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Wednesday, March 30, 2011

MR Study Shows That Amyloid Deposits Occur Years Before Diagnosis


High-resolution magnetic resonance (MR)imaging studies have identified characteristic changes in brain structure -- thinning of key cortical regions and reduced volume of structures such as the hippocampus -- in persons with mild cognitive impairment, in individuals known to carry gene mutations that directly cause Alzheimer's disease and in diagnosed Alzheimer's patients.

The current study, published in the Annals of Neurology, involved 87 cognitively normal older individuals and 32 patients diagnosed with mild Alzheimer's -- matched for age, gender and education -- who had enrolled in the long-term Harvard Aging Brain Study. Participants underwent both high-resolution MR imaging of brain structure and PET scanning with PiB to detect amyloid plaques.

The results showed that those cognitively normal individuals who had amyloid plaques also had structural changes similar to but less pronounced than the neurodegenerative changes seen in the symptomatic patients. Structural changes were most evident in areas comprising what is called the default network, which is known to be affected early in the course of Alzheimer's disease.

The study was well conducted, well controlled and used the latest techniques in brain imaging. This paper provides further evidence that amyloid deposition is occuring in the brain decades before the dementia stage begins, and in fact, even before cognitive impairment develops. It also supports the idea that the mechanism by which cognitive impairment and dementia arise is due to atrophy, or shrinkage, of the brain in selected areas as a consequence of beta-amyloid deposition.

Becker et al, Beta-amyloid associated coretical thinning in Clinically Normal Elderly. Annals of Neurology, 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 10:46 AM 0 Comments

Monday, March 28, 2011

Depression, APOE e4, and the Risk of Dementia in Older Koreans

Dear Readers,

In a recent post this month, I focused on a study from Korea that examined whether the cardiovascular risk factors had similar effects on dementia risk in the Korean population as compared to Western populations. In this blogpost I discuss the latest data from Korea that examined the association of APOE e4 and depression to incident (development of ) dementia in elderly Koreans.

This study used data from the 10/66 International Dementia Research Program in Developing Countries. All persons aged 65 or older from two geographic areas in Gwangiu, South Korea were asked to participate in this study with follow up examinations occurring two years later.

Participants completed a variety of questionnaires that included: (1) 30 questions from Korean Geriatric Depression scale ( including supplemental items from the Geriatric Depression Scale, Beck Depression Inventory, and the Center for Epidemiologic Studies Depression Scale (2) a review of alcohol history, physical activity, disability, vascular risk factors and measured obesity (BMI>25 kg/m2) (3) cognitive assessment testing (Mini-mental state examination, the Clinical dementia rating (CDR) scale, Instrument Activities of Daily living scale) and (4) APOE e4 genotyping.

A diagnosis of dementia was determined using standard criteria for dementia, Alzheimer's Disease (AD) and vascular dementia (VaD) by committee. The diagnosis of clinical depression was determined by utilizing validated cutoff scores (against psychiatric diagnoses specific for the Korean population).

Of the initial 732 participants, 518 (83%) completed all evaluations at follow up with 45 participants developing dementia (34 with AD, 7 with VaD and 4 with "other dementia") over a two year period. APOE e4 and baseline depression were significantly associated with the incident dementia. When other factors were added to the models, the association between APOE 4 and dementia were unchanged, whereas the association of depression and dementia was no longer significant. Persons with a +APOE e4 genotype / + depression had a 9 fold increased risk of developing dementia compared to those with -APOE e4 genotype/- depression. When other factors were added to this model, the associations were weakened but still remained significant. Gender differences were noted, in that, men had approximately a 4x higher risk of developing dementia if they were classified as +APOE e4 /+depression compared to + APOE e4/+ depression women.

