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Thursday, August 30, 2012

Timing is Everything


Timing is Everything…

Immunotherapy Results Illustrate Need for Earlier Intervention


As many of you have undoubtedly read or heard, results from multiple clinical trials were reported this past summer involving both Bapinineuzimab and Solanezumab, two of the leading drug candidates under development for slowing down the progression of AD. Solanezumab and Bapineuzemab are both classified as immunotherapies. These drugs are monoclonal antibodies against beta amyloid, the protein that accumulates in the brain of patients with AD and is thought to be causative of the disease. The studies were all large, Phase 3, double-blind, placebo-controlled trials in patients with mild-to-moderate AD.

Although the trials were negative, a possible efficacy signal was discovered in prespecified secondary analyses of Solanezumab trials, offering a glimmer of hope. When data from the two Solanezumab trials were combined, the results suggested a significant slowing of cognitive decline in the overall study population. Furthermore, a statistically significant effect on cognition was noted in the mild AD patient subgroup, but not moderate AD subgroup, as compared to placebo. In its release of the trial results, Lilly emphasized that these are the first Phase III data with an anti-beta amyloid agent that appear to show a slowing of cognitive decline, and that the pooled data support the amyloid hypothesis.

The results indicate that drugs against beta-amyloid will need to be tested even earlier in the course of the disease, perhaps in the prodromal stage where symptoms are even milder. This concept of earlier treatment is akin to the need to start cholesterol medication years before a heart attack occurs in order to derive benefit from its use.

Despite the negative results for Bapineuzemab, Pfizer and Johnson & Johnson remain committed to its development as a potential therapy, and in fact, will continue with another trial of bapi that is being delivered as a subcutaneous injection, rather than intravenous treatment. This method of drug delivery may actually overcome some of the barriers faced by intravenous Bapineuzemab, in that the drug may linger in the system for longer by virtue of the subcutaneous route, and have longer access times to beta-amyloid in the brain.

The Alzheimer's disease community now awaits the upcoming American Neurological Association (ANA) annual meeting and the Clinical Trials on Alzheimer's disease (CTAD) conference in October, as the full analysis on the pooled and subgroup data are released.

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 3:43 PM 0 Comments

Wednesday, August 22, 2012

The Response to Alzheimer’s Disease


“In some ways disease does not exist until we have agreed that it does, by perceiving, naming, and responding to it," writes Charles E. Rosenberg a noted historian of medicine.

How does this related to Alzheimer’s disease? The entity of Alzheimer’s disease was named and perceived over 100 years ago. The clinical diagnosis of Dementia due to Alzheimer’s disease has been made for the past 30 years, using a specific set of criteria established by expert neurologists. The response to the disease has been manifold, most notably an effort to increase acetylcholine levels in the brain, as it was noted in the 1970s that deficiencies in various neurotransmitters are observed in different neurodegenerative diseases, such as dopamine in Parkinson’s disease and acetylcholine in Alzheimer’s disease. Since the discovery of cholinesterase inhibitors, drugs such as Aricept that increase the level of acetylcholine in the brain, there have been no other major breakthroughs in finding a treatment that stops or even slows down the progression of Alzheimer’s disease.

However, we are at an interesting point in time. We are now able to identify, with great accuracy, those patients who have Alzheimer’s disease years before they develop symptoms of dementia. These individuals constitute about half of all patient s with the syndrome of mild cognitive impairment (MCI). Patients with MCI have specific impairments in memory and half of them progress to dementia within five years. But half do not. Using volumetric MRI, amyloid PET scans and spinal fluid analysis, we can now predict whether a patient with MCI is having symptoms due to underlying Alzheimer’s disease, or if they are having MCI due to some other causes. This ability, paired with a better understanding of how Alzheimer’s disease damages the brain, will be critical in finding disease-modifying treatments that slow the progression of the disease. Treating patients at the earliest stages of the disease, before symptoms appear, will be the most successful approach in battling dementia due to Alzheimer’s disease. For the last decade, focus has been on anti-amyloid treatments, and in the last couple of years, drugs have been evaluated in the MCI stage of the disease.

