RxPG News : Dementia

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.

Time and Money Constraints; other barriers hinder care for dementia

Thu, 11 Oct 2007 14:49:02 PST

( from http://www.rxpgnews.com ) (SACRAMENTO, Calif.) -- Built-in limitations of the health-care system in the United States, such as time and reimbursement constraints, inhibit the ability of primary care doctors to best meet the needs of dementia patients and their families, according to a new study by researchers at UC Davis Health System.

In a study now available in the online edition of the Journal of the Society of General Internal Medicine, the researchers found that physicians often feel challenged in caring for dementia patients, especially those who are more behaviorally complex. Constraints that are intrinsic to the contemporary practice of medicine may lead to the delayed detection of behavioral problems, a reactive as opposed to proactive management of dementia, and an increased reliance on treatment with drugs instead of psychosocial approaches.

However, the researchers also note that short of major organizational changes, there are steps that individual primary care physicians can take to help dementia patients and their families.
Based on interviews with 40 primary care physicians in Northern California, the study assessed a variety of practice constraints, including low reimbursements, lack of teamwork, and rushed office visits. The principal investigator is Ladson Hinton, associate professor in the UC Davis Department of Psychiatry and Behavioral Sciences.

“Our study highlights layer after layer of issues that are contributing to a growing public health crisis where patients with dementia and Alzheimer’s are concerned,” said Hinton. “The present system is just not set up to meet their needs. These structural constraints are clearly very important, but we found that physicians often omit simple interventions that may help families find help for behavioral issues, such as a referral to the local Alzheimer’s Association or the National Institute on Aging’s Alzheimer’s Disease Education and Referral Center, at (800) 438-4380.”

The interviews identified these systemic constraints to providing good care to people with dementia and their families:
· Lack of sufficient time
· Low reimbursement
· Difficult access and communication with specialists and social service agencies
· Lack of an interdisciplinary team approach

The physicians interviewed said it was difficult to care for persons with dementia during the standard 15 minutes typically allotted for appointments. This lack of time and the subsequent failure to systematically assess behavioral problems may delay their detection and management until a time of crisis, according to the study.

Insufficient time, overwhelming workloads and unfamiliarity with dementia-related problems inhibited some physicians’ desire to see patients with dementia.

“We are all trying to keep our heads above water,” said one doctor. “These people (patients with dementia) do take a lot of time and energy. Sometimes … you just don’t want these people in your practice because a 15-minute visit turns into much more than that.”

The time constraints were noted across different types of practice settings. In large group practices, clinicians are pressured to practice in a “time-efficient” manner and have little control over scheduling. In smaller group and solo practices, clinicians had more flexibility but still felt compelled to see patients quickly because of economic pressures.

One of the interviewed physicians said that the lack of time and other barriers to good care leads to “reactive care” that may contribute to family burnout and, ultimately, to the patient’s institutionalization. In addition, the study states, “Clinicians may rely more on medications if they are less familiar with psychosocial approaches or perceive these as potentially more time-consuming.”

An over-reliance on drugs has important public-health implications, the study says, because recent research calls into question “the efficacy and safety of psychotropic medications for older adults with dementia, making non-pharmacological approaches more attractive from a risk-benefit perspective.”

Interviewees also noted that the reimbursement process for physicians inaccurately reflects the time required to care for patients with dementia. They cited limitations of “relative value units,” or RVUs, a nationally standardized scale that is used by Medicare and many health insurance companies, and is intended to reflect the time, technical skill and mental effort required of a provider to perform a service.

“When you deal with a patient who has dementia … as well as hypertension and diabetes, it’s a lot more complicated than the intact 50-year-old hyperintensive diabetic, but the reimbursement is the same,” said one physician.

Because of their relative unfamiliarity with dementia, primary care physicians often seek consultations with specialists such as neurologists and psychiatrists, but just as often find it difficult to do so “because of limited availability and cumbersome referral processes,” the study states. Access to specialists is complicated further by certain insurance plans in which mental health benefits are “carved out” to a mental health care manager. Under this system, patients are required to set up their own appointments.

“I have not had very many patients who have been successful in getting into the system, and they have to be very persistent,” said one physician. “It is really a harsh system the way it is set up.”

Better education of and support for families to be more proactive in making requests for appropriate treatments is one of the study authors’ suggestions for improving care for patients with dementia. Improvement in care also might be achieved via physician education on the management of behavioral problems and availability of community services and agencies. In larger practices, dementia care teams could be established to help manage more complicated cases. Improved medical coding that more accurately reflects time spent with patients and families also could help, the study states.

“More ambitious” reforms include increasing reimbursement for treating patients with “substantial behavioral complexity,” and establishing incentives for delivering more comprehensive, albeit costly, care upfront to delay costlier, subsequent outcomes, such as institutionalization.

Without improvements, “dementia in primary care settings is likely to continue to fall short of standards of good care,” the researchers state. “As a result, persons with dementia, particularly those with difficult behavioral issues, will be unnecessarily exposed to psychopharmacological drugs and increased risk of institutionalization.”

Among the study’s limitations noted by the authors was its reliance on physician perspectives rather than those of other stakeholders, such as families. Also, the surveyed physicians were in a single geographic region and not representative of physicians nationwide.

However, the study stated “that despite this geographic limitation, physicians were practicing in a variety of treatment settings, making it more likely that the findings will generalize across settings.”

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.

A drink a day may delay dementia

Thu, 24 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) In people with mild cognitive impairment, up to one drink of alcohol a day may slow their progression to dementia, according to a study published in the May 22, 2007, issue of Neurology, the scientific journal of the American Academy of Neurology. Mild cognitive impairment is a transitional stage between normal aging and dementia that is used to classify people with mild memory or cognitive problems and no significant disability.

Researchers evaluated alcohol consumption and the incidence of mild cognitive impairment in 1,445 people. They then followed 121 people with mild cognitive impairment and their progression to dementia. The participants, age 65 to 84, were part of the Italian Longitudinal Study on Aging and were followed for three-and-a-half years.

The study found people with mild cognitive impairment who had up to one drink of alcohol a day, mostly wine, developed dementia at an 85 percent slower rate than people with mild cognitive impairment who never drank alcohol.

While many studies have assessed alcohol consumption and cognitive function in the elderly, this is the first study to look at how alcohol consumption affects the rate of progression of mild cognitive impairment to dementia, said study authors Vincenzo Solfrizzi, MD, PhD, and Francesco Panza, MD, PhD, with the Department of Geriatrics at the University of Bari, in Bari, Italy. The mechanism responsible for why low alcohol consumption appears to protect against the progression to dementia isn't known. However, it is possible that the arrangement of blood vessels in the brain may play a role in why alcohol consumption appears to protect against dementia. This would support other observations that drinking moderate amounts of alcohol may protect the brain from stroke and vascular dementia.

The study did not find any association between higher levels of drinking, more than one drink per day, and the rate of progression to dementia in people with mild cognitive impairment compared to non-drinkers.

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.

Vasectomy may put men at risk for dementia

Mon, 12 Feb 2007 08:56:31 PST

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

The dementia is Primary Progressive Aphasia (PPA), a neurological disease in which people have trouble recalling and understanding words. In PPA, people lose the ability to express themselves and understand speech.

Northwestern University researchers have discovered men with an unusual form of dementia have a higher rate of vasectomy than men the same age who are cognitively normal.

The dementia is Primary Progressive Aphasia (PPA), a neurological disease in which people have trouble recalling and understanding words. In PPA, people lose the ability to express themselves and understand speech. It differs from typical Alzheimer's disease in which a person's memory becomes impaired.

Sandra Weintraub, principal investigator and professor of psychiatry and behavioral sciences and of neurology at Northwestern's Feinberg School of Medicine, began investigating a possible link between the surgery and PPA when one of her male patients connected the onset of his language problem at age 43 to the period after his vasectomy.

At a twice-yearly Chicago support group for PPA patients Weintraub sees from around the country, the male patient rushed into the room and asked the men sitting there, "OK, guys, how many of you have PPA?" Nine hands went up.

"How many of you had a vasectomy?" he demanded next. Eight hands shot up.

Weintraub and her team of researchers surveyed 47 men with PPA who were being treated at Northwestern's Cognitive Neurology and Alzheimer's Disease Center and 57 men with no cognitive impairment who were community volunteers. They ranged from 55 to 80 years old.

