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Tuesday, November 22, 2011

Updates from the International CTAD meeting & the Society for Neuroscience meeting

The 4th annual conference on Clinical Trials in Alzheimer’s Disease in San Diego, California was filled beyond its venue's capacity, drawing over 500 researchers from around the world. For the bulk of the meeting, researchers worked on methodological aspects they hope will improve future trials’ chances of success. Clearly, better drugs are needed to treat AD, and there have been no drugs approved in over a decade. These methodological improvements include using more advanced statistical methods to analyze subject data, and to incorporate biomarkers of disease, including brain amyloid levels and measures of brain atrophy, as part of efficacy measures. In addition, there was much discussion on trial designs that target the disease in the pre-dementia phase of Alzhiemer’s disease, sometimes referred to as Mild Cognitive Impairment (MCI).

There is international consensus that Alzheimer’s disease starts some 15 years before symptoms of dementia, and new trial designs will need to be based on a biomarker-supported diagnosis of prodromal AD. Prodromal AD, which is the cause of cognitive impairment in roughly half of patients diagnosed with MCI, is basically defined as patients who are not demented but are destined to develop dementia within a few years because they have the earliest signs of AD developing in their brain. Several companies have begun using such designs to treat patients with prodromal AD, before dementia sets in.

The Society for Neuroscience meeting in Washington D.C. with 42,000 members is the largest meeting in the world on fundamental research on the nervous system. Many presentations were made with direct relevance to AD. One included the work of Dr. Gene Alexander from the University of Arizona, who found that physically fit seniors show fewer age-related changes in their brains. The findings further previous data in the AD field and underscore the importance of exercise for maintaining brain health throughout life.

As people age, some regions of the brain — including those responsible for attention and memory functions — begin to lose volume or shrink. To see how physical fitness affects brain aging and age-associated declines in cognition, Alexander and colleagues scanned the brains of 58 men and 65 women (ages 50 to 89 years) and evaluated their performance walking on an inclined treadmill.

The more physically fit a participant was, the less age-related brain changes they showed. In particular, exercise endurance and breathing efficiency offered the best combination of fitness measures in predicting patterns of brain aging. Individuals with higher levels of aerobic fitness also outperformed their less physically fit counterparts on tests measuring memory, executive function, and information processing. Identifying the fitness indices that are the best predictors of brain aging and cognitive performance may help improve exercise-based interventions to promote healthy brain aging.

Another interesting presentation was on how short-term estrogen treatment increases the volume of cortical gray matter — brain cells and their uninsulated connections — in postmenopausal women. The research reveals a potential benefit from short-term hormone replacement therapy. Researchers, led by Paul Newhouse, MD, of Vanderbilt University, imaged the brains of 24 healthy postmenopausal women who took either estrogen or a placebo for three months. After treatment, the women who took estrogen had more gray matter in parietal, temporal, and prefrontal areas of the brain. These regions are known to be involved in attention, decision-making, and memory.

The findings suggest the brain remains responsive to estrogen treatment even after menopause, and that this responsiveness or plasticity is important for preserving cognitive functioning, especially in the early postmenopausal period. The findings suggest that long-term hormone treatment, shown to have adverse effects on health in postmenopausal women, may be unnecessary for cognitive benefit. Short-term estrogen treatment in normal postmenopausal women is sufficient to increase gray matter in the brain.

By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
Author: Michael Rafii MD,PhD at 10:58 AM 0 Comments

Monday, November 21, 2011

The Biggest Challenge to AD Research

We are lucky to be living in a time of significant scientific advancements - allowing us to live healthier, longer lives. But longer lifespans increase the likelihood of age-related health conditions such as Alzheimer's disease. Alzheimer's is the sixth-leading cause of death in the United States, affecting 5.4 million men and women (and growing). It is also the only top 10 killer in the United States that cannot be prevented, cured or even treated effectively.

Why not? For those of us in the research community working toward a cure, the greatest challenge is not the disease itself. The biggest hurdle in Alzheimer's is finding enough volunteers for studies-like the Alzheimer's Disease Neuroimaging Initiative (ADNI)- to allow the research to continue at the pace needed to be successful against this "silent epidemic." This fight is personal to me not only as a scientist, but because I am watching my mother slowly decline from Alzheimer's. I know what millions of Americans are facing with this disease.

As the largest and most comprehensive Alzheimer's disease (AD) research study of its kind, ADNI is helping to identify the earliest signs of AD, when brain damage begins. With better knowledge of the earliest stages of the disease, we may be able to test potential therapies earlier, when they have the greatest promise for slowing down progression of this devastating disease. I believe strongly in the potential of this study - so much so that I have been volunteering in it myself over the past 6 years, and can attest to the fact that the experience is highly educational and the procedures are safe.

