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Monday, November 29, 2010

Cognitive Functioning, Physical Functioning and Middle Aged Women

Dear Readers,

There are many studies in aging research that have shown this association: a decline in physical function is often related to a decline in cognitive function. The question I am asked from young and old alike, is " Dr. A., at what age do you think these changes are starting to occur?"

Well, according to the recent findings from the Study of Women's Health Across the Nation ( SWAN), the answer appears to be - "at midlife". In this multi site, longitudinal community based study, a total of 3,302 women aged 46-56 years answered questions that assessed the occurence of existing medical conditions (i.e. metabolic syndrome), menopausal status, depression status, and socioeconomic status.

In addition to these tests, cognitive function testing and physical functioning testing occurred at follow up visits 4, 6, and 8 in 2,003 women from the original group. A sample of tests that were thought to represent different aspects of cognition likely to change with aging, or change with hormonal status, were administered and included the Symbol Digit modality test (a measure of attention and processing speed), digit span backward test (a measure for working memory) and the East Boston memory test (a verbal and short term memory test).

Physical functioning was assessed with a 10 item perceived physical functioning scale of the Medical Outcomes scale. This scale assesses difficulty in undertaking activities that range from athletic activity to the ability to bathe and dress. Participants were asked to rate their functioning as "0" (worst) to "100" ( best) and the responses were then categorized into three levels: no limitation, moderate limitation and severe limitation.

The average age of the women in the study was 50 years, 50% Caucasian, 28% African American, 10% Chinese and 12 % Japanese. At follow up visit 4, 7% were premenopausal, 45% early perimenopausal, 11% late perimenopausal, and 25% postmenopausal. At the initial examination, 68% of the women designated themselves as having no physical limitations, 24% reported moderate limitations and 8% were classified with severe limitations. Women who had severe physical limitations had lower scores on all cognitive measures, an association seen in all follow up visits.

Over a period of four years, a change in physical functioning was associated with changes in short term memory and verbal memory but not with attention, processing speed or working memory. These relationships were weakened (but remained significant) when other factors such as socioeconomic status, depressive symptoms and metabolic syndrome were also considered in the statistical models.

These study findings suggest that over a four year period, women at midlife already demonstrate declines in both physical and cognitive functioning and, that socioeconomic status, depression and metabolic syndrome, can contribute to functional decline. Unfortunately, due to the proportionately fewer numbers of Chinese and Japanese women in the sample, no race/ethnicity comparisons could be performed. Future multi ethnic studies in middle aged women ( at varying stages in the menopausal transition) will be needed to provide a better understanding as to the underlying physiological and psychological processes that may link cognitive and physical functioning.

Here are 3 articles you can refer to, to learn about this particular study or research in this area.

Ford K, Sowers MF, Seeman TE et al. Cognitive Functioning Is Related to Physical Functioning in a Longitudinal Study of Women at Midlife. Gerontology 2010; 56: 250-258.

Sowers MF, Crawford S, Sternfeld B, et al: SWAN: a multicenter, multiethnic, community based cohort study of women and the menopausal transition, in Lobo RA, Kelsey J, Marcus R (eds): Menopause: Biology and Pathobiology. San Diego, Academic Press, 2000, pp 175-188

Tabbarah M, Crimmins EM, Seeman TE: The relationship between cognitive and physical performance: MacArthur studies of successful aging. J Gerontol 2992; 57: M228-M235.

Thanks for reading.

Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Associate Professor of Neurological Sciences- Rush University Medical Center
Rush Alzheimer's Disease Center and Rush Institute for Healthy Aging

Author: Neelum Aggarwal MD at 9:01 AM 0 Comments

Wednesday, November 24, 2010

ApoE2 and AD

Following up on last week’s blog about ApoE4 and beta-amyloid transport out of the brain, in today’s blog I will describe some recent findings on ApoE2.

