them in vivo in mice."

Additional good news is that resveratrol may also be effective in fighting other human amyloid-related diseases such as Huntington's, Parkinson's and prion diseases. Studies by a group at the Institut National de la Santé et de la Recherche Médicale in Paris, France headed by Christian Néri have recently shown that resveratrol may protect neurons against amyloid-like polyglutamines, a hallmark of Huntington's disease.

Imaging With Radiotracer FDG in Patients With Mild Cognitive Disorder Has Significantly Higher Accuracy

Thu, 06 Oct 2005 23:19:00 PST

( from http://www.rxpgnews.com ) Positron emission tomography (PET) imagingwith the radiotracer fluorodeoxyglucose (FDG)is a promising tool in detecting Alzheimer's disease in patients who have mild cognitive impairment (MCI), according to a study reported in the October issue of the Society of Nuclear Medicine's Journal of Nuclear Medicine.

"PET imaging with FDG represents one of the most promising tools for diagnosis of Alzheimer's," said Alexander Drzezga, M.D., who is the senior physician with the department of nuclear medicine at the Technical University of Munich in Germany. In fact, using PET imaging with FDG "may be the best indicator for determining which MCI patients are most at risk of developing Alzheimer's," added the lead author of "Prediction of Individual Clinical Outcome in Mild Cognitive Impairment (MCI) by Means of Genetic Assessment and 18F-FDG PET."

Mild cognitive impairment (MCI) is a term used to describe a subtle but measurable deterioration of cognitive capabilities, such as memory function. Individuals with MCI are able to function reasonably well in everyday activities, such as managing finances and purchasing items at stores without assistance, but may have difficulty remembering details of conversations, events and upcoming appointments.

Patients with MCI do not yet exhibit the criteria for the diagnosis of dementia, but the disorder is seen as a precursor to Alzheimer's disease, which takes years to develop in a person, said Drzezga. Many patients with MCI develop a progressive decline in their thinking abilities over time, and Alzheimer's disease is usually the underlying cause. Alzheimer's is the most common form of dementia among older people; it is a progressive, irreversible brain disorder with no known cause or cure. More than 4.5 million Americans suffer from Alzheimer's and its symptoms of memory loss, confusion, impaired judgment, personality changes, disorientation and loss of language skills.

"A high percentage of MCI patients will develop Alzheimer's disease within a year; however, some of these patients will never develop dementia and may even improve with time," said Drzezga. Most MCI patients who showed abnormalities typical of Alzheimer's in their original PET scan developed dementia within 16 months, according to findings from the 30-patient study. Most patients who did not show abnormalities in their original PET scan remained stable, he added.

Patients with Alzheimer's show characteristic changes of the cerebral glucose metabolic pattern, with a decrease in affected brain regions, said Drzezga. PET imaging with FDG allows the analysis of regional cerebral glucose metabolism. The study showed that "the assessment of cerebral glucose metabolism actually reflects ongoing pathological changes associated with Alzheimer's disease on a molecular level and that the molecular imaging method PET is capable of depicting subtle changes in the brain of MCI patients before a diagnosis of Alzheimer's based on neuropsychological evaluation is possible," said Drzezga.

The study revealed that PET with FDG has a significantly higher accuracy for detection of Alzheimer's than the genetic screening for the APOEe4-risk factor. In addition, using both PET with FDG and the APOEe4-genotype as genetic markers "allowed the definition of subgroups of patients with very high risk and with very low risk," he added. This finding could have implications for risk stratifying MCI patients in therapeutic trials, said Drzezga. "This study implies that PETand in consequence nuclear medicineshould continue to be strongly involved in the challenging process of Alzheimer's research for early diagnosis as well as for the development and evaluation of new treatment options," he added.

Although there is currently no cure for Alzheimer's, new treatments are on the horizon as a result of accelerating insight into the biology of the disease. "It is of increasing importance to identify 'converters' at the earliest possible stage of disease to develop and evaluate new and upcoming treatment options for Alzheimer's," added Drzezga, an SNM member.

PET is a safe, effective and painless biological imaging exam that "photographs" or detects the presence and extent of neurological conditions. PET uses very small amounts of radioactive materials that are targeted to specific organs, bones or tissues. Radiotracers (such as FDG) are injected and then detected by a special type of camera that works with computers to provide precise pictures of the area of the body being imaged and molecular images of the body's biological functions. "The combination of molecular imaging with genotype assessment represents the unique opportunity to interpret imaging findings in the context of background information," explained Drzezga. "As we increase our understanding of the human genome, individualized therapy and individualized diagnosis will become increasingly important," he added. "The current study underlines that a genetic disposition does not necessarily represent a determined prognosis, thus, the need for measures that allow the definition of the actual onset of a disease process is apparent. Molecular imaging could play an important role in this context," he stated.

Implicit-memory tests are stronger predictors than Mini Mental exam

Wed, 28 Sep 2005 03:34:00 PST

( from http://www.rxpgnews.com ) Two recent studies may help clinicians and researchers better predict and understand dementia of the Alzheimer's type early in its history. Both studies appear in the September issue of Neuropsychology, which is published by the American Psychological Association (APA). Psychologists focus on early detection in part because current medications are useful only when given very early in the course of the disease.

In the first study, psychologists Pauline Spaan, PhD, and Jeroen Raaijmakers, PhD, from the University of Amsterdam in collaboration with neurologist Cees Jonker, MD, PhD, from the Vrije Universiteit in Amsterdam analyzed the data on 119 participants in the Longitudinal Aging Study Amsterdam, a large, population-based study of older people. The researchers visited older people in their homes and gave them memory tests loaded on laptop computers. Two years later, they compared the test scores of people who went on to develop Alzheimer's with the scores of those who stayed healthy.

The researchers analyzed memory components that included episodic (what happened; what did you hear or read); semantic (vocabulary, facts); and implicit (learning without awareness of learning, priming). Three tests were very good at predicting who would develop Alzheimer's by two years later. Participants for whom priming information didn't aid memory or whose learning wasn't aided by semantic knowledge -- were significantly more likely to develop Alzheimer's.

The strongly predictive tests were, in order of their power, a Paired-Associate Learning Test, which cued participants to recall five semantically related and five semantically unrelated pairs of words; and a Perceptual Identification Task, which measured how fast participants read aloud words briefly presented on a computer screen. To test implicit memory, experimenters repeated some words to see whether priming took place, which would help participants read those words faster. The researchers also gave a Visual Association Test, which cued participants to recall six line drawings of common objects that had been presented earlier in an illogical interaction with another object or cue.

On the word-pair memory test, people destined to develop Alzheimer's disease didn't do any better when words were related than when they weren't. The authors think these participants may already have lost key knowledge of word attributes that normally help people to more easily remember words by means of their semantic associations. Sometimes, at-risk participants reported a vague sense that one word had something to do with another, but they couldn't say exactly what. The authors suspect they couldn't encode the word pairs at a sufficiently deep level because they'd lost the semantic knowledge that stays intact in normally aging people. On the word-reading test, word repetition (to measure priming) didn't help high-risk participants to perform better, a sign that they weren't learning implicitly as well as the people who would stay healthy. The authors speculate that because high-risk participants drew less benefit from word repetition, they did not encode the words properly.

These tests remained sensitive to the risk of developing Alzheimer's disease even within a more homogeneous subset of the broader study population, people with mild cognitive impairment. For both the whole and subset study groups, these tests predicted future Alzheimer's diagnosis as much as two years early.

Equally important, the popular Mini Mental Status Exam (MMSE), a test mainly sensitive to episodic memory, was not as good a predictor. Although clinicians use it for quick, easy-to-administer screening, the authors found it to be "less predictive [than the tests sensitive to semantic and implicit memory]. These [MMSE and other purely episodic memory] tasks may only differentiate between pathological and normal aging when dementia has progressed to a more advanced stage."

In the second Neuropsychology study, an established psychological test has picked up early-warning signs of Alzheimer's disease. A new study in the September issue of Neuropsychology explains how the dichotic listening task, which measures how well people process information when they hear one thing in the left ear and another in the right ear, confirms that very early in the disease, people have problems with selective attention. This problem, although not as obvious as memory loss, may also explain why early-stage patients start to struggle with everyday tasks that call for processing a lot of information such as driving.

At the Alzheimer's Disease Research Center at Washington University in St. Louis, Janet Duchek, PhD and David Balota, PhD, studied 94 participants in their early to mid-70s with healthy, very mild, or mild dementia of the Alzheimer's type. They looked for information-processing breakdowns suspected to happen early in the disease, before the appearance of language and visuospatial problems. Problems with attention, the authors say, could underlie the difficulty with daily activities often seen in the early stages of the disease.

Duchek and Balota used a dichotic listening task, presenting information to participants via headphones. One stream of information computer-generated speech naming three digits (such as 4, 3, 1) went to the left ear; a different stream (such as 9, 2, 5) went to the right ear. The psychologists measured how well participants recalled the digits presented to each ear.

As predicted, people with early dementia remembered the digits presented to the right ear far better than they recalled the digits presented to the left ear. When the researchers controlled for overall recall performance, the mild dementia group recalled 21.7% more information from their right ear vs. left ear, and even the very mildly affected group recalled 11.3% more from the right ear. The control participants only recalled 5.8% more from the right vs. left.

Clearly, people with mild or very mild Alzheimer's relied more heavily on the default pathway for processing information, which for language would be the left side of the brain. In other words, these patients had a harder time switching their attention and reporting what they heard in the left ear, which sent information to the right half of the brain.

The right-ear advantage increased with dementia severity. People farther along in the disease relied even more on the dominant left-side channel; in other words, they found it even harder to override the usual path to process what went through the left ear to the right brain.

The study confirms that attentional processing, like other cognitive processes, is affected early in Alzheimer's disease. Poor attentional controls can leave people falling back on familiar, pre-programmed information pathways. Write the authors, One can speculate about the importance of attentional control in everyday tasks, such as driving. Their speculation is supported by prior findings that performance on dichotic listening predicts accident rates in commercial bus drivers.

Hope for Alzheimer's blossoms in daffodil

Tue, 06 Sep 2005 00:12:00 PST

( from http://www.rxpgnews.com ) A substance found in the Welsh national flower, which could offer hope for sufferers of Alzheimers disease, is being supported for large scale manufacture by Cardiff Universitys Manufacturing Engineering Centre (MEC).

Alzheimers disease is the most common form of dementia, making up 55 per cent of all cases of dementia. Dementia affects one person in 20 over the age of 65 and one person in five over the age of 80.

Certain species of daffodil, which thrive in the Black Mountains of South Powys, produce galanthamine, a leading drug in the alleviation of memory loss symptoms.

The Universitys Manufacturing Engineering Centre is now helping a company Alzeim Ltd (supported by Glasu, the EU funded LEADER+ Programme in Powys) to develop the agricultural potential of the daffodil as a medicinal plant along with the Institute of Grassland and Environmental Research at the University of Wales, Aberystwyth.

The Centre is providing support from harvesting in the field to marketing the pharmaceutical product. This includes assisting with the science of developing crops more than once a year and helping growers to assess when the best time to harvest the crop.

Frank Marsh, Marketing Director, The Manufacturing Engineering Centre said: "Galanthamine has major investment potential. Furthermore, the potential for Welsh hill farms is huge. The benefits are extensive, not only to Welsh bioscience and the pharmaceutical industry, but also to the ageing population."

New dye NIAD-4 could offer early test for Alzheimer's

Sat, 27 Aug 2005 03:37:00 PST

( from http://www.rxpgnews.com ) MIT scientists have developed a new dye that could offer noninvasive early diagnosis of Alzheimer's disease, a discovery that could aid in monitoring the progression of the disease and in studying the efficacy of new treatments to stop it.

Today, doctors can only make a definitive diagnosis of Alzheimer's-currently the fourth-leading cause of death in the United States-through a postmortem autopsy of the brain. "Before you can cure Alzheimer's, you have to be able to diagnose it and monitor its progress very precisely," said Timothy Swager, leader of the work and a professor in MIT's Department of Chemistry. "Otherwise it's hard to know whether a new treatment is working or not."

To that end, Swager and postdoctoral associate Evgueni Nesterov, also from the MIT Department of Chemistry, worked with researchers at Massachusetts General Hospital and the University of Pittsburgh to develop a contrast agent that would first bind to the protein deposits, or plaques, in the brain that cause Alzheimer's, and then fluoresce when exposed to radiation in the near-infrared range. The new dye could allow direct imaging of Alzheimer's plaques through a patient's skull.

Some of the first noninvasive techniques for diagnosing Alzheimer's involved agents labeled with radioactive elements that could enter the brain and target disease plaque for imaging with positron emission tomography (PET). However, these methods were expensive and limited by the short working lifetime of the labeled agents.

Swager and colleagues developed the new dye, called NIAD-4, through a targeted design process based on a set of specific requirements, including the ability to enter the brain rapidly upon injection, bind to amyloid plaques, absorb and fluoresce radiation in the right spectral range, and provide sharp contrast between the plaques and the surrounding tissue. The compound provided clear visual images of amyloid brain plaques in living mice with specially prepared cranial windows.

To make the technique truly noninvasive, scientists must further refine the dye so it fluoresces at a slightly longer wavelength, closer to the infrared region. Light in the near-IR range can penetrate living tissue well enough to make brain structures visible. Swager likens the effect to the translucence produced when one holds a red laser pointer against the side of a finger.

"This procedure could be done in a chamber with a photodetector and a bunch of lasers, and it would be painless," he said, adding that infrared fluorescence and other optical techniques will lead to a whole new class of noninvasive medical diagnostics. Swager says fluorescing dyes like NIAD-4 could be ready for clinical trials in the near future.

