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Thursday, March 27, 2014

What is Gender Medicine and why is it important to Alzheimer’s disease?



By Neelum Aggarwal, M.D.
Rush Alzheimer’s Disease Center

Prior to the mid-1900s, there was very little discussion about gender medicine. However, with the establishment of the Partnership for Gender Specific Medicine at Columbia University (1997), the Karolinska Institute (2002), and the Charité -Universitätsmedizin Berlin (2003), studies began to systematically examine comparisons between women and men. Over the last 20 years research has slowly but steadily begun to demonstrate the extent of these sex differences, but have also produced advancements in treatment, prevention and diagnosis. The result of this progress led to the 2010 Institute of Medicine declaration that being a woman or a man significantly affects disease course and should be considered in both diagnosis and therapy.

What is the difference between sex and gender and how is it related to medicine?
Gender medicine aims to improve treatment for women as well as for men, and differs from women’s health, because it also focuses on men’s health.

Gender medicine deals with the effects of sex, including biological differences between females and males. Examples of sex differences can include different concentrations of sex hormones, different expression of genes on X and Y chromosomes, or simply reporting a higher percentage and deposition of body fat in women.

Gender however, is the result of socio-cultural processes. Associated with behavior, stress, and lifestyle-related diseases, gender has been shown to determine access to health care, help-seeking behavior, and even individual use of the health care system. Recent studies have shown that gender largely determines one’s compliance with preventative measures, and whether one follows up on referrals or accepts invasive strategies like a pacemaker implant, heart transplant, or other surgeries.

Although the definitions of sex and gender appear straightforward, in medicine, it isn't always that easy to separate the influence of sex and gender on disease. For example, clinical manifestations of prevalent diseases have been shown to differ in women and men; with the question remaining, how much of these differences are due to sex differences in disease mechanisms? One area of medicine that has made great strides in this area is in cardiovascular diseases. Cardiovascular disease risk factors, disease and symptoms of atrial fibrillation, myocardial infarction, and heart failure all have been shown to have sex and gender differences, and have resulted in separately developed suggested treatment plans for men and women.

Alzheimer’s disease ( AD) is the latest medical condition to be put front and center in the sex and gender discussion. Data suggests that the risk for AD and memory decline appear to increase in women after menopause.

Reports have noted that a woman’s overall lifetime risk of developing AD is almost twice that of a man – a statistic not solely due to the fact that women live longer than men. Other areas of study are demonstrating notable sex and gender differences in basic brain structure and function between men and women. In addition, specific AD related risk factors that include cardiovascular disease, genetics (APOE 4 genotype) and depression all have shown to have sex and gender differences and could account for these observations.



Dr. Aggarwal is a cognitive neurologist at the Rush Alzheimer’s Disease Center in Chicago and a Steering Committee member of the Alzheimer’s Disease Cooperative Study.


 
Author: Neelum Aggarwal MD at 2:33 PM 0 Comments

Thursday, March 20, 2014

New Protein Implicated as Central to Alzheimer’s Disease


Dear Readers,

As many of you are aware, a major puzzle in the Alzheimer’s field has been the issue of how it is possible that some patients can have amyloid plaques and neurofibrillary tangles in the brain, but not show symptoms of dementia, while other patients are fully symptomatic. For years, researchers have explained that this observation is a result of ‘cognitive reserve,’ that is, some protective ability in certain individuals that provides resilience despite the presence of brain pathology.

Now, we have another possible explanation as to why some individuals are protected while others are not. Researchers at Harvard Medical School have published a monumental effort in the journal Nature, showing that a protein called RE1-Silencing Transcription factor (REST), that functions as a gene regulator during fetal brain development, switches back on later in life to protect aging neurons from various stressors, including the toxic effects of abnormally accumulating proteins such as beta-amyloid.

To understand REST's functions, the team genetically engineered mice that lacked REST only in their brains and watched what happened as they aged. Intriguingly, as the mice grew older, neurons in their brain started to die in the same places as in Alzheimer's patients. The research team also studied the REST protein in the worm C. elegans and found that it is necessary to protect against toxicity, thereby suggesting REST’s protective function in the aging brain is shared across species.

