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Thursday, May 30, 2013

Parsing Conflicting Study Results: Bexarotene Revisited

Late last week the journal Science published new results of additional animal studies of the drug Bexarotene (Targretin) as a potential AD therapy. Readers of this blog may recall a post highlighting the initial Bexarotene study results in February of 2012. For an animal model study, the original report garnered a high level of mainstream media attention.

The new findings warrant further discussion of bexarotene.

The protein called Apolipoprotein E (ApoE) is thought to be involved in removing toxic beta-amyloid from the brain. The ApoE protein actually exists in three major forms (apoE2, E3, E4) and the risk for getting AD differs with each form, with E4 being associated with the highest risk for getting AD. The reason for this is that ApoE4 has been shown to be involved in poor beta-amyloid clearance from brain, and hence, leading to greater accumulation of beta-amyloid within the brain. Also recall that beta-amyloid starts out as a soluble (free-floating) molecule that deposits into (insoluble) plaques.

Bexarotene is a drug that was FDA approved in 1999 for cutaneous T cell lymphomas. However, last year it was discovered that Bexarotene activates retinoid receptors on brain cells and increases the production of ApoE, thereby accelerating the removal of beta-amyloid from the brain. In a series of experiments in AD mice, it was shown that a single dose, Bexarotene lowered the most toxic form of soluble beta-amyloid in the brain by 25 percent within six hours, an effect that lasted for up to three days. After two weeks, there was a 75% decline in the amount of amyloid plaques. The drug did its job with unprecedented speed. Mice that were cognitively impaired resumed normal behaviors after 72 hours of treatment. The data was published in a prestigious medical journal – Science.

Now, three independent research teams report they were unable to replicate some of the findings in the original paper. Specifically, the three teams could not duplicate the reported rapid reduction of plaques in the brain. However, some of the follow up experiments confirmed one of the original (and intriguing) findings - namely that treatment significantly reduces the amount of soluble forms of beta amyloid that float in the fluid that bathes brain cells.

Why the discordance in data?

Conflicting results are not uncommon and there may be many explanations for the different outcomes. Things like drug formulations can differ among facilities. And although AD mice are routinely used in experiments, their genetic background can change over time or may differ between laboratories working on AD. Therefore, the results must be replicated by other labs, using the same genetically engineered strain of mice. In the latest study, multiple mouse models were studied in their response to treatment with Bexarotene.

Simply put, it is fairly common to see lack of reproducibility given the technical challenges across laboratories, but it is also important that researchers devote the time and resources to replicate such important findings. Further studies of Bexarotene will be needed to answer the question as to how much of an effect the drug has on soluble beta-amyloid, and whether this would be duplicated in

So, at least for now, Bexarotene’s effect on cognitive measures and soluble beta-amyloid is mixed and researchers cannot confirm the extent or speed of amyloid plaque reduction.
Author: Michael Rafii MD,PhD at 5:23 PM 0 Comments

Wednesday, May 22, 2013

Nonmelanoma Skin Cancer is Associated with Reduced Risk for Alzheimer’s Disease

Dear Readers,

In a longitudinal study involving more than 1,000 New York City residents older than 70, those with a history of non-melanoma skin cancer had only one-fifth the likelihood of receiving a diagnosis of Alzheimer's disease than those without these cancers. The study was led by Drs. Richard Lipton and Joshua Steinerman of Albert Einstein College of Medicine.

The study looked at 1,102 older adults in the Bronx (mean age 79 at enrollment) with no baseline symptoms of dementia who were followed for an average of about three and a half years. 141 participants (12.8 percent) either reported a history of non-melanoma skin cancer or developed it during the study, while 961 remained skin cancer-free. 76 participants developed Alzheimer’s disease dementia during the study, but only two (2.6 percent) of these subjects had non-melanoma skin cancer. Stated a different way, the risk of developing AD was reduced 79 percent in people with non-melanoma skin cancer.