Statistically, the E3 and E4 forms of ApoE are more common in the population, but the few who have an ApoE2 allele enjoy reduced risk of late-onset Alzheimer’s disease. Now, a new study provides further evidence that ApoE2 is protective.
Analyzing cognitively normal subjects enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), researchers report that E2 carriers not only have biomarker signatures indicating less AD pathology, but also lower hippocampal atrophy rates, relative to E3 homozygotes.

Of the 193 normal ADNI participants with reliable magnetic resonance imaging (MRI) data, 27 were E2 carriers (i.e., E2/E3 or E2/E2) and 111 were E3/3. The researchers compared hippocampal atrophy and cognitive decline in both groups, and also analyzed cerebrospinal fluid (CSF) biomarkers in those who agreed to spinal taps—about half the participants. The study found that, relative to E3 homozygotes, E2 carriers had baseline CSF profiles reflecting little or no AD pathology.

Hippocampal atrophy rates averaged 0.5 percent per year among E2 carriers, compared with 1.3 percent for the E3/3 group. Although these numbers may seem miniscule, over the 10-20 years of disease development, this can translate to significant loss of brain tissue.

How does ApoE2 lead to less beta-amyloid retention in the brain? This question is being hotly research on a molecular level, and will hopefully provide a clearer understanding of the role of ApoE in AD.

Chiang GC, Insel PS, Tosun D, Schuff N, Truran-Sacrey D, Raptentsetsang ST, Jack CR Jr, Aisen PS, Petersen RC, Weiner MW; For the Alzheimer's Disease Neuroimaging Initiative. Hippocampal atrophy rates and CSF biomarkers in elderly APOE2 normal. Neurology. 2010 Oct 27.

Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
Assistant Professor of Neurosciences
Associate Medical Director, Alzheimer's Disease Cooperative Study
Attending Neurologist, Shiley-Marcos Alzheimer's Disease Research Center
University of California, San Diego
Author: Michael Rafii MD,PhD at 2:03 PM 0 Comments

Wednesday, November 17, 2010

Updates from the Annual Society for Neuroscience Meeting: ApoE4 and Beta-Amyloid


The Annual Society for Neuroscience Meeting is where fundamental neuroscience research is presented to a worldwide audience. This year’s meeting includes research presentations from many of the cutting edge labs working on AD. In today’s blog, I will summarize a few of the many findings presented at this meeting that are helping us get a better picture of AD, as well as potential new avenues for its treatment.

Our current thinking about the cause of AD is that beta-amyloid accumulates in the brain, most likely due to its faulty clearance out of the brain, and into the bloodstream. Once in the blood, beta-amyloid is rapidly degraded in the kidney and liver. But within the brain, beta- amyloid is thought to cause damage to synapses (connections between brain cells.

Apolipoprotein E e4 (apoE4) is the most important genetic risk factor for sporadic Alzheimer’s disease. The apoE protein exists in three major forms (apoE2, E3, E4) and the risk for getting AD differs with each form, E4>E3>E2. The exact mechanism by which apoE influences the onset and progression of AD is not completely understood, but we do know that apoE4 binds directly to beta-amyloid and forms a protein complex.

Previous research has shown that the binding of ApoE4 to beta-amyloid shifts the removal of beta-amyloid out of the brain from a rapid export pathway, to a very slow pathway, resulting in poor beta-amyloid clearance from brain, and hence, its accumulation.

Dr. Holtzman’s laboratory at Washington University and Dr. Brad Hyman’s laboratory at Harvard Medical School presented data showing that apoE4 may also facilitate transport of beta-amyloid directly to synapses in the brain of AD patients, and lead to their disruption.

They analyzed 18,000 synapses in human brain tissue from normal and AD patients and found that ~25% of synapses in both AD and normal brains contain apoE protein. In AD brains, a subset of these apoE –containing synapses also contain beta-amyloid, and in fact, have twice as much beta-amyloid as those with apoE3 in the synapses. Moreover, the synapses that have beta-amyloid are 21% smaller than those not containing beta-amyloid, indicating structural damage.