"What we have is a dye that lights up when it binds to amyloids that form in the brains of people with Alzheimer's. It's a completely new transduction scheme-a way of translating a physical or chemical event that's invisible to the naked eye, into a recognizable signal. Further wavelength adjustments in these dyes will allow us to perform in vivo analysis through human tissue."

The new dye was developed as part of a broader effort in sensing technology at MIT's Institute for Soldier Nanotechnologies. In addition to its applications as a medical diagnostic, Swager says fluorescing dyes like NIAD-4 could work as signals in a wide variety of sensing schemes.

Coronary bypass surgery increases risk of Alzheimer's disease

Thu, 25 Aug 2005 13:43:00 PST

( from http://www.rxpgnews.com ) Boston University School of Medicine (BUSM) researchers have discovered that patients who have either coronary artery bypass graft surgery or coronary angioplasty are at an increased risk of developing Alzheimer's disease.

The research, which appears in the current issue of the Journal of Alzheimer's Disease (http://www.j-alz.com), pinpoints stress and trauma of the surgery as the major cause for the increased risk.

Led by Benjamin Wolozin, MD, PhD, professor of pharmacology at BUSM, researchers compared 5,216 people who underwent coronary artery bypass graft surgery (CABG) and 3,954 people who had a percutaneous transluminal coronary angioplasty (PTCA) in 1996 and 1997. Over the course of five years, 78 of the patients who had bypass surgery and 41 of those who had angioplasty developed Alzheimer's disease.

"The coronary bypass patients had a 70 percent increased risk of developing Alzheimer's disease," said Wolozin, co-author of the study. "This increased incidence of neurocognitive degeneration associated with heart bypass surgery provides further incentive for more studies to better characterize the risks of cardiac surgery on the brain."

According to Wolozin, previous studies show some heart surgery patients experience memory problems immediately following the procedure. However, at a one-year follow-up most patients regain cognitive function.

Researchers believe this early cognitive impairment is an immediate reaction to the stress of surgery.

"Heart bypass surgery represents a traumatic insult to the brain, particularly by reducing oxygen supply to the brain and increasing the stress response," said Wolozin.

"We believe that the compensation that occurs by one year masks an underlying deficit in the central nervous system caused by the heart surgery. As individuals age, this underlying deficit might exacerbate progressive cognitive deficits associated with mild cognitive impairment, a precursory phase before diagnosis of Alzheimer's."

Wolozin and his researchers are currently working with researchers from the Framingham Heart Study to determine if these same observations can be duplicated in their studies.

"If these observations are confirmed, there are measures that can be taken to protect the brain during heart bypass surgery," explained Wolozin. "Antioxidants might offer some protection, as well as memantine, a medication that helps slow the progression of Alzheimer's disease. There may also be other neuroprotective agents still in development that could shield the brain from cognitive degeneration during and following surgery."

Mesenchyme homeobox 2 (MEOX2) gene linked to Alzheimer's disease

Mon, 15 Aug 2005 14:05:00 PST

( from http://www.rxpgnews.com ) Scientists at the University of Rochester Medical Center have discovered a link between a prominent developmental gene and neurovascular dysfunction in Alzheimer's disease.

The gene plays a major role in the growth and remodeling of vascular systems. But, in brain cells of people with Alzheimer's disease, expression of the gene is low, the scientists found, revealing a new piece of the Alzheimer's puzzle.

In laboratory studies, the scientists also showed that restoration of the gene expression level in the human brain cells stimulated the formation of new blood vessels. It also increased the level of a protein that removes amyloid beta peptide, the toxin that builds up in brain tissue in Alzheimer's disease.

In further studies, the scientists, led by Berislav Zlokovic, M.D., Ph.D., deleted one copy of the gene in mice, creating echoes of the damage of Alzheimer's, including reduced ability to grow blood vessels in the brain and impaired clearance of amyloid beta.

"This is a new pathway for the study and treatment of Alzheimer's disease," said Zlokovic. "This gene could be a therapeutic target. If we can stop this cycle, we could slow or stop the progression of the neuronal component of this disease."

An article by Zlokovic and his team detailing the research findings appears Sunday Aug. 14 in the online version of Nature Medicine. The article will be published in the September print edition of Nature Medicine.

Zlokovic is a professor in the University of Rochester Medical Center's Department of Neurosurgery and director of the Frank P. Smith Laboratories for Neuroscience and Neurosurgical Research.

The gene targeted in the research is a homeobox gene known as MEOX2 and also as GAX. A homeobox gene encodes proteins that determine development. Zlokovic calls it a "big boss."

The scientists studied human brain endothelial cells taken from autopsy samples from people with Alzheimer's. They found that expression of MEOX2, or mesenchyme homeobox 2, is low in the cells of those with Alzheimer's.

"The cells with low levels can't form any kind of vascular system or any kind of network," Zlokovic said. "They just start dying."

In restoring expression of the gene, the Rochester scientists showed for the first time that it suppresses a specific transcription factor. When the expression of MEOX2 is low, the factor "rampages" and allows apoptosis or programmed cell death in the brain vascular system, Zlokovic said.

When MEOX2 expression is low, the research also showed that a protein that helps with the clearance of amyloid beta is suppressed.

Zlokovic views the findings reported in Nature Medicine as support for his belief that Alzheimer's is a neurovascular disease.

"If you find a problem in the brain, it doesn't necessarily mean that it started in the brain," he said. "It's not that neuronal injury is not important. It's that other things are more important."

But Zlokovic said that it is not clear yet whether the low expression of the gene results in the death of brain cells and Alzheimer's disease or that the disease in neurons results in the low expression of the disease.

"But if we can restore the dysfunctional gene, we might be able to slow or stop the disease wherever it started," Zlokovic said.

Folates more effective in limiting Alzheimer's disease

Sun, 14 Aug 2005 14:27:00 PST

( from http://www.rxpgnews.com ) Adults who eat the daily recommended allowance of folates -- B-vitamin nutrients found in oranges, legumes, leafy green vegetables and folic acid supplements -- significantly reduce their risk of developing Alzheimer's disease, according to results from a long-term National Institute on Aging study of diet and brain aging.

The study also found that folates appear to have more impact on reducing Alzheimer's risk than vitamin E, a noted antioxidant, and other nutrients considered for their effect as a brain-aging deterrent.

Maria Corrada and Dr. Claudia Kawas of UC Irvine's Institute for Brain Aging and Dementia led the effort, which analyzed the diets of non-demented men and women age 60 and older. They compared the food nutrient and supplement intake of those who later developed Alzheimer's disease to the intake of those who did not develop the disease. It is the largest study to date to report on the association between folate intake and Alzheimer's risk and to analyze antioxidants and B vitamins simultaneously.

Results appear in the inaugural issue of the quarterly peer-reviewed research journal, Alzheimer's & Dementia: The Journal of the Alzheimer's Association.

"Although folates appear to be more beneficial than other nutrients, the primary message should be that overall healthy diets seem to have an impact on limiting Alzheimer's disease risk," said Corrada, who like Kawas started with the study while at Johns Hopkins University in Baltimore.

The researchers used data from the Baltimore Longitudinal Study of Aging to identify the relationship between dietary factors and Alzheimer's disease risk. Between 1984 and 1991, study volunteers provided detailed dietary diaries, which included supplement intake and calorie amounts, for a typical seven-day period.

Ultimately, 57 of the original 579 participants developed Alzheimer's disease. But the researchers found that those with higher intake of folates, vitamin E and vitamin B6 shared lower comparative rates of the disease. And when the three vitamins were analyzed together, only folates were associated with a significantly decreased risk.

In turn, no association was found between vitamin C, carotenoids (such as beta-carotene) or vitamin B-12 intake and decreased Alzheimer's risk.

"The participants who had intakes at or above the 400-microgram recommended dietary allowance of folates had a 55-percent reduction in risk of developing Alzheimer's," said Corrada, an assistant professor of neurology. "But most people who reached that level did so by taking folic acid supplements, which suggests that many people do not get the recommended amounts of folates in their diets."

Folates have already been proven to reduce birth defects, and research suggests that they are beneficial to warding off heart disease and strokes. Although folates are abundant in foods such as liver, kidneys, yeast, fruits (like bananas and oranges), leafy vegetables, whole-wheat bread, lima beans, eggs and milk, they are often destroyed by cooking or processing. Because of their link to reducing birth defects, folates have been added to grain products sold in the U.S. since 1998. But even with this supplement, it is thought that many Americans have folate-deficient diets.

Recent research is beginning to show relationships between folates and brain aging. Earlier this year, Dutch scientists showed that adults who took 800 micrograms of folic acid daily had significant improved memory test scores, giving evidence that folates can slow cognitive decline.

"Given the observational nature of this study, it is still possible that other unmeasured factors also may be responsible for this reduction in risk," said Kawas, the Al and Trish Nichols Chair in Clinical Neuroscience. "People with a high intake of one nutrient are likely to have a high intake of several other nutrients and may generally have a healthy lifestyle. But further research and clinical studies on this subject will be necessary."

Elevated Insulin levels may increase the risk for Alzheimer's disease

Wed, 10 Aug 2005 13:11:00 PST

( from http://www.rxpgnews.com ) Moderately elevated levels of insulin increase the levels of inflammatory markers and beta-amyloid in plasma and in cerebrospinal fluid, and these markers may contribute to Alzheimer's disease, according to a new study posted online today from Archives of Neurology, one of the JAMA/Archives journals. The study will be published in the October print edition of the journal.

According to background information in the article, "conditions of insulin resistance and hyperinsulinemia are associated with elevated levels of inflammatory markers and increase the risk for Alzheimer disease (AD). Inflammation has been proposed as a key pathogenic factor for AD."

Mark A. Fishel, M.D., from the University of Washington, Seattle, and colleagues, raised blood insulin levels (while maintaining normal blood sugar levels) in 16 healthy older adults ranging in age from 55 to 81 years, and then measured the changes in levels of inflammatory markers, modulators, and beta-amyloid (a protein associated with AD) in plasma and cerebrospinal fluid.

"Moderate peripheral hyperinsulinemia (increased levels of insulin) provoked striking increases in CNS (central nervous system) inflammatory markers," the authors report. "Our findings suggest that insulin-resistant conditions such as diabetes mellitus and hypertension may increase the risk for AD, in part through insulin-induced inflammation."

"Although this model has obvious relevance for diabetes mellitus, hyperinsulinemia and insulin resistance are widespread conditions that affect many nondiabetic adults with obesity, impaired glucose tolerance, cardiovascular disease, and hypertension. Our results provide a cautionary note for the current epidemic of such conditions, which, in the context of an aging population, may provoke a dramatic increase in the prevalence of AD. More encouragingly, greater understanding of insulin's role in AD pathogenesis may lead to novel and more effective strategies for treating, delaying, or even preventing this challenging disease," the authors conclude.

Slowing Alzheimer's Disease - Quinolinic acid pathway

Thu, 04 Aug 2005 23:40:00 PST

( from http://www.rxpgnews.com ) In a world first, Australian researchers have found a toxin that plays an important role in the progression of Alzheimer's disease (AD), the most common cause of dementia.
The research is significant because drugs that are in the advanced developmental phase for other conditions might be able to be used on Alzheimer's patients, to halt the disease progressing. At present, there are only minimally effective treatments for the condition, which is increasing with the ageing population.

"We found that all of the brains of dementia patients showed quinolinic acid neurotoxicity," said Professor Bruce Brew, Director of Neurology at St Vincent's Hospital and Professor of Medicine at the University of New South Wales (UNSW). "This acid kills nerve cells in the brain, leading to brain dysfunction and ultimately death."

There are currently more than 200, 000 people with Alzheimer's disease in Australia. The number will exceed 730, 000 by 2050.

"Quinolinic acid is part of a biochemical pathway called the kynurenine pathway," said the lead author of the research, UNSW's Dr Gilles Guillemin, who is based at the Centre for Immunology at St Vincent's Hospital. "The activation of that pathway is also found in other major brain diseases including Huntington's disease, stroke, dementia and schizophrenia."

The paper Indoleamine 2, 3 dioxygenase and quinolinic acid Immunoreactivity in Alzheimer's disease hippocampus has been published this week in the leading international journal Neuropathology and Applied Neurobiology. It is the result of collaboration between researchers from St Vincent's Hospital, UNSW, the University of Sydney and Hokkaido University, Japan.

"There are several drugs which can block this pathway, which are already under investigation by our laboratory and others," said Dr Guillemin.

The drugs, which would need to be tested for efficacy, could be used to complement other treatments.

"Quinolinic acid may not be the cause of Alzheimer's disease, but it plays a key role in its progression," said Alzheimer's researcher, Dr Karen Cullen from the University of Sydney. "It's the smoking gun, if you like.

"While we won't be able to prevent people from getting Alzheimer's disease, we may eventually, with the use of drugs, be able to slow down the progression."

The other researchers are Claire Noonan from Sydney University and Osamu Takikawa from Hokkaido University, Japan.

Posiphen(TM) to be evaluated in Phase I study for Alzheimer's Disease

Mon, 01 Aug 2005 23:45:00 PST

( from http://www.rxpgnews.com ) Axonyx, Inc. (NASDAQ: AXYX) a U.S.-based biopharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has approved its Investigational New Drug (IND) application, submitted in June 2005, allowing Phase I clinical testing of Posiphen(TM). The first Phase I clinical study is expected to begin shortly and will primarily evaluate the safety of Posiphen in healthy volunteers. Posiphen is in development by the Company for the potential treatment of Alzheimer's Disease progression.

"The initiation of the Posiphen Phase I program is an important milestone," stated Gosse B Bruinsma, MD, President and CEO of Axonyx Inc. "Alzheimer's disease devastates millions of individuals worldwide and we remain committed to advancing this potential treatment option that may slow or halt the progression of the disease."