So what is the connection? Why would the presence of skin cancer somehow protect against developing AD? Many in the field believe the link may be the enzyme called gamma-secretase. As readers of this blog will recall, gamma-secretase is involved in cleaving amyloid precursor protein (APP) to produce the toxic beta-amyloid protein that accumulates in the brains of people with AD. However, gamma-secretase also acts on other proteins, some of which function as tumor-suppressors. That is, if gamma-secretase does not function properly, there is a deficiency in tumor-suppression, and skin cancers may develop. In support of this notion, genetically engineered mice that have a defective gene for gamma-secretase have been shown to have an increased risk of skin cancer. Additionally, AD subjects treated with gamma-secretase inhibitors also had a slightly higher incidence of skin cancers than placebo in a recently halted clinical trial.

The complete inhibition of the gamma-secretase pathway of beta-amyloid production has been virtually abandoned as a drug target. However, there are intense efforts ongoing in developing drugs that modulate gamma-secretase such as to not affect its actions in the tumor suppressor pathway, while still blocking beta-amyloid production. There is also intense work being done on altering the beta-secretase pathway, which also leads to beta-amyloid production. In papers published as early as 2001, it was shown that mice genetically engineered to lack beta-secretase, produce no beta-amyloid. And these mice have no evidence of skin cancer.

White RS, Lipton RB, Hall CB, Steinerman JR. Nonmelanoma skin cancer is associated with reduced Alzheimer disease risk. Neurology. 15 May 2013

Thanks for reading,

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 1:13 PM 0 Comments

Monday, May 13, 2013

Type 2 Diabetes Risk of Cognitive Impairment Among Older Mexican Americans

Dear Readers,

May is officially "Stroke Awareness " month and so I thought it would be appropriate to talk about cardiovascular risk factors and how they relate not only to stroke but to cognitive decline and dementia. Diabetes continues to be one of the most established and common risk factors for vascular disease, stroke and mortality not only in the US, but also globally. In addition, diabetes appears to increase the risk of dementia by two fold in many populations, yet little is known whether this increased risk is similar among racial and ethnic minorities. Let's take a look at a recent study that followed a specific population.

A total of 1,617 older Mexican Americans, aged 60-98 years, from the Sacramento Area Latino study on Aging were followed for 10 years. They were evaluated for metabolic and cardiovascular risk factors and their relation to cognitive decline and dementia. Enrollment began in 1998 and participants were evaluated and interviewed in their homes every 12-15 months, with phone calls made every 6 months between the home visits. Of the 1,617 persons in the sample, a total of 677 had diabetes during the study (n= 513 baseline diabetes cases, and 164 incident cases), with 940 remaining diabetes "free". Comparing those with treated diabetes to those without diabetes, those with diabetes were younger and more likely to be born in the US. There were no relationships between education level and diabetes status.

Among those who had diabetes, 62.2% met at least two criteria for diabetes in the study (elevated fasting glucose, anti-diabetic medications use or self report) and 37.8 % had one (13.3% fasting glucose, 3.4% anti-diabetic medication use and 21.1% self report). Of those participants who reported a physician diagnosis of diabetes at baseline, the median reported duration of diabetes was 10 years. Of this group, at baseline 64.7% of participants with diabetes were using anti-diabetic medications, 36.1% were using one medication and 28.7% were using two or more. The proportion of persons taking a diabetes medication remained constant throughout the follow up years.

Persons who were treated with diabetes had a two-fold increased incidence of dementia versus those with no diabetes. In addition, those persons with diabetes were more likely to die than those without a history of diabetes. Furthermore, there was an increased risk of death that occurred in those with diabetes and dementia.

This study is unique in that it is the only US population-based longitudinal study of Mexican Americans that was able to assess cognitive function, dementia and mortality. The results of this study demonstrated that among Mexican Americans, the rates of dementia risk was similar to that of studies with predominantly Caucasian participants, and that diabetes is a risk factor for not only cognitive decline and dementia, but also mortality. Further, treated diabetes appeared not to modify the dementia and mortality rates, thus suggesting that the relationship to diabetes and dementia is very robust. Whether the timing of treatment, or aggressiveness of treatment may have the potential to modify these outcomes remains to be investigated, however, this study further alerts public health officials and health care providers to not only screen and treat for diabetes, but also consider cognitive screening as part of their care management.

Want to read more? Here are three articles you can read to learn about this particular study or other latest research in this area.

