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Tuesday, May 31, 2011

Dementia in Puerto Rican Veterans

Dear Readers,

I recently attended the Chicago Latino Film Festival and viewed the documentary screening of "One Day Less" - a story of an elderly Mexican couple waiting for their children to visit them for the holidays at home in Acapulco. Amid the bickering between them, it became clear that their overall health and the wife's memory was declining. As I listened to the commentary after the film regarding the story line, I couldn't help but notice how the memory issues, and changes in behavior exhibited by the wife in this film, were not mentioned or discussed as being "not quite right" by the audience. When I talked to one of the film monitor's after the session and noted that the film did a very good job of depicting how memory issues are consistent with Alzheimer's disease, and can present in everyday life he said, "Oh yes, I agree. My grandmother who lived in Puerto Rico, did and said the same things like the woman in the film-- but she only had dementia."

So, as I left the theater, I wondered, what is the latest data we have regarding dementia (or its subtypes including Alzheimer's disease) in the U.S. Hispanic community? We know that of the 35.3 million Hispanics in the U.S. (based on the Census 2000), it is estimated that by 2050, Hispanics will account for 24.3% of the U.S. population and, of those - 13.4 million will be 65 years or older.

A recent study from the Veteran's Administration, investigated the prevalence of dementia in the second largest group of U.S. Hispanics-the Puerto Rican population. (3.8 million who are on the island, another 3.4 million who live on the mainland). The study also compared the prevalence of dementia between Puerto Rican veterans to all Veterans Affairs Medical Center (VAMC) system users. Diagnostic data were obtained from the Decision Support Service of the VA Caribbean Healthcare System (VACHS) in San Juan, Puerto Rico. All Puerto Rican veterans aged 65 years and older who used the VACHS healthcare facilities from October 2005 to March 2007 were included. Veterans were considered to have a diagnosis of dementia if they had one or more dementia codes as listed by the International Classification of Diseases. Of the more than 35,0000 patients of the VACHS, 12.6% were diagnosed with some type of dementia ( including Alzheimer's disease and Vascular dementia). Between the two groups, (VACHS and the VAMC) cases of dementia subtypes were almost identical between the two samples, with the exception that the percentage of vascular dementia cases were higher in the VACHS than in the VAMC system (15.1% vs. 11.9%).

Further, the prevalence rates of all dementia cases in each age group in the VACHS and VAMC systems showed that the VACHS rates were higher - with Puerto Rican veterans having between 45%-54% greater probability of being diagnosed with dementia than veterans in the VAMC systems. In addition, Puerto Rican veterans also had a significantly higher prevalence of reported diabetes mellitus, hypertension and cardiovascular disease than mainland veterans.

To learn more about this study or the latest research on dementia in elderly Puerto Ricans, please refer to:

Carrión-Baralt JR, Suárez-Pérez E, del Rio R et al. Prevalence of dementia in Puerto Rican veterans is higher than in mainland U.S. veterans. J Am Geriatr Soc. 2010 58(4):798-9.

Krishnan LL, Petersen NJ, Snow AL et al. Prevalence of dementia among Veterans Affairs medical care system users. Dement Geriatr Cogn Disord 2005; 20: 245-253

Ferri CP, Prince M, Brayne C et al. Global prevalence of dementia: A Delphi Consensus study. Lancet 2005; 366:2112-2117

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 10:34 AM 0 Comments

Wednesday, May 25, 2011

Beta-amyloid and Prion Proteins

A prion is an infectious agent composed of protein in a misfolded form. The word prion was coined in 1982 by Dr. Stanley B. Prusiner, and is derived from the words protein and infection. Normal prion proteins are produced naturally in the brain, but can cause disease when they come into contact with an infectious form of the protein that folds into an unusual conformation. These infectious prions convert innocuous prion proteins into the infectious form, which forms clumps and leads to neurodegenerative diseases, such as variant Creutzfeldt-Jakob disease, the human form of mad cow disease.