The team further showed that the REST protein was abundant in normal aging human brains. The brains of people who developed mild cognitive impairment, by contrast, showed an early decline in levels of REST. The affected brain regions of people with Alzheimer's were nearly devoid of the REST protein. The findings were also noted in the brains of patients with other neurodegenerative diseases that cause dementia, including frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB). It appears that the toxic protein in each circumstance, beta-amyloid in AD, Tau in FTD and alpha-synuclein in DLB, bind to and inactivate REST, prohibiting its ability to perform its normal functions.

Getting back to the question about cognitive reserve and why some patients don’t exhibit dementia symptoms despite pathology, the researchers examined brain tissue gathered as part of the Religious Orders Study. Participants in the study were clergy who had detailed annual cognitive assessments performed and donated their brains for study after death. The team sorted the samples into two groups. One group had Alzheimer's pathology and experienced symptoms of dementia. The second group had the same amount of Alzheimer's pathology but did not have dementia. The researchers found that the group with no dementia had at least three times more REST protein within key brain areas. Furthermore, REST levels were highest in the brains of people who lived into their 90s and 100s and who remained cognitively intact. And, the levels were high specifically in the brain areas that are most vulnerable to Alzheimer's disease.

So what do all of these findings mean?

The human body has an incredible capacity for healing, and aging is, in essence a balance between damage and repair. In the liver, cells contain various proteins that process compounds and other molecules, including toxins to maintain health. And so it appears that the brain has its own detoxification system, one that involves the REST protein, a gene regulatory protein that turns on a host of other proteins to help protect neurons from age-related toxicities, including the accumulation of beta-amyloid.

The identification of REST as an endogenous neuroprotection system, so intimately involved in AD, identifies it as a prime target for intervention and drug development. One can imagine that by somehow increasing REST levels in the brain, we could increase resilience and reduce the occurrence of the brain dysfunction we call dementia that results from neurodegenerative disease. Undoubtedly, we will see more research following up on this important discovery.





Thanks for reading,


Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
 
Author: Michael Rafii MD, PhD at 12:18 PM 0 Comments

Thursday, March 13, 2014

A Possible New Blood Test for AD?


Dear Readers,

According to a study published last week in the journal, Nature Medicine, a team of researchers has identified 10 lipids in the blood that may be able to detect the early signs of Alzheimer’s disease (AD).

The study included 525 healthy participants aged 70 and older who gave blood samples upon enrolling at various points in the study. Over the course of the five-year study, 74 participants met the criteria for either mild AD or mild cognitive impairment (MCI). Of these, 46 were diagnosed upon enrollment and 28 developed MCI or mild AD during the study (the latter group called converters.

In the study's third year, the researchers selected 53 participants who developed aMCI/AD (including 18 converters) and 53 cognitively-normal matched controls for the lipid biomarker discovery phase of the study. The lipids were not targeted before the start of the study, but rather, were an outcome of the study.

They discovered a panel of 10 lipids, which researchers say appears to reveal the breakdown of neural cell membranes in participants who developed symptoms of cognitive impairment or AD. The panel was subsequently validated using the remaining 21 MCI/AD participants (including 10 converters), and 20 controls. The lipid panel was able to distinguish with 90 per cent accuracy these two distinct groups – cognitively normal participants who would progress to mild cognitive impairment or Alzheimer’s disease within two to three years, and those who would remain normal over the same time interval.

The study has garnered a significant amount of attention, as the need for an easy, inexpensive, and accurate test for AD cannot be found soon enough. However, it should be kept in mind that the findings of the paper are part of a long standing effort by researchers who have been working for at least a decade on a blood test for AD. For this finding to be truly stand apart from the rest, the lipid panel’s predictive power will need to be confirmed in a larger sample of participants.

As readers will recall, the accumulation of beta-amyloid seems to be the driving force behind brain cell injury in AD, leading to a cascade of events that further damage brain cells and compromise cognitive function. As the disease worsens and more neurons die off, atrophy or shrinkage of brain tissue occurs. Some of the most reliable tests in the field include measurements of brain atrophy with volumetric MRI, measures of beta-amyloid in the spinal fluid and detection of amyloid with amyloid PET scans. The premise behind a blood test would be to find a surrogate in the blood for these brain changes. Many have looked at beta-amyloid itself, as well as markers of inflammation. This most recent paper raises the possibility that we may be closer to finally having a blood-based test for AD.

Thanks for reading,


Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego



 
Author: Michael Rafii MD, PhD at 11:09 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.