Mayeda ER, Haan MN, Kanaya AM, et al. Type 2 Diabetes and 10 year Risk of Dementia and Cognitive Impairment Among Older Mexican Americans. Diabetes Care 2013 pg 1-7

Cheng D, Noble J, Tang MX et al. Type 2 diabetes and late onset Alzheimer's disease. Dement Geriatr Cogn Disord 2011; 31;424-430

Chatterji P, Joo H, Lahiri K. Racial/ethnic and education related disparities in the control of risk factors for cardiovascular disease among individuals with diabetes. Diabetes Care 2012; 35; 305-312.

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 12:03 PM 0 Comments

Tuesday, May 07, 2013

Results of IGIV Study Disappointing But Not Discouraging

The first results from the GAP study of Intravenous Immunoglobulin (IGIV) for Alzheimer’s disease were just announced and are disappointing but not entirely discouraging. The primary results are clear - IGIV did not significantly slow decline of thinking abilities or preserve daily function in a large group of Alzheimer’s patients when compared to an inactive placebo. However, some positive responses were seen in certain subgroups of the participants who received IGIV.

The GAP study was a late-stage clinical trial of IGIV carried out by the ADCS over the past five years with support from Baxter Healthcare and the National Institute on Aging. It enrolled 390 patients with mild to moderate Alzheimer’s disease from 45 ADCS sites in the US and Canada. Participants were given either IGIV or placebo for 18 months. They were tested at regular intervals to see if IGIV was safe and effective in reducing dementia symptoms. The ADAS-Cog, a test of thinking abilities, and the ADCS-ADL, a measure of daily function, were the two primary endpoints measures. A host of other tests, scans and biomarker studies were carried out as secondary or exploratory outcomes to further examine IGIV’s effects. The study was carried out to a very high standard, setting goals that have not yet been reached by any medication for Alzheimer’s that is approved or under investigation.

After 18 months of treatment, the group of patients who received IVIG were not significantly different from those who were given a placebo on either of the two primary endpoints. This means that IGIV was not effective in slowing the progression of Alzheimer’s disease. The news was not all bad, however. IGIV was well-tolerated, and some positive effects were observed in at least two subgroups of participants treated with IGIV. While the subgroup results are encouraging, they do not negate the primary outcomes. A positive result that is limited to a subgroup of patients can be considered a justification for further study, but does not provide the kind of evidence necessary for IGIV to be considered a useful treatment for Alzheimer’s disease. Only positive outcomes on the primary measures could have led to IVIG being accepted as a new treatment for Alzheimer’s and in this case, the primary endpoints were negative.

What we stand to learn from the GAP study cannot be overstated. IGIV was chosen for study because it contains antibodies the human body produces naturally that react with clumps of beta amyloid protein and other molecules thought to be involved in the development of Alzheimer’s disease. In earlier phases of clinical study, IGIV showed considerable promise in slowing dementia-related decline, albeit in small numbers of patients. It was essential to determine whether or not IGIV could help most persons with Alzheimer’s and that is exactly what the GAP study has accomplished. While the negative primary results are undeniably a disappointment, the clear answers provided by the GAP study are a major step forward for Alzheimer’s research.

IVIG is approved to treat a number of disorders, but not Alzheimer’s disease. It is expensive and in limited supply. Over the past several years, some physicians have chosen to administer IVIG to their patients with Alzheimer’s disease in what is called “off label” treatment based on the positive findings from earlier studies. The GAP study’s primary findings should discourage this kind of off-label use of IGIV for treatment of Alzheimer’s for the foreseeable future. However, Alzheimer’s patients already receiving off label treatment with IGIV should discuss their options carefully with their physician, taking into account that there were some positive effects observed in subgroups of IVIG-treated participants in the GAP study.

The study results are still under analysis and a full study report will be presented to the medical and scientific community in July at the AAIC meeting in Boston. This will include some of the brain imaging results and biomarkers that were collected from blood and spinal fluid during the study. These additional analyses will help to put the study’s findings into better focus and may provide new directions for future studies.