Of the non-impaired men, 16 percent had undergone a vasectomy. In contrast, 40 percent of the men with PPA had had the surgery.

"That's a huge difference," said Weintraub, director of neuropsychology in the Cognitive Neurology and Alzheimer's Disease Center. "It doesn't mean having a vasectomy will give you this disease, but it may be a risk factor to increase your chance of getting it."

In addition, the men who had undergone a vasectomy developed PPA at a younger age (58 years) than men with PPA who hadn't had one (62 years.)

While PPA robs people of their ability to speak and understand language, an unusual twist of the disease is patients are still able to maintain their hobbies and perform other complicated tasks for a number of years before other symptoms develop. Some people garden, build cabinets and even navigate a city subway system. By contrast, Alzheimer's patients lose interest in their hobbies, family life and may become idle. As PPA progresses over a number of years, however, patients eventually lose their ability to function independently.

Preliminary evidence from the study also seemed to connect another form of dementia to a vasectomy. In a smaller group of 30 men with a dementia called frontotemporal dementia (FTD,) 37 percent had undergone a vasectomy. The earliest symptoms of FTD are personality changes, lack of judgment and bizarre behavior. As in PPA, FTD usually starts at an earlier age, in the 40s and 50s.

One of Weintraub's patients with FTD was eating lunch in a restaurant with his family and excused himself to go to the bathroom. When he hadn't returned after 10 minutes, his sons went to investigate. They found him doing pushups on the bathroom floor. Other FTD patients begin shoplifting, compulsively gambling, misspending large amounts of money or become sexually demanding.

The most common form of dementia caused by brain deterioration in individuals over age 65 is Alzheimer's disease. Weintraub did not find an increased rate of vasectomy in patients with Alzheimer's.

Many patients with FTD and PPA share a common brain disease that is completely different from Alzheimer's. Whether a patient will get the behavioral or language problems depends on where the disease causes the most destruction in the brain. In FTD, most of the damage is in the frontal lobes; in PPA, it's in the language centers of the left hemisphere of the brain.

Weintraub theorizes a vasectomy may raise the risk of PPA (and possibly FTD) because the surgery breeches the protective barrier between the blood and the testes, called the blood-testis barrier.

Certain organs including the testes and the brain exist in what is the equivalent of a gated community in the body. Tiny tubes within the testes (in which sperm are produced) are protected by a physical barrier of Sertoli cells. The tight connections between these cells prevent blood-borne infections and poisonous molecules from entering the semen.

After a vasectomy, however, the protective barrier is broken and semen mixes into the blood. The immune system recognizes the sperm as invading foreign agents and produces anti-sperm antibodies in 60 to 70 percent of men.

Weintraub said these antibodies might cross the blood-brain-barrier and cause damage resulting in dementia. "There are other neurological models of disease which you can use as a parallel," Weintraub said. Certain malignant tumors produce antibodies that reach the brain and cause an illness similar to encephalitis, she noted.

The next step in Weintraub's research will be to launch a national study to see if her results will be confirmed in a larger population.

"I don't want to scare anyone away from getting a vasectomy," Weintraub stressed. "It's obviously a major birth control alternative. This is just a correlational observation," she said of the dementia connection. "We need to do more research to find out."

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.

Non drug treatments may help cure dementia

Mon, 01 Jan 2007 11:01:08 PST

( from http://www.rxpgnews.com ) New York, Jan 1 - Non drug treatments such as mental training and physical activity may help cure dementia, a disorder characterised by a general loss of intellectual abilities, says a new study.

Researchers led by Sally A. Shumaker at Wake Forest University School of Medicine studied about 3,000 participants. Half of them received 10 sessions of cognitive training and half received no special training, reported the health portal Medical News Today.

Participants who had the training showed immediate improvement in memory, reasoning and speed of processing. When the participants were tested five years later, the improvements had been sustained, the study said.

There are an estimated 24 million people in the world with dementia and 4.6 million new cases are diagnosed each year.

'Cognitive decline is a rapidly growing problem because of our aging population,' Shumaker said.

'The latest research suggests that mental training and physical activity both have promise for preventing declines in cognition,' the researcher said in the Journal of the American Medical Association.

'It's possible to envision a future treatment approach that combines lifestyle and drug treatments to meet the specific needs of each individual,' she said.

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.'

How frontotemporal dementia affects brain at cellular level

Tue, 26 Dec 2006 08:26:24 PST

( from http://www.rxpgnews.com ) UCSF scientists have identified a cell population that is a primary target of the degenerative brain disease known as frontotemporal dementia, which is as common as Alzheimer's disease in patients who develop dementia before age 65.

Because the cells arose only recently in evolutionary history -- in a common ancestor of great apes and humans-- and are particularly abundant in humans, and the finding supports the concept that evolution has rendered the human brain vulnerable to disease, including frontotemporal dementia, and, possibly, disorders such as autism and schizophrenia, the researchers say.

In addition, because the disease erodes aspects of social behavior and emotions – self awareness, moral reasoning and empathy – that are highly developed in humans, the finding suggests that the cells may play a role in what makes humans "human," they say.

The finding is reported in the December 22 on-line issue of Annals of Neurology.

The cells, known as von Economo neurons, were first comprehensively described in 1925 by their Romanian-Austrian namesake, who determined that the unusually shaped cells -- large, cigar-shaped and tapered at each end, with only a few dendritic processes extending away from them – were localized in only two regions of the frontal lobes.

The cells received only limited attention in the ensuing years, but in the meantime scientists determined that the brain regions in which von Economo neurons arise -- the anterior cingulate and frontoinsular cortex -- are key targets of frontotemporal dementia. And in 1999, a team of U.S. scientists made the surprising discovery that, among primates, von Economo neurons were seen only in great apes and humans.

In the current study, the UCSF team set out to explore whether von Economo neurons could be the target of FTD.

Working in the laboratory of senior author Stephen J. DeArmond, MD, PhD, UCSF professor of pathology, they compared the numbers of von Economo neurons and neighboring neurons in the anterior cingulate cortex, looking specifically at brain tissue from three sets of deceased patients -- seven who had no neurological disease, five who had Alzheimer's disease and seven who had frontotemporal dementia.

The results were striking. In frontotemporal dementia, there was early, severe and selective loss of von Economo neurons compared to control subjects. In Alzheimer's disease, von Economo neurons were not significantly depleted.

"This finding provides new insight into how frontotemporal dementia erodes the brain at the cellular level," says the first author of the study, William Seeley, MD, UCSF instructor of neurology and a clinician-scientist at the UCSF Memory and Aging Center.

Progress has been made in illuminating some of the genetic and molecular aspects of the disease – two mutated genes are associated with most inherited forms of the disease and major misprocessed proteins have been identified – but "discoveries at the genetic and molecular level do not yet explain why specific populations of neurons are dying," he says.

"This observation gives us a new window into the early and cell-specific degenerative process, and we can use this window to better understand disease pathogenesis."

The team, led by Seeley, is currently trying to study von Economo neuron-rich regions in living patients using neuroimaging. They also are studying VENs, themselves, in autopsy studies using neuropathological techniques.

As FTD is a disease for which there is as yet no disease-modifying therapy, studies of von Economo neurons could provide new strategies.

Why the cells are vulnerable is still a mystery, says Seeley. But given the fact that they are evolutionarily new, the explanation may be that there are still "kinks" in the genetic programming of the neuronal circuits.

"VENs probably help us in some wonderful way, which would explain why natural selection has pushed their rapid evolution in humans," he says. "Still, in the context of FTD, something about VENs makes them vulnerable."

Notably, cell-specific degeneration is a unifying feature of all the neurodegenerative diseases. Dopamine-producing neurons in the substantia nigra region of the brain deteriorate in Parkinson's disease, motor neurons of the spinal cord and motor cortex degenerate in ALS and specific memory-forming medial temporal lobe neurons die in early Alzheimer's disease.

"We hope to add von Economo neurons to that list," says Seeley. "It's a pretty important list to fill in, but for FTD there just hasn't been a good candidate until now. We think we've found it, and that is the most exciting part of the discovery for those of us who treat patients."

At the same time, he says, the finding "gives us a sense that we might be able to start to figure out what makes us unique as humans, what makes our brains different from those of other species. And that's pretty exciting, too."

