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Thursday, October 28, 2010

Beta-amyloid from Outside the Brain Leads to Amyloid Plaque Formation


As readers of this blog will recall, Alzheimer’s disease and a brain vascular disorder called cerebral beta-amyloid angiopathy are characterized by the accumulation of the protein fragment known as Abeta. In Alzheimer´s disease, misfolded Abeta is deposited mainly in so-called amyloid plaques, whereas in cerebral beta-amyloid angiopathy, the Abeta protein aggregates in the walls of blood vessels, interfering with their function and, in some cases, causing them to rupture with subsequent intracerebral bleeding. Eighty percent of all Alzheimer’s patients have co-existing amyloid angiopathy.

In 2006, scientists in Tübingen, led by Mathias Jucker, reported that injection of dilute extracts from Alzheimer's disease brain tissue, or from Abeta-laden mouse brain tissue, into the brains of transgenic mice (genetically modified to produce the human form of Abeta) stimulated Abeta aggregation within the mouse brain.

In a paper published this week in the prestigious journal Science, Professor Jucker and colleagues report that Abeta deposition can be induced in the transgenic mouse brain by the intraperitoneal (into the abdomen) administration of mouse brain extract containing misfolded Abeta. This induced Abeta deposition was primarily associated with the vasculature, but was also evident as amyloid plaques between nerve cells. The time needed to induce amyloid deposition in the brain was much longer for peripheral as compared to direct brain administration. In both cases, the induced amyloid deposition also triggered several neurodegenerative and neuroinflammatory changes commonly observed in the brains of patients with Alzheimer´s disease and cerebral beta-amyloid angiopathy.

The results show that mechanisms exist allowing for the transport of Abeta aggregates from the periphery to the brain and raises the question of whether protein aggregation and propagation, which may also be involved in other neurodegenerative brain diseases, can be induced by agents originating outside the brain.

The present findings provide new clues on pathogenetic mechanisms underlying Alzheimer’s disease; further investigation will likely lead to new strategies for prevention and treatment.

Michael S. 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 5:23 PM 0 Comments

Monday, October 18, 2010

Obesity, Women and Cognition



Dear Readers,

I just received a "Save the Date" email for the upcoming Building a Healthier Chicago (BHC) Stake holder meeting in Chicago. BHC is a collaborative project of local and national stakeholders working to strengthen efforts to promote the health of Chicago residents and employees. The goal of the BHC is to "promote and increase physical activity levels, improve healthy eating habits, prevent, detect and control high blood pressure."

Many of our patients and their physicians are aware that physical inactivity and obesity are at epidemic proportions in the U.S, which has resulted in an increased prevalence of chronic diseases. Relatively few however, realize that both these conditions, may be associated with poor memory function.

Let's consider the issue of Obesity. Over the years, obesity has truly become a woman's issue. Sixty five (65) million of the 72 million American adults who are considered obese or overweight are women. In addition African American and Hispanic women are much more likely to be obese than White women. So what does being obese or overweight have to do with cognition in women?

Well, recent findings from the Women's Health Initiative, suggest that the more an older woman weighs, the poorer her memory will be. In this study, a total of 8,745 cognitively normal, post-menopausal women ages 65 to 79 underwent baseline cognitive testing as part of their routine evaluation. This study used the Modified MMSE examination ( a 100 point memory test) as the measure of cognitive function. The 3MSE has been widely used in large population based studies as a cognitive tool, and has demonstrated good consistency, reliability, sensitivity and specificity for detecting cognitive impairment and dementia. For all women, both waist and hip measurements in addition to body mass index ( BMI) calculations were obtained. All the women were classified into BMI categories that corresponded to the standard World Health Organization classifications for normal weight, underweight, overweight and obesity.

The majority of women in this sample ( 86.6% white) were classified as overweight or obese ( 70%). For every one-point increase in a woman's BMI, her memory score dropped by one point.( p<0.001). These findings were adjusted for age and educational level and remained unchanged after controlling for common chronic conditions such as diabetes, heart disease and stroke.