This work is beginning to give us a glimpse as to how apoE4 may influence the onset and progression of AD. Not only may ApoE4 lead to accumulation of beta-amyloid in the brain, but it may also be routing it to synapses. Certainly, the binding of ApoE4 and beta-amyloid is a potential therapeutic target, and researchers are working on identifying such molecules.

Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
University of California, San Diego
Author: Michael Rafii MD,PhD at 2:33 PM 0 Comments

Friday, November 12, 2010

Amyloid Imaging Moving Towards Center Stage

Eli Lilly announced on Monday, November 8, that they are acquiring Avid Radiopharmaceuticals, the maker of the PET tracer agent florbetapir that is likely to be the first to gain FDA approval in early 2011 for amyloid imaging. Given an acquisition price of up to $800 million (depending on achievement of certain milestones), for a company with no sales, it is safe to say that big pharma is sold on the value of biomarkers in diagnosing Alzheimer's disease with PET imaging.

Avid Radiopharmaceuticals tested florbetapir (formerly 18F AV-45) in 35 people who were expected to die within six months. The idea was that imaging people near the end of their lives would minimize the time interval between PET scan and histopathological evaluation, allowing researchers to more effectively compare the two measures of brain amyloid load. To test their PET tracer’s accuracy, the team also imaged people who were highly unlikely to have detectable brain amyloid—namely, young, cognitively normal subjects without an ApoE4 allele. Of the 19 subjects who met criteria for AD pathology, all 19 came out positive on quantification of PET data (100 percent accuracy). For both PET analysis methods, all 16 who lacked postmortem AD pathology were also amyloid-negative by live brain imaging, giving the tracer 100 percent specificity in this study.

Florbetapir may therefore be useful for predicting whether asymptomatic or patients with mild cognitive impairment are likely to decline further. One point of agreement in the field is that Alzheimer’s disease develops over decades and that by the time symptoms appear, interventions are unlikely to be effective. This realization has resulted in a rethinking of the diagnostic criteria for the disease, and tools such as amyloid imaging will be invaluable for assessing efficacy of anti-amyloid drugs.

Michael S. 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 2:16 PM 0 Comments

Wednesday, November 03, 2010

Sepsis and the Risk for Future Cognitive Decline

Dear Readers,

About 750,000 people in the United States develop sepsis each year. Known in lay terms as blood poisoning, sepsis occurs when the bloodstream is overwhelmed with bacteria, usually in response to the body's attempt to fight severe infection.
Sepsis is a leading cause of death in hospital ICUs, and the elderly are particularly vulnerable to the life-threatening blood infection.

The thinking had been that once the crisis is over, older people who survive sepsis make full recoveries. But new research finds the opposite to be true. Elderly people in the study had a threefold increase in life-altering cognitive declines after surviving sepsis. Study participants with no history of sepsis showed no increase in risk over the course of the study.

As reported in the October 27 issue of the Journal of the American Medical Association, seniors hospitalized for severe sepsis faced tripled odds of cognitive impairment during the study’s eight-year follow-up. This retrospective analysis indicates that episodes of delirium are associated with an increased rate of disease progression in dementia.

Drawing from the ongoing longitudinal Health and Retirement Study involving some 22,000 Americans, Researchers led by Dr. Jack Iwashyna at the University of Michigan in Ann Arbor, analyzed 1,194 elderly who were hospitalized for severe sepsis between 1998 and 2005, as determined by information on Medicare claims. More than 40 percent of those patients died within 90 days. Among the 516 participants who survived sepsis and had at least one follow-up two years later, 6.1 percent had moderate to severe cognitive impairment when surveyed just prior to sepsis. The prevalence of cognitive decline two years afterward jumped nearly threefold, to 16.7 percent. Based on the new data, it may give rise to some 20,000 new cases of moderate to severe cognitive impairment each year.

In addition to assessing cognition, the researchers also scored, every two years, the participants’ functionality in 11 areas—six daily skills, such as walking and dressing, and five harder tasks like preparing meals and managing finances. Patients with three or fewer deficiencies prior to severe sepsis developed, on average, about 1.5 additional limitations after being hospitalized.