Bruce Miller, MD, the A.W. & Mary Margaret Clausen Distinguished Professor of Neurology, director of the UCSF Memory and Aging Center and a co-author of the study, concurs.

"The social and behavioral skills that you lose in frontotemporal dementia are so characteristically human, or at least strongly associated with higher primates," he reflects.

"I think it's fascinating from an evolutionary perspective that we have these new neurons that are involved in social behavior that are selectively vulnerable in the second major degenerative disorder."

Notably, VENs are located in regions of the brain that are in a good position to transmit raw emotional signals to other brain centers. In addition, VENs have characteristics that suggest they play a role in analyzing sparse inputs and sending rapid output signals, further supporting the idea that they may impact behavior.

It's possible, says Seeley, that scientists will be able to figure out what these neurons normally do. But it won't be easy.

"These are such abstract brain capacities we're talking about…It's not like analyzing movement of your right arm or color vision. We're talking about understanding how we read others' minds. The philosopher in me sees the opportunity to really learn something interesting about human nature, here."

Still, he says, "It's the neurologist in me that brings me to work everyday, and as a neurologist what I want is to help cure the disease."

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.

Diet rich in fish cuts dementia risk

Mon, 20 Nov 2006 18:04:02 PST

( from http://www.rxpgnews.com ) New York, Nov 20 (IANS) A diet rich in fish could significantly lower the risk of dementia, says a new study.

The key appears to be docosahexaenoic acid or DHA, an omega-3 fatty acid often found in fish. DHA is essential for the growth and development of the brain in infants. It is also required for maintenance of normal brain function in adults.

It appears to cut dementia risk and to be important for the proper functioning of the central nervous system, reported health portal HealthDay News.

Mackerel, lake trout, herring, sardines, albacore tuna and salmon are high in DHA.

'If you have a high level of DHA, it reduces your risk of dementia by about half, said Ernst J. Schaefer, director of the lipid metabolism laboratory at the Human Nutrition Research Centre on Aging in Boston.

The study, published in the latest issue of the Archives of Neurology, found that people with the highest blood levels of DHA had a 47 percent lower risk of developing dementia and a 39 percent lower risk of developing Alzheimer's.

Dementia is an organic mental disorder characterised by a general loss of intellectual abilities involving impairment of memory, judgment and abstract thinking.

Omega-3 fatty acids in fish are also known to protect the heart and the circulatory system.

'Just as fish is good for your heart, it's probably good for your brain as well,' added Schaefer, who led the study.

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."

Occupational therapy improves quality of life for dementia patients

Fri, 17 Nov 2006 13:34:00 PST

( from http://www.rxpgnews.com ) Occupational therapy can help to improve the ability of people with dementia to perform daily activities and can also reduce the pressure on their caregivers, says a BMJ study published today.

Dementia can have far reaching effects for patients and their caregivers and is a major driver of costs for both health and social care systems across the developed world. The most significant problems associated with dementia are the losses in independence, initiative and participation in social activities factors which affect the quality of life for both patients and their caregivers and families.

Previous research had suggested that non-pharmalogical treatment could have the same or better effects than drug treatment for people with dementia.

Researchers from The Netherlands set out to measure the effect of occupational therapy on people with dementia and their main carer. A group of 135 patients with mild to moderate dementia and their caregivers were randomly split into two groups. The first group received 10 home-based sessions of occupational therapy - provided by an experienced occupational therapist - over a period of five weeks, whilst the second group received no occupational therapy. The groups were then assessed six weeks and 12 weeks after the therapy sessions.

At both six weeks and three months the patients who received occupational therapy functioned significantly better in daily life than those who did not with 75% of those in the group showing an improvement in process skills and 82% needing less assistance in day to day tasks. Primary caregivers who received occupational therapy also felt significantly more competent than those who did not.

The authors suggest that occupational therapy is likely to be more effective than drugs or other psychosocial interventions as the levels of improvement in their trial outstrip the effects recorded in previous trials of drugs and other interventions.

They add that they 'strongly advocate' the inclusion of occupational therapy in dementia management programmes; 'the clinical gainsobtained with occupational therapy for both patients and their caregivers underlines the importance of adequate diagnosis and pro-active management in dementia' they conclude.

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.

Cognitive Decline is Often Undetected - Study

Sat, 28 Oct 2006 05:30:00 PST

( from http://www.rxpgnews.com ) Many patients over the age of 65 who are hospitalized with an acute illness experience a subtle change in their cognitive ability that often goes undiagnosed, untreated and underreported. As a result, a patient's ability to make decisions about his or her medical treatment may be negatively impacted.

These findings by Sharon Inouye, M.D., M.P.H., director of the Aging Brain Center at Hebrew SeniorLife and Professor of Medicine, Division of Gerontology, Beth Israel Deaconess Medical Center, Harvard Medical School, identified symptoms, such as disorientation, forgetfulness and an inability to follow directions, that may go undetected except by those individuals such as family members who know the patient well enough to notice the changes. A report of Dr. Inouye's findings, "Recoverable Cognitive Dysfunction at Hospital Admission in Older Persons," will appear in the December issue of the Journal of General Internal Medicine (JGIM).

"Acute illness can represent a life-altering event for an older person, yet the impact of acute illness on cognitive functioning has not been systematically examined," Dr. Inouye said. "Understanding a patient's cognitive functioning is also necessary for developing effective and appropriate discharge planning."

According to Dr. Inouye's paper, no previous studies exist that establish just how much change in cognitive function regularly occurs in older patients or how it impacts their care. The subtle cognitive decline that she examined is referred to as recoverable cognitive dysfunction (RCD) and is determined by the results of a questionnaire called the

Mini-Mental State Examination (MMSE), a brief, standardized method used to assess cognitive status. "MMSE assesses orientation, attention, immediate and short-term recall, language, and the ability to follow simple verbal and written commands," Dr. Inouye said. "Furthermore, it provides a total score that places the individual on a scale of cognitive function."

Dr. Inouye's study revealed very high rates of RCD in the patients they surveyed (39%), as well as identified predictors for incidence of the condition. Predictors included higher educational level, high level of functional impairment at admission, and high severity of illness.

"We propose that all older adults should be considered at risk and screened for RCD when hospitalized with an acute illness," she said. "In addition, interventions need to be developed and put in place to prevent or treat the condition."

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.

Exercise helps sustain mental activity as we age

Fri, 11 Aug 2006 20:05:00 PST

( from http://www.rxpgnews.com ) Based on a review of studies on exercise and its effect on brain functioning in human and animal populations, researchers find that physical exercise may slow aging's effects and help people maintain cognitive abilities well into older age. Animals seem to benefit from exercise too and perform spatial tasks better when they are active. Furthermore, fitness training an increased level of exercise may improve some mental processes even more than moderate activity, say the authors of the review.

Findings from the review will be presented at the 114th Annual Convention of the American Psychological Association (APA).

Varying opinions still exist on the benefits of exercise and activity, said authors Arthur F. Kramer, PhD, Kirk I. Erickson, PhD and Stanley J. Colcombe of the University of Illinois at Urbana Champaign, "but our review of the last 40 years of research does offer evidence that physical exercise can have

a positive influence on cognitive and brain functions in older animal and human subjects." Different methodologies were examined to comprehensively study what effects exercise can have.

The researchers first examined the epidemiological literature of diseases to determine whether exercise and physical activity can at certain points in a person's lifetime improve cognitive ability and decrease the likelihood of age-related neurological diseases, like Alzheimer's. The authors then reviewed longitudinal randomized trial studies to see if specific fitness training had an affect on cognition and brain function in older adults. Finally, animal studies were examined to understand the molecular and cellular mechanisms responsible for exercise effects on the brain as well as on learning and memory.

Based on a review of the epidemiological literature, the authors found a significant relationship between physical activity and later cognitive function and decreased occurrence of dementia. And the benefits may last several decades. In a few of the studies that examined men and women over 65 years old, the findings showed that those who exercised for at least 15-30 minutes at a time three times a week were less likely to develop Alzheimer's Disease, even if they were genetically predisposed to the disease.

By examining the human intervention studies, a relationship was also found between fitness training and improved cognition, more efficient brain function and retained brain volume in older people, said Kramer. He cautions that different fitness training regimens and aspects of mental functions need further study to solidify a causal relationship. But, he added, there are some preliminary positive findings. In a four year study looking at the relationship between physical activity on cognition and brain function in 62-70 year olds, "those who continued to work and retirees who exercised showed sustained levels of cerebral blood flow and superior performance on general measures of cognition as compared to the group of inactive retirees," said Kramer.

