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Thursday, April 28, 2011

Revised AD Diagnostic Guidelines Published

As most readers of this blog have probably heard, the clinical diagnostic criteria for Alzheimer's disease dementia have been revised, and research guidelines for earlier stages of the disease have been characterized to reflect a deeper understanding of the disorder.

The original criteria published in 1984, were the first to address the disease and focused on the later stages of AD, when symptoms of dementia are emerging. The updated guidelines cover the full spectrum of the disease as it gradually changes over many years. They describe the earliest (1) preclinical stage of the disease, (2) The mild cognitive impairment stage, and (3) The dementia stage of Alzheimer's disease.

The new guidelines were developed by expert panels convened last year by the National Institute on Aging (NIA), part of the NIH, and the Alzheimer's Association, and define AD as follows:

Preclinical — This stage, for which the guidelines only apply in a research setting, describes a phase in which brain changes, including amyloid buildup and other early nerve cell changes, may already be in process. At this point, significant clinical symptoms are not yet evident. In some people, amyloid buildup can be detected with positron emission tomography (PET) scans and cerebrospinal fluid (CSF) analysis, but it is unknown what the risk for progression to Alzheimer’s dementia is for these individuals.

Mild Cognitive Impairment (MCI) — These criteria clarify the diagnosis of MCI in the clinical setting. The MCI stage is marked by symptoms of memory problems, enough to be noticed and measured, but not compromising a person’s independence. People with MCI may or may not progress to Alzheimer's dementia. Currently, biomarkers include proteins in CSF, reduced glucose uptake in the brain as determined by PET, and atrophy of certain areas of the brain as seen with volumetric magnetic resonance imaging (MRI). These tests will be used primarily by researchers, but may be applied in specialized clinical settings to supplement standard clinical tests to help determine possible causes of MCI symptoms.

Alzheimer's Dementia — These criteria apply to the final stage of AD, the stage of the disease most often recognized by doctors and patients. The guidelines expand the concept of Alzheimer's dementia beyond memory loss. A decline in other aspects of cognition, such as word-finding, vision/spatial issues, and impaired reasoning or judgment may be the first symptom to be noticed.

But do these guidelines go far enough? That is, do they have any relevance to the clinic? The answer is yes, most notably for MCI. For one thing, physicians will now be able to more confidently diagnose and classify patients as having MCI based on specific recommended testing. Only about half of people with MCI progress to dementia within five years, while the other half does not progress to more serious symptoms. With a proper review of the patient’s medical history and neurological exam, and this specialized testing, as well as specialized brain imaging such as volumetric MRI, physicians can make a more accurate diagnosis of Alzheimer’s disease that is in the MCI stage. This means that they can reliably identify those MCI patients who are more likely to progress to the dementia stage of Alzheimer’s disease. The other half of MCI patients who do not progress to dementia are, in reality, experiencing memory impairment due to many other causes, including sleep issues, thyroid disease, depression, and medication side effects, among others. The same diagnostic testing described above can help physicians determine if these conditions are causative of the observed memory impairment. This also allows for timely, proper treatment of the true underlying cause of the problem.

What the guidelines also bring with them is a movement in the clinic towards recognizing Alzheimer’s disease earlier in its course, when symptoms may be subtle. This is definitely a big step in the right direction. As specialists increase in number, and technologies become more standardized and prevalent in the community, these guidelines can be implemented to a greater extent and identify patients at risk for developing AD dementia in the future.

Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Director, ADCS
University of California San Diego
Author: Michael Rafii MD,PhD at 12:49 PM 0 Comments

Monday, April 25, 2011

Risk factors and Correlates of Dementia in Older Malaysians

Dear Readers,

Over the last few blog posts I have focused on dementia and Alzheimer’s research from Asia – a region that will experience an exponential increase in the number of persons with dementia over the next 10 years. This month’s post will focus on a report from a large nationwide study of risk factors for dementia in the multiethnic country of Malaysia.

This study used data from the Mental Health and Quality of Life of Older Malaysians project. The goal of this project was to investigate the prevalence of mental health problems, identify the relationship between mental health status and quality of life in older Malaysians. Field work was initiated in 2004, and persons >60 years were invited to participate from all the 13 Malaysian states and the Federal territory of Kuala Lumpur.