Sepsis is one of the few factors shown to influence rate of disease progression. Inflammation has been implicated in all kinds of health issues, including cognitive decline, and it is a hallmark of severe sepsis. The findings highlight the importance of preventing sepsis in older patients. One of the best strategies for doing this is to vaccinate vulnerable elderly populations against diseases like flu and pneumonia.

Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010 Oct 27;304(16):1787-94.

Michael S. 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 11:15 AM 0 Comments

Tuesday, November 02, 2010

Women, Stress and Alzheimer's Disease

Dear Readers,

Whenever I give a presentation about the signs and symptoms of Alzheimer's disease and discuss the known risk factors for the disease, I am asked this question . . . ( 90% of the time by the women audience members) . . . "Dr. A, is "stress" a risk factor for Alzheimer's disease?"

Well, based on research findings from a variety of studies, the short answer is "Yes". Let's consider the latest finding from a study that revealed that stress in middle aged women could lead to the development of dementia later on in life.

This research was based on a 35 year study of 1,415 women from the Prospective Population Study of Women in Gothenburg, Sweden, who were initially examined in 1968 (the age ranged from 38y-60y), and then re-examined in the following cycles: 1974, 1980, 1992 and 2000. In addition to neuropsychiatric tests and questions on activities of daily living, the following question was asked by a physician to measure the level of stress in the first three cycles of data collection: "Have you experienced any period of stress (1 month or longer) in relation to circumstances or everyday life, such as work, health or family situations?"

The measure of "stress" was defined as a sense of irritation, tension, nervousness, anxiety, fear or sleeping problems. Participants were asked to choose "0" if they never experienced stress, "1" if they have experienced stress more than 5 years ago, "2" if have experienced one period of stress during the last 5 years, "3" if they have experienced several periods of stress during the last 5 years, "4" if they have constant stress during the last year or "5" if they have experienced constant stress during the last 5 years.

In addition, data was collected on a variety of factors (i.e. confounders) that may affect the association of stress to dementia, such as lifestyle factors (smoking and wine consumption), coronary heart disease, blood pressure, and use of antihypertensive medication.

Participants were classified as having dementia at each cycle if they fulfilled the criteria put forth by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). The diagnosis of Alzheimer's disease was based on criteria put forth by National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. The diagnosis of vascular dementia was based on the criteria proposed by the National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et 1"Enseignement en Neurosciences.

One hundred and sixty one (161) women, who were initially assessed in 1968, developed dementia during the follow up period of 35 years (105 diagnosed with Alzheimer's disease, 40 diagnosed with vascular dementia, 16 with another type of dementia). The average age of dementia onset was 76 years. Stress that was rated as "frequent/constant" at the baseline and follow up cycles - 1968, 1974 and 1980, was related to increased risk of developing dementia and these associations did not change when adjusted for potential confounding variables.

In addition, among women who participated in all three examinations, the risk of dementia, increased with the number of examinations when stress was reported. Compared to a woman who never reported stress, if a woman reported stress at one examination cycle her risk for dementia was 1.10, stress at two examination cycles - 1.73, and stress at 3 examination cycles the risk of dementia rose to 2.51.

These findings suggest that long standing psychological stress in middle aged females is related to the development of dementia later in life. How the present findings could result in a better understanding of the risk factors for dementia and Alzheimer's disease will need to be confirmed in studies that aim to study the potential neurobiological mechanisms for these associations.

Here are 3 articles you can refer to, to learn about this particular study or research in the area of Stress and dementia.

Johansson L, Guo X, Waern M et al. Midlife psychological stress and risk of dementia: a 35 year longitudinal population study, Brain 2010

Hange D, Bengtsson C, Sundh V et al. The natural history of psychosomatic symptoms and their association with psychological symptoms: observations from the Population Study of Women in Gothenburg. Eur J Gen Pract 2007

Wilson RS, Evans DA, Bienias JL et al. Proneness to psychological distress is associated with risk of Alzheimer's disease. Neurology 2003

Thanks for reading.

Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Author: Neelum Aggarwal MD at 10:42 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.