Other studies confirmed the evidence that fitness does have positive effects on brain function in older adults. A study of older adults who were randomly assigned to either a walking group or a stretching and toning control group for six months found that those in the walking group were better able to ignore distracting information in a distractibility task than those in the control group. "Aerobically trained older adults showed increased neural activities in certain parts of the brain that involved attention and reduced activity in other parts of the brain that are sensitive to behavioral conflict," said Kramer.

Animal studies also provide support for the aging benefits of physical activity. Analyzing the effects of exercise in animal populations provides a unique window into learning about exercise-induced neurological and cognitive plasticity the ability of parts of the brain to function in place of other parts of the brain, said Dr. Kramer. Some of the animal studies reviewed used voluntary-wheel running experiments to show the existence of performance benefits of wheel running on hippocampus-related spatial learning tasks. Moreover, a few studies found that aged rodents that exercised in a water maze learned and retained information about a hidden platform better than age-matched controls.

Exercise also protected both young and aged animals from developing some age-related diseases as indicated by increases in certain neurochemical levels that can offset or prevent certain pathological diseases.

"From this review we have found that physical and aerobic exercise training can lower the risk for developing some undesirable age-related changes in cognitive and brain functions," said Dr. Kramer, "and also help the brain maintain its plasticity - ability to cover one function if another starts failing later in life."

More research is needed to know exactly how much and what types of exercise produce the most rapid and significant effects on thinking and the brain; how long exercise effects last following the end of training; or how much exercise is needed to get continued benefits, said Kramer.

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.

HIV mutation is clue to why only some people develop AIDS dementia

Wed, 26 Jul 2006 13:12:00 PST

( from http://www.rxpgnews.com ) The study of 18 HIV-positive subjects shows that HIV in the brain and central nervous system is genetically different from HIV that lives in the blood and peripheral tissues.

Moreover, serious cognitive impairment among the study subjects was correlated with the presence of a particular mutation in the HIV envelope gene.

The study appears in the July 2006 issue of Brain. It was led by Satish K. Pillai, PhD, a staff research associate at SFVAMC and a postdoctoral fellow at the University of California, San Francisco.

Pillai and his associates generated 456 nucleotide sequences of HIV from the blood and cerebrospinal fluid of the study participants. They chose to focus on the viral envelope gene, which interacts with receptors on the surfaces of host cells. "That's the gene that's most likely to vary between tissues, because it evolves rapidly and allows the virus to dock with different cell types," Pillai says.

According to Pillai, an analysis of the sequence data suggests that HIV is "genetically compartmentalized" between the central nervous system (CNS) and the blood, "which means that the virus is replicating in relative isolation in these tissues, with very little exchange of genetic information between the two populations."

The researchers also analyzed the sequences in search of a "genetic signature" common to the CNS-specific viruses in all 18 individuals, recounts Pillai. They found such a pattern, consisting of four amino acids, within a subregion of the viral envelope gene known as the V3 loop. "The identification of these signature mutations presents convincing evidence that HIV adapts to the local environment within the central nervous system and, moreover, that commonalities in this environment exist across individuals," he asserts.

Another mutation in the V3 loop appeared consistently in virus from study subjects who demonstrated the most severe cognitive impairment. This mutation was absent in sequences from subjects with little or no cognitive deficit. "In other words," says Pillai, "there appears to be a particular HIV mutation that is associated with dementia." He cautions that this result is "suggestive, not conclusive," because of the study's small sample size.

This information "may be clinically relevant in terms of treatment," Pillai explains. "If we identify the quintessential neurotoxic variant of HIV, could we use that as a predictor of HIV dementia?" He says that such knowledge could also help care providers make "guided therapeutic decisions â for example, the detection of particular viral genotypes may lead physicians to select for antiretroviral regimens that cross the blood-brain barrier into the CNS most efficiently." Or, he speculates, "we might actually try to design a drug to target these genetic variants that are responsible for the neurological damage."

Pillai notes that the issue of HIV dementia is particularly important in regions outside North America and Europe where state-of-the-art antiretroviral medications are not widely available and HIV infection frequently leads to dementia.

SFVAMC staff physician Joseph K. Wong, MD, associate professor of medicine at UCSF and senior author of the study, adds, "In addition to the implications of this new knowledge for the 40 million people infected with HIV, this study may also contribute to our general understanding of viral encephalitis," or brain inflammation caused by other viruses. "These results suggest that specific features of viral components themselves, and not just the immune response to viral infection, may be responsible for direct damage to the nervous system."

Pillai says that even though the study included almost 500 gene sequences, it is still exploratory: "We are now in the process of expanding this to a survey of 100 to 150 individuals."

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.

High estrogen levels associated with dementia in older men

Mon, 24 Jul 2006 19:30:00 PST

( from http://www.rxpgnews.com ) A prospective population-based study has found that higher estrogen levels in older men are associated with an increased risk of dementia. By contrast, levels of testosterone were not associated with cognitive decline. The study is in the August issue of Annals of Neurology, a journal published by John Wiley & Sons. (http://www.interscience.wiley.com/journal/ana).

As our population ages, the impact of dementia will grow. By the year 2050, some 13 million Americans could have Alzheimer's disease, which is the most common cause of dementia. Researchers are searching to understand risk factors and some studies have suggested that sex hormones play a role. One large study showed that women receiving estrogen therapy had an increased risk of cognitive impairment and dementia. However, the evidence for how testosterone levels affect men is contradictory.

To better understand the role of sex hormones in dementia, researchers led by Mirjam Geerlings, Ph.D. of the University Medical Center Utrecht, studied whether older men's levels of testosterone and estrogen were associated with their risk of cognitive decline and developing dementia, including Alzheimer's disease.

They examined data from the prospectively studied population-based cohort of 2974 Japanese-American men aged 70 to 91 who participated in the Honolulu-Asia Aging Study. Participants showed no signs of dementia at baseline in 1991-1993, at which time fasting blood samples were drawn. The researchers measured the levels of testosterone and estradiol, the major estrogen in humans, in the samples and the men were reexamined for evidence of cognitive decline or dementia in 1994-1996 and 1997-1999 using the Cognitive Abilities Screening Instrument (CASI). At each exam, researchers also collected physical, demographic and medical information.

A total of 2300 men completed the study and 223 were diagnosed with incident dementia during the follow-up period. 134 men developed Alzheimer's disease, and 44 developed vascular dementia. The researchers used Cox regression analyses, adjusting for age and other covariates, to see if hormone levels were associated with risk of developing dementia

"Levels of bioavailable testosterone were not associated with risk of cognitive decline and incident dementia," they report. "In contrast, higher levels of bioavailable estradiol were associated with an increased risk for cognitive decline and Alzheimer's disease." For each standard deviation increase in estradiol level, the risk for the disease went up by 25 percent. Furthermore, compared with the lowest tertile of estradiol, men in the middle and highest tertile had .24 and .28 points lower CASI scores, respectively, for each year increase in age.

The researchers hypothesize that the estradiol association could be explained by increased aromatase activity in the brain which may be associated with a neurodegenerative process. It is then possible that the high levels of estradiol are a consequence or early marker of Alzheimer's disease rather than a cause.

Some caution is needed when interpreting the results, as, due to death or refusal, some men could not be given a diagnosis of dementia or follow-up cognitive testing.

In conclusion, the authors report, "our findings of an increased risk of cognitive decline and Alzheimer's disease associated with higher estradiol are similar to recent findings in postmenopausal women. Further studies are needed to examine whether there are mechanisms by which estradiol may increase risk of cognitive decline and dementia."

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."

Mental faculties in Dementia not improved by homocysteine-lowering supplements

Thu, 29 Jun 2006 04:50:00 PST

( from http://www.rxpgnews.com ) Giving healthy older people supplements to reduce high blood levels of an amino acid linked to dementia does not help their cognitive performance, according to a major University of Otago clinical study published today in one of world's top medical journals.

In a two-year clinical trial involving more than 250 healthy older people, a multidisciplinary Otago research team investigated whether lowering their high blood levels of the amino acid, homocysteine, would positively influence their cognitive function, says study co-author Dr Jennifer McMahon, who conducted the trial as part of her PhD in Human Nutrition.

