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Thursday, September 22, 2011

Phase II Clinical Trial Results of Inhaled Insulin for Alzheimer’s Disease


Dear Readers,

In the past week, the results from a clinical trial of insulin for the treatment of AD has garnered a great deal of media attention. Before discussing the research, it is worth reviewing insulin’s role in the brain.

Insulin is critical for normal brain function, and abnormal insulin metabolism has been shown to contribute to the development of Alzheimer's disease. Because patients with Alzheimer's disease also exhibit decreased levels of insulin in the central nervous system, it has been hypothesized that raising these levels to normal might help maintain cognitive ability. Studies involving animals have suggested that insulin deficiency in the brain may possibly be a key factor in the progression of Alzheimer's.

The trial, published online in the Archives of Neurology, is in fact, a randomized, double blind placebo controlled Phase II clinical trial which included 104 people. In the study, researchers at the University of Washington divided the subjects into three groups. One group received placebo, one received 20 international units of aerosolized insulin a day, and the third received 40 international units a day.

The average age of the participants was 72, and more than half were men. Sixty-four of them had amnestic mild cognitive impairment, and forty had mild to moderate Alzheimer's disease. Readers of this blog will recall that amnestic MCI is thought to represent the pre-dementia phase of Alzheimer’s disease. Importantly, no serious treatment-related adverse events occurred during the study.For four months, 36 participants received 20 International Units (IUs) of insulin a day, 38 received 40 IUs a day, and 30 received a daily placebo, all delivered via nasal spray.

The researchers looked at the effect of the treatment on cognition, daily function, and for some participants, they measured biomarkers of cerebral glucose metabolism and cerebrospinal fluid. The primary measures were delayed story recall (how well participants recalled a story told to them immediately after and a short time later), and Dementia Severity Rating Scale (DSRS) scores of the participants (a multiple choice questionnaire that is filled in by caregivers).

For the primary measures, the results showed that compared to the placebo group: The participants who took 20 IUs of insulin a day showed improved delayed story recall, which was statistically significant. However, there was no improvement for the participants who took 40 IUs of insulin a day. The DSRS caregiver-rated functional ability was maintained for the insulin groups, while those on placebo worsened.
Although there appeared to be no change in cerebrospinal fluid biomarkers for insulin-treated participants as a group, exploratory analyses showed changes in memory and function were linked to changes in the beta-amyloid level, and in the tau protein to beta-amyloid ratio in cerebrospinal fluid.

A third group also had scans to assess their brains’ use of glucose. One hallmark of Alzheimer’s disease is reduced metabolism in the brain, which shows up on scans as less use of glucose, the fuel for brain cells. In this assessment, those getting insulin used more glucose in their brains while those receiving placebo used less.
Although the trial achieved statistical significance for its primary outcome measures, the observed effects were small in absolute terms, and thus their clinical significance is unclear. The trial was a small, single-site pilot study, which presents special challenges in the interpretation of results; clearly, a longer, larger, multisite trial is needed to confirm and extend the findings.

Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment: A Pilot Clinical Trial. Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B. Archives of Neurology. 2011 Sep 12.


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 8:55 AM 0 Comments

Monday, September 19, 2011

Risk Factors for Dementia in North India



Dear Readers,

I recently read an article from the journal of Aging & Mental Health, that examined risk factors for dementia in a northern Indian population. The study was conducted in a tertiary care center of northern India, and included 150 cases of dementia from a Cognitive Disorders Clinic and 150 age and sex matched "controls" (predominantly relatives)attending the outpatient clinic. The average age of the dementia cases compared to controls was similar (65.7 yrs vs. 66.2 yrs, as was gender representation (21.3% female for dementia cases vs. 25.3% for controls).