In preclinical studies, Posiphen has been shown to lower beta amyloid precursor protein ((beta)APP) and beta amyloid (A(beta)) levels in rodents as well as demonstrating a favorable side-effect rate. The presence of toxic beta-amyloid in the brains of Alzheimer's disease (AD) patients is considered by many experts to be a key pathological event in the causation as well as the progression of AD.

Dr. Bruinsma continued, "In addition to the start of the Posiphen Phase I clinical study, we look forward to the submission of an IND application for BisNorCymserine (BNC), our butyrylcholinesterase inhibitor for the potential treatment of the symptoms of memory and cognition loss in severe AD. We also continue to evaluate additional opportunities to further expand our pipeline of CNS compounds."

About Posiphen(TM)

Posiphen(TM) is the positive isomer of Phenserine in development for the treatment of mild to moderate Alzheimer's Disease. Posiphen's mechanism of action has been shown to result in a dose dependent reduction of A(beta), which may potentially result in slowing AD progression. Axonyx has world-wide patent rights to Posiphen(TM) with NIH/NIA.

Preclinical diagnosis of Alzheimer's Dementia - muliti variable approach needed

Mon, 01 Aug 2005 16:47:00 PST

( from http://www.rxpgnews.com ) Washington -- By combing through dozens of Alzheimer's disease (AD) studies, psychologists have gained a clear picture of cognitive problems in people who will develop the degenerative brain disease. The meta-analysis reveals that people can show early warning signs across several cognitive domains years before they are officially diagnosed, confirming that Alzheimer's causes general deterioration and tends to follow a stable preclinical stage with a sharp drop in function. The findings appear in the July issue of Neuropsychology, which is published by the American Psychological Association.
Researchers at the Karolinska Institute and Stockholm Gerontology Research Center, affiliated also with the Max Planck Institute for Human Development and the University of South Florida, crunched the data from a decade's worth of studies: Published reports that met stringent criteria had records on 1,207 people with preclinical Alzheimer's (they later developed the disease) and 9,097 controls who stayed healthy.

Neuropsychologists are striving to understand the preclinical stage for two reasons: On the theoretical level, understanding the transition from normal aging to dementia is vital to understanding how the disease evolves. On the clinical level, treatment can work best when doctors can identify at-risk individuals as early as possible.

The authors studied 47 peer-reviewed studies published between January 1985 and February 2003. The year 1985 marked the introduction of more systematic and reliable diagnostic criteria for Alzheimer's.

The analysis showed that no matter what kind of study, people at the preclinical stage showed marked preclinical deficits in global cognitive ability, episodic memory, perceptual speed, and executive functioning; along with somewhat smaller deficits in verbal ability, visuospatial skill, and attention. There was no preclinical impairment in primary memory.

The generalized nature of the problem is consistent, say the authors, with recent observations that multiple brain structures and functions are affected long before the AD diagnosis. They remind readers that the deficits seen in preclinical AD mirror quite closely those seen in normal aging, such as impairments in episodic memory, executive functioning, and cognitive speed. Still, says lead author Lars Bäckman, PhD, these problems are exacerbated in those who will go on to be diagnosed with dementia.

He explains, "There are no clear qualitative differences in patterns of cognitive impairment between the normal old 75-year old and the preclinical AD counterpart. Rather, we think of the normal elderly person, the preclinical AD person, and the early clinical AD patient as representing three instances on a continuum of cognitive capabilities. This presents an obvious challenge for accurate early diagnosis."

The data also supported the emerging consensus that AD's preclinical period is characterized by an early onset followed by relative stability until a few years before diagnosis, when functioning plummets.

Bäckman and his colleagues endorse a multi-variable approach to understanding the preclinical stage of AD because this approach will help clinicians to more accurately predict the likelihood of disease.

The study traced other interesting patterns. People younger than 75 years at baseline were more impaired at the outset than people older than 75 at baseline. Impairment was also greater for the patients with shorter periods (fewer than three years) to diagnosis. These findings suggest that preclinical impairment is greater when the disease starts younger and progresses more quickly, due to more widespread and severe brain lesions among younger cases.

Anti-inflammatory function of Alzheimer's disease drugs revealed

Sun, 31 Jul 2005 00:47:00 PST

( from http://www.rxpgnews.com ) The mechanism in anti-Alzheimer's disease drugs that inhibits the production of a destructive, inflammation-causing protein in the brain has been revealed by researchers at the Hebrew university of Jerusalem.

Their work, described in a recent issue of the American journal, Annals of Neurology, is likely to lead to the development of more efficient drugs than are currently in use for treating Alzheimer's Disease as well as other neurological conditions resulting from infections, autoimmune diseases such as multiple sclerosis, or brain inflammation resulting from trauma or stroke.

The research team working on this project was headed by Prof. Raz Yirmiya of the Psychology Department at the Hebrew University, Dr. Yehuda Pollak, a post-doctoral fellow in Prof. Yirmiya's laboratory; and in cooperation with Hermona Soreq, the Charlotte Slesinger Professor of Cancer Studies at the Silberman Institute of Life Sciences at the Hebrew University, and Prof. Tamir Ben-Hur of the Hebrew University Faculty of Medicine.

Alzheimer's Disease is a degenerative disease of the brain, characterized by a deterioration of both cognitive and physical abilities. It first affects memory and the ability to carry out complex, coordinated tasks. It also can bring on depression, inattention and outbursts of anger. In a more progressive stage, the disease can cause difficulties in the ability to perform even simple tasks such as speaking and comprehending, eating and sleeping. The affected person can even forget his name and identity.

The medicines administered today to Alzheimer's Disease patients focus on preventing the breakdown of acetylcholine, a chemical produced by brain cells which transmits information within the brain and is vitally involved in cognitive processes that include memory, attention and thought. Because acetylcholine-producing cells are among the first to die in Alzheimer's Disease patients, drug-induced elevation of acetylcholine levels partially attenuates the cognitive deterioration.

In recent years it has been shown that another pathological process that occurs in the brain of Alzheimer's Disease patients is excessive immune activation and inflammation, which are induced by overproduction of an inflammation-producing protein called interleukin-1, as well as a few other related compounds. This process can impair the functioning of nerve cells and can even lead to their death. Furthermore, genetic alterations in the interleukin-1 gene have been associated with increased risk for the appearance and severity of Alzheimer's Disease symptoms.

The Hebrew University researchers found that anti-Alzheimer's Disease drugs currently in use not only block the activity of the enzyme responsible for breaking down acetylcholine but also cause a marked reduction in the production of interleukin-1. Furthermore, they describe the use of a novel drug (EN101), developed by Prof. Soreq's team, which produces these effects in a more efficient way than known heretofore by destroying the molecular antecedent (messenger RNA) of the enzyme, rather than simply blocking the enzyme's activity.

In a series of experiments, conventional anti-Alzheimer's Disease drugs, as well as the novel drug EN101, were injected into mice with brain inflammation. It was found that these injections reduced significantly the activity of the enzyme that breaks down acetylcholine and blocked almost entirely the production of interleukin-1.

"These findings suggest a new role for acetylcholine in the brain," said Prof. Yirmiya. "When the anti-Alzheimer's Disease drugs block the enzyme which breaks down acetylcholine, the level of this chemical in the brain goes up, and there is a reduction of the production of the inflammatory material, interleukin-1, and its destructive influence in the brain."

"The discovery of this mechanism in the anti-Alzheimer's Disease medicines points the way towards development of new forms of these medicines which will block even more efficiently and specifically the inflammatory and destructive activity of inteleukin-1," Prof. Yirmiya stressed. "Beyond that, it is likely that the drugs that are currently used for treatment of Alzheimer's Disease, and particularly the new drug EN101, will also be effective in dealing with other inflammatory illnesses."

Alternative approach opens up new prospects for developing a treatment

Thu, 28 Jul 2005 22:49:00 PST

( from http://www.rxpgnews.com ) Scientists from the Flanders Interuniversity Institute for Biotechnology (VIB) associated with the University of Antwerp have achieved a new breakthrough in their research on the origins of Alzheimer's disease. Their alternative approach opens up new prospects for developing a treatment which can slow the disease's progress. The researchers have shown that 'the plaques' which form in the brain of patients are linked to damage to nearby blood vessels. Leakage appears to occur between the blood vessels and the brain, as a result of which the plaques develop and the disease manifests itself.

Alzheimer's disease

Alzheimer's disease, a degenerative disease that gradually and progressively destroys brain cells, affects between 50% and 70% of all dementia patients and is therefore the major form of dementia. About 100,000 people suffer from this disease in Belgium. The damage caused to memory and mental functioning makes it one of today's most frightening syndromes. In particular, the first realization of the loss of any sense of reality is extremely difficult to accept. So, science continues to search feverishly for ways to treat the disease.

The formation of plaques plays a key role

Alzheimer's disease is characterized by an increasing deposit of the amyloid-β protein in the brain. The accumulation of this protein results in 'plaques'; deposits which settle in the brain cells responsible for memory and observation. How the plaques develop is the key in the search for a treatment. Samir Kumar-Singh and his colleagues on a team headed by Christine Van Broeckhoven have unraveled how certain plaques are formed. In various mouse models, they demonstrate that the plaques attach primarily onto the blood vessels. The vessels show clear structural damage, so that the strictly-controlled separation between blood vessels and brain is compromised and leakage occurs.

A new model as a first step towards a treatment?

Under normal circumstances, the blood vessels transport the excess amyloid-β protein away from the brain. However, the protein has a harmful effect on blood vessel walls. This effect is perhaps strengthened as a result of ageing, which causes the protein to be removed less efficiently. The blood vessel loses strength and in its immediate vicinity the accumulation of the amyloid-β protein increases and plaques develop. Finally, the damage to the blood vessel is so great that it is no longer functional and other blood vessels take over its tasks.

The results of the research of Samir Kumar-Singh opens up alternatives for developing new treatments. For example, a treatment which promotes the removal of the amyloid-β protein from the brain can significantly impede the onset of Alzheimer's disease. A new approach which might have far-reaching consequences. Additional research should make it possible to verify this in greater detail.

Phenserine may Reduce Progression of Alzheimer's Disease

Wed, 27 Jul 2005 13:35:00 PST

( from http://www.rxpgnews.com ) Axonyx Inc. (NASDAQ: AXYX) announced today that it conducted a second interim statistical analysis of 59 patients in an ongoing Phase IIb double-blind placebo-controlled clinical trial (designated AX-CL-06a) designed to evaluate the effects of Phenserine tartrate (PT) treatment for 6 months on plasma and cerebrospinal fluid (CSF) levels of beta-amyloid (AB 1- 42) and other biomarkers in mild to moderate Alzheimer's Disease (AD) patients.

This analysis, which follows the first interim analysis reported on March 11, 2005, was undertaken to assess the benefit of continuing enrollment. Pre-defined criteria for the interim analysis were based on beta amyloid 1 - 42 levels in patients who completed the study according to the clinical trial protocol.

These interim analyses, with small patient numbers, are intended to guide the Company in conducting the trial and are rarely statistically significant.

An additional 22 patients were added to the 37 patients analyzed in the first interim analysis for a total of 59 patients. While this second interim analysis appears to again confirm that Phenserine may have an impact on the levels of beta amyloid, there is still insufficient evidence due to the variability of the data to draw definitive conclusions. Further detailed analyses as well as additional laboratory bio-assay activities are being undertaken by the Company, its scientific advisors and biostatisticians to investigate the variability in the data. Meanwhile, the enrollment in the Phase IIb trial will continue at the 15mg dose level and placebo.

The presence of toxic beta-amyloid in the brains of AD patients is considered by many experts to be a key pathological event in the causation as well as the progression of AD. A reduction of beta-amyloid levels could correlate to a reduced progression of AD. The interim data is comprised of patients who received Phenserine 10mg or 15mg twice daily or placebo for a period of 6 months.

About Phenserine

Phenserine is a highly selective acetylcholinesterase (AChE) inhibitor that binds with an enzyme that is responsible for the breakdown of a neurotransmitter important in memory and cognition. Unlike other AChE inhibitors, which only suppress the activity of this enzyme,

Phenserine has been shown to have two mechanisms of action: (1) the inhibition of the AChE enzyme, and
(2) in preclinical studies, the inhibition of the synthesis of AB, the protein in the brain that is thought to be a cause of brain cell death in Alzheimer's disease.

Gender May Play Role in Alzheimer's Disease

Sat, 23 Jul 2005 18:15:00 PST

( from http://www.rxpgnews.com ) Researchers from the Rush Alzheimer's Disease Center found that plaques and tangles in the brain, the changes seen in people with Alzheimer's disease (AD), are more likely to be expressed as dementia in women than in men.

In the June 2005 issue of Archives of General Psychiatry, "Sex Differences in the Clinical Manifestations of Alzheimer Disease Pathology," principal investigator Lisa L. Barnes, PhD, sought to determine whether the relation between levels of AD pathology and clinical symptoms of AD differed in men and women. Alzheimer's disease is the leading cause of dementia in older people, she noted. The researchers studied older Catholic nuns, priests, and brothers in the Religious Orders Study, a longitudinal clinicopathologic study of aging and AD. The study involves annual clinical evaluations and brain donation at death. The analyses were conducted on 64 men and 77 women. Women were slightly older at death than men; four cortical regions of the brain were counted, and a global measure of AD was derived.

Barnes found women had more global AD pathology than did men due primarily to more neurofibrillary tangles. "On a global measure of AD pathology that ranged from 0 to three, each additional unit of pathology increased the odds of clinical AD nearly three-fold in men compared with more than 20-fold in women. The findings suggest that AD pathology is more likely to be expressed clinically as dementia in women than in men. Our results suggest that the clinical manifestation of AD is stronger in women than in men."

Barnes says that "Understanding why the association between AD pathology and dementia differs in men and women could yield important clues about the pathophysiology of AD or eventually lead to sex-specific preventive or therapeutic strategies.

Another possibility is that women have a relative lack of some protective factor, such as the estrogen deficiency of postmenopausal women, which could increase their vulnerability to AD pathology."