Previous international studies have shown an inverse relationship between homocysteine levels and cognitive function in older people, leading to hopes that lowering homocysteine might be the key to combating cognitive decline, says Associate Professor Murray Skeaff, another co-author.

"A high blood concentration of homocysteine is known as a significant risk factor for developing Alzheimer's, and is also linked to other forms of dementia and cardiovascular disease," says Assoc Prof Skeaff.

Over a two-year period, the Otago team of Human Nutrition, Psychology and Preventive & Social Medicine researchers tested whether lowering elevated levels of homocysteine in healthy over-65 year-olds through supplements would improve their performance in memory, thinking, language and learning tests.

The 253 trial participants (none of whom had been diagnosed with dementia but all of whom had high homocysteine levels) were divided into two groups. One group received a daily pill containing folate and vitamins B6 and B12, and the other group a placebo.

The researchers administered a battery of cognitive tests at the outset, one year in, and at the end of the two-year trial. While homocysteine levels fell sharply in the supplement group, the researchers found no significant overall difference between the groups' respective combined performances on a variety of cognitive tests, says Dr McMahon.

"Our study adds to the growing evidence pointing towards homocysteine as being merely a marker or a consequence of a number of health problems, rather than - as had previously been hoped - a key risk factor that could be tackled to prevent or treat them."

Doctors who are currently advising older patients to take supplements as a preventive measure against cognitive decline might need to reconsider that advice, she says.

The researchers wished to thank the Dunedin Community for the strong response when they called for volunteers to participate in the study.

Assoc Prof Skeaff added: "This incredible support from local people was vital in making this a high-powered trial that met the demanding standards of the New England Journal of Medicine.. Researchers from around the world continue to be amazed at the unique levels of participation Otago nutrition studies enjoy."

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.

Factors associated with physical aggression among nursing home residents with dementia

Tue, 27 Jun 2006 04:06:00 PST

( from http://www.rxpgnews.com ) Depressive symptoms, delusions, hallucinations and constipation are associated with physical aggression among nursing home residents with dementia, according to a report in the June 26 issue of the Archives of Internal Medicine, one of the JAMA/Archives journals.

About 88,000 (6.8 percent) of U.S. nursing home residents are physically aggressive every week-hitting, shoving, scratching or sexually abusing others. This aggression can inflict physical and psychological harm on staff and other residents, according to background information in the article. Verbal aggression, when residents threaten, scream or curse at others, also can cause difficulties.

Ralph Leonard, M.D., M.P.H., of CALM-MD, LLC, St. Louis Park, Minn., and colleagues studied nursing home residents age 60 years and older with dementia who resided in one of five states: California, New York, Ohio, Pennsylvania or Texas. The authors used data from the participants' Minimum Data Set (completed in 2002), a health assessment completed regularly for all residents of nursing homes that receive federal funds. The assessment contains information about the resident's medical condition and functional status.

Of 103,344 residents (average age 84 years) who met the criteria for the study, 7,120 (6.9 percent) had been physically aggressive in the week before their assessment and 10.5 percent had been verbally abusive. After the researchers considered other factors that may play a role in aggression, including age, sex and the level to which residents were able to perform daily tasks on their own, they found that symptoms of depression, delusions, hallucinations and constipation were associated with physical aggression. With the exception of constipation, the same factors also contributed to verbal aggression.

Histopathogic image of senile plaques seen in the cerebral cortex in a patient with presenile onset of Alzheimer disease.

Previous studies have linked psychological conditions to aggression, but this study was one of the first to examine the effects of constipation, the authors write. "We chose to study constipation a priori because it is common, modifiable and recognized by clinicians to be a cause of many non-specific symptoms," the authors write. "It is not clear whether physical aggression may be related to factors that predispose to constipation (e.g., anticholinergic medications such as tricyclic antidepressants), the symptoms associated with constipation or interventions such as suppositories that may elicit a defensive action by some residents."

"Physical or verbal aggression among nursing home residents with cognitive impairment may be a major cause of distress among staff and other residents injured by the aggressor, as well as to the aggressor," they conclude. "We found that aggressive behavior among residents was associated with depression, delusions and hallucinations, and that physical aggression was also associated with constipation. All of these factors may be amenable to intervention and, in addition to reducing the morbidity associated with these entities themselves, effective treatment may reduce the risk of violence in nursing homes."

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.

Social Mealtimes Boost Wellbeing of Nursing Home Residents

Wed, 10 May 2006 02:55:00 PST

( from http://www.rxpgnews.com ) Providing a convivial and social environment at mealtimes improves the quality of life and physical performance of nursing home residents, finds a study published on bmj.com.

Residents of nursing homes not only face physical deterioration but also loss of independence, privacy, and a familiar environment. These factors lead to high levels of loneliness and depression and a low perceived quality of life.

Mealtimes in nursing homes provide an opportunity to integrate physical care with measures to improve quality of life. But in most nursing homes, meals are individually served on trays in a non-stimulating social environment.

Researchers in the Netherlands assessed the effect of eating together (family style mealtimes) on the quality of life of nursing home residents without dementia.

Their theory was that quality of life, physical performance, and body weight would remain stable among residents offered family style mealtimes but would decline in those receiving the usual pre-plated service.

A total of 282 residents in five Dutch nursing homes took part in the study. Each nursing home had a control ward and an intervention ward. The control wards maintained the pre-plated service, while the intervention wards introduced social family style mealtimes. All meals were similar in weight and nutrient content.

The intervention lasted for six months and results were adjusted for age, sex, and length of stay.

Family style mealtimes improved quality of life and prevented a decline in physical performance and body weight of residents.

These results support earlier research that found family style mealtimes improved the mood of nursing home residents with dementia. Although this study excluded residents with dementia, the authors believe that their conclusion may be extended to all nursing home residents.

This was a simple intervention that did not need extra staff, or increase workload or costs, say the authors. With motivated staff, this programme is easy to achieve on a low budget.

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.

Mediterranean diet could reduce risk of dementia

Tue, 18 Apr 2006 14:21:00 PST

( from http://www.rxpgnews.com ) A Mediterranean diet of low saturated fat and high fibre content could reduce the risk of developing dementia, says a study.

The Mediterranean diet is a nutritional model inspired by the traditional dietary patterns of the countries of the Mediterranean basin, particularly Italy, Greece, Portugal and Spain. The diet comprises high consumption of fruit and vegetables, bread and other cereals, olive oil and fish, making them low in saturated fat and high in monounsaturated fat and fibre.

Researchers from the Columbia University Medical Centre looked at the diet and health of 2,200 people over four years, assessed their neurological health and noted their dietary habits, reported the online edition of BBC News.

Their food intake was given a 'Mediterranean Diet score' of between zero and nine. During the course of the study, 262 people were diagnosed with Alzheimer's disease, a common form of dementia.

Dementia is a disorder of the brain that sometimes causes emotional disturbances and personality change.

The researchers found that, for each additional point on the Mediterranean diet scale, the risk of Alzheimer's dropped by almost 10 percent.

Compared to the third of people who scored worst on the Mediterranean diet scores, those in the mid-ranking group had a 15 percent to 21 percent lower risk of developing Alzheimer's disease, and those with the highest score had a 39 percent to 40 percent lower risk.

The association remained significant even after the researchers adjusted their findings for age, gender, ethnicity, education, caloric intake, weight, smoking and other conditions.

The researchers accept their findings relied heavily on people's memories of what they ate, but said a tested dietary assessment technique had been used.

Nicholas Scarmeas, who led the research, said: "Higher adherence to the Mediterranean diet is associated with a reduction in risk for Alzheimer's disease."

Sustained blood pressure treatment lowers risk of dementia

Fri, 07 Apr 2006 14:03:00 PST

( from http://www.rxpgnews.com ) Maintaining high blood pressure treatment may reduce the risk of dementia in old age, researchers reported in the rapid access issue of Stroke: Journal of the American Heart Association.

Lead author of the study Rita Peila, Ph.D., an epidemiologist at the National Institute on Aging (NIA), said "For every year of hypertension treatment, there is increased protection against dementia."

Some physicians hesitate to treat hypertension in the elderly because of concerns that lowering blood pressure might impair cognitive functioning. However, clinical trials have shown no harmful effects on cognitive function in elderly patients undergoing hypertension therapy.