This study adds to the few population based studies from Asia, that have examined the association of depression and APOE e4 to the development of dementia. The gender differences noted for risk of dementia are interesting, yet it is unclear as to the possible biological mechanisms underlying these findings. Nevertheless, this study supports findings from Western studies regarding the role of depression and APOEe4 to increased risk of dementia, and suggests that perhaps treating a potentially modifiable risk factor such as depression could modify this relationship and delay the development of dementia.

Here are 3 articles you can refer to, to learn about this particular study or the latest research on APOE4, depression and dementia in the Korean population:

Kim JM, Kim SY, Bae KY et al. Apolipoprotein E4 Genotype and Depressive Symptoms as Risk factors for Dementia in an Older Korean Population. Psychiatry Investig 2010;7:135-140

Prince M, Acosta D, Chiu H et al. 10/66 Dementia Research Group: Dementia diagnosis in developing countries: A cross cultural validation study. Lancet 2003; 361: 909-917

Kim JM, Stewart R, Kim SW et al. Interactions between life stressor and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders. Biol Psychiatry 2007; 62:423-428

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 10:28 AM 0 Comments

Wednesday, March 23, 2011

UK Extends Approved AD Drugs to Early AD Patients

There is news from the United Kingdom today, where their governing health authority has extended coverage of approved drugs for Alzheimer's patients in earlier stages of the disease. New guidance from the National Institute for Health and Clinical Excellence (NICE) comes into effect today, marking a significant change to an earlier 2007 ruling which restricted access to medication for patients with moderate disease only. Authorities cited "better evidence" about treatment efficacy as the key motivator for the decision.

This change encourages the early detection and proactive management of Alzheimer's disease to minimize the burden of the condition on patients, their caregivers and society. In addition, the need for greater access to dementia-specific treatments is in line with the recent Alzheimer's Disease International report which calls for governments to make AD a higher health priority, to help tackle the huge burden of the disease.

Clinical trials have continued to show the positive effects of currently approved drugs and have reduced the uncertainty about their clinical effectiveness. We also have more information about the costs of living with and treating the disease, as it progresses through its mild, moderate and severe stages.

Clearly, there is a shift in the medical field towards earlier diagnosis and treatment of Alzheimer's disease. With new discoveries in the biology of AD, and ongoing clinical trials being conducted using our latest understanding, we hope to soon be able to diagnose and treat this disease at its earliest stage, where we have the greatest chance of slowing its progression.

Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Director, ADCS
University of California San Diego
Author: Michael Rafii MD, PhD at 1:34 PM 0 Comments

Thursday, March 17, 2011

CTAD Now Accepting Abstracts

Dear Readers,

Thr 4th annual scientific conference on Clinical Trials in Alzheimer's Disease (CTAD) is taking place in San Diego in November of this year. For those of you are interested CTAD is now open for registration and are also accepting abrstracts from the scientific community. This conference will provide CMEs through the University of California San Diego. Exactly how many CMEs will be provided will be posted soon.

Topics that will be addressed:

Promote the discovery of early markers in asymptomatic people at risk for dementia

Explore new therapeutic targets for disease modification or prevention

Identify new outcome measures for efficacy of disease modifying treatments

Harmonization of multinational, multicenter large-scale prevention trials

Recruitment and compliance of asymptomatic subject/volunteers for prevention trials

International regulatory issues

Designing primary prevention trials using biomarkers

CSF biomarkers

Cognitive assessments and new generation of cognitive assessment tools

AD criteria

Neuroimaging biomarkers

Plasma biomarkers

Health Economics

Quality of Life

For more information visit
Author: Jeffree Itrich at 11:03 AM 0 Comments

Wednesday, March 16, 2011

Studies Reveal Very Early Cognitive Declines

Last month researchers Francisco Lopera and colleagues reported in the journal Lancet Neurology that they were able to capture a clear decline in cognition starting in people’s early thirties in the largest-known population with autosomal-dominant(inherited)Alzheimer’s disease. They define an earlier disease stage prior to what is called pre-MCI, in effect pushing the line of detectability back toward younger ages by some four years.

