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Wednesday, November 28, 2012

Higher DHEA Sulfate Levels Protectively Associated with Depressive Symptoms

Dear Readers,

Recently, I met with a colleague trained in psychiatry, who commented that at this time of year in his community clinic-based practice, he sees more patients and families complaining about "mood changes" which he describes as depression. I asked him about his experience in treating depression in the community, was it consistent with studies that suggest, women may have a higher prevalence of depression, and if so, what did he think about possible biological mechanisms for this? He commented about a study in the American Journal of Geriatric Psychiatry that examined the role of dehydroepiandrosterone (DHEA) levels to depression in a community based study of older Japanese men and women.

In this paper, a total of 1,294 persons, aged 65 years and older, took part in a health survey and of them 834 persons participated in more detailed health examinations. Of these, those who did not exhibit depressive symptoms (as measured by the Geriatric Depression Scale 5 item version) and had blood samples available measuring DHEAs in addition to cholesterol, were enrolled in the study. A total of 573 persons (256 men and 317 women) were included in this analysis. Data collection for this sample group included information regarding, medications (antidepressant, anxiolytic and cognitive enhancing), living circumstances, social activities, smoking status, alcohol consumption, stroke, coronary heart disease, diabetes, cancer and Parkinson's disease. As vision and hearing have been reported to be associated with depression, data was also obtained for these variables. Physical performance measures included using a hand held dynamometer to evaluate hand grip strength for upper extremity performance and the Timed Up and Go test for lower extremity performance. Cognitive function was assessed with the clock drawing test.

Several findings were noted in this study. Serum DHEAs levels were higher in men than in women and in both sexes they decreased with age. In men, those who were in the highest segment of DHEAs levels had good lower extremity performance, were current smokers and drank alcohol. In contrast, women in the highest segment were more likely to participate in social activities, had hyperlipidemia and better cognitive function. Over the course of the study, both men and women developed depression, with an incidence rate of 12.1% in men and 19.6% in women.

In men, the incidence of depression was highest in the lowest segment of DHEAs compared to the highest and this relationship persisted after controlling for medical, social and physical function factors. Interestingly, these types of relationships between DHEAs levels and depression were not found in women.

This last finding, that DHEAs was protectively associated with the risk of depressive symptoms in men but not women, has been reported in some but not all previous studies. Some plausible explanations for these findings include differences in the sex steroid environment between men and women. Perhaps sex hormones and their regulation of receptor levels related to DHEAs may be different (lower) in men and women, or perhaps, metabolism of DHEAs may be different. As noted in this study, men had higher levels that helped to maintain a "threshold" for protection against developing depression. Due to the lack of evidence from intervention studies, the authors caution against using DHEA supplementation as a counter measure to prevent depression or depressive symptoms. This study however is important as it furthers the research in biochemical aspects for sex/gender differences in the study of depression.

Want to read more? Here are three articles you can read to learn about this particular study or the latest research on depression.

Michikawa T, Nishiwaki Y, Nakano M et al. Higher DHEA levels are protectively associated with depressive symptoms in Men, but not in Women: A community Based Cohort Study of Older Japanese. Am J Geriatr Psychiatry 2012

Erdincler D, Bugay G, Ertan T, et al: Depression and sex hormones in elderly women. Arch Gerontol Geriatr 2004: 39 (3): 239-244

Goldman N, Glei DA: Sex differences in the relationship between DHEAS and health. Exp Gerontol 2007; 42(10): 979-987..

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 8:34 AM 0 Comments

Wednesday, November 21, 2012

New Susceptibility Gene for AD Identifed

Dear Readers,

Last week, results were published in the New England Journal of Medicine from two separate studies, conducted independently, implicating a new gene that leads to an increased risk of developing AD when present as a certain variant. The gene, called TREM2, has been found to regulate the clearing of cell debris including beta-amyloid. TREM2 has also been shown to exert regulatory control of brain inflammation, which has been associated with Alzheimer’s and cognitive decline.

After carrying out a large number of genome sequencing and genotyping operations, the researchers identified approximately 41 million markers, including 191,777 variants, from 2,261 Icelandic samples. These variants were then analyzed against the genomes of 3,550 persons with confirmed Alzheimer’s disease and a control population over the age of 85 without a diagnosis of the disease. The association analysis used to identify the variant TREM2 in the Icelandic population was then replicated against other control populations with Alzheimer’s disease maintained in the U.S., Germany, the Netherlands, and Norway.

The second group, included scientists from 44 institutions, and was led by University College London, which followed 25,000 individuals. They found a set of rare mutations that appeared more frequently in 1,092 Alzheimer's patients than in the 1,107 healthy control-group subjects. It turns out, they also had identified TREM2.

The results of both studies suggest that a TREM2 mutation raises the risk for developing Alzheimer's between three- and four-fold. As readers of this blog will recall, having two copies of the APOE4 gene increases risk by about fifteen-fold.
As more large scale genetic studies are conducted, on vast numbers of subjects, many more such susceptibility genes will be discovered, which help explain the increased prevalence of AD in certain families. Such findings also open up new venues for targeted drug development.

By Michael 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 11:09 AM 0 Comments

Wednesday, November 14, 2012

The Earliest Indications of AD: 20 Years Before Impairment

Dear Readers,

Last week, researchers led by Dr. Eric Reiman of the Banner Alzheimer’s Institute in Phoenix, and by Dr. Francisco Lopera at the University of Antioquia in Colombia, reported on the appearance of biomarkers of AD in patients in Medellin, Columbia, who have an inherited form of AD and develop dementia at the age of about 50.

The study extends many of the findings from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and demonstrates that changes in the brain occur approximately 20 years before any cognitive impairment can be observed.
In the Colombian family, researchers saw these changes in people ages 18 to 26; on average, members of whom develop symptoms of mild cognitive impairment at 45 and of dementia at 53.

To understand how biomarkers are affected in the earliest stages of AD, researchers examined 44 relatives between ages 18 to 26. Twenty had the mutation that causes Alzheimer’s, and twenty-four did not. The cerebrospinal fluid of those with the mutation contained much more beta-amyloid than that of relatives without it. This make sense, as we know that when people develop amyloid plaques —whether they have early-onset or late-onset Alzheimer’s — beta-amyloid levels in spinal fluid are lower than normal,because the beta-amyloid gets sequestered into the plaque form. But before they settle in the plaques, beta-amyloid molecules are free-floating (soluble), and elevated.

A good analogy here is the relationship between the soluble form of cholesterol and the cholesterol plaques. Although soluble levels of cholesterol can be measured in the blood, they are typically elevated for many years before they deposit within arteries as atherosclerotic plaques, which are made mostly of cholesterol. The study also found that amyloid plaques increased steadily until about age 37, after which the brain did not seem to gain many more plaques. This phenomenon has been referred to as the amyloid plateau in previous blogs. It is important to understand when exactly this occurs, as it may be a point of saturation in the brain, and hence the onset of brain injury leading to cognitive impairment progressing to dementia.

More data will undoubtedly be coming from this group of subjects, as we try to identify the best biomarkers of AD.
Author: Michael Rafii MD,PhD at 3:08 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.