Barnes suggests more research is needed to explore these and other possibilities.

Three molecules may be developed into new Alzheimer's drugs

Sat, 23 Jul 2005 01:16:00 PST

( from http://www.rxpgnews.com ) A team of scientists has discovered three molecules from a search of 58,000 compounds that appear to inhibit a key perpetrator of Alzheimer's disease.

Each of the three molecules protects the protein called "tau," which becomes hopelessly tangled in the brains of patients with Alzheimer's. The finding is promising news for the development of drugs for the disease.

Ken Kosik, co-director of the Neuroscience Research Institute at the University of California, Santa Barbara, headed the effort to find these molecules. The results of the study are published in the July issue of the journal Chemistry and Biology, released on Friday, July 22.

As baby boomers grow older, the incidence of Alzheimer's, already increasing, will rise much more. "Our approaches to the disease are flagrantly inadequate," said Kosik.

"There are a couple of FDA-approved drugs that help a little, but don't modify the disease. They give a little bit of symptomatic relief, but don't change the inexorable progression of the disease."

He said that new insights made over the past decade help to understand the molecular and genetic basis of the disease and these can now be built upon for the development of treatments. "There is no doubt that we need new approaches," said Kosik. "The insights gained about the mechanisms of the molecular and genetic basis of the disease are beginning to add up and can be harnessed for treatments."

Alzheimer's involves a complicated, interwoven series of regulatory steps of genes and proteins "talking" to each other, he explained. "When the conversation goes awry the disease process begins. And it is not just one gene or one protein causing the damage."

The complexity of Alzheimer's means that several different medications will likely be needed to control it, said Kosik. The same is true for many other diseases from AIDS to cancer. "It is likely that we will need to strategically target different aspects of the disease and put them together."

Kosik and his team chose to focus on the neurofibrillary tangles of neurons in the brain that, along with senile plaques, characterize Alzheimer's disease. The tangles are made of "tau," a protein that is also present normally in the brain.

"Tau goes wrong and becomes pathological when it becomes intensely phosphorylated," said Kosik. "This means that many phosphate groups attach to tau--modify it--and cause it to become dysfunctional."

The culprit is an enzyme, called CDK5, that attaches the phosphate to the tau protein, facilitating the disease process. The researchers set out to find a way to inhibit this enzyme, to keep it from putting any phosphate on tau.

In the laboratory, they purified the enzyme and purified tau protein, and watched tau get phosphorylated by the enzyme. They then performed a library search of small molecules (58,000 of them) in an attempt to find those that would prevent phosphorylation. Small molecules are preferred because they are more easily used as a drug since they can get through the body and into cells. It is also important to find molecules that will cross the blood brain barrier.

They then set up a test of nearly 400 small molecules that fit their criteria. The test results showed three small molecules that can inhibit the enzyme. These are candidates for development as drugs.

Kosik explained that proteins are strings of amino acids folded into small globs. All proteins that happen to be an enzyme involved in phosphorylation have one thing in common. They have a pocket that is almost always in the same place and this is where the phosphate attaches to the enzyme, in this case CDK5. To get a molecule that specifically prevents the enzyme from binding at the pocket is difficult.

Of the three compounds that the research group found, the scientists were able to locate where they bind. They found that one binds in the pocket, another binds at the edge of the pocket, and a third appears to bind completely outside the pocket. The scientists are most interested in the second and third compounds.

"This is the first demonstration that we can find small molecules that can more specifically affect the phosphorylation of tau by CDK5," said Kosik.

In terms of future directions, Kosik said, "There is lots to do here, lab testing, testing in animals, etc. But we have made an important step forward toward developing treatments for this disease."

He noted that this work is of a type usually performed by pharmaceutical companies, but in this case was completed in an academic environment.

Impaired clearance of amyloid-beta causes vascular damage in Alzheimer's disease

Fri, 22 Jul 2005 00:30:00 PST

( from http://www.rxpgnews.com ) New research suggests that accumulation of amyloid-β peptides in cerebral blood vessels, as opposed to the brain itself, may be a more important pathological mediator of Alzheimer's disease. Two independent yet related articles describe such findings in the August issue of The American Journal of Pathology. Both articles are highlighted on the Journal's cover.

Alzheimer's disease, the most common form of progressive dementia, affects an estimated 4.5 million Americans according to the Alzheimer's Association. Amyloid-β (Aβ) deposition is a hallmark of Alzheimer's disease and other cerebral amyloid angiopathies. However, exactly how Aβ accumulates and causes damage is not fully understood.

In the first article, "Cerebral microvascular Aβ deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant AβPP," Miao et al. describe early-onset Aβ deposition in Tg-SwDI mice. These mice express Aβ protein with mutations that are found in human early-onset cerebral amyloid angiopathy, causing specific accumulation of Aβ in cerebral blood vessels.

The Aβ peptides accumulated because they could not adequately cross the blood-brain barrier to be cleared from the brain. Over time, Aβ accumulation increased in the cerebral microvessels of the thalamus and subiculum of the brain. This resulted in degeneration of blood vessels as evidenced by reduced vessel density and increased apoptosis. Neuroinflammation also occurred as large numbers of microglia, along with inflammatory cytokines, were found at sites of Aβ accumulation.

The authors conclude that early-onset Aβ accumulation occurs predominantly in the cerebral microvasculature and appears largely responsible for the neuroinflammation in these mice. They also demonstrate the utility of Tg-SwDI mice in studying cerebral amyloid angiopathies, such as Alzheimer's disease.

The second article, by Kumar-Singh et al., "Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer's disease are centered on vessel walls," utilizes two different transgenic mice: Tg2576 and PSAPP. Both models produce dense-core plaques, highly concentrated deposits of Aβ, and were used to investigate the possible association of blood vessels with Aβ deposits.

In these mice, dense-core plaques associated with cerebral vessels with high specificity. There was also evidence of vessel damage and blood-brain barrier damage, resulting in release of Aβ through the vessel walls and accumulation of plaques next to the vessels. These data confirm previous observations in humans that senile plaques associate with blood vessels, especially in the vasculotropic Flemish type of Alzheimer's disease.

The authors propose a model of dense-core plaque formation that is dependent on cerebral vessels. As Aβ is cleared from the brain, it exerts a cytotoxic effect on the endothelial cells of the vascular wall (a process that may be exacerbated if clearance is impaired). This leads to loss of vessel integrity and accumulation of Aβ in the area surrounding the compromised vessel wall. Eventually, the damage is so great that the blood vessel deteriorates beyond functional use and new vessels form to pick up the slack. The result is a multicentric dense-core plaque that associates with multiple vessels.

These studies describe several animal models for further examining the pathogenesis and treatment of Alzheimer's disease and related cerebral amyloid angiopathies. And both studies confirm that Aβ generated by neurons accumulates in blood vessels following attempted clearance of excess Aβ peptides. Thus, study of novel therapies that reduce the blood vessel-associated deposition of Aβ may prove beneficial to patients with Alzheimer's disease.

Plaque isn't the cause of Alzheimer's disease

Tue, 12 Jul 2005 13:07:00 PST

( from http://www.rxpgnews.com ) A ground-breaking new research approach to understanding the cellular processes of Alzheimer's and other degenerative diseases has revealed a promising pathway to the development of new types of drugs for these diseases.

The discovery, made in the laboratory of Ratnesh Lal, research scientist in the Neuroscience Research Institute (NRI) at the University of California, Santa Barbara, is published in this week's online issue of the Proceedings of the National Academy of Sciences (PNAS).

The research describes a new way of understanding the degeneration of brain cells in patients with Alzheimer's, Huntington's, and Parkinson's diseases, as well as other degenerative diseases. Misfolded proteins in the cell membrane, and subsequent changes in the electrical properties of cells, provide the explanation for the cell degeneration. Specific three-dimensional structures of misfolded proteins are embedded in the cell membrane.

"It has long been thought that amyloid plaque, which has been studied for 30 years, was the cause of Alzheimer's disease," said Lal. "Plaque isn't the cause." He explained that the fibers of plaque are too large to directly affect small cells.

The answers may come from small globs of misshapen, misfolded proteins that make well-defined holes in cell membranes and disrupt their electrical activity, according to the study.

Amyloid protein is a sticky, globular substance created when normal cellular proteins become twisted and contorted into abnormal shapes. While amyloid formation has been associated with diseases like Alzheimer's, Parkinson's, and Huntington's, scientists have puzzled over whether and how it actually kills cells and causes disease. To gain insight into this mysterious process, Lal and his research team examined the three-dimensional structure of several different proteins associated with these diseases. The researchers observed that all of the proteins folded into structures resembling ion channels, or pores within cell membranes. These pores control the electrical properties of the cell by regulating the flow of charged particles (ions) such as calcium.

When embedded into artificial membranes, the misfolded proteins were able to produce electrical currents, confirming their similarity to ion channels. Since abnormal ion balance is known to disrupt cell function and cause degeneration, these results provide proof of a possible mechanism by which amyloid formation may lead to the cellular destruction seen in these neurodegenerative diseases.

"These ion channels could serve as a model system for designing preventive and therapeutic drugs," said Lal. "You don't need large aggregates of these amyloid proteins, the plaque, to have this disruption. Rather, small aggregates, when in contact with membrane, form ion channels and allow passage of ion current. By controlling activity and designing specific drugs to regulate these channels, we might be able to prevent and/or treat various diseases related to the amyloids."

These findings provide a major piece of the puzzle about the underlying protein misfolding associated with these degenerative diseases. Besides the diseases already mentioned, other degenerative diseases that also result from misfolded proteins include cystic fibrosis, type II diabetes, cerebrovascular dementia, arthritis, tuberculosis, as well as British and Danish famial dementias.

The researchers used atomic force microscopy (AFM) to view the ion channels. By using the AFM they were able to view these "bio-nano" molecules. The AFM allows for a look at these very small channels, which would be very difficult if not impossible to see in their native, cell-like environment with electron microscopy.

New computer program "HipMask" to assess risk of Alzheimer's

Mon, 20 Jun 2005 16:21:00 PST

( from http://www.rxpgnews.com ) New York University School of Medicine researchers have developed a brain scan-based computer program that quickly and accurately measures metabolic activity in a key region of the brain affected in the early stages of Alzheimer's disease. Applying the program, they demonstrated that reductions in brain metabolism in healthy individuals were associated with the later development of the memory robbing disease, according to a new study.

"This is the first demonstration that reduced metabolic activity in the hippocampus may be used to help predict future Alzheimer's disease," says Lisa Mosconi, Ph.D., a research scientist in the Department of Psychiatry, who developed the computer program and led the new study. "Although our findings need to be replicated in other studies," she says, "our technique offers the possibility that we will be able to screen for Alzheimer's in individuals who aren't cognitively impaired."

Dr. Mosconi and colleagues have recently published the technical details of the program, called "HipMask," in the June 2005 issue of the journal Neurology. She will present the new findings on June 20 at the Alzheimer's Association International Conference on Prevention of Dementia held in Washington.

The computer program is an image analysis technique that allows researchers to standardize and computer automate the sampling of PET brain scans. The NYU researchers hope the technique will enable doctors to measure the metabolic rate of the hippocampus and detect below-normal metabolic activity.

The technique grew out of years of research by Mony de Leon, Ed.D., Professor of Psychiatry and Director of the Center for Brain Health. His group was the first to demonstrate with CT and later with MRI scans that the hippocampus, a sea-horse shaped area of the brain associated with memory and learning, diminishes in size as Alzheimer's disease progresses from mild cognitive impairment to full-blown dementia.

Yet until now there has been no reliable way to accurately and quickly measure the hippocampal area of the brain on a PET scan. The hippocampus is small and its size and shape are affected greatly in individuals with Alzheimer's, making it difficult to sample this region. HipMask is a sampling technique that uses MRI to anatomically probe the PET scan.

MRI relies on electromagnetic energy to excite water molecules in the brain to create an anatomical map of the brain. The MRI was used in the study to determine the total volume of the hippocampus and then to define that portion (namely the HipMask) that was shared by all persons regardless of their disease status. PET employs radioactively labeled glucose to show the brain at work and the HipMask was applied to these scans to derive estimates of the hippocampal glucose metabolism.

The researchers followed 53 healthy, normal subjects between the ages of 54 and 80 for at least 9 years and in some cases for as long as 24 years. All subjects received two FDG-PET scans -- one at baseline and a follow-up after 3 years. Thirty individuals had a second follow-up scan after another seven years. Altogether there were 136 PET scans.

The researchers applied the HipMask to all 136 scans. The results showed that hippocampal glucose metabolism, as determined by the HipMask, was significantly reduced 15% to 40% on the first scan, compared to controls, of those 25 individuals who would later experience cognitive decline related to either mild cognitive impairment or to Alzheimer's. The researchers found that the baseline hippocampal glucose metabolism was the only brain or clinical measure that predicted the future cognitive decline.

"Right now, we can show with great accuracy who will develop Alzheimer's nine years in advance of symptoms, and our projections suggest we might be able to take that out as far as 15 years," says Dr. de Leon, whose longitudinal study is funded by the National Institutes of Health (NIH).

"Our basic results will need to be replicated in other studies and expanded to include PET data from diverse patient groups," adds Dr. De Leon. "But we're confident this is a strong beginning, demonstrating accurate detection of early Alzheimer's disease. Now we have a better tool to examine disease progression, and we anticipate this might open some doors to prevention treatment strategies."

Arterial spin labeling distinguishes between Alzheimers disease and frontotemporal dementia

Mon, 20 Jun 2005 16:18:00 PST

( from http://www.rxpgnews.com ) A non-invasive magnetic resonance imaging (MRI) technique called arterial spin labeling is just as accurate as invasive scanning techniques in distinguishing Alzheimer's disease from frontotemporal dementia (FTD) in the brains of elderly people, according to a new study at the San Francisco VA Medical Center (SFVAMC).

