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Wednesday, January 26, 2011

Updates in the World of AD Research

Dear Readers,

There are two notable updates in this week’s blog. First, The U.S. Food and Drug Administration’s (FDA) Advisory Committee decided that it could not recommend approval of Amyvid™ (florbetapir) at this time based on the currently available data (13-3); but, voted unanimously (16-0) to recommend approval of Amyvid conditional on specialized training being instituted for the medical professionals who would administer it. They must train readers in a consistent technique, and then re-evaluate florbetapir scans from both a recent phase III and a previous phase II clinical trial. Amyvid is one of the imaging compounds that allows Amyloid to be visualized using PET imaging. It is expected that this training will be formalized, and FDA approval granted by the end of this year.

As a follow up to last week’s blog about recent developments in blood markers for AD, Kristine Yaffe and colleagues at UCSF published an article in JAMA this week in which they report on a new blood test that predicts subsequent cognitive decline. In the study, they took baseline plasma samples from nearly 1,000 elderly normal volunteers and then followed the participants for nine years, regularly measuring their cognitive performance. Unlike similar previous studies, Yaffe and colleagues looked at cognitive decline rather than conversion to AD. They found that a low ratio of two forms of beta-amyloid at baseline correlated with a greater drop in cognition over the duration of the study. Intriguingly, this association was strongest in participants with low levels of education, and much weaker in subjects with more education. This is in accord with the long-standing view that a person’s cognitive reserve can protect against cognitive decline. If the result proves robust in future studies, it may lead to further development of blood tests to monitor for AD.

Yaffe K, Weston A, Graff-Radford NR, Satterfield S, Simonsick EM, Younkin SG, Younkin LH, Kuller L, Ayonayon HN, Ding J, Harris TB. Association of plasma beta-amyloid level and cognitive reserve with subsequent cognitive decline. JAMA. 2011 Jan 19;305(3):261-6.

Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
University of California, San Diego
Author: Michael Rafii MD,PhD at 4:49 PM 0 Comments

Thursday, January 20, 2011

A Potential Blood Test for AD?

Dear Readers,

Using a new technology that relies on thousands of synthetic molecules to fish for disease-specific antibodies, researchers have developed a potential method for detecting Alzheimer's disease with a simple blood test. The same methodology might lead to blood tests for many important diseases, according to the report published by Thomas Kodadek’s group at the Scripps Research Institute in the January 7th issue of the journal Cell.

The new method relies on the notion that many diseases lead to the production of modified proteins. At some point, the adaptive immune system might begin to recognize those proteins as foreign and mount a response. If tests could be developed to recognize those disease-specific proteins or the antibodies that recognize them, it could be the basis for early diagnosis. But in most cases, researchers have had little luck identifying those abnormal proteins.
Kodadek's team decided to take a different tack. They used a large library of randomly selected, unnatural molecules known as "peptoids" to screen for antibodies found in the bloodstream of animals or patients with specific diseases and not in healthy controls.

Their method uncovered three peptoids that appear to discriminate between healthy and Alzheimer's disease blood samples with high accuracy. Three of them reacted strongly to the blood of six patients with the condition, but not that of 16 healthy individuals used as controls. Although this is encouraging the findings must be corroborated by further studies to demonstrate that antibodies can indicate whether the attack opens a picture for diagnosing the disease.

** Reddy MM, Wilson R, Wilson J, Connell S, Gocke A, Hynan L, German D, Kodadek T. Identification of candidate IgG biomarkers for Alzheimer’s disease via combinatorial library screening. Cell 2011 January 7;144:132-142.

Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
University of California, San Diego
Author: Michael Rafii MD,PhD at 9:12 AM 0 Comments

Wednesday, January 12, 2011

Dietary Vitamin D and Cognition in Older Women

Dear Readers,

I was recently on a conference call with women physicians discussing the latest in Women’s Health and was asked about vitamin D and its effect on cognition. Indeed vitamin D has received a lot of media attention lately; attention focused on its potential effect on cardiovascular and bone health, in addition to its anti-inflammatory and anti-oxidative effects. Thus, it was not a surprise to me when the discussion turned to “cognitive health” and whether or not (1) Vitamin D levels were associated with cognitive function and (2) whether its supplementation would provide an “added cognitive benefit” to female patients.