"Hypertension treatment in the very old -- those aged 80 and older -- protects against stroke, heart disease and heart failure, and now we see that there is no harm -- and perhaps a benefit -- on cognitive function," said Peila, who is also a scientist at the Pacific Health Research Institute in Honolulu.

Researchers analyzed data from the long-term Honolulu-Asia Aging Study on Japanese-American men born between 1900 and 1919. They focused on 848 men (ages 50-65) who had mid-life high blood pressure and were free of dementia at age 77 (on average). Then, at follow-up visits three and six years later, the men had a thorough diagnostic evaluation for dementia and took the Cognitive Abilities Screening Instrument, a well-recognized test of cognitive function in Japanese and Western populations.

Of the 848 men, researchers identified 142 who had never been treated for their hypertension and 706 who were being treated at the age 77 examination. Researchers divided the treated group based on the duration of treatment:

* 195 men were on medication for less than five years;
* 149 were treated from five to 12 years; and
* 362 men were treated for more than 12 years prior to the exam.

Researchers found that each year of treatment reduced the risk of developing dementia during the follow-up period by about 3 percent. Compared with men who were never treated for hypertension, the risk of developing dementia during the follow-up period was:

* 6 percent lower in those treated less than five years;
* 48 percent lower in those treated from five to 12 years;
* 60 percent lower in those treated more than 12 years -- similar to the risk in a control group of 446 men with normal blood pressure.

"We found protection against both Alzheimer's disease and vascular dementia," Peila said. "There is more and more recognition that there is a vascular component to Alzheimer's disease."

Long-term hypertension can damage blood vessels of the brain, and the brains of Alzheimer's patients often have tiny blood clots and small infarcts, she said.

While only 7.8 percent of the 848 men were diagnosed with dementia, even those who did not have dementia showed cognitive declines. But men who had untreated hypertension had significantly more cognitive decline than men with normal blood pressure and hypertensive men treated for at least five years.

"Even if you're very old, have your blood pressure checked and talk to your doctor about treatment if it is high," Peila said.

In the study, hypertension was defined as:

* 160 mmHg or higher systolic blood pressure (the pressure when the heart contracts to pump blood to the body); or
* 95 mm Hg or higher diastolic blood pressure (the pressure when the heart rests between beats).

This cutoff is higher than the current definition of high blood pressure (140/90 mmHg) but is the same as treatment guidelines used when the men were first evaluated (from 1965 to 1974).

The study did not assess the type of blood pressure medications used. Many men had been switched from one type of medication to another during the lengthy study.

Ovary removal could increase dementia risk

Fri, 07 Apr 2006 14:01:00 PST

( from http://www.rxpgnews.com ) Women who undergo an ovary removal may have the risk of facing dementia - a disorder of the brain that sometimes causes emotional disturbances and personality change.

Every year, about 23,000 US women are diagnosed with ovarian cancer and 14,000 women die from the disease. To reduce the risk of this disease surgeons often prescribe the removal the ovaries.

Researchers led by Walter Rocca at Mayo Clinic studied 2,511 women who had these operations between 1950 and 1987 and matched them with the women who did not undergo ovary removal, reported health portal WebMD.

Rocca's team determined whether the women developed dementia by interviewing a family member or by giving the women a test over the phone.

"If before age 46 you remove two ovaries, you get a 70 percent increased risk of dementia. And we discovered that women who have only one ovary removed before age 38 -- this is a surgery more often done in younger women -- we see a 260 percent increase in dementia, Rocca said.

Dementia is an organic mental disorder characterised by a general loss of intellectual abilities involving impairment of memory, judgment and abstract thinking as well as changes in personality.

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."

Raised levels of stress hormones linked with age-related dementia

Tue, 28 Feb 2006 21:20:00 PST

( from http://www.rxpgnews.com ) Researchers at the University of Edinburgh have identified for the first time a certain area of the brain which can shrink in old age and cause depression and Alzheimer's disease. The scientists believe the shrinkage may be caused by high levels of stress hormones.

They examined the size of a special region of the brain, the anterior cingulate cortex, that might be involved in controlling stress hormones. In a significant discovery, scientists found that people with a smaller anterior cingulate cortex had higher levels of stress hormones.

Doctors analysed stress hormone levels and brain volume in two groups of ten healthy male volunteers aged 65-70 for the study. Lead author Dr Alasdair MacLullich said: "Doctors have known for several years that ageing, and certain diseases common in ageing like Alzheimer's disease and depression, can be associated with shrinkage of the brain, but this is the first time we have been able to show that increased levels of stress hormones may cause shrinkage of this critical area of the brain.

"This is an important new finding because the anterior cingulate cortex shows damage in ageing, depression, and Alzheimer's disease, and stress hormones are often high in these conditions. The discovery deepens doctors' understand of ageing, depression and Alzheimer's diseases, and will help in the development of treatments based on reducing high levels of stress hormones."

Results of the study are published in the current on-line edition of The Journal of Clinical Endocrinology and Metabolism.

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.

Anticholinergic drugs for the elderly could cause dementia

Fri, 03 Feb 2006 15:38:00 PST

( from http://www.rxpgnews.com ) Some commonly used drugs by the elderly to treat illnesses like Parkinson's or urinary incontinence may lead to mild mental impairment, says a study.

Those who take anticholinergic drugs over an extended period showed poorer cognitive performance, researchers said. The drugs are also used to treat illnesses such as irritable bowel syndrome and tremors.

Researchers interviewed 372 elderly people without dementia about current and past illnesses and drug use. Cognitive performance was assessed and participants were monitored for up to eight years, reported Newswise wire.

About 10 percent of the people in the sample took anticholinergic drugs over an extended period. They showed poorer mental performance compared with non-users and 80 percent met the criteria for mild cognitive impairment compared with 35 percent of non-users.

However, drug users were not at increased risk of developing dementia, the researchers said.

Even after taking account other known risk factors for cognitive impairment, anticholinergic drugs remained the most highly significant predictor of this condition, say the authors.

The study published in the British Medical Journal suggests doctors assess current use of anticholinergic drugs in elderly people with mild cognitive impairment before considering treatment for dementia.

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.

Reduced brain volume may predict dementia

Sun, 22 Jan 2006 16:19:00 PST

( from http://www.rxpgnews.com ) Reduced volume, or atrophy, in parts of the brain known as the amygdala and hippocampus may predict which cognitively healthy elderly people will develop dementia over a six-year period, according to a study in the January issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

New strategies may be able to prevent or delay the onset of Alzheimer's disease (AD), the most common cause of dementia among older adults, according to background information in the article. Accurate methods of identifying which people are at high risk for dementia in old age would help physicians determine who could benefit from these interventions. There is evidence that adults with AD and mild cognitive impairment, a less severe condition that is considered a risk factor for AD, have reduced hippocampal and amygdalar volumes. However, previous research has not addressed whether measuring atrophy using magnetic resonance imaging (MRI) can predict the onset of AD at an earlier stage, before cognitive symptoms appear.

Tom den Heijer, M.D., Ph.D., of the Erasmus Medical Center, Rotterdam, the Netherlands, and colleagues used MRI to assess the brain volumes of 511 dementia-free elderly people who were part of the Rotterdam Study, a large population-based cohort study that began in 1990. They screened the participants for dementia at initial visits in 1995 and 1996 and then in follow-up visits between 1997 and 2003, during which they asked about memory problems and performed extensive neuropsychological testing. The authors also monitored the medical records of all participants. During the follow-up, 35 participants developed dementia and 26 were diagnosed with AD.

People with severe amygdalar or hippocampal atrophy had the highest risk of developing dementia or AD over the course of the study, which followed participants for an average period of six years. "Concerning the extent of atrophy, we found in those destined to develop dementia volume reductions between 17 percent and 5 percent, depending on how long before the diagnosis of dementia the MRI was conducted," the authors report. "In persons with mild to moderate Alzheimer disease, volume reductions compared with healthy elderly persons are between 25 percent and 40 percent, suggesting that atrophy rates accelerate in patients with Alzheimer disease."

"Our study suggests that structural brain imaging can help identify people at high risk for developing dementia, even before they have any memory complaints or measurable cognitive impairment," they write. "However, we must bear in mind that most people with atrophy did not develop dementia, even after six years. Further prospective population studies are therefore required to find additional biomarkers, including other brain imaging parameters, that alone or in combination with clinical and genetic characteristics can help separate those who are at risk for developing dementia from those who are not."