Two other papers go in the same direction. Last year in the journal Brain, Mario Parra and colleagues published a new test that appears to detect a specific visual memory deficit perhaps even earlier, at ages when mutation carriers perform as well as controls on standard neuropsychometric tests. And in last December’s Annals of Neurology, Yakeel Quiroz and colleagues report the first of what is expected to be a wave of preclinical brain imaging findings. Carriers in their thirties, while still performing the memory test at hand as well as non-carriers, push their hippocampus harder to achieve that parity.

Together, these three papers push back the preclinical phase of AD that is detected by neuropsychology and imaging. They characterize the 20 to 15 years prior to symptoms of dementia.

Each of the previous familial AD studies was small. In this paper by Lopera and colleagues, the Colombian scientists retrospectively analyzed descendents of the largest-known cohort of autosomal-dominant AD, including 1,784 patients age 17 to 70 who came to Lopera for treatment and research between 1995 and 2010. This study is by far the biggest study of its kind. Four hundred forty-nine people carried the mutation. Four hundred ninety-nine non-carriers served to establish normal parameters on the battery of cognitive tests that the scientists administered to the participants at follow-ups every other year where possible. The studies are helping us get a better sense of the continuum of Alzheimer's disease, from its asymptomatic stage into the mild cognitive impairment /prodromal stage, followed by the well characterized mild, moderate and severe dementia stage.

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

Thursday, March 10, 2011

Vascular Risk Factors and Dementia in Korean Adults

Dear Readers,

I recently attended an event hosted by the American Heart Association and Go Red Chicago, where a panel of physicians and healthcare providers discussed the effect of diet, hormones and cardiovascular risk factors on the heart and brain. The physicians also touched on emerging data that suggest there may be racial/ethnic differences in the prevalence and effects of cardiovascular risk factors to the development of heart disease and brain functioning in these diverse populations. Thus, I was very interested in reading the following article from Korea that examined the effects of vascular risk factors in mid and late life to dementia risk.

The initial study population included over one million persons aged 30-95 years who participated in at least one biennial National Health Insurance Corporation (NHIC) medical evaluation between 1992 and 1995. The NHIC provides health insurance to government employees, teachers and their dependents and it was estimated that at the time of this study, approximately 11% of the Korean population was insured by this organization. Persons were excluded from the study if they reported having cardiovascular disease, cancer, liver disease prior to their initial visit, or if they had missing data on any study variables. Thus the final sample size for this study was 848,505 participants, aged 40 years or older, followed for up to 14 years.

As is typical with many studies focusing on cardiovascular disease, questions regarding history of cigarette use and alcohol consumption were obtained along with height, weight (for body mass index calculations) and blood pressure. Fasting blood samples were obtained for both serum glucose and serum cholesterol. The specific criteria for hypertension were a systolic blood pressure of at least 140 mmHg or a diastolic blood pressure of at least 90 mmHg. Cholesterol was characterized as "desirable" if the serum cholesterol was 200 mg/dl, "borderline high" if it was between 200-239 mm/dl, and "high” if it was greater or equal to 240 mg/dl. Diabetes was defined as a fasting serum glucose level of 126 mg/dl or higher.

As this was a large sample of persons evaluated in clinical hospitals, the main variable of interest was a dementia diagnosis. For these analyses, the dementia categories included Alzheimer's dementia (AD), Vascular dementia (VaD), and "unspecified" dementia.

Of the 848,505 persons who were evaluated at the baseline examination, there were 358,060 women (age at baseline 53.6 yrs) and 490,445 men (age at baseline 51.9 yrs). The entire population had a low level of body mass index. Both cigarette smoking and alcohol consumption were more common in men compared to women. During the 14 years of follow up, 3,252 persons were hospitalized for issues related to dementia; the majority of those dementias were listed as AD. Increasing dementia incidence of AD was noted as age increased, peaking at the ages of 75-80 years, then decreasing at older ages.