Participants completed a variety of questionnaires, that included information regarding age, sex, marital status, self reported health status, employment status (employed versus unemployed), place of residence (urban and rural), educational attainment and ethnicity. Ethnicity categories included Malays, Bumiputeras (indigenous people), Chinese, Indians, and other ethnic groups. Overall mental health status and dementia status was determined using the Geriatric Mental State (GMS) B3 exam. This exam, validated in poorly educated populations from developing countries, was previously used in assessing cognition and determining the prevalence of dementia in an urban sample of elderly Malays.

A total of 2980 community dwelling older Malaysians (1503 women, 1477 men - average age of 70.5 yrs) took part in the study. The prevalence of dementia for the entire sample was 14.3%. The prevalence rate of dementia increased with age, doubling every 10 years, from 9.5% in the 60-69 years age group, to 26.3% in those aged 80 and above.

Women had a higher dementia prevalence rate (24%) compared to men (8.8%), outnumbering men by a 2:1 ratio. The prevalence of dementia was almost two times higher in rural populations than in urban populations. Among the various ethnic groups, the Bumiputeras had the highest prevalence rate of dementia (32.1%), compared to ethnic Malays (14.8%), Chinese (6.3%) followed by Indians (5.8%). Risk of dementia was considerably higher among those with no formal education (24.1%) compared to those with primary (6.8%) or secondary or tertiary education (2.5%).

Of the three health indices (HTN, stroke, self rated health status) higher prevalence rates were noted among respondents with stroke, compared to those without stroke. The prevalence of dementia was correlated with self reported health, increasing from 5% in those reporting “good health” to 33% in those who reported “very poor health.”

This study not only adds to the growing literature regarding the prevalence of dementia in multiethnic populations, but also highlights socio-demographic and health associations among older Malays, that may help to develop strategies to prevent the onset of dementia.

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

Hamid TA, Krishnaswamy S, Abdullah SS, Momtaz YA. Sociodemographic risk Factors and correlates of Dementia in Older Malaysians. Dement Geriatr Cogn Disord 2010: 30: 533-539

Prince M, Acosta D, Chiu H, et al: Effects of education and culture on the validity of the Geriatric Mental State and its AGECAT algorithm. Br J Psychiatry 2004; 185:429-436

Krishnaswamy S, Kadir K, Ali RA, Sidi H, Mathews S: Prevalence of dementia among Malaysians in an urban settlement in Malayisa Neurol J Southeast Asia 1997; 2: 159-162

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 9:30 AM 0 Comments

Thursday, April 21, 2011

Interethnic Differences in Dementia: The Asia-Pacific and Global Perspective

Dear Readers,

Dementia is becoming increasingly recognized in the Asia-Pacific region -- an area that is home to 60% of the world’s population. As life expectancy increases in the region, a series of questions regarding the prevalence of dementia arises. Do the Asia-Pacific rates differ from Western population rates? Within each country in the Asia-Pacific region(especially those with multiethnic populations) do the rates of dementia vary between ethnic groups? These questions were recently addressed in a review paper by Venketasubramanian et al, in the Journal of Dementia and Geriatric Cognitive Disorders.

Globally, the numbers of dementia cases in developed countries is expected to double between 2001 and 2040, however in India, China and other South Asian countries, the numbers are projected to quadruple. Among studies conducted in Asia–Pacific countries, dementia prevalence rates are higher in Japan (11.0%) and Korea (6.3%) compared to other Asian countries- China (2.99%), India (3.77%), Thailand (2.35%), and Taiwan (3.7%).

Interethnic studies within countries from the Asia-Pacific region are few, however a study from Singapore- a multiethnic country comprising 74.2% Chinese, 13.4% Malays, 9.2% Indians and 3.2% other ethnicity- suggest that dementia prevalence was lowest among ethnic Chinese, compared to ethnic Malays and ethnic Indians. These findings were not explained by differences in gender, age or education, and were minimally explained by cardiovascular factors, depression, or leisure activities.

The APOE genotype is a well established risk factor for Alzheimer’s disease, and appears to play a role in explaining some of the ethnic differences in dementia prevalence in Asian populations. APOE e4 and e2 both appear to be low in ethnic Indians, whereas Malays have been reported to show the highest frequency of the e4 allele. The role of genetic studies, specifically genome wide association studies (GWAS), may help to detect the biologic basis for population specific differences in disease.