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.

Exercise is linked to later onset of dementia

Sun, 22 Jan 2006 15:37:00 PST

( from http://www.rxpgnews.com ) Regular exercise is associated with a delay in the onset of dementia and Alzheimer's disease, according to a Group Health Cooperative/University of Washington study that will appear in the January 17 issue of Annals of Internal Medicine. The study--the most definitive investigation of exercise and dementia to date--also found that the more frail a person is, the more he or she may benefit from exercise.

"Even those elderly people who did modest amounts of gentle exercise, such as walking for 15 minutes three times a week, appeared to benefit," says Eric B. Larson, director of Group Health Cooperative's Center for Health Studies and the lead investigator for the study.

"Based on these findings, we can advise older people to 'use it even after you start to lose it,' because exercise may slow the progression of age-related problems in thinking," said Larson.

The study followed 1,740 Group Health members, aged 65 and older over a six-year period. The researchers contacted the participants every two years to assess factors potentially affecting dementia, including exercise frequency, cognitive function, physical function, symptoms of depression, and lifestyle characteristics. After six years, 158 participants had developed dementia and 107 of those with dementia 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 for developing dementia compared with those who exercised fewer than three times per week.

Larson's study was designed to be more definitive than previous research into exercise and dementia--the results of which have been mixed. In this study, Larson's team used tests scores to ensure that all participants had a minimum level of function at the time the study began. Doing so eliminated participants who might already be developing Alzheimer's disease, but not showing overt signs of the disease--a factor that would make it difficult to determine the true effects of exercise over the duration of the study.

Larson believes that exercise may improve brain function by boosting blood flow to areas of the brain used for memory. "Earlier research has shown that poor blood flow can damage these parts of the brain," he explained. "So one theory is that exercise may prevent damage and might even help repair these areas by increasing blood flow."

Larson advises older people that it's never too late to begin exercising. "Even if you're 75 and have never exercised before, you can still benefit by starting to exercise now."

Simply walking or swimming for 15 minutes three times a week may be enough, added Larson. And programs such as the "EnhanceFitness" classes that Group Health offers to its Medicare Advantage members can be especially helpful because they are designed with attention to senior safety issues, such as avoiding falls.

"As our population ages, strategies are needed to reduce the risks and delay the onset of dementing disorders such as Alzheimer's disease," Larson said. "These findings indicate that programs that encourage elderly people to exercise should be part of those strategies."

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.

Atypical Antipsychotic Drugs in Dementia Associated With Increased Mortality - Meta-Analysis

Wed, 19 Oct 2005 20:12:00 PST

( from http://www.rxpgnews.com ) Patients with dementia who took atypical antipsychotic drugs had a slightly increased risk of death compared to patients who took placebo, according to a meta-analysis published in the October 19 issue of JAMA.

A majority of elderly patients with dementia develop aggression, delusions, and other neuropsychiatric symptoms during their illness, according to background information in the article. Antipsychotic medications are commonly used to treat these behaviors, along with psychosocial and environmental interventions. During the last decade, newer atypical antipsychotic drugs (i.e., risperidone, olanzapine, quetiapine, and aripiprazole, in order of introduction) have largely replaced the older conventional or first generation antipsychotic drugs (e.g., haloperidol and thioridazine) and have been considered preferred treatments for these behavioral disturbances associated with dementia. However, concerns have arisen about possibly increased risks for cerebrovascular adverse events, rapid cognitive decline, and death with their use.

Lon S. Schneider, M.D., M.S., and colleagues at the University of Southern California, Los Angeles, conducted a meta-analysis of atypical antipsychotic drug trials to assess the evidence for death associated with their use in elderly patients with dementia. After a search of databases and meeting presentations, the researchers selected 15 trials (9 unpublished) that met criteria, generally 10 to 12 weeks in duration, including 16 contrasts of atypical antipsychotic drugs with placebo (aripiprazole [n = 3], olanzapine [n = 5], quetiapine [n = 3], risperidone [n = 5]). A total of 3,353 patients were randomized to study drug and 1,757 were randomized to placebo. Outcomes were assessed using standard methods to calculate odds ratios (ORs) and risk differences based on patients randomized and relative risks based on total exposure to treatment. There were no differences in dropouts.

The researchers found that death occurred more often among patients randomized to drugs (118 [3.5 percent] vs. 40 [2.3 percent]; OR, 1.54), indicating a significantly increased risk. Sensitivity analyses did not show evidence for differential risks for individual drugs, severity, sample selection, or diagnosis.

"These findings emphasize the need to consider certain changes in some clinical practices. Antipsychotic drugs have been dispensed fairly frequently to patients with dementia and used for long periods. The established risks for cerebrovascular adverse events together with the present observations suggest that antipsychotic drugs should be used with care in these patients. The fact that excess deaths and cerebrovascular adverse events can be observed within 10 to 12 weeks of initiating medication, coupled with observations from individual clinical trials results that there is substantial improvement in both drug and placebo groups during the first 1 to 4 weeks of treatment, lead to the consideration that antipsychotic drugs should be prescribed and dosage adjusted with the expectation of clinical improvement within that time. If improvement is not observed, the medication could be discontinued," the authors write.

"As a meta-analysis, our results should be taken as hypothesis-generating for an increased risk for deaths in patients with dementia receiving atypical antipsychotic drugs. No drug is individually responsible for the effect, but rather each contributes to the overall effect. This effect may not be limited to atypical drugs as a class and may be associated with haloperidol and other drugs that have not been subjected to efficacy trials in elderly patients with dementia," the researchers conclude.

In an accompanying editorial, Peter V. Rabins, M.D., M.P.H., and Constantine G. Lyketsos, M.D., M.H.S., of Johns Hopkins Medical Institutions, Baltimore, examine the results of the meta-analysis by Schneider et al.

"So what should a clinician do when caring for a patient with dementia who develops psychotic symptoms or aggression? First, etiologies other than dementia need to be considered. Delirium, untreated or undertreated medical illnesses, overmedication, environmental triggers, lack of engaging activities, and misinterpretation of disease symptoms are among the potential etiologies of such behaviors and symptoms. Because all have specific therapies, they should be considered when such symptoms first develop. Second, clinicians should consider the risk/benefit ratio for each patient. For example, patients with hallucinations and delusions that are neither distressing nor placing them or others at risk or harm should not be treated with antipsychotic drugs. Third, once antipsychotic drugs have been prescribed, careful assessment and documentation of the need for continued care is necessary. The Omnibus Budget Reconciliation Act (OBRA) regulations of 1987 require such a reassessment in long-term care, but the need for medication continuation should be regularly reassessed and justified for all individuals. Given the high rates of dementia in assisted living homes, similar practices should be instituted in those settings as well."

Eating fish is inversely associated with cognitive decline

Tue, 11 Oct 2005 19:16:00 PST

( from http://www.rxpgnews.com ) Consuming fish at least once a week was associated with a 10 percent per year slower rate of cognitive decline in elderly people, according to a new study posted online today from the Archives of Neurology, one of the JAMA/Archives journals. The study will be published in the December print edition of the journal.

Fish is a direct source of omega-3 fatty acids, which have been shown to be essential for neurocognitive development and normal brain functioning, according to background information in the article. Fish consumption has been associated with lower risk of dementia and stroke and recent studies have suggested that consumption of one omega-3 fatty acid in particular, docosahexaenoic acid (DHA), is important for memory performance in aged animals.

Martha Clare Morris, Sc.D., of Rush University Medical Center, Chicago, and colleagues analyzed six years of data from an ongoing study of Chicago residents, 65 years and older, first interviewed between 1993 and 1997 and every three years in two follow-up interviews. Interviews included four standardized cognitive tests and dietary questions on the frequency of consumption of 139 different foods, as well as questions of daily activities, exercise levels, alcohol consumption and medical history.

"Dietary intake of fish was inversely associated with cognitive decline over six years in this older, biracial community study," the researchers report. "The rate of decline was reduced by 10 percent to 13 percent per year among persons who consumed one or more fish meals per week compared with those with less than weekly consumption. The rate reduction is the equivalent of being three to four years younger in age." The researchers examined whether overall dietary consumption patterns accounted for the association of cognitive decline and fish consumption, but the rate differences did not change after adjusting for consumption of fruit and vegetables.