At the time the question was posed, I immediately thought about an article I read in Neurology that examined whether weekly dietary intake of vitamin D was associated with cognitive function in older women. Participants in this study came from the EPIDOS, a French community dwelling cohort study that was designed to evaluate the risk factors for hip fracture among women aged 75 years and older. Over a course of two years (1992- 1994) over 7000 women – free of a previous history of hip fracture or hip replacement - were recruited from five French cities to participate in this study. At baseline evaluation all participants received a full medical examination, which consisted of structured questionnaires, information about everyday dietary habits, chronic diseases, disability, sun exposure and a clinical examination. Medications and vitamin supplements were reported by interviewer questions and also by direct inspection of medications brought to the visit. Women were excluded from the study if over the last 18 months they had taken vitamin D drug supplements. A total of 5,596 women met the inclusion criteria and analyses were based on this sample size.

Dietary habits were assessed at baseline examination using a 21 question food frequency questionnaire that included questions on intake of fish (two items), dairy intake (six items) and the consumption of eggs, fruits, vegetables, starchy foods, chocolate and drinking history. The dietary intake of vitamin D per week was calculated by multiplying the content of individual food items (across all areas) by the frequency of consumption and adding this together. The vitamin D content for all food items was based on a dietary content database - continually updated by the French food and safety agency. For the French adult population, the dietary intake of vitamin D was 400 IU /day (or 35 micrograms/week). The assessment of cognitive function used– the Pfeiffer Short Portable Mental State Questionnaire (SPMSQ). This is a 10 item measure that has been in use in large scale studies as a screening tool to assess moderate to severe cognitive deficits. A score of 8 or below indicates cognitive impairment.

Although the mean weekly dietary intake of vitamin D for the entire group was well above the suggestive value of > 35 micrograms/week (mean 62.3 micrograms/week), approximately 14% of the women had inadequate dietary intakes of vitamin D. Based on the cognitive testing results, a total of 11% of the women were deemed to have cognitive impairment. Further, women who had lower levels of weekly vitamin D intakes had lower mean SPMSQ scores. These women were also older and reported more disability on a disability scale. To further examine the association between weekly vitamin D intake and cognitive function, other factors such as body mass index, sun exposure, number of chronic diseases, history of hypertension, depression, disability or use of antidepressants or other medications, were controlled for in their analyses. The association between dietary vitamin D and cognitive function remained significant even after adjusting for all of these factors.

This study nicely demonstrates that in women free of vitamin D drug supplementation, weekly dietary intake of vitamin D was significantly associated with the cognitive performance. Few studies have examined the association of dietary vitamin D to cognition in a large population sample. Such studies are needed to clarify whether the associations reported in this study exist in other populations (i.e. U.S. based and those that involve substantial numbers of minority participants) and will guide future research as to whether or not to persue large scale clinical trials that examine the benefits of vitamin D supplementation to treat or prevent cognitive impairment.

Here are 3 articles you can refer to, to learn about this particular study or the latest research on Vitamin D and cognitive function:

Annweiler C, Schott AM, Rolland Y et al. Dietary intake of vitamin D and cognition in older women- A large population based study, Neurology 2010

Annweiler C, Allali G, Allain P, et al. Vitamin D and cognitive performance in adults: a systematic review. Eur J Neurology 2009

Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr 2005.

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 9:33 AM 0 Comments

Friday, January 07, 2011

The Amyloid Plateau

Researchers from the Karolinska Institute in Stockholm, Sweden, report in last month’s issue of the journal Brain, on the postmortem examination of the first-ever AD patient to be followed prospectively by positron emission tomography using Pittsburgh Compound B (PIB-PET), which allows visualization of amyloid plaques.

They analyzed the brain of a woman with AD who had volunteered for the first PET-PIB scan ever performed. She received an additional PIB scan two years later, and three PET scans using fluorodeoxyglucose (FDG), a marker for glucose use and therefore brain metabolism. Over the eight years she was studied, the woman’s score on the Mini-Mental State Examination declined from a near-normal score of 27 down to five. The FDG PET scan data showed that her brain’s glucose metabolism decreased in parallel with her cognitive abilities. By contrast, the amyloid signal as seen by PIB PET, already high at first examination, showed little change over two years during which her cognition declined steeply. This pattern matches data from other recent studies, in which amyloid deposits in the brain increase during the mild cognitive impairment (MCI) stage of AD, but seem to plateau during the dementia stage of AD.

