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Thursday, September 27, 2012

Reduced Alzheimer's Brain Pathology With Angiotensin Receptor Blocker Use


Dear Readers,

In a paper published in the Sept. 10 issue of the Archives of Neurology, Angiotensin receptor blockers (ARBs), drugs commonly taken to control high blood pressure, appear to significantly reduce the amount of plaque in the brains of Alzheimer's patients. Candesartan (Atacand), irbesartan (Avapro), olmesartan (Benicar), valsartan (Diovan), telmisartan (Micardis) and eprosartan (Teveten) are other angiotensin receptor blockers approved by the U.S. Food and Drug Administration.

The results were found when patients with high blood pressure on such drugs, including losartan (Cozaar) died and underwent an autopsy. These results were seen only among those who had been taking angiotensin receptor blockers and not among patients taking any other blood pressure medications. The study did not determine whether angiotensin receptor blockers improve mental function in Alzheimer's patients, as cognition was not measured.

For the study, the research team autopsied the brains of 890 patients with hypertension who had been taking various medications to lower their blood pressure. Some of these patients had Alzheimer's disease while others didn't.
The researchers found that participants treated with ARBs, with or without AD, showed significantly fewer amyloid deposition markers than those treated with other anti-hypertensive medications. In addition, compared with other anti-hypertensive medications, treatment with ARBs was associated with a 32% to 35% lower likelihood of AD diagnosis. Compared with untreated hypertensive patients, patients treated with ARBs also had less AD-related pathology.
The mechanisms by which ARBs may decrease amyloid accumulation have not been described, but the authors suggest that ARB treatment may reduce total beta-amyloid content in the brain in part by activating insulin degrading enzyme (IDE), which as readers of this blog will recall, is one way the brain destroys excess beta-amyloid.

Prospective studies are needed to investigate whether ARBs may have an effect on cognitive decline in those with dementia or AD, in addition to what appears to be a possibly modest plaque-lowering effect.

Impact of Angiotensin Receptor Blockers on Alzheimer Disease Neuropathology in a Large Brain Autopsy Series, Archives of Neurology Sept, 2012.



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 10:08 AM 0 Comments

Friday, September 21, 2012

Sex and Gender Differences in Alzheimer’s Disease


Dear Readers,

Over the last year I have had the opportunity to attend conferences devoted to Sex and Gender Issues in Medicine and have been an active member of the Sex and Gender Women’s Health Collaborative – Women’s Health Working group. (http://sgwhc.org). Thus, I was pleased to see that the Society for Women’s Health Research recently published an article that outlined the latest state of the science in sex and gender differences in Alzheimer’s Disease (AD).

It comes as no surprise that most clinician researchers in the field of AD see predominantly more women than men in their offices and clinics. The question has always been, “Do women really develop AD more than men or is it a function of age - women live longer than men?

The recent article by Carter and colleagues in the Journal of Women’s Health, attempts to frame this issue by discussing the latest research and data in three themes: clinical, basic science, and psychosocial. The clinical research group, identified three areas that highlighted questions about potential differences among men and women-

1) Are there sex linked risk factors for AD?
2) Do sex and gender differences affect risk rate of progression or response to treatment?
3) Does the timing (early stages of menopause vs. late stages of menopause) of hormonal replacement therapy affect cognitive status, and if so, would changing gynecologic practices contribute to preventing dementia and AD in women?

The basic science research group also identified three areas such as metabolism, physiology of hormonal regulation and AD genetics as areas of intense sex/gender research. It is known that brain hypo-metabolism and loss of mitochondria (also known as the “powerhouse or energy center of the cell”) function often occur before the development of AD. What is interesting is that in persons who have a maternal history of AD, greater reductions in brain glucose metabolism occur compared to persons without a maternal history of AD. This finding points to a basic biologic and genetic predisposition for AD, as mitochondrial inheritance is known to occur from the maternal line. In addition, questions regarding differences in bioenergetics and aging between the sexes also are raised. Are there sex-specific modulators of aging that influence rate of decline in aging? The final area of inquiry centered around Psychosocial themes and the sex and gender differences in service use, outcome measures and societal expectations. Research in all of these areas is available, however more studies are needed that are specifically designed to include sex/gender interventions to provide effective services.