In 2009, researchers led by Dr. Stephen Strittmatter at Yale, showed that prion proteins produced naturally in the brain interact with the amyloid-ß peptides that are hallmarks of Alzheimer's disease. Blocking this interaction in preparations made from mouse brains halted some neurological defects caused by the accumulation of amyloid-ß peptide.

Now, researchers in Ireland have produced evidence that cellular prion protein mediates Aß’s toxic effects on synapses. In this week’s Journal of Neuroscience, Dr. Michael Rowan and colleagues at Trinity College Dublin report that blocking the Aß-binding domain of the prion protein keeps Aß from disrupting synaptic plasticity. They show it by delivering Alzheimer patient-derived Aß into the brains of live rats.

The researchers demonstrated disruption of Long Term Potentiation (LTP), the physiological basis for synaptic strengthening and memory, by injection of soluble extracts from an AD patient brain into the hippocampus of anesthetized rats. Importantly, they achieved the LTP effects with Aß doses that did not affect other measures of synaptic function, such as baseline transmission.

Further experiments confirmed that Aß and its interaction with Prion protein are required for the LTP inhibition. Potentiation occurred just fine when antibodies were used to pre-clear Aß from the injected AD brain material. Injections of antibody fragments specific for Prion protein's Aß-binding region also normalized LTP in the rat hippocampus; antibody fragments recognizing a different Prion protein region did not.

Additional experiments are on going to further understand the relationship between Prion proteins and Beta-amyloid.

Barry AE, Klyubin I, Mc Donald JM, Mably AJ, Farrell MA, Scott M, Walsh DM, Rowan MJ. Alzheimer’s disease brain-derived amyloid-beta-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein. J. Neurosci. 18 May 2011;31(20):7259-7263.

Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Director, ADCS
University of California San Diego
Author: Michael Rafii MD,PhD at 1:33 PM 0 Comments

Monday, May 16, 2011

Body Mass Index and Cognitive Function among China's Oldest Old

Dear Readers,

As the month of May is Asian Pacific American Heritage Month, I have been asked to attend many health related events serving the diverse Asian community. At the last event I attended, I was asked about cognitive research involving the "oldest old"- persons over the age of 90 years. Specific questions asked of me were centered on two themes: "What characteristics of this aged group keep them healthy, and what leads to cognitive decline?" This month’s post will focus on a report from a community based study from the Sichuan province in southwest China.

This study used data from the Project of Longevity and Aging in Dujiangyan(PLAD). The goal of PLAD was to study the relationship between environment, lifestyle, genetics and cognitive function in older aged adults. Participants completed a variety of questionnaires, that included information regarding age, sex, self reported health status, educational attainment, and "habits" that included, smoking, alcohol, tea consumption and exercise. Cognitive status was assessed using the Minimental Status Examination (MMSE).

BMI was calculated using standard protocols (kg/m2), and cutoff were based on WHO Asian population criteria. Thus, four categories were noted: underweight(<18.5), normal weight (18.5-23.0), overweight (23.0-27.5) and obesity (>=27.5). Because association changes in body composition with advancing age have been noted, cutoffs were also adjusted based on quartiles: 1st ( <16.6), 2nd (16.6-18.9), 3rd (18.9-21.1) and 4th (>21.1).

Of the 870 community participants, a total of 638 community dwelling elders(427 women, 211 males) had complete data and took part in the study. The mean age was 93.36 years, and 64 participants were centenarians and 427 were women. The mean MMSE was 15.57 (SD: 5.41), with 35 volunteers scoring higher than a 24 on the MMSE. The prevalence of dementia was 54.%, with higher prevalence rates among women (67.4% compared to men 39.0%).

The prevalence of dementia was associated with higher cholesterol levels and lower tea consumption. Average BMI measurements were 19.05 (SD: 3.65), with 45.5 % of the sample characterized as underweight, and 9.4% and 1.7% characterized as overweight and obese.