ADNI's research has made significant inroads into this complex disease, and has put us at the cusp of further discoveries that could help better treat AD. To continue the momentum, we must spread the word that everyone can contribute to furthering research. No medical degree required.

I encourage you to lend your voice to this issue and raise awareness of the importance of clinical trials in the fight against Alzheimer's. Better yet, consider participating in the ADNI trial. We are seeking normal persons, patients with AD, and individuals with mild cognitive impairment to better understand the breadth and progression of the disease. The age range is 55 to 90.

Changing the face of AD is possible, but we can't find the answers we need without volunteer partners in science. It will take everyone's involvement - researchers and clinicians, doctors, patients, friends and family members, and trial participants - to fight this disease effectively. Together we can continue to enhance lives by contributing to the advancement of science. To learn more, please go to or call 1-800-432-4380.

Michael W. Weiner, M.D.
Director, Center for Imaging of Neurodegenerative Diseases
San Francisco Veterans Affairs Medical Center
Professor of Medicine, Radiology, Neurology and Psychiatry
University of California, San Francisco
Author: Jeffree Itrich at 10:37 AM 0 Comments

Monday, November 14, 2011

Mild Cognitive Impairment and Dementia among Oldest Old Women

Dear Readers,

In an article from the Archive of Neurology, Yaffe and colleagues examined the prevalence of MCI, its subtypes and dementia among the oldest old women from the Study of Osteoporotic Fractures (SOF). This multi center prospective observational study recruited over 9,000 women aged 65 and older, between 1986 and 1988 from four areas in the US: Baltimore, Maryland; Minneapolis, Minnesota; Portland, Oregon and the Monongahela Valley, Pennsylvania. All the women attended the clinics every two to four years and from 2006-2008; three of the four SOF sites participated in a cognitive sub-study. A total of 1,338 women participated in the sub-study, of whom 1,299 were over the age of 85 years.

Baseline interviews consisted of structured questions that obtained data for demographic characteristics, psychosocial variables, medical history, depression and cognitive performance tests. Cognitive tests were based on the Mini-mental State Examination (MMSE), modified Mini-mental State Examination (3MS), Trails B, Digit Span, and the California Verbal learning Test. Other variables assessed were race, education in yrs (range 0-30), and the history or presence of medical conditions (heart disease, TIA, stroke, hypertension, diabetes, and Parkinson’s disease). Assessment of cognitive impairment was determined by adjudication of each case and the diagnosis of dementia was based on the DSM IV criteria. The likely cause of dementia etiology (AD, vascular dementia, mixed dementia) or other (head injury, Parkinson’s disease, depression) was determined. MCI was diagnosed using the Peterson criteria with further characterization of amnestic and non amnestic and single or multiple domain MCI determined.

Of the 1,299 women who participated in the study, the mean age was 88.2 years, a mean education level of 12.8 years and a mean MMSE score of 24.9. Among the oldest old in the cohort, 17.8% were diagnosed with dementia and 23.2% with MCI, for a combined total of 41.0% with clinical cognitive impairment. The remaining 59% were cognitively normal.

The prevalence of dementia among women over 90 years or older was double that among those 85-89 years with clinical features consistent with AD and mixed dementia the most common. Of the women diagnosed with dementia, about 25 % reported to already having a dementia diagnosis with about 20% taking dementia medications. The prevalence of MCI was also higher among women aged 90 or older than among women 85-89 years. The most common subtype of MCI was amnestic MCI followed by non-amnestic single domain and amnestic single domain.

Compared to women with normal cognition, those with dementia were older, less likely to have completed high school and more likely to live in a nursing home. In addition women with dementia were more likely than women with normal cognition to be depressed, have a history of stroke and have an APOE e4 allele. Similar characteristics were seen in women with MCI.

This study is one of the few that examined the prevalence of dementia, MCI and its subtypes in the oldest old. Unfortunately, this study did not include minority women, and thus was not able to comment on any differential findings that may have been influenced by race/ethnicity. However, understanding the prevalence of dementia and its subtypes in this age group, is very important from a public policy perspective. Not only does the treatment of dementia vary by subtype but one could argue that the disease course also varies. Further, epidemiologic projections suggest that the growth of the “oldest old” population will increase in number with a parallel increase in the proportion of dementia cases among the “oldest old.” How we, as a society, will be able to care for the health care needs of this group will be one of our greatest healthcare challenges.