The roundtable experts suggested several action items for future sex/gender based research with the goal to further improve early diagnosis, quality of life and safer and more effective treatments. Briefly they included:

1) Analyze sex-based differences systematically and comparatively
2) Incorporate sex and gender into experimental designs, especially in clinical trials
3) Determine how biomarkers relate to disease burden and risk for AD for sex and gender
4) Integrate sex differences in AD drug discovery


Here are three articles you can read to learn about this particular report and the latest research in the area of Sex and Gender Medicine.


Carter CL, Resnick EM, Mallampalli M et al. Sex and Gender Differences in Alzheimer’s Disease: Recommendations for Future Research. Journal of
Women’s Health Vol 21, Number 10, 2012.

Liu E, Sui X, Laditka JN, et al. Cardiorespiratory fitness as a predictor of dementia mortality in men and women. Med Sci Sports Exerc 2012; 44: 253-259

Mosconi L, Mistur R, Switalski R, et al. Declining brain glucose metabolism in normal invidviuals with a maternal history of Alzheimer‘s disease. Neurology 2009; 72: 513-520.


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 11:43 AM 0 Comments

Wednesday, September 19, 2012

New form of beta-amyloid metabolism discovered


Readers,

As most of you will recall, beta-amyloid is a fragment of a larger protein, known as APP, and is produced by enzymes that cut APP at two places as it is secreted. Its deleterious effects on the brain and in plaques have been written about in previous blogs.

BACE1 is the enzyme responsible for making the first cut that generates beta-amyloid. This week, researchers at the Mayo Clinic published the finding that a related protein, called BACE2, directly cuts beta-amyloid into smaller pieces, thereby destroying it.

Although other enzymes are known to break down beta-amyloid, BACE2 is particularly efficient at this function, and comes in at second, only after Insulin Degrading Enzyme(IDE).

The discovery suggests that impairments in BACE2 might increase the risk of Alzheimer’s disease. And, it makes BACE2 a potential therapeutic target.
Previous work had shown that BACE2 can also lower beta-amyloid levels by a second mechanism: by cutting APP at a different spot from BACE1. BACE2 cuts in the middle of the beta-amyloid portion, which prevents beta-amyloid production.
Although BACE2 can lower beta-amyloid by two distinct mechanisms, only the newly discovered mechanism — direct beta-amyloid destruction — is likely relevant to the disease. This is because the second mechanism, which involves BACE2 cutting APP, does not occur in the brain.

As the biology of Alzheimer’s disease is better understood, it appears that the underlying problem leading to Alzheimer’s disease is an imbalance between production in the brain and removal of beta-amyloid from the brain. For example, a genetic mutation in APP has been shown to lead to early onset Alzheimer’s disease, and another mutation in APP has been shown to be protective Alzheimer’s disease. Genetic variations have also been shown to cause differences in removal of beta-amyloid from the brain, that is ApoE2 being efficient and ApoE4 being very inefficient. Hence, carriers of the ApoE4 version of the gene have a much higher risk of getting Alzheimer’s disease.

It is only by better understanding the biology of molecules such as APP, beta-amyloid, the enzymes such as BACE, that we can attempt to develop drugs that will slow down or prevent this disease. Moreover, understanding the interplay between genetics and environmental factors, such as diet, will also aid in finding treatments.



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 4:45 PM 0 Comments

Wednesday, September 12, 2012

What AD Research Can Learn from Cancer Research


“The greatest need we have today in the human cancer problem, except for a universal cure, is a method of detecting the presence of cancer before there any clinical symptoms” - Sidney Farber, November, 1962.

Dear Readers,

Dr. Sidney Farber is regarded as the father of modern cancer chemotherapy, and after whom the Dana-Farber Cancer Institute is named. He understood that to treat cancer, even to prevent it, early detection is essential. In the last 50 years, significant advances have been made in this regard.