The study, led by Norbert Schuff, PhD, a Principle Investigator at SFVAMC, used arterial spin labeling to measure perfusion, or blood flow, in the areas of the brain affected by the two diseases. "Blood flow indicates brain activation," said Dr. Schuff. "So the area with less blood flow is the area affected by disease." In the study, arterial spin labeling successfully distinguished between Alzheimer's patients, FTD patients, and people without dementia.

Frontotemporal dementia is a degenerative condition involving the front part of the brain. It is the second-most common dementia after Alzheimer's disease, which mainly affects other brain areas such as the hippocampus and the temporal lobe. In their early stages, the two diseases present similar symptoms, making accurate diagnosis difficult, said Schuff, who is also an associate professor of radiology at the University of California, San Francisco (UCSF). In its later stages, FTD affects social conduct, social inhibitions, and personality, while Alzheimer's is a progressive impairment of multiple cognitive functions, often involving memory decline. "Progression of frontotemporal dementia is usually faster than Alzheimer's, and the underlying pathology is different, so it is important to know the difference," Schuff observed.

Currently, brain blood flow can be measured using positron emission tomography (PET) and single proton emission computerized tomography (SPECT). However, these techniques involve injecting patients with radioactive tracers. In addition, Schuff noted, they can be expensive -- about $2,000 for a PET scan -- can take up to half a day to perform, and are not widely available. "So if you can acquire blood flow information with MRI, that would be very beneficial. MRI is totally non-invasive, making it much safer for patients. It's more widely available, it's cheaper, and arterial spin labeling can be done in ten minutes together with a conventional MRI scan."

In simple terms, MRI is a non-radioactive imaging technique that measures the magnetic alignment of protons in the body. In arterial spin labeling, a technique invented by researchers at the University of Pennsylvania, protons in arterial blood are magnetically aligned in the opposite direction from the rest of the protons in blood and brain tissue. By measuring the intensity of the magnetic signal from these so-called inversely polarized protons when they reach the brain, researchers can calculate the amount of blood flow, and thus neuron activity, in a particular section of the brain.

In the study, Schuff and his fellow researchers measured brain perfusion in 24 Alzheimer's patients, 21 FTD patients, and 25 control subjects without dementia. The subjects were 62 to 90 years old, with an average age of just under 63. They were studied using an MRI system with a magnetic field strength of 1.5 Tesla, a common system in clinics and hospitals in the United States. The researchers successfully used arterial spin labeling to replicate PET and SPECT data on brain perfusion in all subjects. They also found that the perfusion data, added to structural information about the brain obtained with conventional MRI, significantly improved the classification of FTD from normal aging. Thus, "we gained specificity and sensitivity," said Schuff.

Schuff emphasized that because this was a research study, the aim of which was to accurately replicate PET and SPECT perfusion data, it did not prove that arterial spin labeling can be used to diagnose an individual patient. The next step for future research, he said, is to demonstrate that the perfusion abnormalities correlate with specific clinical symptoms. "At the moment, we have just dichotomized [patients] into Alzheimer's and FTD," he said. "But of course cognitive impairment is usually more complex -- you have a range of impairments."

The technique has the potential to distinguish other types of dementia as well. Schuff plans to study a larger sample in a clinical setting, with the goal of determining whether this is possible. "Once we have a large database of images," he predicted, "we can better determine what is normal, and then compare an individual subject with this normal range."

Schuff intends to continue his studies using a more powerful MRI system that operates at a magnetic field strength of 4 Tesla. This state-of-the art system was recently installed at SFVAMC with support funds from the National Institutes of Health (NIH) and the Department of Defense. "At 4 Tesla, measurements of brain blood flow will be more accurate than at 1.5 Tesla due to a higher signal intensity and prolonged lifetime of the polarized protons," Schuff said.

Early exposure to inflammatory disease multiplies Alzheimer's risk,

Mon, 20 Jun 2005 15:58:00 PST

( from http://www.rxpgnews.com ) A new study of dementia in identical twins suggests that exposure to inflammation early in life quadruples one's risk of developing Alzheimer's disease.

If confirmed, the link would add inflammatory burden to the short list of preventable risk factors for Alzheimer's.

Previous studies by Gatz and others have shown that Alzheimer's is strongly genetic: If one twin has the disease, his or her identical twin has a 60 percent chance of developing it.

Stroke and a short period of formal education both increase the odds of dementia, but not of Alzheimer's specifically, the new study found.

Dementia is an umbrella term for many conditions, including Alzheimer's.

"People can plan a life span that will alter dementia risk," Gatz said. "And these aren't risk factors that are unique to dementia. Many of these are also risk factors for other disorders. This is good news."

Gatz's team, which included researchers from the Karolinska Institute in Stockholm, Sweden, sifted the 20,000 participants in the Swedish Twin Registry for the 109 "discordant" pairs where only one twin had been diagnosed with dementia.

Information about participants' education, activities and health history came from surveys they completed in the 1960s, when the registry was created, and from hospital discharge records.

The surveys included questions about loose or missing teeth. Gatz and colleagues used the answers to build a crude indicator of periodontal disease.

"We're talking about gum disease, but it was measured by teeth lost or loose," Gatz said. "It's not perfect. Given it's not perfect, it's even more striking that it's such a solid risk factor."

The conclusion is not that good oral health can prevent Alzheimer's, but that an inflammatory burden early in life, as represented by chronic gum disease, may have severe consequences later.

Gatz was inspired to focus on inflammation by the work of USC gerontologists Caleb Finch and Eileen Crimmins, who published a paper in the journal Science linking today's record life spans to lower rates of childhood infectious diseases, such as gum disease, flu, rheumatic fever, tuberculosis and other illnesses.

Such diseases are often preventable, raising hope for prevention of Alzheimer's.

"If what we're indexing with periodontal disease is some kind of inflammatory burden, then it is probably speaking to general health conditions," Gatz said. "There was in our twins quite a lot of periodontal disease, and at that time in Sweden there was a lot of poverty."

The study, titled "Potentially Modifiable Risk Factors From Dementia: Evidence From Identical Twins," also found that mental activities at age 40, such as reading or attending cultural events, did not seem to lower the risk of developing Alzheimer's.

Participants who had more education than their twins were at slightly lower risk of developing dementia, but the influence of education on Alzheimer's risk was statistically negligible.

"Once one controls for genes, the level of education is not a huge risk factor," said Gatz, who questioned popular attitudes linking Alzheimer's or dementia to mental inactivity.

"We go around saying, 'Well, it can't hurt to do crossword puzzles.' There is a way it can hurt," she said. "The way it can hurt is if we start blaming the people who are demented for not exercising their brains enough, or overselling activities that could make a difference where it's really unsubstantiated. I think we have got to be real careful in our messages about risk reduction."

New strategy for protecting brain against Alzheimer's disease

Sun, 12 Jun 2005 05:33:00 PST

( from http://www.rxpgnews.com ) The human body has its own defense against brain aging: the innate immune system, which helps to clean the brain of amyloid-beta waste products. However, UCLA researchers discovered that some patients with Alzheimer's disease have an immune defect making it difficult to clean away these wastes. This may lead to over-saturation of the brain with amyloid beta, which form amyloid plaques, the definitive hallmark of Alzheimer's disease.

Published in the June 10 issue of the Journal of Alzheimer's Disease, the findings could lead to a new approach in diagnosing and treating Alzheimer's disease by helping to diagnose and correct this immune defect. This is the first time that researchers have discovered that the innate -- or more primitive -- part of the immune system may play a role in the development of Alzheimer's disease.

Using blood samples, investigators found that in healthy people, cells belonging to the innate immune system called macrophages, cleared amyloid-beta in a test tube test developed at UCLA. However, the macrophages of some Alzheimer's patients could not adequately perform this cleaning job.

"Macrophages are the janitors of the innate immune system, gobbling up waste products in the brain and throughout the body," said Dr. Milan Fiala, first author and UCLA researcher.

Fiala notes that there may be a problem either with the macrophages not effectively binding to amyloid beta or a problem in the absorption or uptake, which is called "phagocytosis." He adds that this immune defect may also be present in other diseases where a build-up of waste and plaques occur, such as in cardiovascular disease and Gaucher's disease.

"If further study shows that this defective macrophage function is present in most Alzheimer's disease patients, new hormonal or immune-boosting approaches may offer new approaches to treating the disease," adds Fiala.

Researchers add that this new approach differs from the amyloid-beta immunization method, which utilizes another part of the immune system called the adaptive immune system. According to Fiala, the immunization approach has resulted in amyloid-beta clearance in the lab in an animal model, but in a human clinical trial led to brain inflammation in a subset of patients.

In future studies, investigators plan to regulate the innate immune system by natural substances such as hormones, and natural products such as curcumin (from the curry powder). Currently in their lab, Fiala and Dr. George Bernard who is a professor in the UCLA Department of Oral Biology and Medicine,are testing the effectiveness of a naturally occurring hormone, called insulin-like growth factor I, in conjunction with a research team from the MP Biomedicals LLC Company.

The study was funded by the Alzheimer's Disease Association. The Sence Foundation and MP Biomedicals LLC Company are supporting current studies involved in testing the effectiveness of insulin-like growth factor I.

Amyloid Spine Atomic Structure Deciphered

Thu, 09 Jun 2005 18:03:00 PST

( from http://www.rxpgnews.com ) Howard Hughes Medical Institute researchers have provided the first detailed look at the core structure of the abnormal protein filaments found in at least 20 devastating diseases, ranging from Alzheimer's to Creutzfeldt-Jakob disease, the human version of mad cow disease.

The images reveal that the filaments form a short zipper that is closed and stuck. To get a more realistic picture of what the fibrils look like, however, one should picture a towering stack of zippers, each of which is tightly bonded to the one below.

In each disease, a different protein transforms into the misfolded threads known as amyloid fibrils. Scientists believe that the various proteins share a common underlying feature that explains how they assemble into the persistent fibrils that can accumulate in the brain and other tissues.

"To do something about these diseases, you have be able to see the parts at the atomic level," said senior author David Eisenberg, a Howard Hughes Medical Institute (HHMI) investigator at the University of California, Los Angeles. "Only then can you design an intervention."

The common trait of these different proteins was discovered more than thirty years ago. But even the most advanced technologies have been unable to capture anything more than a fuzzy image.

"We call it the spine of the amyloid," said Eisenberg, who is also director of the UCLA-Department of Energy Institute of Genomics and Proteomics. "A little bit of each protein forms the spine, and the rest of the protein is hanging out in globular domains that decorate the spine and give the fibril its thickness and bumpiness. Once these amyloid fibrils form in tissues or cells, they are very hard to get rid of."

Now, he and his colleagues report the first detailed look at one protein's version of the shared core feature. In this case, it was a yeast prion, a misfolded protein that has the additional knack of being able to infect other cells or organisms, said first author Rebecca Nelson, a graduate student. Unlike in people, the yeast prion causes a condition which may be beneficial. In people, scientists do not know the role of the fibrils in the disease process in most associated diseases, but the formation of fibrils is associated with diseases.

According to yeast prion expert Jonathan Weissman, an HHMI investigator at the University of California, San Francisco, determining this structure is a monumental achievement that will open up a new era in the structural analysis of amyloids.

The path to the discovery began several years ago, when co-author Melinda Balbirnie had narrowed down the stretch of prion necessary for fibrils to only seven amino acids, which were located at one end of the entire protein. Filling a test tube with just those snippets was enough to form short thin threads with the same essential characteristics of the common amyloid spine, a structure known as a cross-beta sheet.

Once it begins, the structure of a growing amyloid fiber is irresistible to other identical proteins or, as in this study, the crucial peptide subcomponents. The fibril spine elongates as pairs of the short beta-sheet segments stack up like teeth in a zipper.

When Balbirnie added more peptides to the test tube, she found that microcrystals formed and dropped to the bottom of the test tube. The crystals were about 50,000 times smaller than those normally used to determine atomic details of protein architecture. The researchers tried one mathematically intensive technique to analyze the microcrystals. It showed a fuzzy picture similar to other fibrils, telling them they were on the right track but not giving them the details they were seeking.

Nelson picked up the project four years ago. "Because the crystals were so small, we ended up trying lots of techniques," she said. "We formed collaborations with people who were experts in those areas. Every time we'd come up with a new idea, it was exciting. Then, when we were able to determine the structure, it was twice as exciting."

The breakthrough came when the researchers teamed up with European crystallographer Christian Riekel, who had designed and built a special x-ray beam as narrow as the crystals were tiny, and Anders Madsen, a Danish student working at the synchrotron in France who was skilled in special methods for mounting and manipulating the samples to collect good x-ray diffraction data.

"With the first calculation, we were able to see the structure and how we would be able to model atoms into that map," Nelson said. "That was really the ah-ha moment."

The final detailed structure is broadly consistent with other lower-resolution models, such as the two stacked beta sheets composed of the main chain of amino acids. The surprise came with the molecular side chains that give each amino acid its unique identity and hold the pairs of beta sheets in formation.

Nelson expected to see only the ends of the side chains reaching out and touching each other, they way they do in the DNA double helix. Instead, she found interdigitated connections akin to zippers and Velcro.

"This gives a structural explanation about why the fibers grow almost infinitely, and why prions are infectious," said Roland Riek of The Salk Institute. "Like a zipper, you have one end that never ends; you always have a free binding site for a growing fiber." In a related paper in Nature, Riek reported that the infectious ability of a fungal prion depends on its beta sheet structure, which he proposed would look similar to the detailed structure from Eisenberg's lab.

In another interesting finding, the zipped up fibril core is dry. "Proteins love water," said Eisenberg. "When they are soluble, there is water all around them. When the zipper is formed, water is forced out of the interface between the two beta sheets. Once you have this dry interface, it's hard to open up. Imagine trying to pry open two long pieces of Velcro."

