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Thursday, January 24, 2013

Stress and Alzheimer’s disease: A Hormonal Connection


Dear Readers,

This week, findings were published in the Journal of Alzheimer’s Disease that may help explain why people who are susceptible to stress are at more risk of developing AD and why increasingly we are finding evidence that physical activity, which reduces stress levels, may reduce the chances of developing AD.

It is widely believed that the stress hormone CRF — or corticotrophin-releasing- factor — may have a protective effect on the brain, including the memory changes brought on by AD. CRF is associated with the production of stress and is found in high levels in people experiencing various forms of anxiety. Normal levels of CRF are beneficial to the brain, keeping cognitive abilities sharp and aiding the survival of nerve cells. Interestingly, previous studies have shown that people with Alzheimer’s disease have a reduced level of CRF.

In this paper, researchers used an experimental drug to prevent CRF from binding to the brain receptor called CRFR1 in mice with AD that were free from memory impairments, therefore blocking its effects. They discovered that the mice had an abnormal stress response with reduced anxiety and impaired learning. Moreover, they found that interrupting the hormone from binding to the CRFR1 receptor blocked the improvement of memory normally promoted by exercise. However, in mice with Alzheimer’s disease, moderate exercise restored the normal function of the CRF system allowing its memory enhancing effects.

The effects of stress on the brain have been studied for decades, including its hormonal basis, ever since the initial work by Canadian endocrinologist Hans Selye, who coined the terms ‘stress’. Selye himself went on to publish 33 books and over 1,600 scientific articles, almost all of them on the subject of stress. This study of biological stress and its effects is a science that continues to make advances today by connecting stress to illness, including Alzheimer’s disease. Certainly, more research is needed to map out the functions of CRF and CRFR1 in normal aging, stress, as well as in AD, and the findings published here are compelling for such work.

Thanks for reading

Pardon et al. Corticotropin-Releasing Factor Receptor 1 Activation During Exposure to Novelty Stress Protects Against Alzheimer's Disease-Like Cognitive Decline in AßPP/PS1 Mice, Journal of Alzheimer’s Disease


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 11:13 AM 0 Comments

Tuesday, January 15, 2013

What Statin Drug Development Can Teach Us About AD Drug Development


Dear Readers,

Since the analogy between cholesterol and beta-amyloid is becoming so widely used, I thought it may be worthwhile to look at the challenges faced by researchers during the development of statins as a treatment for heart disease and how it may inform us about the development of potential AD treatments.

Although cholesterol is essential for the normal functioning of all human organs, it is nevertheless the main cause of atherosclerosis, heart disease and stroke when its levels are too high. The first hint that cholesterol was related to atherosclerosis goes back to 1910, when it was found that atherosclerotic plaques from human aortas contained over 20-times the concentrations of cholesterol than did aortas without plaques. A few years later, it was noted that rabbits fed pure cholesterol developed extremely high levels of blood cholesterol as well as severe atherosclerosis of the aorta and greater mortality. This was essentially one of the first animal models of atherosclerosis.

About two decades later, the genetic connection between high cholesterol and heart disease was made after several large families were discovered who had very high blood-cholesterol levels and premature heart attacks. Two decades after that, the epidemiologic connection between blood cholesterol, atherosclerosis and heart disease was firmly established when it was found that the incidence of heart attacks in 15,000 middle-aged men followed for 10 years was linearly proportional to the blood level of cholesterol. The monumental Framingham Heart Study solidly confirmed this link by looking at thousands more patients who were followed over decades with longitudinal blood measurements of cholesterol.

Nonetheless, a debate about the role cholesterol played in heart disease was still taking place in the medical community. It was well accepted that cholesterol accumulated in the plaque that narrowed the arteries of people with atherosclerosis. Yet some researchers insisted that this increase in cholesterol was not the cause of the disease, but merely an innocent bystander in the disease process. These skeptics pointed out that if a high level of cholesterol was a cause of heart disease, then why didn’t all patients who suffered heart attacks show high cholesterol levels? (Note similar arguments have been made regarding the role of beta-amyloid in AD).

However, it was soon discovered that it wasn’t the total level of cholesterol in the blood that was so important for heart disease, but rather which type of cholesterol was elevated in the bloodstream, that is, LDL versus HDL. Regulation of cholesterol metabolism was intensively studied in the 1960s, and one enzyme, the cholesterol-producing HMG-CA reductase was identified as a potential drug target. It was not until 1984 that a large scale clinical trial of statins (which inhibit HMG-CoA reductase) was conducted. And it was not until 1987 when the FDA finally approved the first statin drug to reduce the risk of heart disease and stroke due to high cholesterol that the first drug became available to the public. It is now well known that statins reduce the risk of mortality from heart disease by 45% and are the most widely prescribed medications in the world.

Alzheimer’s disease was described in 1900 and its genetic linkage to beta-amyloid was eventually made in the 1990’s. Since then, studies including ADNI, have allowed for techniques to be developed that allow direct visualization and measurement of beta-amyloid in the brain (which is far more difficult to do than simply measuring blood cholesterol). Moreover, drugs are being actively developed that enter the brain and lower beta-amyloid levels. Many of these drugs are entering large-scale clinical trials. Finally, identification of people with high beta-amyloid is now possible with non-invasive means years before they develop the dementia phase of AD. It took almost 80 years before statins were successfully employed to treat atherosclerosis and reduce heart disease and stroke. Hopefully, we are on the road to finding a similarly successful treatment for AD, in a shorter time span.




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 11:33 AM 0 Comments

Thursday, January 03, 2013

Amyloid Imaging Can Predict Subsequent Cognitive Decline in Cognitively Normal & MCI patients


Dear Readers,

As you will recall, there is now an approved brain PET scan, the Amyvid scan that shows deposits of beta-amyloid plaques. A recent study prospectively evaluated the accuracy of the scan in detecting which patients would be most at-risk for progressive cognitive decline.

In the study, a total of 151 subjects were recruited for longitudinal assessment. Subjects included 51 with recently diagnosed mild cognitive impairment (MCI), 69 cognitively normal controls , and 31 with clinically diagnosed Alzheimer disease dementia. The scans were scored as either positive or negative for pathologic levels of amyloid plaques. Subjects were then followed for 18 months to evaluate changes in cognition and diagnostic status.

Interestingly, in both MCI and cognitively normal control subjects, baseline amyloid positive scans were associated with greater clinical worsening on various measures of cognition. In MCI patients with amyloid positive scans there was also a much greater decline in memory. In addition, higher levels of plaque at baseline correlated with greater subsequent decline on various tests of cognition. And finally, MCI subjects with more amyloid plaques converted to AD dementia at a higher rate than those with MCI and low amyloid plaques.

This study was well conducted, and further supports the idea that measuring amyloid plaques in patients with MCI, and possibly even in cognitively normal patients, may help predict progression to Alzheimer’s dementia based on amyloid plaque levels in the brain, before dementia has set in.


Doraiswamy et al. Amyloid-ß assessed by florbetapir F 18 PET and 18-month cognitive decline: a multicenter study. Neurology. 2012 Oct 16;79(16):1636-44.



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 3:34 PM 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.