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Wednesday, October 31, 2012

Update from the Clinical Trials in Alzheimer's Disease Conference

Dear Readers,

This week, researchers from around the world met to discuss the latest findings from clinical trials involving AD. One of the main highlights of the meeting was a pair of talks centered around the phase III bapineuzemab and solanezumab results from earlier this month.

Presentations by Dr. Paul Aisen, director of the ADCS, and Dr. Reisa Sperling, Professor of Neurology at Harvard Medical School, and an investigator with the ADCS, reviewed the results and described what they mean for future drug development in AD.

Dr. Aisen evaluated the data from the independent ADCS analysis of the solanezumab trial. Solanezumab slowed down the rate of cognitive decline in patients with mild AD by about 34%. It did not slow down the rate of decline on functional scales, however. Moreover, in looking at subjects who had positive amyloid PET scans, there was a statistically significant change in total beta-amyloid in cerebrail spinal fluide (CSF). Both of these findings are quite exciting, and indicate that this anti-beta amyloid drug has a statistically significant effect on cognition, and a biomarker of AD; a first in AD research.

Dr. Sperling discussed results of both the bapineuzemab and solanezumab trials, and provided a larger context of what the results of these two studies really mean. As readers will recall, the bapineuzemab study failed to meet its primary endpoint, that is, it did not show any benefit in efficacy compared to placebo. However, it did lower beta-amyloid levels in the brain. Her talk focused on the use of biomarkers as real surrogates of pathology, and the impact of their use in AD trials.

The next step for solanezumab will most likely include a confirmatory trial, and researchers are optimistic about its chances given the fact that there was significant effect in cognition and biomarkers.

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 9:51 AM 0 Comments

Monday, October 29, 2012

Sleep Quality and Functional Decline in Older Women

Dear Readers,

How well do you sleep at night? Do you have restful sleep or do you feel that the quality of your sleep has changed as you have grown older? Recent data suggests that approximately half of elderly adults have a complaint about their sleep. Complaints range from difficulty falling asleep, maintaining sleep or having poor “quality of sleep”. The extent of how these sleep related complaints are related to functional impairment in specific domains was the topic of a recent study by Spira et al. in the Journal of the American Geriatric Society.

A total of 817 women from the Study of Osteoporotic Fractures (SOF), with baseline and follow up data on instrument activities of daily living (IADL’s), gait data, grip strength and sleep characteristics, formed the basis for this study. Evaluations of sleep were made by the use of a wrist actigraph in addition to obtaining information on time to bed, time attempted to go to sleep, time out of bed and the number of times that the actigraph was removed. Each of these categories were averaged across nights of actigraphy into three themes: total number of minutes in bed asleep after lights off, total number of minutes in bed spent awake after the first 20 minutes block of sleep and, percentage of time in bed after lights off spent asleep. IADL’s measured, included information regarding difficulty preparing meals, doing heavy housework or shopping for groceries or clothes. Performance based measures of physical function that included grip strength and gait speed were also obtained.

The average age of this group was 82.4 years (3.3), with 12.6% non white and ~ 40% post high school education. On average they slept 409 minutes (+/- 66.0 minutes), spent 65.9 minutes (+/- 40.4) awake after initial sleep onset. The findings suggested that women with the shortest total sleep time have over 90% odds of having IADL impairment compared to longest sleepers. In addition, women with the lowest sleep efficiency (percentage of time in bed after lights out, spent asleep) have over 60% odds of impairment than those with the highest. Lastly, in those women with the shortest time spent in bed asleep after “lights out” had twice the odds of declining grip strength as those with the longest time spent in bed asleep.

This article is important in that it provides quantitative and qualitative data regarding the relationship between various sleep parameters to functional and physical function measures. These relationships are highly relevant in that improvement of older adults’ sleep might help maintain functioning, independence and quality of life.

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

Spira AP, Covinsky K, Rebok GW., et al. Poor Sleep Quality and Functional Decline in Older Women. JAGS 60: 1092-1098, 2012

Goldman SE, Stone KL, Ancoli-Israel S et al. Poor Sleep is associated with poorer physical performance and greater functional limitations in older women. Sleep 2007; 30: 1317-1324

Quan SF, Katz R, Olson J et al. Factors associated with incidence and persistence of symptoms of disturbed sleep in an elderly cohort: The Cardiovascular Health Study. Am J Med Sci 2005; 329: 163-172.

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 2:56 PM 0 Comments

Wednesday, October 17, 2012

Leptin, MCI, Dementia and Elderly Women

Dear Readers,

Multiple studies have attempted to discuss the associations between body mass index, waist circumference and dementia in middle and older age. Some studies suggest that obesity and BMI in midlife may be associated with increased risk of dementia, while other studies suggest an inverse association between late life BMI and risk of dementia. The apparent complexity of these relationships across the lifespan, warrant further understanding as the potential effect of modifying the risk factors for obesity, could have important implications in delaying cognitive impairment. Lately, investigations in this area of research have focused more on a component of adipose tissue - leptin (considered a metabolic biomarker of body fat) - rather than traditional BMI and adiposity measurements, as a key player in cognitive decline and dementia.