With more than five million Americans affected, Alzheimer’s disease will cost taxpayers an estimated two trillion dollars over the next decade. During the so called ‘silver tsunami’, these numbers will explode, more than doubling in the next 20 years. Setting aside the tragic impact on tens of millions of baby boomers’ family members, the looming health care costs will be unsustainable.

Congress passed the National Alzheimer’s Project Act earlier this year, out of which a National Alzheimer’s Plan has been developed and launched. The plan’s lofty goal is to identify within the next 13 years, a treatment that will stop the disease from progressing. This is perhaps one of the most important steps towards truly responding to Alzheimer’s disease. In the upcoming months, multiple research programs will come online to evaluate novel treatments for Alzheimer’s disease, including its earliest stages.



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 3:48 PM 0 Comments

Thursday, August 16, 2012

Dementia Incidence, Mortality, and Cognitive Reserve


Dear Readers,

As I read the recent paper from Prince et al, in The Lancet, I was happy to see the authors acknowledge a question that seems to come up frequently at presentations that discuss dementia and cognitive function in diverse populations. The question?

“Why isn't there an epidemic of dementia in countries with very low levels of education?” One answer: we are not sure, but perhaps it has to do with how we diagnose dementia or measure the impact of cognitive reserve on cognitive function in those countries.

In this paper, data was taken from the 10/66 Dementia Research study and compared dementia rates based on the 10/66 criteria and the DSM IV criteria. The 10/66 study consists of a series of cross sectional geographic catchment areas (7 countries) surveyed between January 2003- 2007. The target sample size was 2,000 persons from each country, and all community residents aged 65+ were eligible for participation. Participants for this paper were living in Cuba, the Dominican Republic, Venezuela, Peru, Mexico and China. Incidence waves (for dementia) were completed in 6 of the 7 countries (India excluded) and a mortality screen was done on the whole baseline sample. Participants were reevaluated from 2007-2010 in their homes and if participants moved away, and it was feasible, visits were done out of area. In case of death, a completed informant verbal autopsy was done to obtain data on cognitive and functional decline that may suggest dementia prior to death.

Interviews included questions regarding socio-demographic status, education, risk factors for dementia, chronic disease, disability, use of health services, occupation status, literacy (assessed by “ Can you read a newspaper?”) and care arrangements. For this study cognitive reserve was defined by the following variables: educational level, occupational attainment, literacy, and executive function. Participants also underwent physical function tests that included resting blood pressure, anthropometric measures, and a structured neurological examination. The battery of cognitive assessments included a screening instrument for dementia (utilizing the animal-naming test, ten word list and recall tasks from the CERAD battery), the Geriatric Mental State exam and the Luria three-step motor sequencing fist edge palm (FEP) test. Dementia diagnosis was made according to the 10/66 and the DSM IV criteria.

A total of 12,887 participants were interviewed at baseline; 11,718 were free of dementia and 8,686 were re-interviewed at follow up. Mortality at follow up was highest in China, followed by the Dominican Republic and Cuba. Sixty four percent (64%) of those were women, and 41% of the total group sampled did not complete primary education. Those countries with low levels of education also had high prevalence of illiteracy, the highest being rural China (63% illiterate). Thirty seven percent (37%) of the sample were laborers, 27% semi skilled, 13% trade workers and 21% professionals.

Among those who were re-interviewed in the dementia-free cohort, the mean age at follow up ranged from 75.7 years to 78.6 years. A total of 770 incident cases of dementia diagnosed by the 10/66 criteria (of which 284 met DSM IV criteria for dementia) were noted. Dementia incidence was higher in women and increased with age. Occupational attainment was not associated with 10/66 dementia incidence, in any of the sites, and after controlling for multiple co variates, literacy was independently associated with a reduced incidence of dementia (diagnosed by 10/66 criteria). Higher verbal fluency scores were associated with a lower incidence of dementia and worse performance on the motor sequencing task was associated with a higher incidence of dementia.