In preliminary follow-up experiments, Eisenberg and his colleagues have found 10 short segments from other amyloid and prion proteins from hamsters, mice, and people that exhibit the same behavior in the test tube.

"We think virtually any protein can be converted into this type of structure," said Christopher Dobson of Cambridge University, United Kingdom, who wrote an accompanying commentary in Nature. "This is the first model that gives an atomic-level image of how the molecules might be stacked together in such a fibril."

'Molecular zipper' may hold important clues to Alzheimer's

Thu, 09 Jun 2005 17:58:00 PST

( from http://www.rxpgnews.com ) An international team of chemists and molecular biologists has discovered a fundamental molecular mechanism that seems to play an important role in Alzheimer's disease, Parkinson's disease, mad cow disease and two-dozen other degenerative and fatal diseases.

Amyloid fibrils, rope-like structures formed by linked protein molecules, are the common feature of these diseases and may well hold important clues to these diseases, said David Eisenberg, director of the UCLA-DOE Institute of Genomics and Proteomics, a Howard Hughes Medical Institute investigator, and a member of the research team.

Eisenberg and his colleagues report in Nature the three-dimensional structure of a small piece of a fibril-forming protein from yeast that behaves similarly to proteins involved in Alzheimer's and these other diseases. Knowledge of the structure of this small peptide -- known by the code of its amino acids, GNNQQNY -- reveals a surprising "molecular zipper" that Eisenberg described as "pathologically dry."

"Proteins live in water, but here all the water is squeezed out as the fibril is sealed and zipped up," Eisenberg said. "Our hypothesis is that this dry steric zipper forms in all of these diseases, and is universal in the fibrils. Once this steric zipper has formed, it's very difficult to reverse because it's so tight."

"Knowing the structure may provide a rational basis for developing drugs to fight these diseases," said Melinda Balbirnie, a UCLA postdoctoral scholar and a member of the research team.

Can scientists prevent the steric zipper from forming in the first place, or pry it open once it has formed?

Balbirnie is able to produce fibrils from the small peptide, and has developed a test, called an assay, to determine whether the fibrils break up.

"Her strategy is to add to this assay a wide variety of chemical compounds to see whether any will break up the fibrils," Eisenberg said. Balbirnie said she is "hopeful" her strategy will succeed in breaking up the fibrils.

Eisenberg and his colleagues also are investigating whether disease-forming proteins have similar structures. Their hypothesis is that Alzheimer's and other fatal "amyloid fibril" diseases have proteins containing the steric zipper.

"Our Nature paper presents the first atomic-level look at any of these structures," said Rebecca Nelson, a UCLA graduate student in biochemistry and molecular biology, and member of the team that determined the precise positions of all the atoms in the peptide.

The UCLA chemists and molecular biologists had difficulty analyzing tiny crystals from the small peptide using standards methods of X-ray crystallography. Nelson and coworker Robert Grothe, formerly of the Howard Hughes Medical Institute, worked indefatigably from 2000 to 2004 trying to develop new methods that would work.

"We wanted to learn which atomic-level interactions were giving the peptide the property to form fibrils of the type which the body cannot break down," Nelson said. "We tried many techniques with promising technologies that didn't work, but we never got discouraged. We thought if we could better understand the structure of the molecules inside the fibrils, we would understand more about why they have the properties they do, how they form, why they might be involved in disease and conceivably how to get rid of them or even prevent their formation."

A key breakthrough occurred when the UCLA team began working with a distinguished scientist in Grenoble, France, Christian Riekel, who conducts X-ray microcrystallography with an instrument designed to analyze very small crystals.

"We sent some of our crystals to Christian Riekel and his student, Anders Madsen, and we worked closely with them," said Michael Sawaya, a research scientist with UCLA and the Howard Hughes Medical Institute, and a member of the team. "Christian invented ways to get a fine beam of X-rays to bombard tiny crystals. He and Anders were able to collect diffraction data that allowed us to determine the structure of the peptide, as well as a second, related peptide that also contains the steric zipper."

"So many times I thought we were close," Nelson said, "but it didn't work until we tried this approach. When we solved the structure, I started dancing in the lab."

Nelson describes the proteins associated with Alzheimer's and other amyloid fibril diseases as "transformer" proteins that instead of doing their normal work, start forming pathological fibril structures.

"Like a transformer toy -- a car that changes its shape and turns into a robot -- the protein changes its shape, going from its normal function to a diseased state," Nelson said.

"Other proteins just do their jobs," Eisenberg said, "but these transformer proteins are different, and exceedingly strange. We believe we are now coming to grips with these proteins."

The researchers discovered that their measurements from the fibrils can all be characterized by what they describe as a "cross-beta diffraction pattern," Sawaya said. "They diffract in such a way that tells us there are many extended protein chains stacked like a spine or the rungs of a latter," he said. "That pattern is a common feature in these amyloid diseases."

Summarizing the connections, Eisenberg said, "All of these diseases have fibrils as their common feature; all of these fibrils have the same characteristic X-ray diffraction pattern, which is called cross-beta; our fibrils also have the cross-beta diffraction pattern in a small section of the protein that we call the spine. Because all of these diseased fibrils have a spine with the same diffraction pattern, and because diffraction patterns are characteristic of the arrangement of atoms, our hypothesis is that the two-dozen other diseases will each have a similar arrangement of atoms.

"Our hypothesis is that in all these diseases, a water-tight steric zipper has formed in the fibrils," Eisenberg said. "We have seen the teeth of the zipper in two related peptides."

The research was funded by the National Institutes of Health, the National Science Foundation and the Howard Hughes Medical Institute.

Balbirnie made the discovery that a small fragment of a protein -- a mere 1 percent of the protein -- can behave similarly to the entire protein, and is able to form fibrils. She and her colleagues reported this surprising finding in the journal Proceedings of the National Academy of Sciences in 2001.

"Like a detective, Melinda traced this fibril-forming property down to a little peptide," Eisenberg said. "Nobody expected that 1 percent of the protein could have the essence of the whole protein and could form fibrils on its own; I certainly didn't expect that. There were only seven amino acids in that fragment. Rebecca later found the peptide could be cut to only four amino acids and form fibrils."

"No one has known the details of these structures before, which we can now see," Balbirnie said. "The fibrils are stable in all of these diseases; we can account for that stability, which suggests this may be a common feature. We are learning how these biological machines work."

Biomarker may predict Alzheimer's disease progression

Thu, 26 May 2005 19:05:00 PST

( from http://www.rxpgnews.com ) According to Dr. John DeBernardis, President and CEO of Applied NeuroSolutions and a co-author of the study, "Finding a biomarker that effectively predicts who will get Alzheimer's disease has been considered the Holy Grail of Alzheimer's research for many years. We now believe that variations in the levels of p-tau 231 (tau protein phosphorylated on amino acid 231) may be used to effectively predict structural progression of Alzheimer's disease."

Harald Hampel, M.D., of the Alzheimer Memorial Center and Geriatric Psychiatric Branch of the Department of Psychiatry at Ludwig-Maximilian University in Munich, Germany was the lead investigator of the study. The data in the study agree with the notion that variations in p-tau 231 levels reflect differences in the degree of neuronal damage across AD patients, thus, p-tau 231 levels may be used to predict progression of brain atrophy in AD patients.

In the study of 22 Alzheimer's disease patients, all underwent Magnetic Resonance Imaging (MRI) to image the brain and had CSF samples taken. Levels of p-tau 231 predicted the rate of subsequent hippocampal atrophy as measured by MRI. In contrast, levels of total tau, another biomarker also used in the study, did not. In the end, higher p-tau 231 levels were found to correspond with higher rates of neuronal degeneration of the hippocampus.

In numerous other studies, the p-tau 231 assay developed by Applied NeuroSolutions has been shown to discriminate Alzheimer's disease patients from patients with other neurodegenerative disorders. Currently there is no FDA-approved diagnostic test for Alzheimer's disease. The market for an effective, easy to use, AD diagnostic test has been estimated to be approximately $5 billion.

Applied NeuroSolutions, Inc. is developing products to diagnose and treat Alzheimer's disease based on a novel hypothesis of AD cause and pathology. In partnership with Dr. Peter Davies and a scientific team at Albert Einstein College of Medicine, Applied NeuroSolutions has developed a cerebrospinal fluid (CSF) test to detect Alzheimer's disease at a very early stage with 85%-95% accuracy in more than 3,000 patient samples.

The company is also developing a blood serum-based screening test, as well as a new class of therapeutics to treat AD. Alzheimer's disease currently afflicts over 4 million Americans, and the market for AD therapy is expected to grow to 21 million patients by 2010 in the seven major pharmaceutical markets (USA, France, Germany, Italy, Spain, U.K. and Japan) according to BioPortfolio, Ltd.

Gamma Secretase Modulator Program Announced for Alzheimer's disease

Tue, 24 May 2005 10:27:00 PST

( from http://www.rxpgnews.com ) Cellzome Inc. today announced that Ortho-McNeil Pharmaceutical, Inc. has exercised its option to license and develop Cellzome's Gamma Secretase Modulator (GSM) program, under the terms of their March 2005 collaboration agreement. The program includes identifying new medicines for the treatment of Alzheimer's disease.

Under the terms of the collaboration, Cellzome will receive an additional technology access fee and continued research funding to deliver clinical drug candidates to Ortho-McNeil Pharmaceutical. Johnson & Johnson Pharmaceutical Research and Development, L.L.C. (J&JPRD), an affiliate of Ortho-McNeil Pharmaceutical, will supply research support for the discovery research that will be conducted at Cellzome.

Tim Edwards, Cellzome's CEO, said: "I am delighted that Ortho-McNeil Pharmaceutical has exercised its option over the Cellzome GSM project. In collaboration with J&JPRD, we are working towards identifying clinical candidates, to be tested as potential treatments for this devastating disease."

Under the terms of the collaboration, Cellzome provides access to its existing Alzheimer's disease program technology, including insights into its Amyloid Precursor Protein (APP) processing pathway map and new drug targets. Cellzome's chemical proteomics technology and lead optimisation capability along with J&JPRD's pharmaceutical research capability will be applied to identify additional compounds Ortho-McNeil Pharmaceutical had an option to license Cellzome's Gamma Secretase Modulator program, which includes novel small molecules for development as orally active treatments. J&JPRD will provide research support for the discovery research that will be conducted at Cellzome. Ortho-McNeil Pharmaceutical will be responsible for development, manufacturing and commercialisation of drugs that result from the collaboration.

RAZADYNE : A New Once-daily Treatment for Alzheimers Disease

Tue, 24 May 2005 10:19:00 PST

( from http://www.rxpgnews.com ) RAZADYNE ER (galantamine hydrobromide), a new once-daily treatment for the symptoms of mild to moderate Alzheimers disease, is now available by prescription nationwide. The product is marketed by Ortho-McNeil Neurologics, Inc.

Approved by the U.S. Food and Drug Administration (FDA) in December 2004, RAZADYNE ER contains galantamine hydrobromide first approved by the FDA in February 2001 as a twice-daily medication, REMINYL®. In April 2005, the product name was changed to RAZADYNE. Approximately two million patients have been treated with REMINYL to date. In clinical trials, RAZADYNE ER provided comparable efficacy, safety, and tolerability to twice-daily galantamine with the convenience of once-daily dosing.

In a six-month clinical study, patients who started treatment with RAZADYNE ER and stayed on it throughout the trial had significantly better overall cognition (thinking and memory) and daily activities compared to patients taking placebo, said Stephen Aronson, M.D., clinical assistant professor, University of Michigan Medical School.

The RAZADYNE ER capsules contain a rate-controlling membrane that allows the medication to be released gradually over a 24-hour period. This new formulation contains an immediate and extended release dose that allows for the convenience of once-daily dosing.

Alzheimers is an overwhelming diagnosis for the patient, for his or her spouse, for adult children and even for extended family members, said Joanne Koenig Coste, renowned Alzheimers care pioneer and author of Learning to Speak Alzheimers. Anything that may help make treatment more convenient for patients and their family members is always a welcome addition.

In the clinical study, 965 patients were randomly assigned to receive RAZADYNE ER, twice-daily galantamine or placebo. Patients treated with RAZADYNE ER had significant improvement in cognition as measured by the mean change in Alzheimers Disease Assessment Scale (ADAS-cog/11) scores compared to patients treated with placebo at six months.

The Alzheimers Disease Cooperative Study Activities of Daily Living (ADCS-ADL) inventory was used as a secondary outcome measure in the clinical study. Patients treated with RAZADYNE ER had significantly better scores than the placebo group at six months.

Dosage began at 8 mg/day for four weeks and was increased to 16 mg/day for an additional four weeks, after which the dose could be increased to 24 mg/day based on safety and tolerability. Approximately 80 percent of patients completed the trial.

In clinical trials, the most frequent adverse events with RAZADYNE ER were similar to those seen with RAZADYNE. The most common side effects are nausea, vomiting, diarrhea, loss of appetite, and weight loss. Typically, these side effects are mild and temporary. RAZADYNE may not be for everyone. Some people experience a slowed heart rate, which may lead to fainting. Serious stomach problems can occur in people taking medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) or those at risk for stomach ulcers. Please see www.RAZADYNE.com for full prescribing information or call 1-800-526-7736 for more information.

Unsuspecting Protein Regulating Plaque Formation

Sun, 15 May 2005 15:25:00 PST

( from http://www.rxpgnews.com ) "Alzheimer's is worse than a disease it takes the soul of a human being," says Bing Jap of Berkeley Lab's Life Sciences Division, in whose laboratory the new component was identified. "As the population of this country ages, the incidence of Alzheimer's is increasing, at a terrible increase in cost to society. Research leading to prevention or treatment is urgent."