Postmortem examination confirmed the patient’s diagnosis of pure AD. Interestingly, the researchers found that the density of a certain receptor in the brain, which binds to acetylcholine, and known to be involved in learning and memory, was lower in brain regions with the highest amyloid, suggesting an interaction.

This study provides further evidence that amyloid deposits appear to reach a plateau early in the disease course, when patients experience very mild symptoms or no symptoms at all. Moreover, it suggests that amyloid may be negatively affecting receptors involved in learning and memory, before it has deposited into plaques.

Michael S. Rafii, MD, PhD
Associate Medical Director
Alzheimer's Disease Cooperative Study

Author: Michael Rafii MD,PhD at 10:46 AM 0 Comments

Monday, January 03, 2011

Does Bilingualism Delay the Onset of Alzheimer’s Disease?

On a recent trip to Canada over the holidays I was asked by friends and family about the latest news that hit the Canadian print media, “Could being bilingual actually prevent the onset of Alzheimer’s disease?”

According to investigators from the Rotman Research Institute at Baycrest in Toronto, the answer appears to be, “Possibly…. yes”. Cross sectional data was reported from a group of 211 Alzheimer’s disease patients who received care at the Baycrest clinic in Toronto, Canada. As is typical for most visits to a memory clinic, information regarding age of onset of cognitive problems, information about occupation, education, and language history were taken. Other information obtained unique to this group was fluency in English and other languages, place of birth, and date of immigration to Canada. To be classified as “bilingual” a person had to have spent the majority of his/her life (at least from early adulthood) regularly using at least two languages. A total of 102 patients were classified as bilingual (60 women) and 109 were monolingual (60 women). The bilingual patients included speakers of 23 first languages of which the five most common were Yiddish (n= 24), Polish (n= 12), Italian ( n= 11), Hungarian ( n=9) and French (n= 7).

In simple statistics that compared groups, persons who were monolingual presented with memory complaints at a younger age- 72.6 y (SD=10) compared to 77.7y (SD=7.9) in those who were bilingual. This main finding suggested that the “onset of the dementia” process was delayed by 5.1 years in those patients who spoke more than one language. In order to see if any differences occurred within the monolingual and bilingual groups that could possibly explain these findings, the investigators conducted further analyses, that looked at the duration of time between symptom onset and “clinic appointment”, immigrant status, years of education, and potential gender effects in both groups.

On average it took approximately 3.5 years for a patient to present to the clinic for a formal evaluation: 3.8y (SD=2.9) for monolingual patients, and 3.1y (SD=1.9) for bilingual patients. However, monolingual patients presented to the clinic at younger ages (76.5y, SD=10.0) than bilingual patients (80.8y, SD=7.7). Neither immigrant status, years of education, or gender were thought to contribute to the main findings.

This study suggests that bilingualism- a cognitively demanding task – may contribute to the “cognitive reserves” of the brain thus enhancing intellectual functioning in advancing age. Most research in this area, has touted the positive effects of intellectual ( i.e. crossword puzzles, playing bridge), physical and social activities as building up “cognitive reserve” and thus promoting overall well being. This study adds to the literature that speaking more than one language can build up “cognitive” reserve which ultimately may delay the onset of Alzheimer’s disease. Further work will require study of a larger group of patients over time to assess how bilingualism may affect the changes seen in cognition that occur in patients with Alzheimer’s disease.

If you would like to read more on this topic please check out the following articles:

Craik F, Bialystok E, Freedman M. Delaying the onset of Alzheimer’s disease- Bilingualism as a form of cognitive reserve. Neurology 2010; 75:1726-1729

Valenzuela MJ, Sachdev P. Brain reserve and dementia: a systematic review. Psychol Med 2006; 36: 441-454

Bialystok E, Craik F, Freedman M. . Bilingualism as a protection against the onset of symptoms of dementia. Neuropsychologia 2007; 45:459-464

Thanks for reading.

Dr. A

ADCS Steering Committee Member
Rush Alzheimer’s Disease Center
Rush Institute for Healthy Aging
Chicago, Illinois
Author: Neelum Aggarwal MD at 11:02 AM 0 Comments

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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.