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Wednesday, June 27, 2012

ApoE4's Different Effects in Men and Women

For every three women with Alzheimer’s disease, only about two men have the neurodegenerative disorder. And although women live longer than men do, on average, the disparity persists even if you correct for the difference in longevity. In a paper published June 13 in the Journal of Neuroscience*, research suggests that ApoE4 status may be the source of this difference, as it has different effects in healthy women versus men.

The main finding is that apoE4 disrupts brain function in healthy, older women but has little impact on brain function in healthy, older men. Women carrying a copy of apoE4 show brain changes characteristic of AD that can be observed before any outward symptoms manifest.

To come to this conclusion the researchers obtained functional MRI scans of 131 healthy people, with a median age of 70, to examine connections in the brain’s memory network. They found that in older women carrying the apoE4 allele, this network, which normally shares a synchronized pattern of activity with other brain areas, exhibits a loss of that synchrony, and this is typically seen in Alzheimer’s patients. But in men, the synchrony was preserved even if ApoE4 was present.

When the researchers checked spinal fluid (CSF), they found that the CSF of women, but not men, who carried at least one E4 allele was substantially enriched in tau, which readers of this blog will recall is an important marker of neurodegeneration in AD.

This study is quite important in that it opens up a new understanding of the interplay between ApoE and gender, and the observed differences in the incidence of AD between men and women.

*Greicius et al, Gender Modulates the APOE e4 Effect in Healthy Older Adults: Convergent Evidence from Functional Brain Connectivity and Spinal Fluid Tau Levels The Journal of Neuroscience, 13 June 2012, 32(24):8254-8262.

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 1:29 PM 0 Comments

Wednesday, June 20, 2012

PTSD in Veterans

Dear Readers,

Not too long ago, I attended a Symposium on "Best Practices: Assisting Veterans and Military Families" in which the topic of Post Traumatic Stress Disorder (PTSD) was discussed at length. The main questions from the health professional and lay audience centered around what type of "thinking problems" can be related to PTSD and more importantly, how do they affect daily functioning? Many of the discussants at the symposium addressed this issue, and a paper was cited from the International Journal of Geriatric Psychiatry that examined the pattern of cognitive impairment in elderly veterans.

In this paper, of the 272 patients who visited the San Francisco Veterans Affairs Memory Disorder Clinic between 2006 and 2009, a total of 24 were diagnosed with current PTSD based on the DSM IV criteria. Because of insufficient neuropsychological data, 5 were excluded and 19 individuals comprised the study sample. The mean age of the group was 69.0 years (SD = 9.9), mean level of education was 14.1 yrs (SD= 2.9) and 63% were white, 32% were African American and 5% were Asian. Seventeen persons reported experiencing "acute onset PTSD" and 14 reported experiencing combat related PTSD. The mean MMSE score for the sample was 25.6 (SD= 3.5) and the mean Geriatric Depression scale score was 5.4 (SD = 3.4).

Data collection for this sample group included information regarding, medications (antidepressant, anxiolytic and cognitive enhancing), head injury, substance abuse, seizure disorder, and past psychiatric history. Medical history included history of cardiovascular heart disease and stroke.

Cognitive tests included, the Mini-Mental Status Examination (MMSE), and performance on specific measures for Verbal learning and memory (2), Attention (4), Information Processing Speed (1), Language (3) and Executive functioning (1) . Raw scores for each cognitive test were converted to z scores using normative data for age matched controls. Impairment falling 1.5 standard deviation below age matched controls, was considered as "cognitive impairment" on each of the specific tests.

Several findings were noted in this study. (1) Cognitive impairment was noted in 57% of the sample on tests of a single trial list learning. (2) When evaluating lists of information over several trials, none of the participants in the sample demonstrated clinical significant impairment. (3) A large proportion of patients in the sample had poorer cognitive impairment on memory measures for lists of information, after a short delay (44%) versus long delay (31%) and that cognitive impairment was decreased when information was presented as "stories" (14%) (4) Cognitive impairment on measures of language, attention, and information processing speed were not noted in this sample.

The last finding to note centered around the role of comorbid medical conditions to cognitive performance. As expected, this group exhibited many of the common comorbidites noted in older adults, but interestingly, with the exception of hypertension and closed head injury), none of the comorbid conditions were related to cognitive performance. The authors noted that many of the findings presented would need to be replicated, as this was a study with a very small sample size. However, this study is important as it sets the stage for more studies that attempt to identify patterns of cognitive impairment in older adults with PTSD in order to understand how these symptoms impact functional activity and also guide the development of potential treatment modalities.

Thanks for reading.