Characterizing BMI using the widely recognized cutoff points, revealed no differences in MMSE scores across groups or differences in the prevalence of dementia. Characterizing BMI by quartile cutoffs revealed significant differences in MMSE scores and prevalence of dementia. Those in the 3rd quartile- (18.9-21.1) had the highest MMSE scores and lowest prevalence of dementia.

This study not only adds to the growing literature regarding the prevalence of dementia in Asian populations, but begins to shed light on characteristics for poorer cognitive function and dementia in the "oldest old" populations. Limitations of this study include its cross sectional design and the use of the MMSE as the only cognitive test used to ascertain cognition and dementia status.

Here are 3 articles you can refer to, to learn about this particular study or the latest research on dementia in the "oldest old".

Zhou Y, Flaherty JH, Huang CQ et al. Association between Body Mass Index and Cognitive Function among Chinese Nonagenarians/Centenarians Dement Geriatr Cogn Disord 2010: 30: 517-524

Huang CQ, Dong BR, Zhang YL et al. Association of moderate or severe dementia with smoking, alcohol consumption, tea consumption, and exercise among Chinese nonagenarians/centenarians. Cogn Behav Neurol 2009; 22: 190-196

Huang CQ, Dong BR, Zhang YL et al. Moderate or severe dementia and hypertension among Chinese nonagenarians and centenarians. Hypertens Res 2009; 32: 554-558

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 8:28 AM 0 Comments

Thursday, May 12, 2011

A Potential Blood Test for Alzheimer's Disease

Oxidation and free radical damage are natural occurrences as our bodies are subjected to toxins and stressors from everything we encounter throughout our lifespan. When oxidation occurs, our bodies respond in the best way they know how: they reach for protective resources from within our cells to combat the damage and maintain our health. If these resources are unavailable, inflammation will occur. The processes of oxidation, free radical production, and cell damage are thought to be involved in cancer, heart disease, Alzheimer's disease, and even aging itself. Inflammation is also known to be part of many disorders as well.

In a recent study that was published last week in the Journal of Alzheimer's Disease, researchers induced oxidation in blood samples from Alzheimer’s patients and found that it was lower in a natural steroid called dehydroepiandrosterone (DHEA) as compared to healthy people. DHEA is a hormone produced naturally in the adrenal glands. The body then converts it into the hormones estrogen and testosterone. DHEA helps the brain work and protects it from damage and interestingly, the level of DHEA in the body peaks between ages 20 and 30 and then decreases progressively with age. This difference in DHEA levels observed in the present study between Alzheimer’s patients and healthy people means that a simple blood test could potentially be used to help diagnose the disease.

In blood taken from healthy people, oxidation led to a 53 percent increase in DHEA. However, when the test was repeated on blood from people with Alzheimer’s, there was a much smaller increase in DHEA - around 14 percent for people with mild Alzheimer’s, and just 4 percent for severe Alzheimer’s.

The researchers hypothesize that in people with Alzheimer’s, the brain has used up the chemicals needed to produce DHEA in an effort to protect the brain. So, when treated in a lab, blood from healthy people can produce more DHEA, but not blood from Alzheimer’s patients.

The study looked at just 86 people. It’s not clear yet exactly how reliable the test would be in practice. The differences in DHEA between healthy people and those with the early stages of Alzheimer’s may not be big enough for the test to accurately identify Alzheimer’s until the more advanced stages, which would limit its usefulness.
There were also signs that the test could give different results for men and women, although it is difficult to say with the relatively small number of people in the study.

This paper raises the possibility of a new simple blood test for Alzheimer’s that could be used alongside the current methods of diagnosis, which include a medical history, neuroimaging and tests of memory. Certainly, the results of this paper will need to be validated on a larger sample of subjects, but the findings are quite encouraging.