The discovery and role of CD147 as a subunit of gamma-secretase by Jap and his colleagues Shuxia Zhou, Hua Zhou, and Peter Walian is reported in Proceedings of the National Academy of Sciences, in an article now in the online early edition of PNAS at http://www.pnas.org/cgi/content/abstract/0502768102v1?etoc.
How Alzheimer's works

The most persuasive hypothesis of how Alzheimer's disease invades the brain is the so-called "amyloid beta protein cascade," in which a protein called APP is clipped into shorter pieces by enzymes known as secretases. (APP stands for "amyloid precursor protein"; it is found in many tissues besides brain, but its functions are largely unknown.) If the portion of APP clipped by the beta form of secretase is further clipped by a third form, gamma secretase, the resulting fragments are amyloid beta peptides, A-beta 40 and A-beta 42. A-beta 42 in particular is toxic and causes the formation of amyloid plaques.

Unlike the majority of membrane proteins, gamma-secretase performs its proteolytic function neither inside nor outside the cell; instead, the crucial cut is made within the cell's thin membrane. In fact all the proteins and protein complexes involved APP and the alpha, beta, and gamma secretases are cell-membrane proteins, which penetrate the walls of the brain's neural cells. Alzheimer's research would greatly benefit if their structures, particularly that of gamma-secretase, could be established at high resolution by x-ray crystallography.

But membrane protein structures are particularly difficult to obtain. "Membrane protein complexes can be very difficult to purify in an intact form," says Jap. "Moreover, it's extremely difficult to get enough pure membrane protein to crystallize." Nevertheless Jap's laboratory has earned a reputation for solving the structures of important membrane proteins.

As the first step to producing enough gamma-secretase to make crystals, Jap asked postdoctoral fellow Shuxia Zhou to lead the effort to characterize the native protein complex. Zhou is a biochemist with M.D. and Ph.D. degrees from Shanghai Medical University; before coming to Berkeley Lab she studied and taught in Shanghai and at Oxford University and Kyoto University.

"Previous experiments establishing the role of gamma-secretase were genetic experiments done by causing its overexpression in cell lines and animal models," Zhou explains. "We wanted to isolate the native form and purify the whole gamma-secretase complex."
An unexpected factor

Zhou and her colleagues isolated the native complex from cells of the HeLa line and separated its subunits by gel electrophoresis, which pulls the components apart according to their molecular weights.

"There were six strong bands in the gel, five of which we could identify because we expected to find them," says Zhou. The expected bands represented the four known subunits of gamma-secretase, the proteins named Nct (nicastrin), APH-1 (anterior pharynx defective 1), PEN-2 (presenilin enhancer protein 2), and Psn-1 (presinilin 1) which is cleaved into two parts in the mature complex, Psn-1 NTF (the N-terminal fragment) and Psn-1 CTF (the C-terminal fragment). In prior Alzheimer's investigations, complexes made up of just these four components were shown to be an enzymatically active form of gamma-secretase, but whether they constituted the native form was not known.

From the evidence of gel electrophoresis, apparently not: "In addition to these five bands we found an extra band," Zhou says. "We didn't know what it was." To find out, she and her colleagues clipped the band from the gel, extracted the protein, and sequenced its amino acids.

The mystery protein turned out to be the membrane protein CD147. CD147 is expressed in many tissues and has many biological functions besides its role in tumor invasion, including reproduction, inflammation, and protein transport and sorting within cells. It also has a role in neural function: when the CD147 gene is deleted in mice, the result is defective nervous system development, loss of working memory, spatial learning deficits, and disorientation behaviors remarkably suggestive of Alzheimer's disease.

To investigate CD147's part in the activity of gamma-secretase, the researchers used targeted RNA to silence CD147 in cell cultures. The four previously known components of the gamma-secretase complex, as well as the APP protein on which they operate, were unaffected by this silencing. But when CD147 was silenced, the production of amyloid beta peptides increased markedly.

The researchers established that the native form of gamma-secretase, incorporating CD147, appears in other cell lines, including kidney cells and neuronal cells, and is not unique to HeLa cells (which are derived from cervical cancer). CD147 itself is found in many contexts besides gamma-secretase, but only as a part of gamma-secretase does it regulate the production of A-beta peptides and thus amyloid plaques.

Goals for further research

Just how does CD147 do what appears to be its normal job of preventing excessive production of A-beta 42 peptides, and what causes it to fail? Zhou says, "We know CD147 is a regulatory subunit of gamma-secretase, but we don't know how it works. As yet we don't know its mode of action with respect to the other members of gamma-secretase and its substrates. Determining this mode of action is a key goal of our future efforts."

About 25 amino-acid residues make up the length of CD147 that crosses through the cell membrane, one of which, glutamic acid, has net electrical charge. Such an unlikely placement for a charged residue suggests that this region of CD147 may seek to align with another protein's oppositely charged region, perhaps that of Psn-1. Disruption of this transmembrane teamwork could lead to increased production of amyloid beta peptides which, in turn, may result in the amyloid beta plaque formation that is a hallmark of Alzheimers disease.

"The answer to how the components of gamma-secretase components fit together inside the cell membrane has to wait for high-resolution structural work," says Zhou, "and for that we first have to make enough of the native complex to make crystals."

Bing Jap adds, "Determining the atomic structure of the gamma-secretase complex, including CD147, is the next crucial step in understanding the molecular mechanisms by which the substrates are cleaved in various forms and the next crucial step to designing Alzheimer's disease therapeutics."

Interrupted Alzheimers Vaccine Study Yields Hopeful Results

Tue, 10 May 2005 18:05:00 PST

( from http://www.rxpgnews.com ) That's the conclusion of two new papers published in the journal Neurology by an international team of researchers who vaccinated hundreds of Alzheimer's disease patients with beta amyloid, a protein that builds up in Alzheimer's-affected brains.

The study was stopped early in 2002 after a few participants developed brain inflammation. But the researchers continued to monitor the patients for up to a year after their last injection. The new papers, including one led by the University of Michigan Health System neurologist who headed the study's safety committee, summarize the results of that effort.

Even as those results are published, doctors at U-M are preparing to recruit participants for a phase II clinical trial to test a new Alzheimer's immunotherapy vaccine strategy that has been through a phase I safety trial. The phase II study, which aims to stimulate an immune attack against beta amyloid without raising brain inflammation risk, is being conducted at 30 centers in the United States and dosing has already begun at some sites. All the trials have been funded by Elan Corporation and Wyeth Pharmaceuticals.

Results from the interrupted trial show that on the whole, study participants whose immune systems mounted a response against beta amyloid performed significantly better on a series of memory tests than those who received a placebo injection.

Brain scans also showed that patients who had an immune response experienced a decrease in brain size, possibly indicating the removal of built-up protein due to an immune system attack. A smaller group of immune responders also had a decrease in levels of a protein called tau in their spinal fluid, compared with participants who received placebo possibly indicating a slowing in the death rate of their brain cells.

The idea of inducing the immune system to view beta amyloid as a foreign protein, and to attack it, holds great promise, says Sid Gilman, M.D., F.R.C.P., the first author on one of the new papers and the head of the Data Safety Monitoring Board for both clinical trials. We now need to see whether we can create an immune response safely and in a way that slows the progression of Alzheimer's disease and preserves cognition.

Gilman is the William Herdman Professor of Neurology at the U-M Medical School and director of the Michigan Alzheimer's Disease Research Center, one of 32 in the country funded by the National Institute on Aging.

Nancy Barbas, M.D., M.S.W., a U-M neurologist who will soon begin recruiting participants for the new trial, calls the approach, known as immunotherapy, exciting. Safety is paramount, given the experience with the last trial, and the new study is designed to be extraordinarily cautious and conservative, she says. But if we can show an effect, it will mean we're that much closer to giving patients and their families better options for treatment.

Rather than injecting participants with beta amyloid itself, the new trial is based on injections of humanized antibodies against part of the beta amyloid molecule. The antibodies should help trigger the immune system to attack beta amyloid, but will be cleared by the body soon after injection. That means a series of six injections to remind the body to attack beta amyloid.

As in the previous study, participants will be randomly assigned to receive either antibodies or a placebo; neither they nor the researchers will know what they got until the 27-month study ends. The new study will enroll 180 adults between the ages of 50 and 85 who have a diagnosis of probable Alzheimer's and a caregiver who can bring them to frequent appointments for brain imaging, neuropsychological testing and blood tests. Some participants will have additional blood tests or spinal fluid tests; they will also have a slightly higher chance of getting antibodies.

Gilman explains that the concept of vaccinating against beta amyloid was first proposed by scientist Dale Schenk. In the late 1990s, Schenk and his colleagues showed that vaccination from birth could prevent mental decline in mice that had been bred to develop Alzheimer's-like disease. They and others also showed that older mice receiving the vaccine appeared to regain cognitive function.

The exciting animal research results led to a Phase I trial in humans with Alzheimer's disease that showed no ill effects and then the Phase II trial that was stopped early.

With the full agreement of both sponsors, Elan and Wyeth, we halted the study as soon as we heard of the first few cases of meningoencephalitis, or brain inflammation, says Gilman, referring to the trial's Data Safety Monitoring Board of independent experts not involved in treating trial participants. But for a year afterward, we kept participants and researchers blinded to which patients had received beta amyloid and which had received placebo.

In all, 59 of the 300 participants who received at least one injection of beta amyloid developed significant quantities of antibodies against it in their blood. All but three of these 59 patients, who were called antibody responders, had received at least two injections before the study was stopped; nine of them had received three injections. Thirteen of the 59 developed some level of encephalitis, as well as five of the patients whose immune systems did not react as strongly.

Although the study showed no statistical difference between the placebo and beta amyloid groups in results on five tests often used in patients with Alzheimer's disease and other dementias, there were significant differences on a battery of other tests that measure memory, executive function and verbal ability. The difference reached statistical significance in immune responders compared with patients who received placebo.

Spinal fluid samples taken from 21 of the participants in the study before it was stopped also reveal some intriguing hints. The 11 immune responders had a significant decline in levels of the tau protein, a structural protein considered a hallmark of cell death in the brain, when compared with 10 participants who received placebo.

Also encouraging, but not conclusive, is evidence from autopsies conducted on Phase I and II trial participants who have died in the years since the studies were completed or stopped, Gilman says. Three participants died of causes unrelated to the vaccination, two of whom had developed encephalitis and one other did not develop encephalitis. All had large patches of their brains where beta amyloid had apparently been cleared out the tangles of tau protein were still visible, he explains.

The first three cases from the Phase II trial have been published in separate papers. The fourth case of a patient in the Phase I trial was recently presented at an international meeting. The participant received four injections of beta amyloid and had evidence in the brain tissue of immune system cells (microglia) removing beta amyloid protein a sign of an active immune response.

The MRI images taken of study participants before and after their injections also showed shrinking of brain tissue that was more pronounced in the 45 immune responders than in 57 placebo patients. This was the opposite of what we expected, and it's exciting because it was associated with relative preservation of memory, says Gilman. It may be that beta amyloid was taken out of the brain as a result of the immune response, and that the protein carried water with it, causing further shrinkage.

The new clinical trial builds on the interrupted study's design, Barbas says, by including MRI and electrocardiogram exams, blood and urine tests, regular vital sign exams, and tests of memory and thinking ability. All of the injections will be in the first year, with the second year for follow-up exams.

Overview of Gene Therapy for Alzheimer's

Tue, 26 Apr 2005 19:46:00 PST

( from http://www.rxpgnews.com ) In a groundbreaking procedure, physicians at the University of California, San Diego (UCSD) School of Medicine surgically implanted genetically modified tissue into the brain of an Alzheimers patient in 2001. This launched the first phase of an experimental gene therapy protocol for Alzheimers disease. After four years, in April 2005, PET scans demonstrated an increase in the brains use of glucose, an indication of increased brain activity, while mental-status tests showed a slowing of the patients rate of cognitive decline was reduced by 36 to 51 percent. In addition, researchers examined the brain tissue of a study participant who had died and found robust growth of extensions from the dying cholinergic cells near the site of growth factor gene delivery. Cholinergic neuron loss is a cardinal feature of Alzheimers disease, a progressive brain disorder affecting memory, learning, attention and other cognitive processes.

The 11-hour surgical procedure was performed on April 5, 2001 at UCSDs John M. and Sally B. Thornton Hospital in La Jolla on a 60-year-old Caucasian woman in the early stages of Alzheimers disease.

The study, led by UCSD neurologist Mark H. Tuszynski, M.D., Ph.D., is the first attempt to use human gene therapy to treat a disease of the nervous system. The researchers will attempt to prevent cell loss in Alzheimers disease using gene therapy to deliver a natural brain-survival molecule called nerve growth factor (NGF) to the dying cells in the brain. The surgical procedure was led by UCSD neurosurgeon Hoi Sang U, M.D., who implanted the tissue in the patients brain using specially designed surgical tools.

This Phase I clinical trial, also called a safety/toxicity study, was designed to determine whether the gene-transplantation procedure is safe. The patient is a former teacher from Oregon, diagnosed with Alzheimers disease three years ago. She and her family have requested anonymity.

We have four children and one grandchild. If there is a genetic trail associated with this disease, we are concerned about their future, said the patients husband. Our main motivation is to see if we can contribute to patient care in the future by participating in this study. If there are benefits for my wife, that will be a plus.

According to Tuszynski, NGF gene therapy is not expected to cure Alzheimers disease, but we hope that it might protect and even restore certain brain cells and alleviate some symptoms, such as short-term memory loss, for a period that could last a few years.

This procedure targets a class of cells located deep within the brain in an area called the cholinergic system, important for supporting memory and cognitive function. The cholinergic system profoundly degenerates in the course of Alzheimers disease. These cells have been shown to respond to NGF in primate studies, and researchers hope that preventing extensive loss of these cells may slow intellectual decline seen in Alzheimers patients.