Oncologists today will tell you that the treatment of early stage cancer is very different from the treatment of widely spread, metastatic cancers, even with the same type of cancer. It is also widely recognized that early treatment is much more successful than later treatment. The key to successful treatment of cancer is early detection.

One example of this type of success in early detection of cancer is the Papanicolaou test or so called “pap smear.” In 1952, 150,000 women had pap smears done as part of a clinical trial and were followed over time. About 500 of these women were discovered to have invasive cancer at that time, and were treated accordingly. Interestingly, another 500 women who were completely asymptomatic had precancerous lesions that were curable by a relatively simple surgical procedure. These women were on average, twenty years younger than the women with the invasive lesions. The pap smear, in effect, allowed for cancer detection, and treatment twenty years earlier than previously possible. Since then, the discovery of the human papillomavirus (HPV) as the cause of almost all cases of cervical cancer has led to development of a vaccine against HPV, which in turn, has led to prevention of cervical cancer.

In primary prevention, a disease is prevented by stopping its cause, such as HPV vaccination that reduces the risk for cervical cancer. In secondary prevention, a disease is prevented by screening for its early, presymptomatic stage. In the case of the pap smear, detection of abnormal cervical cells allows for prevention of cervical cancer.

In Alzheimer’s disease, the question is, are we detecting the disease early enough to make a difference? One way to answer this will be to look at the effect of the anti-amyloid drugs, including bapineuzemab and solaneuzemab, to see if they have any effect on biomarkers that demonstrate the presence of early AD. Even if the phase 3 studies of these drugs did not reach their clinical endpoints, a strong enough effect in reducing beta-amyloid will indicate that we are headed in the right direction and that perhaps with earlier detection and treatment could prevent the dementia stage of AD.




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 1:15 PM 0 Comments

Thursday, September 06, 2012

Higher Dose of Exelon Patch Approved and a New Target for AD Therapeutics


Dear Readers,

There have been two developments this week in the world of AD worth noting:

First, the FDA has approved a higher dose of Exelon Patch for the treatment of mild to moderate Alzheimer's disease. The new dose at a 40% higher rate than the previous maximum strength has been cleared by the FDA for patients with mild to moderate Alzheimer's disease. Approval of the Exelon Patch 13.3 mg/24 h was based on a 48-week, double-blind, placebo-controlled trial in mild to moderate AD patients who met the pre-defined criteria for functional and cognitive decline on the 9.5mg/24 h dose. Patients treated with the 13.3 mg/24 h patch experienced statistically significant (p<0.05)improvement in their overall function compared to the 9.5 mg/24 h patch as measured by the instrumental activities of daily living scale (ADCS-IADL)at the end of the study. This was one of the longest double-blind cholinesterase inhibitor trials to date.

During the 48-week dose-comparison phase of the study, no unexpected adverse events leading to discontinuation were reported, and the safety profile of the higher dose was consistent with that of the currently approved doses of the Exelon Patch.

Second, in an article published in the prestigious journal Neuron*, researchers were able to show that by eliminating an enzyme called ‘JNK3’ from Alzheimer's mice, they were able to reduce beta-amyloid production by 90 percent. JNK3 is an enzyme that modifies APP, which readers of this blog will recall is Amyloid Precursor Protein, and the protein that leads to beta-amyloid formation.
When the researchers saw that elimination of JNK3 dramatically lowered beta-amyloid, they also looked for effects on cognitive function at 12 months. The deletion of JNK3 improved cognitive function significantly, reaching 80 percent of normal, while cognitive function in disease model mice was 40 percent of normal. Drugs that block the functions of JNK3 protein may in fact have a potential role in AD, and will need to be fully evaluated.