"Cognitive decline is common among older people and is very much associated with advancing age," the authors write. "Our data offer no insight as to whether this cognitive decline is pathological or the result of a normal aging process. Nonetheless, data from the United States and other countries indicate that it is a widespread and increasing public health problem."

"This study suggests that eating one or more fish meals per week may protect against cognitive decline associated with older age," the authors conclude. "More precise studies of the different dietary constituents of fish should help to understand the nature of the association."

Midlife Obesity Linked With Increased Dementia Risk

Tue, 11 Oct 2005 19:16:00 PST

( from http://www.rxpgnews.com ) Individuals who were obese at midlife had an increased risk for dementia later in life compared to individuals of normal weight, according to an article in the October issue of the Archives of Neurology, one of the JAMA/Archives journals.

Obesity is on the rise all over the world and is related to vascular diseases, which may be linked to dementia and Alzheimer's disease (AD), according to background information in the article. However, the link between obesity and dementia risk has not been extensively studied and long-term follow-up studies performed thus far have yielded somewhat conflicting results.

Miia Kivipelto, M.D., Ph.D., from the Karolinska Institutet, Stockholm, Sweden, and colleagues re-examined participants in the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study to investigate the relationship between midlife body mass index (BMI; weight in kilograms divided by square of height in meters) and a group of vascular risk factors, and subsequent dementia and AD. Participants in the CAIDE study were derived from random, population-based samples previously studied in a survey carried out in 1972, 1977, 1982, or 1987. After an average follow-up of 21 years, 1,449 individuals aged 65 to 79 years participated in the 1998 re-examination.

The researchers discovered dementia and AD to be prevalent significantly more among those with a higher midlife BMI. One-third of the participants had a BMI lower than 25 (normal weight), half had a BMI from 25 to 30 (overweight), and the remaining 16 percent had a BMI higher than 30 (obese) at midlife. A history of heart attack and diabetes mellitus were more prevalent in those with the highest midlife BMI.

A total of 61 participants were diagnosed as having dementia, and 48 of them fulfilled the diagnostic criteria for Alzheimer's disease. Midlife obesity, high systolic blood pressure, and high total cholesterol level were all significant risk factors for late-life dementia. Being overweight in midlife was not significantly associated with dementia later in life.

"This study shows that obesity at midlife may increase the risk of dementia and AD later in life," the authors write. "...midlife obesity, high SBP, and high total cholesterol level were all significant risk factors for dementia, each of them increasing the risk around two times. Clustering of these vascular risk factors increased the risk of dementia and AD in an additive manner so that persons with all three risk factors had around a six times higher risk for dementia than persons having no risk factors."

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.

Exercising could decrease risk of dementia

Thu, 06 Oct 2005 00:36:00 PST

( from http://www.rxpgnews.com ) Being physically active in midlife could decrease a person's risk of dementia and Alzheimer's disease (AD) later in life, concludes an article published online today (Tuesday October 4, 2005) by THE LANCET NEUROLOGY.

Miia Kivipelto (Aging Research Centre, Karolinska Institutet, Sweden) and colleagues randomly selected 1449 people aged 65-79 who had been surveyed about their leisure-time physical activity in 1972, 1977, 1982, and 1987. The investigators re-examined the participants in 1998 and found that individuals participating in leisure-time physical activity at least twice a week had a 60% lower odds of AD compared to sedentary people (individuals participating in physical activity less than twice a week). The active group had 50% lower odds of dementia compared to the sedentary group. The researchers also found that in individuals who are genetically susceptible to AD (carriers of the gene variant APOE 4), physical activity had more pronounced effects against developing dementia or AD in later life.

The authors state that interventions that could postpone the onset of AD even modestly would have a major public health impact, as the proportion of old people is increasing.

Dr Kivipelto states: "These findings may have wide implications for preventive healthcare; if an individual adopts an active lifestyle in youth and at midlife, this may increase their probability of enjoying both physically and cognitively vital years later in life".

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.

"Complex work" protects against dementia

Fri, 09 Sep 2005 16:15:00 PST

( from http://www.rxpgnews.com ) Publishing in the September issue of the Journal of Gerontology: Psychological Sciences, University of South Florida School of Aging Studies researcher Ross Andel and James Mortimer, professor, USF College of Public Health, examined the relationship between complexity of main lifetime occupation and risk for Alzheimer's disease and dementia in general. He and co-researchers discovered that people engaging in "complex work" had a reduced risk of dementia and Alzheimer's disease.

"Occupations with high mental demands may provide a form of 'mental exercise' that supports brain function into older adulthood," said Andel.

Recent research has focused on lifestyle issues, such as smoking, drinking, exercise and leisure activities and the roles they may play in the risk for dementia and Alzheimer's disease. Occupation as an intellectual stimulus, said Andel, is yet another factor that needs consideration, particularly given the amount of time people spend at work. While occupational classification has been a previously studied variable, and occupations with low social status have been found to be a risk factor for dementia and Alzheimer's disease, occupational complexity as a source of intellectual stimulation has not been looked at sufficiently.

Andel and his co-researchers studied risk of dementia in cases and controls and in complete twin pairs using data from a Swedish Twin Registry, through which sets of twins were followed for more than 40 years and whose main occupations were recently recorded. Within the twin pairs, one twin was diagnosed with dementia and the co-twin was dementia-free. The sample included 10,079 members of a subset of the Swedish Twin Registry called the Study of Dementia in Swedish Twins (HARMONY), a study led by Margaret Gatz from the University of Southern California.

The authors found that those who performed complex work with data or people had lower risk of dementia and Alzheimer's disease.

"Those performing complex work with people, such as speaking to, instructing or negotiating with people, appeared particularly protected in this sample," Andel said.

Results were adjusted for gender, level of education and, in case-control analyses, for age.

"Our results suggest that intellectually demanding activity at work may facilitate brain health in old age," concluded Andel. "However, further research is needed to understand why complex work appears to offer a buffer against dementia and whether occupational complexity is protective independent of occupational status."

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."

Cerebral Blood Flow Linked to Late-Onset Dementia

Tue, 30 Aug 2005 19:30:00 PST

( from http://www.rxpgnews.com ) The amount of blood flowing into the brain may play a larger role in the development of dementia than previously believed, according to a study in the September issue of the journal Radiology.

Researchers from Leiden University Medical Center in the Netherlands used magnetic resonance imaging (MRI) to examine the brains of elderly patients with and without dementia related to Alzheimer's or Parkinson's disease. As expected, MR images showed that the patients with late-onset dementia had more brain damage compared with young adults and with seniors who had optimal cognitive function. But researchers found that the late-onset dementia group also had a much lower rate of blood flow to the brain than the other two groups.

"Our findings not only support the hypothesis that vascular factors contribute to dementia in the elderly, they are highly suggestive that a diminished cerebral blood flow indeed causes brain damage," said Aart Spilt, M.D., a Leiden radiology resident and lead author of the study. "This gives us a clue to the genesis of dementia."

Dementia is a loss of cognitive functions, such as thinking, remembering and reasoning, that interferes with normal activities. Although many conditions can produce these symptoms, Alzheimer's disease is the most common cause of dementia. Some patients with Parkinson's disease also develop dementia.

In the Dutch study, researchers examined 17 patients with late-onset dementia (dementia occurring after age 75), another 16 seniors of the same age with optimal cognitive function and 15 healthy younger individuals. Researchers used MRI to measure cerebral blood flow and the extent of structural brain damage in each person and then compared the results of the three groups.

Average total cerebral blood flow in the healthy young individuals was 742 milliliters (mL) per minute. Cerebral blood flow in the two elderly groups averaged 496 mL per minute, or 246 mL per minute lower than the younger group. In patients with dementia, average cerebral blood flow was 443 mL per minute, or 108 mL per minute lower than seniors of the same age with optimal cognitive function (551 mL per minute).

Although patients with dementia have been shown to require less cerebral blood flow as the brain becomes less active, Dr. Spilt's research provides some evidence that the decreased blood flow may lead to some types of dementia.

"The findings emphasize the importance of monitoring both high and low blood pressure in older adults," Dr. Spilt said. "Possible causes of low cerebral blood flow include heart failure and a narrowing of cerebral or cervical arteries."

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.

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