In both women and men, diabetes was associated with all types of dementia, and appeared to be higher for VaD than AD in women. Hypertension (HTN) was also associated with all dementias; strongly associated with VaD in men, but did not appear to be associated with AD in women. In both groups total cholesterol was not associated with dementia.

Further analyses were conducted measuring the impact of vascular risk factors measured in midlife (<65 years old) compared to later (>65 years old). Diabetes appeared to be associated with AD in both the younger and older age groups for men, whereas smoking was associated with AD in midaged men (< 65 years) compared to older men (> 65 years). HTN had a strong association with VaD in both men and women before and after 65 years old. There were no notable interaction effects between HTN and diabetes on the risk of dementia for either gender.

This study in the Korean population supports data from Western population studies, suggesting that diabetes and HTN are important risk factors for the development of both AD and VaD. Further, this large study also suggests that vascular risk factors in midlife appear to have a higher risk for dementia development as compared to later risk factors. One limitation of the study, as noted by the authors, was the relatively high rate of "unspecified dementia cases" (36% for men, 39% for women) which could affect the strength of these associations. Nevertheless, this study provides support that there is an increased risk of dementia associated with these factors in this Asian population, and highlights the need for aggressive vascular risk reduction treatment as a dementia prevention method.

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 10:37 AM 0 Comments

Wednesday, March 09, 2011

The Liver and Alzheimer's


Two recent papers have shed light on the role of the liver in modulating beta-amyloid levels in the brain, and potentially the course of Alzheimer's disease.

First, researchers at the University of California, Irvine discovered that markedly depleted amounts of an omega-3 fatty acid in brain tissue samples from Alzheimer's patients may be due to the liver's inability to produce the complex fat. Low levels of docosahexaenoic acid, or DHA, have been associated with AD, but no cause had been identified. In postmortem liver tissue from Alzheimer's patients, the UCI team found a defect in the organ's ability to make DHA from shorter molecules present in leafy plants and other foods. Previous studies have shown that most brain DHA is manufactured in the liver. Additionally, they found that the greater the amount of Alzheimer's-related cognitive problems experienced in life by the patients, the lower were their liver DHA levels.

Secondly, researchers from the Scripps Institute in La Jolla, compared two strains of mice that were genetically engineered to develop Alzheimer's disease. Earlier work had found that one strain was protected against the buildup of beta amyloid in the brain, compared with the other. The research team identified three genes that could confer such protection. They showed that cells in the liver of the protected mice did not express, or turn on, these genes, as much as liver cells of the other mice. Further, they found this lower level of expression protected against accumulation of beta amyloid in the brain. One of these genes, called Presenilin 2, is involved in the production of beta amyloid, and has been linked to early onset Alzheimer's disease in humans. But previous work had focused on expression of this gene in the brain, not other tissues that produce beta amyloid.

The researchers wanted to give the mice a drug that would reduce levels of beta amyloid in only the blood. They chose the drug Gleevec (which is used to treat leaukema) because it cannot cross the blood-brain barrier. Gleevec had previously been shown to reduce the amount of beta amyloid in the brain when pumped into the brain, but researchers had not yet looked for this effect after injecting it into the bloodstream. They found that administering Gleevec for a week reduced the amount of beta amyloid in the brain by 50 percent, even though the drug cannot get into the brain. Thereby, raising the possibility that by lowering beta-amyloid in the liver, we may be able to lower it in the brain as well.