This study is one of the few larger population-based studies to measure dementia incidence in ethnically diverse populations. Not only were incident dementia rates higher using the 10/66 dementia criteria compared to the DSM IV criteria by a magnitude of 1.5-2.5x, dementia at baseline based on 10/66 criteria was higher than that noted by the DSM IV criteria. This was an interesting finding, suggesting that perhaps many early and mild stages of dementia are missed using the DSM IV and suggests using more culturally appropriate tests and criteria as incorporated in the 10/66 criteria in these populations. Regarding the indicators of cognitive reserve used in this study, some findings were expected:

(1) the protective effects of education can be extended to the middle income country settings and (2) a strong performance on category fluency and tests of executive function also provide “protection “ from the diagnosis of dementia. What was unexpected was that occupational attainment did not confer protection in this setting and that literacy was an independent positive predictor of better cognitive function and lower risk of dementia.

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

Prince M, Acosta D, Ferri CP et al. Dementia incidence and mortality in middle-income countries, and association with indicators of cognitive reserve: a 10/66 Dementia Research Group population based cohort study. Lancet. 2012 Jul 7; 380(9836):50-8.

Valenzuela MJ, Sachdev P. Brain reserve and dementia: a systematic review. Psychol Med 2006; 36: 441-54.

Siedlecki KL, Stern Y, Reuben A et al. Construct validity of cognitive reserve in a multiethnic cohort: The Northern Manhattan Study. J Int Neuropsycchol Soc 2009; 15: 558-69


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 9:39 AM 0 Comments

Thursday, August 09, 2012

Bapi Beyond the Headlines: There is More Work to Be Done


Dear Readers,

As many of you have undoubtedly read or heard, Pfizer and Johnson & Johnson announced earlier this week, the failure of a second Phase III trial of bapineuzumab, the anti-amyloid antibody known as “bapi,” for the treatment of Alzheimer’s disease. Pfizer said that bapi failed to show positive results in a phase III study being conducted in mild-to-moderate Alzheimer’s disease patients who do not carry the ApoE4 (apolipoprotein E epsilon 4) genotype.

Two weeks ago, I blogged about the July 23 announcement made by Pfizer that bapi failed to show positive results in a phase III study that was conducted in patients with mild-to-moderate Alzheimer’s disease who carry the ApoE4 genotype. Results showed that bapi failed to show benefit, namely change in cognitive and functional performance compared to placebo.

The results of both of these trials are disappointing. The failure to show benefit in the ApoE4 negative subjects is quite disappointing, as it indicates that drugs against beta-amyloid will need to be tested even earlier in the course of the disease, perhaps in the prodromal stage where symptoms are even milder. This concept of earlier treatment is akin to the need to start cholesterol medication years before a heart attack occurs in order to derive benefit from its use.

In addition to the need for earlier intervention, it will also be critical to evaluate how well bapi actually lowered beta-amyloid in the brain in these trials. That is, how well did bapi engage its target, beta-amyloid. We will need to carefully review the biomarker results of these failed trials, to see the extent to which this target engagement has been confirmed.

So, not only is it important when the drug is given in the course of the disease, but just as important is how strongly the drug interacts with its target. In the case of intravenous bapi, this interaction may not have been strong enough or for long enough in patients with mild to moderate AD.

Pfizer and Johnson & Johnson remain committed to the development of bapi as a potential therapy, and in fact, will continue with another trial of bapi that is being delivered as a subcutaneous injection, rather than intravenous treatment. This method of drug delivery may actually overcome some of the barriers faced by intravenous bapi, in that the drug may linger in the system for longer by virtue of the subcutaneous route, and have longer access times to beta-amyloid in the brain.

We await the results of that trial, as well Eli Lilly’s solanezumab, which is in two phase III studies, with results likely to be reported later this year.
 
Author: Michael Rafii MD, PhD at 10:21 AM 0 Comments

Wednesday, August 01, 2012

Association of Grip Strength & Dementia in Koreans


Dear Readers,

Perhaps many of you read the recent headlines of walking speed and its association with cognitive decline and dementia. More and more papers are now focusing on "physical function" in addition to medical factors that may lead to declining cognitive functioning or dementia. The reason? One thought is that because both physical functioning and cognitive functioning involve the central nervous system, they may also share common age-related processes. Therefore knowledge of changes in motor function may be able to predict changes in cognitive function.