Data collection for this sample group included information regarding education level, dietary habits (vegetarian, non vegetarian, amount of salads, pickles and juices consumed), smoking and drinking history, head injury and exercise. Psychosocial factors assessed were: living environment (extended family living environments), social and community activities, cognitive stimulating activities and spirituality. Other information collected were blood samples for serum homocysteine, serum vitamin B12, thyroid levels, lipid profiles and APOE gene analysis


Cognitive tests included the Mini-Mental Status Examination (MMSE), and performance on the All India Institute Medical Sciences (AIIMS) neuropsychological battery. The diagnosis of the prevalent cases of dementia was made by the DSM IV criteria, or the NINDS ADRDA criteria or the NINDS AIREN criteria. Differences between the dementia groups and control groups were analyzed and the odds ratios (OR) and 95% confidence intervals were calculated for each of the potential risk factors.

Of the 300 cases in total, 88 cases were diagnosed as probable or possible AD and 62 as vascular dementia. Medical and personal factors associated with dementia were diabetes, depression, lower education, urban living, living in non extended family environments, absence of socialization, lack of daily exercise and lack of participating in cognitive activities. Dietary factors such as a vegetarian diet (use of pickles), salads, fruit juices, usage of tea were found to be protective. Neither, serum triglycerides, HDL cholesterol, and serum vitamin B12 were found to be significant for the development of dementia however high LDL, APOE e4, serum homocysteine levels and a BMI >25 were found to be associated with dementia.

This study is one of the few studies from India that sought to compare and contrast various factors including dietary, socio-cultural and medical conditions to dementia prevalence. Common risk factors noted in Western populations, also appear to be associated with dementia in this South Asian sample, thus suggesting that prevention strategies employed can be applied cross nationally. Data interpretation however, must be cautious as this was a case control study and the various clustering of factors associated with dementia in this population would need to be replicated in longitudinal studies.


Here are 3 articles you can refer to, to learn about this particular study or the latest research on dementia in India.

Tripathi M, Vibha D, Gupta P et al. Risk factors of dementia in North India: a case-control study Dement Geriatr Cogn Disord 2010; 30: 479-485

Gupta S, Khadelwal, S, & Tandon. P ( 2000). AIIMS Comprehensive Neuropsychological Battery in Hindi ( adult form). Journal of Personality and Clinical Studies 16, 75-102

Shaji S., Bose, S., & Verghese, A ( 2005). Prevalence of dementia in an urban population in Kerala, India. TheBritish Journal of Psychiatry: The Journal of Mental Science, 186, 136-140


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 8:49 AM 0 Comments

Thursday, September 08, 2011

Brain Cells Created from Skin Cells


In a paper in this month’s journal Cell, researchers led by Asa Abeliovich MD, PhD at Columbia University, New York City, describe how they took skin cells from people with familial forms of AD and converted them directly into neurons. When Abeliovich and colleagues compared the AD neurons to neurons made from healthy people, they found differences in how the cells handled amyloid precursor protein (APP), shedding light on potential disease mechanisms.

The skin-derived neurons exhibited electrical activity that is found in typical neurons. When the skin came from patients with familial Alzheimer’s disease, which contain the presenilin-1 or presenilin-2 mutations, they had abnormalities of processing of the amyloid precursor protein (APP) and increased production of beta amyloid. APP was found to collect in the cells’ endosomes, cellular compartments that sort molecules for degradation or recycling. These findings suggest that this form of Alzheimer’s is caused, at least in part, by abnormal endosomal function.
The researchers transplanted the skin-derived neurons into the central nervous system of mice and demonstrated that these cells were able to integrate into the brains of the mice as functional neurons.

Skin-derived neurons will allow scientists to study the endogenous human pathology in a dish, complementing traditional approaches such as mouse models. The findings offer a new and potentially more direct way to produce replacement cell therapies for Alzheimer’s and other neurodegenerative. Such cells may prove especially useful for testing new therapeutic leads.