This article highlights the growth projections of dementia prevalence in the countries that comprise the Asia-Pacific region, while also providing important information on possible interethnic differences that could be useful in developing targeted interventions for dementia prevention.

Here are 3 articles you can refer to, to learn more about this research paper and other related papers.

Venketasubramanian N, Sahadevan S, Kua E.H. et al: Interethnic Differences in Dementia Epidemiology: Global and Asia-Pacific Perspectives. Dement Geriatr Cogn Dis 2010: 30-492-498.

Kalaria RN, Maestre GE, Arizaga R et al. World Federation of Neurology Dementia Research Group: Alzheimer’s disease and vascular dementia in developing countries: prevalence, management, and risk factors. Lancet Neurol 2008; 7:812-826.

Ng TP, Leong T, Chiam PC et al. Ethnic variations in dementia: the contributions of cardiovascular, psychosocial and neuropsychological factors. Dement Geriatr Cogn Disord 2010: 29 131-138

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 9:12 AM 0 Comments

Wednesday, April 20, 2011

New Study Shows that Beta-Amyloid Leads to Other Changes in AD Brain

Dear Readers,

Researchers led by Dennis Selkoe of Harvard Medical School, who is one of the principle architects of the amyloid theory of Alzheimer's disease, have provided the clearest results thus far that the protein beta-amyloid leads to the abnormalities seen inside brain cells of patients with AD, including those neurofibrillary tangles and hyperphosphosphorylated tau so often mentioned in the same breath as beta-amyloid plaques.

Using extracts purified directly from the brains of Alzheimer’s disease patients, the researchers found that beta-amyloid dimers (pairs of beta-amyloid protein)—applied to cultured neurons at physiological concentrations—trigger tau hyperphosphorylation and neuritic degeneration, two of the key hallmarks of AD. This damage occured in the absence of beta-amyloid plaques, which are thought to be deposits of such dimers in the brain that occur year after the dimers have been floating around wreaking havoc in the brain. In this study, dimers from the human brain appear to have a conformation that is highly potent in inducing damaging neuronal changes and lead to collapse of the cytoskeleton, the scaffolding that maintains brain cell structure and is held together by the protein tau. Of course, this does not let plaques off the hook. Indeed, the presence of dimers within amyloid plaques suggests that plaques serve as local reservoirs of toxic dimer that can diffuse away from them and cause surrounding brain cell injury as well.

The study provides further evidence that there is a cascade in which beta-amyloid proteins bind to one-another and form pairs, or dimers, which are then toxic to brain cells. Readers of this blog will recall that last year I wrote about the discovery that beta-amyloid activates a protein inside brain cells called 'Fyn', which then leads to abnormalities in the protein tau, and subsequent brain cell injury. This current paper uses actual beta-amyloid dimers from patients with AD and demonstrates that the damage is clearly mediated by them.

An even more interesting result from this study is that by using antibodies against the beta-amyloid dimers, the researchers were able to prevent their negative effects. In fact, by comparing various antibodies, they showed that those antibodies that block the "head" of the beta-amyloid protein, as opposed to "tail", were much more potent in blocking its negative effects. Bapineuzumab is one such antibody that is currently being tested in a phase 3 clinical trial in patients with AD.

This paper is in agreement with the growing body of evidence that beta-amyloid is the main culprit in AD, and that it directly leads to the other changes seen in the brains of patients with the disease.

The next challenge will be figuring out what beta-amyloid dimers bind to on brain cells. Many candidates exist, including receptors. By identifying such receptors, we may be able to develop antagonists, or blockers, that would prevent beta-amyloid from exerting its deleterious effects on brain cells.

*Jin M, Shepardson N, Yang T, Walsh D, Selkoe DJ. Soluble amyloid-beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. PNAS. March 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 11:46 AM 0 Comments

Wednesday, April 13, 2011

Does Multi-Tasking Impair Memory? Maybe So.