Giuseppe Astarita, Kwang-Mook Jung, Nicole C. Berchtold, Vinh Q. Nguyen, Daniel L. Gillen, Elizabeth Head, Carl W. Cotman, Daniele Piomelli, Silvana Gaetani. Deficient Liver Biosynthesis of Docosahexaenoic Acid Correlates with Cognitive Impairment in Alzheimer's Disease. PLoS ONE, 2010; 5 (9): e12538

Peripheral reduction of ß-amyloid is sufficient to reduce brain ß-amyloid: Implications for Alzheimer's disease"
J. Gregor Sutcliffe, Peter B. Hedlund, Elizabeth A. Thomas, Floyd E. Bloom, Brian S. Hilbush
Journal of Neuroscience Research: 3 MAR 2011 DOI: 10.1002/jnr.22603

Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Director, ADCS
University of California San Diego
Author: Michael Rafii MD, PhD at 3:30 PM 0 Comments

Wednesday, March 02, 2011

Concussions in NFL Players and Dementia

Repeated concussions are thought to have contributed to the depression and ultimate suicide of Philadelphia Eagles' cornerback and safety Andre Waters, who shot himself at age 44 in 2006. According to Dr. Bennett Omalu, a neuropathologist at the University of Pittsburgh, Waters' brain was similar to that of an 85-year old with early-stage Alzheimer's disease.

When former Chicago Bears defensive back Dave Duerson committed suicide last month with a gunshot to the chest, he left a handwritten note near his body that read:"PLEASE, SEE THAT MY BRAIN IS GIVEN TO THE NFL’S BRAIN BANK." Duerson's apparent intention was that his brain be studied for the debilitating effects concussions can have on players years after they retire.

Duerson's brain will be sent to the Boston University Center for the Study of Traumatic Encephalopathy, which has found that NFL players with a history of concussions show abnormal amounts of tau protein, which injures neurons. As readers of this blog will recall, abnormalities in tau are also seen in AD.

A study by the Center for the Study of Retired Athletes, based at the University of North Carolina, of 2,500 former NFL players found that cognitive impairment, Alzheimer's-like symptoms and depression rose in direct proportion to the number of concussions a player had sustained. The same group conducted a 2003 study which found a link between multiple concussions and depression among former pro players with histories of concussions.

A concussion is a bruise to the brain. A mild concussion is a blow that causes confusion and short-term memory loss; the so-called classic concussion entails a loss of consciousness, and the after effects can be far worse. Symptoms that linger after a concussion are often referred to as post-concussion syndrome. These include anxiety, headaches, nausea, memory lapses, dizziness and difficulty sleeping and concentrating. It is believed that the forces involved in recurrent, traumatic blows to the head, disrupt cellular processes in various circuits in the brain for days or weeks, and perhaps, even longer.

Concussions are classified into three grades, the first grade being the least severe (with no amnesia or loss of consciousness) and the third grade the most severe (loss of consciousness. A grade-one concussion will force a player out of the game for at least twenty minutes, pending further evaluation. A grade-two concussion keeps a player out of the game and practice for at least a week; a grade-three concussion benches the player for at least a month.

It turns out, the connection between dementia and repeated concussions has been known for some time. It has been referred to as Dementia Pugilistica (DP), a type of neurodegenerative disease which affects boxers that was first described in 1928. The word pugilistica comes from the Latin root pugil, for boxer. Symptoms and signs of DP develop progressively over a long latent period sometimes reaching decades, with the average time of onset being about 12–16 years after the start of a career in boxing. The condition is thought to affect around 15-20% of professional boxers and is characterized by the development of declining mental ability, problems with memory, and parkinsonism, or tremors and lack of coordination. Patients with DP may be prone to inappropriate or explosive behavior and may display pathological jealousy or paranoia.

Many researchers are beginning to investigate the molecular changes that occur in the brains of patients who have suffered repeated concussions, traumatic brain injury or dementia pugilistica, to better understand the relationship between head injury and the development of neurodegenerative diseases. It may be that by identifying shared pathways in these conditions and AD, we will find better methods to diagnose and treat all of these devastating illnesses.

Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Director, Alzheimer's Disease Cooperative Study
University of California, San Diego
Author: Michael Rafii MD, PhD at 10:40 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.