Qiang L, Fujita R, Yamashita T, Angulo S, Rhinn H, Rhee D, Doege C, Chau L, Aubry L, Vanti WB, Moreno H, Abeliovich A. Directed conversion of Alzheimer’s disease patient skin fibroblasts into functional neurons. Cell. 2011Aug 5;146(3):359-71




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 2:51 PM 0 Comments

Monday, September 05, 2011

Metabolic syndrome, executive function and white matter hyperintensities in Japanese adults



Dear Readers,

As I continue to present research findings on aging, dementia and Alzheimer's disease in the community, I am routinely asked to discuss diabetes. The topic is highly relevant to all minority communities, especially Asians. Lately the questions are related to " pre-diabetes" and whether or not this condition is just as bad for brain health as full blown diabetes. To answer this question, I often discuss research surrounding the "metabolic syndrome", and recently quoted findings from this Japanese article by Bokura and colleagues.

Participants in this study presented to the Shimane Institute of Health Science for a full medical checkup that included, a medical, neurological exam; a psychiatric history; neuropsychological testing, bloods tests and a MRI. A total of 1543 persons (age range 44-86yrs, mean age 62.0+/6.2 years) were evaluated. Metabolic syndrome was diagnosed based on the modified criteria of the National Cholesterol Education Program Adult Treatment Panel adapted for the Japanese population. Because waist circumference was not measured at the time of the initial evaluation, BMI was used, and central obesity was defined as a BMI greater than 25. Two or more other criteria were needed to satisfy the definition of metabolic syndrome: elevated blood pressure or hypertension, elevated fasting glucose or diabetes mellitus, and/or dyslipidemia. MRI evaluations were performed and white matter hyperintensities were evaluated based on a commonly used grading scale. Infarcts were defined as a focal lesion of 3 mm or larger in diameter. Cognitive function testing was administered using the Japanese version of the Wechsler Adult Intelligence Scale- Revised. Executive function was assessed using two tests -- a Block design test and the Frontal Assessment Battery (FAB).


Of the 1543 persons who participated in this study, 186 (12.1%) were classified as having metabolic syndrome. The metabolic syndrome group had a higher preponderance of men and had higher education compared to the normal group. Further, those with metabolic syndrome had higher rates of smoking, alcohol use and incidence of cardiovascular disease, than the non metabolic syndrome group. The occurence of infarcts was statistically significant between the groups: 13% in the non metabolic syndrome group compared to 24% in the metabolic syndrome group, however no differences were noted in between groups for white matter hyperintensity severity. Metabolic syndrome was associated with poorer performance on both tests for executive functioning.

In statistical models that examined the role of metabolic syndrome to tests of executive functioning, controlling for the occurence of infarcts and various vascular risk factors, the association with poor executive functioning remained. On further examination, only the elevated fasting glucose appeared to act as an independent risk factor for poorer scores on both tests of executive functioning.

This study suggests that Metabolic syndrome affects executive functioning independent of the vascular neuroimaging markers typically associated with poor cognitive function. Thus, this lends further evidence to suggest that a neurodegenerative process impacting cognition is occuring rather than a vascular process; a finding that has been replicated in other Western population based studies.

The present study however does have some limitations -- namely, the use of BMI instead of waist circumference as one measure for the classification of metabolic syndrome. Further longitudinal studies will be needed to address whether cognitive impairment in this cohort is associated with future development of dementia.

Here are three articles you can refer to, to learn about this particular study or the latest research on behavior symptoms and mild cognitive impairment:

Bokura H, Ngai A, Oguro H et al. The Association of Metabolic Syndrome with Executive Dysfunction Independent of Subclinical Ischemic Brain Lesions in Japanese Adults. Dement Geriatr Cogn Disord 2010; 30: 479-485

Segura B, Juardo MA, Freixenet N et al. Mental slowness and executive dysfuncitons in pateints with metabolic syndromes. Neurosci Lett 2009; 462: 49-53

Yaffe K, Haan M, Blackwell T et al. Metabolic syndrome and cognitive decline in elderly Latinos: findings from the Sacramento Area Latino Study of Aging study. J Am Geriatr Soc 2007; 55: 758-762


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 9:17 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.