Dear Readers,

As you will recall, we use the term “dementia” to describe cogntive impairment which is severe enough that it leads to loss of normal daily functioning. We use the term “mild cognitive impairment” (MCI) to describe more subtle symptoms that may represent “predementia” Alzheimer’s. However, only about half of people with MCI progress to dementia within five years, while the other half does not progress. Proper neurological evaluation, specialized testing, such as blood tests and volumetric brain imaging, reliably identify those MCI patients who are more likely to progress to the dementia stage of Alzheimer’s.

Patients with MCI have a memory complaint and, on specific testing, show memory problems that are more serious than would be expected as part of normal aging. However, half of MCI patients are experiencing memory impairment due to myriad causes, including sleep problems, thyroid disease, depression, and medication side effects and not Alzheimer's.

Well, we now have evidence for another possible cause of MCI - too much mulitasking.

In a recent paper published in the Proceedings of the National Academy of Sciences, subjects were asked to look at a scene, then were interrupted for several seconds by an image of a person’s face. They were asked to identify the person’s gender and approximate age, and then returned to answer questions about the earlier scene. Older subjects found it much harder to disengage from the interruption and reestablish contact with the scene.

The study, in addition to standard neuropsychological assessment, used functional magnetic resonance imaging (fMRI) to look at the neural mechanisms involved. The scans showed differences in the brains of younger people and older people following an interruption; in the younger subjects, the brain areas that had been engaged during interruption ceased to be engaged more quickly, but in the older subjects, those areas continued to remain stimulated.

Even though the study did not specifically look at interruptions from cellphones, text messages, emails, phone calls, or faxes, the constant barrage of information into our brains may very well have a similar an impact on our attention, which is inextricably linked to our ability to remember important experiences.

Deficit in Switching Between Functional Brain Networks Underlies the Impact of Multitasking on Working Memory in Older Adults, Clapp et al, PNAS 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 9:53 AM 0 Comments

Wednesday, April 06, 2011

What Does the Identification of New Genes Related to AD Mean for Research?

Dear Readers,

This week, two groups reported in the journal Nature Genetics that they had identified five new genes linked to an increased risk of late-onset Alzheimer's — doubling the total number of genes known to contribute to the risk of the neurological disorder. Researchers are particularly excited by the discoveries, because they further implicate biological pathways — such as inflammation, cholesterol and cell transport systems — that have been suspected to play a role in Alzheimer's, but had never been confirmed to do so.

Each gene individually adds to the risk of having this common form of dementia later in life. These new genes offer a portal into what causes Alzheimer’s disease. The study, conducted by the Alzheimer’s Disease Genetics Consortium, reports genetic analysis of more than 11,000 people with Alzheimer’s disease and a nearly equal number of elderly people who have no symptoms of dementia. Three other consortia contributed confirming data from additional people, bringing the total number of people analyzed to over 54,000. The consortium also contributed to the identification of a fifth gene reported by other groups of investigators from the United States, the United Kingdom, France, and other European countries.

Until recently, only four genes associated with late-onset Alzheimer's had been confirmed, with the gene for apolipoprotein E-e4, also called APOE4, having the largest effect on risk. The Nature Genetics studies add another five -- MS4A, CD2AP, CD33, ABCA7, and EPHA1, thereby doubling the number of genes known to contribute Alzheimer's disease. Each of the new susceptibility genes is associated with a small increase in risk for the AD, of about 10-12 percent. As discussed in prior blogs, ApoE4, is believed to increase risk of AD by two- to fourfold if one copy is inherited, and by up to 15-fold when two copies are present. The ApoE4 allele is found in approximately 15 percent of the population and more than half of clinically diagnosed Alzheimer’s patients.

Will such genes be tested as part of the routine evaluation of patients with memory concerns? Probably not. But, the genes, and the proteins that they encode, as well as the functions of these proteins will be carefully studied, so that we may better understand how the disease develops, and perhaps identify targets for therapy.

These papers are both the result of massive scientific efforts, and such collaborations will undoubtedly continue to make major contributions to our understanding of complex diseases such as AD.

Naj et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nature Genetics online. 2011, April 3.

Hollingworth et al. Common variants at ABCA7, MS4A6A/ MS4A6E, EPHA1, CD33, and CD2AP are associated with Alzheimer’s disease. Nature Genetics online. 2011, April 3.

Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Director, ADCS
University of California San Diego
Author: Michael Rafii MD,PhD at 10:57 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.