*Yoon et al, JNK3 Perpetuates Metabolic Stress Induced by Aß Peptides, Neuron Sept 6, 2012


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 12:02 PM 0 Comments

Thursday, September 06, 2012

Cognitive Response, Estradiol, Post Menopausal Women & Cortisol


Dear Readers,

I recently participated in a Senior Women’s Health forum, discussing the movie “Happy” and the role that emotional happiness and fulfillment (leading to a less “stressful” way of life ) played in one’s overall general medical health.. One of the participants asked me to elaborate on the recent findings about the role of stress and cortisol to overall medical health and “thinking” in women across the lifespan. Specifically, does the research suggest an “age” effect? As I discussed the topic, I recalled reading an article that not only examined the role of cortisol to cognitive function, but also examined how this relationship was affected by the level of estradiol in post menopausal women.

A total of 44 post menopausal women with normal cognitive status (as noted by neuropsychological testing) were recruited and invited to participate in a double blind, parallel group design study, to receive either 0.10 mg/day of transdermal 17 beta-estradiol or a placebo skin patch for 8 weeks. The skin patches were changed weekly, and during the last 4 days of the trial, subjects were randomized to receive 90 mg/day of oral hydrocortisone or a matched placebo. This resulted in 4 groups of women: group 1 receiving placebo patch/placebo pill, group 2: receiving placebo patch/hydrocortisone; group 3: receiving estradiol patch/placebo pill, and group 4: receiving estradiol patch and hydrocortisone. At the end of 8 weeks, a 10 day progesterone challenge (200 mg/d of oral progesterone) was given to women with an intact uterus who received the active skin patch.

Both at baseline and at week 8, cognitive tests were administered, mood was assessed and blood was collected. Tests administered were a short term memory battery, including the Story Recall, List Learning and Delayed Match to Sample. Executive function testing included tests for selective attention, visual working memory and semantic memory.

A total of 39 subjects completed the study and all 4 groups were comparable with respect to age, education, BMI, history of past hormone therapy, and hysterectomy status at the study outset. As expected, estradiol levels were elevated for women who received the active patch and rose by 144% for the estradiol-only group and 191% for the estradiol + hydrocortisone group over the 8 week duration. Regarding cortisone, after 4 days of administration, the levels of cortisone increased for both the cortisone treated group and for the estrogen + cortisone treated group.

At 8 weeks of estradiol, improvements in delayed recall (especially on the story test) were noted, and that these improvements occurred more in the estradiol only group, as compared to the estradiol + cortisone group. For executive functioning, again, the estradiol only group showed improved testing on measures for attention, relative to the estradiol + cortisol group. Both of these results were unchanged when analyses included age, education and BMI.

This study was important as it took into consideration the various factors that may play a significant role in the cognitive health of older women. As stress and the hormone cortisol appear to gain more important roles in cognitive brain health and potentially the development of Alzheimer’s disease; the effect of cortisol on women, who may have a higher risk for developing AD, needs to be further studied. Thus examining the role of varying levels of hormone + cortisol to cognitive function is a logical extension to this area of research and suggests that one could potentially modulate the effect of an important female hormone to cognitive function, through modulating the levels of cortisol.

So, how does this relate to women, cognition and stress? Think of it this way: If you can make an effort to monitor and control your stress, cortisol levels that are known to increase with stress, may come down enough so that the effect of estradiol on cognitive functioning is enhanced.

Here are 3 articles you can refer to, to learn about this particular study or the latest research in the area of hormones and cognitive function in women.

Baker LD, Asthana S, Cholerton BA et al., Cognitive response to estradiol in post menopausal women is modified by high cortisol. Neurobiology of Aging 33 (2012) 829, e9-829 e20.

Asthana S, Baker LD, Craft S., et al. High dose estradiol improves cognition for women with AD: results of a randomized study. Neurology 57: 605-612

Chopra KK, Ravindran A, Kennedy SH et al. Sex Differences in hormonal responses to a social stressor in chronic major depression. 2009 Psychoneuroendocrinology 34, 1235-1241

Happy- the movie, the movement
By Roko Belic
http://www.thehappymovie.com/film/


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 10:35 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.