As the GAP study leader, I want to acknowledge and express my gratitude to all of the participants in this study, especially the Alzheimer’s patients and their study partners for their invaluable and selfless contribution to Alzheimer’s research. I would also like to acknowledge the extraordinary efforts of the investigators and the research teams at the 45 ADCS sites that took part in the study as well as the many highly skilled persons at the ADCS, Baxter and the NIA that helped to bring this important study to fruition.

Norman Relkin MD, PhD
ADCS Project Leader
Gammaglobulin Alzheimer Partnership (GAP) Study
Associate Professor of Clinical Neurology and Neuroscience
Weill Cornell Medical College
New York, New York

Author: Jeffree Itrich at 2:38 PM 0 Comments

Wednesday, May 01, 2013

Phobic Anxiety and Cognitive Performance in Older Women

Dear Readers,

During the past month while at community presentations, I have been asked to comment more on the contribution of “personality characteristics” to decline in memory and cognitive function, than traditional medical or lifestyle characteristics. I am not sure as to why there is a sudden rash of these types of questions, however some participants mention that they are having feelings of uncertainty, or anxiousness about getting older and thinking about how they will manage financially, physically and emotionally as they age. These comments made me research the current literature on this topic, and led me to an interesting paper by Grodstein et al, that examined the relationship between anxiety and cognitive function.

In this paper, a total of over 16,000 women from the Nurses’ Health study answered questions from the phobic anxiety scale of the Crowne Crisp Index ( CCI). The average age at the time of questionnaire administration was 63 years. This index measured common symptoms of phobic anxiety, and consisted of self-rated questions of phobias and avoidance desire. Scores ranged from 0 to 16 (higher scores = higher anxiety). CCI scores were categorized into five groups 0-1 (reference group), 2, 3, 4, 5 and 6 or more (highest phobia score).

Cognitive function was measured by the Telephone Interview for Cognitive Status (TICS). 31 points or less are consistent with cognitive impairment in addition to four extra cognitive tests (East Boston Memory Test, fluency, delayed 10 word recall and digit span). All analyses took into account the participant’s age, education, anxiety level, body mass index, smoking history, post menopausal hormone use, hypertension and cholesterol history, heart disease diabetes and physical activity history.

Women in the highest phobic category were generally less healthy, i.e. they had higher BMI’s, increased history of hypertension, heart disease, diabetes and cholesterol, lower physical activity and were current smokers. In addition, those with higher phobic anxiety had lower levels of educational attainment. The findings also suggested that women with higher phobic anxiety also had lower cognitive scores not only on the global measure of all the tests, but also with tests on verbal memory, executive function and attention. Interestingly however, these cognitive scores did not appear to worsen or decline over time.

What could be the biological mechanism at work to explain these findings? One prominent theory states that stress, and the associated factors such as anxiety that may accompany stress, may lead to chronically elevated levels of pro-inflammatory cytokines and stress hormones that injure key brain regions such as the hippocampus, thus accounting for the poor performance on cognitive tests. Another theory implicates genetic vulnerability, the COMT polymorphism gene that has been associated with late life cognitive impairment in other cohorts. What is still unclear however is why the lower level of cognitive function associated with phobic anxiety did not decline over time as one would have expected.

Perhaps, phobic anxiety represents a different type of behavioral construct than other measures such as distress proneness or depression. Indeed research suggests that phobic anxiety and symptoms have an earlier age of onset and persistent course. This fact may be important, since treatments for anxiety exist, and thus earlier treatment, may delay the onset of cognitive impairment in old age.

Want to read more? Here are 3 articles that you should read to learn about this particular study or other research in this area.

Okereke OI, Grodstein F. Phobic Anxiety and Cognitive Performance Over 4 years among Community Dwelling Older Women in the Nurses’ Health Study. Am J Geriatr Psychiatry 2013

Crown S, Crisp AH. A short clinical diagnostic: self rating scale for psychoneurotic patients. The Middlesex Hospital Questionnaire Br. J Psychiatry 1966; 112:917-923

Bierman EJ, Comijs HC, Rijmen F, et al. Anxiety symptoms and cognitive performance in later life: results from the longitudinal aging study Amsterdam. Aging Ment Health 2008; 12 (4): 571-523.

Thanks for reading.

Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Rush Alzheimer’s Disease Center
Chicago, IL

Author: Neelum Aggarwal MD at 11:22 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.