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

Interested in learning more? Here are 3 articles you can refer to:

Mackin RS, Lesselyong JA, Yaffe K. Pattern of cognitive impairment in older veterans with post-traumatic stress disorder evaluated at a memory disorders clinic. Int J Geriatr Psychiatry

Yaffe K, Vittinghoff E, Lindquist, K et al. 2010 Post traumatic stress disorder and risk of dementia among US veterans. Arch Gen Psychiatry, 67, 608-13

Vasterling JJ, Duke LM, Brailey K et al. 2002. Attention, learning and memory performances and intellectual resources in Vietnam veterans: PTSD and no disorder comparisons. Neuropsychology 16, 5-14.
Author: Neelum Aggarwal MD at 10:29 AM 0 Comments

Tuesday, June 12, 2012

Vaccine Therapy for AD Advances Through Phase I

Dear Readers,

Last week, a research team from the Karolinska Institute's Alzheimer's Disease Research Center in Sweden, published results from a Phase I clinical trial looking at the safety, tolerability, and antibody response of active immunization with the anti-beta amyloid vaccine CAD106 in 58 patients with Alzheimer's disease. The goal of the study was to see if those receiving the vaccine developed an antibody response to beta-amyloid. Vaccines work by inducing the body’s immune system to ‘attack’ the introduced agent, whether it is a microbe, virus, cancer protein, or in this case, beta-amyloid.

The study participants, aged 50 to 80, had mild-to-moderate Alzheimer's disease and were split into two groups for a study period lasting a year. In one group of 31 patients, 24 received 50mcg of CAD106 and seven received a placebo. In the second group of 27 patients, 22 received 150mcg of CAD106 and five received the placebo. Neither the patient nor the person giving the injection knew whether the patient was receiving CAD106 or a placebo shot. Each patient received three injections.

In the first group, 67 percent of the patients receiving the vaccine developed the antibody response the researchers were looking for. In the second higher-dose group, 82 percent of the CAD106-treated participants had the antibody response. One person who received the placebo had the antibody levels as well.

All but two of the 58 patients reported side effects. The most common ones reported included inflammation of the nose and throat, headache, muscle aches, and fatigue. The researchers concluded that CAD106 appears to be safe so far and leads to an antibody response in a substantial number of those who received the shot.

The first human vaccination trial in AD, Elan’s AN-1792, which was done almost a decade ago, had too many adverse reactions and was discontinued. The vaccine used in that study activated certain white blood cells (T cells), which started to attack the body’s own brain tissue. Interestingly, in long-term follow ups, 20% of subjects had developed high levels of antibodies to beta-amyloid. While placebo-patients and non-antibody responders worsened, these antibody-responders showed a degree of stability in cognitive levels as assessed by the neuropsychological test battery (although not by other measures), and had lower levels of the protein tau in their cerebrospinal fluid. These results may suggest reduced disease activity in the antibody-responder group. Autopsies found that immunization resulted in clearance of amyloid plaques, but did not prevent progressive neurodegeneration. Of course, these patients already had dementia, and the current belief is that treatment should begin in the prodromal stage to reduce progression.

It will require long-term follow-up to see if the antibody response results in actually reducing or preventing beta-amyloid and whether this prevents clinical deterioration. The results of this study are very encouraging and should allow for the drug to move to a larger phase II trial. Keep in mind that development of any therapy, including vaccination, that can delay the onset of Alzheimer’s dementia by five years would reduce the prevalence of AD dementia by half. The study appeared online June 6 in the prestigious journal Lancet Neurology and was funded by Swiss pharmaceutical company Novartis.

*Winblad B et al. Safety, tolerability, and antibody response of active Aß immunotherapy with CAD106 in patients with Alzheimer's disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol.2012 Jun 1.

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 12:25 PM 0 Comments

Wednesday, June 06, 2012

Positive Results from a Phase II Trial for AD

Dear Readers,

Results from a phase II clinical trial of the drug Lu AE58054 have shown that the drug has met its primary endpoint in a randomized, placebo-controlled study in 278 patients suffering from Alzheimer's disease (AD). As readers of this blog will recall, primary endpoint is the main result that is measured at the end of a study to see if a given treatment worked, and is pre-selected before the study begins.

The drug was given as augmentation therapy, that is, in addition to the currently prescribed cholinesterase inhibitor Donepezil. The study looked at performance on the ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive sub-scale) over a 24 week treatment period versus placebo and Donepezil. This is the same endpoint that was used to measure effects of the current FDA-approved drugs for AD. Other endpoints, including measures of global functional status and activities of daily living, also showed positive trends with the addition of Lu AE58054, compared with patients who received only Donepezil. The study also showed that treatment with Lu AE58054 was well tolerated.

Lu AE58054 is a potent and selective serotonin receptor blocker. The specific receptor, called the 5-HT6-receptor, is primarily found in areas of the brain involved in cognition. A number of early trials, including those in animal models of AD, have demonstrated that a 5-HT6-receptor blocker could offer potential benefits in the treatment of AD.

The 5-HT6 receptor was first identified in 1993 and is localized in many brain areas. These include brain structures associated with learning and memory processes such as the hippocampus and the cerebral cortex . Blocking 5-HT6 receptors leads to an increase in the release of acetylcholine (Ach) and improvements in cognition. This is thought to be its main mechanism of action in AD.

The study was conducted in selected European countries as well as Canada and Australia. The next step will likely include a large scale phase III trial.

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 12:37 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.