The role of leptin to cognitive function was examined in a group of 579 women from the Study of Osteoporotic Fractures.(SOF) The SOF study enrolled women aged 65 years and older between 1986-1988 from multiple centers in the US and followed participants for an average of 20 years. Every 2-4 years biological and clinical data were obtained including serum leptin samples from a total of 1,040 persons at year 16 of the study. After excluding persons who (1)died before a formal evaluation could be made,(2)had a diagnosis of dementia or AD at the time of evaluation or (3)lacked cognitive assessments or leptin samples, a total of 579 participants remained comprising the final analytic cohort.

The mean age of women at baseline was 82.6 years (SD= 3.1), 89% were white and had a mean of 12.9 years of education. Over a third (35.4%) of the participants had normal BMI, 40.6% were overweight and the remaining 24% were obese. A total of 11.1% reported a diagnosis of type 2 diabetes, 8.6% reported stroke, and more than half of the sample had hypertension. Women in the higher leptin tertile group compared to those in the lower leptin tertile group, were younger, had less education, had higher BMI, a history of hypertension and were non white.

Leptin, BMI, weight and height were not associated with dementia/MCI in unadjusted models and were similar after adjustment for age, race, education, and hypertension. When models further examined the interaction between log leptin and categorical BMI (adjusting for age, race, education and hypertension), every one SD difference in log leptin was significantly associated with lower odds of dementia/MCI in women with normal BMI but was not associated with those with higher BMI.

These findings suggest that although traditional anthropometric measures that include weight, height and BMI did not predict the odds of dementia/MCI, leptin, was associated with a decreased odds of dementia/MCI in women that had normal BMI. This interaction suggests that perhaps in those who have higher BMIs (in the obesity range), leptin’s ”protective” effect on cognitive function may be compromised. Potential biological mechanisms include the fact that obesity may cause an increased level of inflammatory biomarkers which may then interfere with leptin receptors and inhibit the neuroprotective effect of leptin in the brain. These results are intriguing as they suggest that in older age, BMI may not be an accurate measure for adiposity and risk of dementia and that leptin may play an important role in cognitive function and constitute a path through which obesity influences cognitive function.

Here are 3 articles you can refer to, to learn about this particular study or research in the area of Adiposity, Leptin, BMI and MCI/Dementia.

A Hazzouri AK, Stone KL, Haan MN, Yaffe K. Leptin, Mild Cognitive Impairment, and Dementia Among Elderly Women. J Gerontol A Biol Sci Med

Luchsinger JA, Patel B, Tang MX et al. Measures of adiposity and dementia risk in elderly persons. Arch Neurol 2007; 64 (3): 392-398

Holden KF, Lindquist K, Tylavsky FA et al. Serum leptin level and cognition in the elderly: findings from the Health ABC Study. Neurobiol Aging,2009; 30 (9): 1483-1489

Thanks for reading.

Neelum T. Aggarwal, MD
Steering Committee Member, ADCS


Author: Neelum Aggarwal MD at 11:04 AM 0 Comments

Wednesday, October 10, 2012

New Results from Solanezumab Clinical Trials


At the annual American Neurological Association meeting this week, results from the Solanezumab clinical trials called Expedition 1 and Expedition 2 were presented. As readers of the blog will recall, these were international trials looking at the effect of the antibody drug in slowing down the progression of mild to moderate AD.

Expedition 1 had 1,040 patients and Expedition 2 had 646 patients. There were no statistically significant benefits for giving patients Solanezumab for eighteen months, compared to placebo, on either the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), a test used to measure patients' cognitive symptoms, or the Activities of Daily Living Inventory (ADCS-ADL), a measure of how well patients are functioning.

In the first study, called EXPEDITION 1, patients with mild Alzheimer’s had a 42% reduction in cognitive decline at 18 months. In the second study, EXPEDITION 2, there was just a 20% reduction in cognitive decline and 19% functional decline. When the mild patients from both studies were pooled together, there was a 34% reduction in cognitive decline and a 17% reduction in functional decline.

Combining the two studies to increase statistical power resulted in a statistically significant reduction in how fast patients’ cognitive function worsened, measured by the ADAS-cog scale; the patients on Solanezumab got a bit more than six points worse, while those on placebo got a little less than eight points worse. There was still no evidence that the drug helped patients function better.

The FDA requires improvements be made in both cognitive and daily functioning skills in order to approve a drug for treatment. The good news is that there is a signal towards improvement on drug compared to placebo, which further strengthens the amyloid hypothesis of AD. And this signal was seen in the mildest patients, which further strengthens the argument for earlier detection and treatment of AD using anti-amyloid therapies. The next question is whether the FDA will require additional clinical trials, perhaps in earlier stage patients such as prodromal AD, before approving the medication.

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 2:49 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.