G. Rammouz, L. Lecanu, P. Aisen, V.Papadopoulos, A Lead Study on Oxidative Stress-Mediated Dehydroepiandrosterone Formation in Serum: The Biochemical Basis for a Diagnosis of Alzheimer's Disease, Journal of Alzheimer's Disease, May 4th, 2011.

Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Director, ADCS
University of California San Diego
Author: Michael Rafii MD,PhD at 9:57 AM 0 Comments

Wednesday, May 04, 2011

The Relationship Between HSV Infection and AD

New studies further indicate that HSV-1, the virus that causes the common 'cold sore' or oral herpes, may be a contributing factor in the development of Alzheimer’s disease. The research team was led by Elaine Bearer, MD, PhD from the University of New Mexico School of Medicine, and included colleagues at Brown University, and House Ear Institute in Los Angeles. A possible link between HSV-1 and AD was first reported in 1979, and over the last 30 years, there has been evidence mounting that HSV1 may play a role in AD.

The researchers tagged the herpes virus inside cells with a green fluorescent protein and watched the virus particles emerge from infected cells via video imaging. These newly produced viruses exit the cell nucleus and then bud into cellular membranes containing amyloid precursor protein (APP). The findings, published in the presitgious journal PLoS ONE, indicate that this APP-covered membrane surrounding the virus facilitates its transport out of infected cells. APP, iin essence, provides mobility to the HSV1 virus, inside neurons, and delivers viral particles to the surface.

This interaction between viral particles and APP also results in changes in cellular architecture and the distribution of APP itself, which is the precursor to beta-amyloid, the major component of senile plaques found in the brains of Alzheimer's disease patients. APP becomes mis-localized in HSV1 infected cells, and this may lead to beta-amyloid production.

In 2008, Professor Ruth Itzhaki and colleagues found DNA evidence of HSV1 in 90% of plaques in Alzheimer's disease patients' brains. That same year, Canadian researchers Luc Letenneur and colleagues demonstrated a dramatic increase in antibodies directed against HSV1 in Alzheimer’s patients compared to age-matched individuals without the disease. Moreover, in the presence of APOE4, HSV-1 appears to be particularly damaging to the nervous system and increases one’s risk of developing Alzheimer’s disease.

Why such interest in HSV1? Herpes Simplex Encephalopathy (HSE) is a rare but very severe acute infection of the brain. Although it has a very different course from AD, it leads to the occurrence of bilateral hippocampal-medial temporal lobe lesions resulting in profound verbal memory loss, characteristic of AD. This is the same area of the brain where AD first develops. The thought has been, could HSV1 infection possibly produce a milder and chronic brain disease which selectively damages the very same brain areas and lead to AD?

In developed countries such as the U.S., approximately 20 percent of children are infected with HSV1 prior to the age of five. By the second and third decades of life, as much as 60 percent of the population is infected, and late-in-life infection rate reaches 85 percent. These prevalence rates could explain the ubiquity of AD in old age.

Symptoms of primary HSV1 infection include painful blisters of the mouth, lips or eyes. After infection, HSV1 persists in nerve cells by becoming latent. Upon re-awakening, new viral particles are made in the neuron and then travel back out its pathways to re-infect the mucous membrane. Many infected people experience sporadic episodes of viral outbreaks as the well-known recurrent cold sore. It is yet to be determined if re-activation contributes to AD, or is it the chronic, latent, infection that causes more damage.

More studies will also be needed to better understand the effect of anti-viral medications on disease progression, and to elucidate the manner in which HSV1 directly increases beta-amyloid in the brain.

Shi-Bin Cheng, Paulette Ferland, Paul Webster, Elaine L. Bearer. Herpes Simplex Virus Dances with Amyloid Precursor Protein while Exiting the Cell. PLoS ONE, 2011; 6 (3): e17966

Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Director, ADCS
University of California San Diego
Author: Michael Rafii MD,PhD at 12:57 PM 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.