The implanted cells were expected to affect brain function in a month or two, but Tuszynski cautions that it may take several years to test the procedure in a large enough number of patients to determine whether it will be useful therapy.

THE PROCEDURE

The process leading to this first surgery began several months ago. A small sample of the patients own skin cells was collected in a biopsy procedure, and NGF genes isolated from nervous system tissue were inserted. Over a three-month period the genetically engineered cells were grown in culture in a commercial-grade GMP (Good Manufacturing Practices) facility. As they divided and increased in number, they began producing large quantities of NGF.

Before implantation, the scientific team verified that the genetically engineered cells produced the appropriate amount of NGF, and that no harmful contaminants were present.

In the surgical procedure on April 5, 2001, the patient received five implants of modified cells, targeting a region located at the base of the frontal lobe called the nucleus basalis of Meynert. This area contains cholinergic cells, and undergoes profound degeneration in Alzheimers disease, which is thought to contribute to the decline of cognitive function.

Dr. Hoi Sang U developed special instruments for the procedure.

First, the precise coordinates of the targets in the brain were determined with the use of a device called a stereotaxic head frame, which identifies the three-dimensional location for the implantation of the tissue. Surgical instruments designed by U and Peter Amis were used to insure that the cells would be injected in exactly the right location. Magnetic resonance scanning further verified the targeted area.

U then made a small hole on the right side of the patients skull, exposing approximately one inch of the brains surface. A fine needle was inserted and the genetically modified cells were inserted through the needle.

The patient underwent memory and neuropsychological testing before the surgery. Over the next several weeks, she will be monitored for any adverse events, and physicians will continue measurements of cognitive function. The size and location of the NGF implants will be monitored by MRI scans. She will be closely monitored for a year and then evaluated annually for an indefinite period.

BACKGROUND

This clinical trial is based upon a large body of experiments performed first in rats, then in monkeys, over the last 12 years by Tuszynski, U and Fred Gage Ph.D., who was on the faculty at UCSD before joining The Salk Institute for Biological Studies in 1995 (Gage is President-Elect of the Society for Neuroscience).

Early studies in rats demonstrated the feasibility of NGF therapy. For these studies, the researchers infused NGF via pumps directly into fluid-filled areas of animal brains. Although damaged brain cells were regenerated, the NGF also caused a proliferation of cell growth where it was not intended. To more precisely target NGF to specific brain regions, Tuszynski and Gage utilized a gene therapy method for inserting NGF into cells.

Tuszynski, in collaboration with Gage and Jeffrey Roberts, D.V.M., of the UC Davis Regional Primate Center, continued to demonstrate the feasibility of this gene therapy procedure in primates over the next several years. Skin biopsies from monkeys were modified to produce and secrete NGF. Then, the modified cells were surgically grafted directly into the brain tissue of aged monkeys.

In a study published in the Sept. 14, 1999 issue of Proceedings of the National Academy of Sciences (PNAS), the Tuszynski team reported that 40 percent of cholinergic neuron cell bodies had shrunk and atrophied in normal monkey aging, but were returned to nearly normal size and quantity following the surgical implant of cells genetically altered to produce NGF.

In February 2001, the researchers reported in PNAS that essential cellular connections called axons were also restored in primate brains using genetically modified tissue implants. The axons, which are essential for transmitting messages to and from neurons within the brain, had shriveled up and disappeared in aged monkeys. However, in monkeys that received genetically engineered NGF cells, the axons were restored to normal levels, and sometimes exceeded those levels.

In 1999, the initiation of human trials was approved by the Food and Drug Administration and the protocol was reviewed by the National Institutes of Health Recombinant DNA Advisory Committee (RAC).

UCSD ALZHEIMERS DISEASE RESEARCH CENTER

The current patient clinical trial is taking place through the UCSD Alzheimers Disease Research Center (ADRC), established in 1984 as one of the five original Alzheimers Disease Centers supported by the National Institute on Aging of the National Institutes of Health. Currently there are 30 ADRCs in the U.S.

Under the leadership of Leon J. Thal, M.D., chair of neurosciences at UCSD, the ADRC provides patient evaluation, community outreach and education, clinical trials and basic research. Thal is also a co-investigator in the current clinical trial with Tuszynski and U. Mary Margaret Pay of the ADRC is the clinical trial coordinator for this study.

According to the Alzheimers Association, one in 10 persons over 65 and nearly half of those over 85 have Alzheimers disease. This neurodegenerative disorder is characterized by build-up of protein plaque and tangles, leading to loss of function and death of brain cells. Alzheimers patients suffer progressive loss of mental functions such as memory and learning.

THE SURGICAL TEAM

The team involved in this first surgery included U and UCSD neurosurgeon John F. Alksne, M.D.; Tuszynski; UCSD neuroradiology fellow Timothy Duncan, M.D.; neurosurgery resident Soren Singel, M.D; anesthesiologists Piyush Patel, M.D., and Christine Yeun, M.D.; nurses Robin Adduano, R.N., and Kathy Rajner, R.N., and from Tuszysnkis laboratory, Armin Blesch, Ph.D., project scientist and Lee Vahlsing, M.S., research specialist.

Consulting on the surgery were Roy Bakay, M.D., neurosurgeon from Rush- Presbyterian Hospital in Chicago, and Phil Starr, M.D., Ph.D., neurosurgeon from UCSF. Also in attendance were Peter Amis, who developed the surgical instruments with U, and Fred Gage, Ph.D., from the Salk Institute.

Some of the technology being utilized in this procedure has been licensed for commercial development to a company in which the University of California and some of the investigators have a financial interest.

This project is supported by donations from the Shiley family and the Institute for the Study of Aging in New York.

ALZHEIMERS DISEASE

Alzheimers disease is a progressive, neurodegenerative disease characterized by loss of function and death of nerve cells in several areas of the brain, leading to loss of mental functions such as memory and learning. One of the characteristic structural abnormalities found in the brains of individuals with Alzheimers are amyloid plaques, clusters of dead and dying nerve cells, other brain cells and amyloid protein fragments. Upon autopsy, the presence of amyloid plaques and neurofibrillary tangles is used to positively diagnose Alzheimers.

Alzheimers disease is the most common cause of dementia, a term used to describe the loss of cognitive or intellectual function. First described by Dr. Alois Alzheimer in 1906, Alzheimers disease usually begins gradually, causing a person to forget recent events or familiar tasks. How rapidly it advances varies from person to person, but the brain disease eventually causes confusion, personality and behavior changes, and impaired judgment. Communication becomes difficult as the affected person struggles to find words, finish thoughts, or follow directions. Eventually, most people with Alzheimers disease become unable to care for themselves.

According to the Alzheimers Association, one in 10 persons over 65 and nearly half of those over 85 have Alzheimers disease. Today, four million Americans have Alzheimers disease. Unless a cure or prevention is found, that number will jump to 14 million by the year 2050. Worldwide, it is estimated that 22 million individuals will develop Alzheimers disease by the year 2025. Caregivers are affected by this disease, too. In a national survey, 19 million Americans said they have a family member with Alzheimers disease, and 37 million said they knew someone with the disease.

CHOLINERGIC SYSTEM

The cholinergic system of the brain includes neurons that produce neurotransmitters, the chemical signals used by the brain to process information and function normally. Nerve cells in this system atrophy and stop producing neurotransmitters in the brains of Alzheimers patients.

NERVE GROWTH FACTOR (NGF)

Nerve Growth Factor (NGF) is one of several naturally occurring proteins found in the brains of all vertebrate animals. NGF promotes nerve cell growth and survival.

RESEARCH TIMELINE

1950s NGFs were first discovered by developmental biologist Rita Levi-Montalcini, who won a Nobel Prize in 1986 for the finding.

Mid 1986-88 Studies by three separate groups of scientists - headed by Franz Hefti (1986), Fred Gage and Silvio Varon at UCSD (1986), and Lawrence Kromer (1987), - demonstrated NGFs potential to protect or repair the adult brain. They showed that pumping NGF into the adult brain could completely prevent injury-induced cell death in the rat. In addition, in 1987, Gage and his team demonstrated functional anatomical and behavioral recovery in aged rats. It was later found that pumping NGF into the brain caused side effects, and a better method of delivering growth factor to just the degenerating cells was needed.

1988 To better target NGF to specific brain regions, UCSD researchers Gage and Theodore Friedmann, M.D., devised a method to genetically modify cells that produce and deliver the NGF. In culture dishes, skin biopsies from monkeys were modified to produce and secrete NGF. The genetically modified cells were then surgically grafted directly into the brain tissue.

1990 Studies by Mark Tuszynski, Gage, Hoi Sang U, and colleagues at UCSD and The Salk Institute demonstrated that pumping NGF into the primate brain also prevented cell death in the adult primate brain. However, once again side effects occurred due to the pumping. Thus, an attempt began to deliver NGF to specific areas of the primate brain using gene therapy.

1994 Studies by Tuszynski, Gage and colleagues demonstrated that NGF could successfully be introduced into the primate brain by gene therapy.

1996 Studies by Tuszynski, Gage and colleagues demonstrated that NGF gene therapy would prevent cell death in the young monkey brain.

September 14, 1999 The first studies of NGF gene therapy in aged monkeys were reported in the Proceedings of the National Academy of Science. Tuszynskis team reported that 40 percent of cholinergic neuron cell bodies had atrophied in normal monkey aging, but were returned to nearly normal size and quantity following the surgical implant of cells genetically altered to produce NGF.

October 1999 The researchers received federal regulatory approval (U.S. Food and Drug Administration) to conduct human clinical trials of the gene implant procedure for people suffering from early Alzheimers disease.

December 1999 The gene therapy protocol presented by Tuszynski and Hoi Sang U and Leon Thal was reviewed by the Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health. As an advisory group, the RAC does not take action, but its review is considered an important step in the process of launching a patient trial involving gene transfer.

February 2001 In research that built upon previous work with atrophied brain cells in aging monkeys, Tuszynskis team found that essential brain fibers called axons were restored to normal levels in primate brain cells, with infusion of tissue that had been genetically altered to produce NGF. This research was reported in the Feb. 12, 2001 issue of Proceedings of the National Academy of Science.

April 5, 2001 UCSD team performs first implant of genetically modified tissue into the brain of an Alzheimers patient.

April 25, 2005 - PET scans and cognitive tests have suggested that Alzheimers disease patients with genetically modified tissue inserted directly into their brains show a reduction in the rate of cognitive decline and increased metabolic activity in the brain, according to a study published in the April 24, 2005 online issue of the journal Nature Medicine by researchers at the University of California, San Diego (UCSD) School of Medicine.

First-ever Gene therapy for Alzheimer's disease

Mon, 25 Apr 2005 21:09:00 PST

( from http://www.rxpgnews.com ) PET scans and cognitive tests have suggested that Alzheimer's disease patients with genetically modified tissue inserted directly into their brains show a reduction in the rate of cognitive decline and increased metabolic activity in the brain, according to a study published in the April 24, 2005 online issue of the journal Nature Medicine by researchers at the University of California, San Diego (UCSD) School of Medicine.

PET scans demonstrated an increase in the brain's use of glucose, an indication of increased brain activity, while mental-status tests showed a slowing of the patients' rate of cognitive decline was reduced by 36 to 51 percent. In addition, researchers examined the brain tissue of a study participant who had died and found robust growth of extensions from the dying cholinergic cells near the site of growth factor gene delivery. Cholinergic neuron loss is a cardinal feature of Alzheimer's disease, a progressive brain disorder affecting memory, learning, attention and other cognitive processes.

"If validated in further clinical trials, this would represent a substantially more effective therapy than current treatments for Alzheimer's disease," said Mark Tuszynski, M.D., Ph.D., UCSD professor of neurosciences, neurologist with the VA San Diego Healthcare System, and the study's principal investigator. "This would also represent the first therapy for a human neurological disease that acts by preventing cell death."

In this first-ever gene therapy for Alzheimer's disease, UCSD physician-scientists took skin cells from eight patients diagnosed with early Alzheimer's disease. The tissue was modified in the lab to express nerve growth factor (NGF), a naturally occurring protein that prevents cell death and stimulates cell function. In surgeries that took place in 2001 and 2002 at UCSD's John M. and Sally B. Thornton Hospital, the genetically modified tissue was implanted deep within the brains of the eight patients who had volunteered for the study.

The human clinical trial was undertaken following extensive studies in primates conducted by Tuszynski and colleagues, which showed that grafting NGF-producing tissue into the brains of aged monkeys restored atrophied brain cells to near-normal size and quantity, and also restored axons connecting the brain cells, essential for communication between cells. The recent human studies were a Phase I clinical trial, designed to test safety and toxicity. The procedure was initially performed while patients were awake but lightly sedated, and two patients moved as the cells were being injected, resulting in bleeding in the brain. One of these patients died five week later. As a result of the bleeds, the protocol was redesigned to perform the procedure under general anesthesia and all subsequent procedures were performed without complication.

Cognitive outcomes were assessed in the six patients who completed the NGF delivery procedure safely. The Mini Mental Status Examination (MMSE), which evaluates cognitive function, was administered at screening, the time of treatment and at several intervals after treatment. Over an average post-treatment follow-up period of 22 months, the rate of decline on the MMSE among NGF-treated patients was reduced by as much as 51 percent. An additional test, called the Alzheimer's Disease Assessment Scale-Cognitive Subcomponent, or ADAS-Cog, also showed improvements in rates of decline followed the MMSE findings.

Post-operative PET scans in four subjects showed significant increases in the brain's absorption of a radioisotope called 18-fluorodeoxyglucose, an indicator of increased metabolic activity in the brain. The researchers noted that the increase was observed in most cortical regions that receive cholinergic input from forebrain nerve cells called the nucleus basalis, and in the cerebellum, a structure associated with cortical plasticity.

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