Here are three articles you can refer to, to learn about this study, and other studies examining the oldest old.

Yaffe K, Middleton LE, Lui LY et al. Mild Cognitive Impairment, Dementia and Subtypes among Oldest Old Women. Arch Neurol. 2011 68(5): 631-636.

Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for Hip Fracture in White Women. New England Journal of Medicine. 1995; 332 (12): 767-774

Pioggiosi PP, Berardi D, Ferrari B et al. Occurrence of cognitive impairment after age 90: MCI and other broadly used concepts. Brain Research Bulletin. 2006; 68(4):227-232.

Thanks for reading.

Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Rush Alzheimer’s Disease Center
Rush Institute for Aging
Chicago, IL

Author: Neelum Aggarwal MD at 11:22 AM 0 Comments

Wednesday, November 02, 2011

Beta-amyloid’s Damaging Effects Require Tau

It is currently believed that beta-amyloid triggers the entire process underlying Alzheimer's disease that eventually leads to dementia. The presence of beta-amyloid has been shown to cause the loss of brain cell synapses or ‘connections’ and disruption of neuronal networks. Initially, this shows up as memory loss, but over years, it leads to full blown dementia, with loss of language, problem solving, and other cognitive skills. Beta-amyloid is observed to accumulate into plaques outside of cells, while the protein Tau has been observed to accumulate inside of cells. Moreover, Tau has been noted to change its shape (become phosphorylated) as it accumulates.

However, in humans, amyloid plaques are observed to be present in cognitively normal adults, and their presence correlates poorly with memory decline. In fact, a clinical trial with a vaccine that led to amyloid plaque removal, did not seem to prevent subsequent dementia, suggesting that other proteins, including Tau, may be required for dementia to progress. Recent studies using mouse models show that by blocking the phosphorylation of Tau, researchers can block beta-amyloid-induced cognitive impairment.

As readers of this blog will recall, beta-amyloid is a protein that resides outside of brain cells, floating in the cerebrospinal fluid. It causes brain cells to malfunction, and leads to loss of synapses between the brain cells. When there is a lot of beta-amyloid outside a brain cell, a number of changes occur inside the cell. One manifestation of beta-amyloid induced damage is that the scaffolding of the cell, which is held together by the protein Tau, becomes unstable and falls apart. This instability is due to direct effects of beta-amyloid activating a chemical pathway that phosphorylates and alters the shape of the protein Tau. When Tau is phosphorylated and changes its shape, it can no longer hold the scaffolding together, and the brain cells literally begin to fall apart. This is believed to be one of the mechanisms by which brain cells are lost in Alzheimer’s disease.

We can measure levels of beta-amyloid and phospohorylated Tau in the cerebrospinal fluid, and we find that as Tau increases, there is more brain cell loss. In a recent study published last week in the prestigious journal Annals of Neurology, Dr. Rahul Desikan and colleagues suggest that beta-amyloid may be around for quite some time, and it cannot exert its effects until Tau becomes abnormal (phosphorylated), which leads to a breakdown of the scaffolding inside brain cells. What tips things over towards Tau changing its shape is still being worked out, but it may have to do with the amount of beta-amyloid that is present and the duration of its presence. From a clinical perspective, this work suggests the importance of examining both beta-amyloid and phospohorylated Tau, as the combination of these markers, rather than either marker by itself, may best identify which non-demented older individuals will develop brain changes of Alzheimer’s disease and thus eventually progress to develop dementia.

Desikan RS, McEvoy LK, Thompson WK, Holland D, Roddey JC, Blennow K, Aisen PS, Brewer JB, Hyman BT, Dale AM. Amyloid-ß associated volume loss occurs only in the presence of phospho-tau. Ann Neurol. 2011 Jun 7.

By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
Author: Michael Rafii MD,PhD at 9:14 AM 0 Comments

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About Us

The Alzheimer's Disease Cooperative Study (ADCS) was formed in 1991 as a cooperative agreement between the National Institute on Aging (NIA) and the University of California, San Diego. The ADCS is a major initiative for Alzheimer's disease (AD) clinical studies in the Federal government, addressing treatments for both cognitive and behavioral symptoms. This is part of the NIA Division of Neuroscience's effort to facilitate the discovery, development and testing of new drugs for the treatment of AD and also is part of the Alzheimer's Disease Prevention Initiative.

The ADCS was developed in response to a perceived need to advance research in the development of drugs that might be useful for treating patients with Alzheimer's disease (AD), particularly drugs that might not be developed by industry.