In a recent paper from Shin et al, the authors examined one type of activity associated with physical functioning - grip strength- and its association with dementia and cognitive function. In this paper, community dwelling older persons aged 65 and older were recruited through national registration lists from a geographic area in south Korea. Community surveys were carried out from 2001 and 2006 in collaboration with the 10/66 Dementia in Developing Countries Research Program and utilized similar scales and interviews used by the research program.

Of the 2,201 residents identified a total of 1,038(47%)completed the interview. The mean age of the group was 73.4 years with 65% of those participating being female. All visits were carried out in a home-based interview. Socio-demographic information on age, gender, marital status, and education were collected from participants and family members. Self reported diagnoses and treatment histories for hypertension, diabetes, heart disease and stroke were also recorded. Body mass index,(weight in kilograms divided by height in meters squared) was also calculated. Grip strength was measured (in kilograms) for both hands and with a handled dynamometer. The test was administered by a trained interviewer. Measures for both hands were averaged to yield a composite measure of grip strength. Participants were also asked to sit and stand and scored on a three point scale: 1) cannot stand or stands with others' help, 2) stands with support of hands; 3) stands without support.

The assessment of dementia was done using the Korean version of the Geriatric Mental State schedule B3 scale, the Community Screening Interview for dementia (CISID) and the modified 10 word list learning of the Consortium to Establish a Registry of Alzheimer's Disease. The dementia diagnosis algorithm was made with the 10/66 dementia diagnostic algorithm using the results from the above three measures.

A total of 114 persons were found to have dementia at baseline. Compared to those without dementia statistical significant associations in those with dementia were noted for age, gender, education and BMI. Dementia was not associated with diabetes, hypertension, heart disease, or stroke.

The rate of dementia for each quintile decrease of grip strength showed a trend that indicated older persons with lower grip strength had a higher prevalence of dementia. This trend was also seen for the sit-to-stand score; those with the lowest sit-to-stand score had the highest prevalence of dementia. On further analyses, the odds for dementia were over 2.7 for each standard deviation decrease in grip strength and over 2.8 for each 1 point decrease in sit-to-stand score. Further adjustment of age, education, marital status, and associated medical conditions, weakened these associations however they remained significant. Analyses adjusted for gender did not show any statistical significance, whereas there was an interaction between grip strength and BMI. Older persons with low BMI and reduced grip strength were likely to be at higher risk for dementia - a finding that was not replicated when analyses replaced BMI with the sit-stand score.

The findings from this study are notable in that the results presented were similar to that of studies done in Western populations. In addition, this study underscores the relationship between physical and cognitive function and thus interventions to prevent cognitive decline should also include interventions to prevent physical function decline. Such interventions include exercising that focus on strength building in addition to walking.

There are however limitations of this study, mainly the fact that this was a cross sectional study, and thus no longitudinal relationships could be established between exposure and disease. Another issue involves the baseline diagnosis of dementia in about 10% of the study sample. This is somewhat problematic as it begs the question as to whether persons with dementia (many of whom may already have poorer diets, weight loss and reduced physical activity), already had resultant poorer grip strength, versus poorer grip strength "causing" the dementia. Larger study samples followed longitudinally will be needed to clarify these results.

Here are three articles you can read to learn about this particular study or the latest research on physical function and health.

Shin HY, Kim SW, Kim JM et al. Association of grip strength with dementia in a Korean older population. Int J Geriatr Psychiatry 2012; 27: 500-505

Buchman AS, Schneider JA, Leurgans S, et al. 2008. Physical frailty in older persons is associated with Alzheimer's disease pathology. Neurology 71: 499-504

Anstey KJ, Smith GA. 1999. Interrelationship among biological markers of aging, health, activity, acculturation, and cognitive performance in late adulthood. Psychol Agin 14: 605-618.


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 9:28 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.