When the analyses included waist-hip ratio (WHR), BMI and 3MSE, the 3MSE scores for women with low WHR decreased as the BMI category increased, although this relationship reversed for women with the highest WHR's. The 3MSE score increased (i.e. better cognition) with increasing an BMI in the highest WHR category. These results suggest that women who have a "pear shaped" body type (fat deposited around the hips) have poorer cognitive function compared to "apple shaped" body type women (fat deposited around the waist).

One explanation for these findings, is that the production of endogenous estrogen (i.e. "natural" estrogen produced by the body) by abdominal adipocytes ( fat cells) may play a protective role for cognitive function, and may be less detrimental than fat in other areas. Further research in this area, and whether any notable differences in the strength and nature of these associations across diverse ethnic groups will need to be explored.

Check out the articles and links below to learn more about this study, Building a Healthier Chicago and the Stop Obesity Alliance.

Kerwin DR, Zhang Y, Kotchen JM et al. The Cross-Sectional Relationship Between Body Mass Index, Waist-Hip Ratio, and Cognitive Performance in Postmenopausal Women Enrolled in the Women's Health Initiative. J Am Geriatr Soc. 2010
Anderson GL, Manson J, Wallace R et al. Implementation of the Women's Health Initiative study design. Ann Epidemiol 2005

http://www.healthierchicago.org

www.stopobesityalliance.org ( Strategies to Overcome and Prevent (STOP) Obesity Alliance)

Thanks for reading.


Neelum T. Aggarwal, MD
Steering Committee Member, ADCS

















 
Author: Neelum Aggarwal MD at 9:33 AM 0 Comments

Wednesday, October 13, 2010

Gene Variant of Tau Protein Predicts Rate of Decline in AD


As readers of this blog will recall, one hallmark of Alzheimer's disease is the presence in patients' cerebrospinal fluid of high levels of a protein called tau, and of a specific version of tau known as ptau181. Researchers have now linked a variant of a gene that is involved in tau modification to faster progression of the neurodegenerative disease. This is the first genetic marker to be associated with the rate of progression of AD. This marker does not seem to be linked to the risk of having Alzheimer's or to the age of onset, which makes sense because increased levels of the protein levels is not associated with onset.

For some time, we have known that a specific gene, APOE4 — the only genetic variant commonly thought to increase AD risk — is present in 50% of individuals with late-onset AD. However no variant had previously been associated with rate of progression.

Carlos Cruchaga at Washington University in St. Louis, Missouri, and his co-workers screened hundreds of spinal-fluid samples for 384 variants of 34 tau-related genes. They teased out one, rs1868402, that was associated with ptau181 levels. In another group of 259 patients, the researchers found that those carrying the version of rs1868402 associated with high ptau181 levels had clinical symptoms that worsened twice as fast as expected in AD, and six times faster than those with the variant linked to low ptau181 levels.

In patients with AD, a specific type of modification of the protein tau leads to disruption of the microtubule network, the scaffolding within neurons. It also impairs transport of molecules within cells, and leads to formation of neurofibrillary tangles, which are a hallmark of AD.

The researchers suggest that rs1868402 ultimately causes a change in metabolic processes that leads to a pathological form of tau proteins, and subsequent neurodegeneration. The benefits of this work include the possibility of identifying those patients who are more likely to have rapid degeneration among newly diagnosed Alzheimer's patients; and, perhaps, developing a pharmaceutical intervention targeting the abnormal phosphorylation of tau.

Cruchaga, Carlos, Kauwe, John, Mayo, Kevin, Spiegel, Noah, Bertelsen, Sarah, & Et.Al. (2010). SNPs Associated with Cerebrospinal Fluid Phospho-Tau Levels Influence Rate of Decline in Alzheimer's DiseasePLoS Genetics, 6 (9)

Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Director, Alzheimer's Disease Cooperative Study
University of California, San Diego



 
Author: Michael Rafii MD, PhD at 4:38 PM 0 Comments

Thursday, October 07, 2010

The Global Cost of Dementia


The Global Economic Impact of Dementia,the first study of such scope to examine the macroeconomics of all types of dementias, released by the non-profit group Alzheimer's Disease International 2010 includes some hard-to-ignore data. About 35.6 million people worldwide live with some type of dementia — about four times the population of Sweden. That caseload will increase to 65.7 million by 2030 and 115.4 by 2050. It seems that with each new study, the numbers get bigger and scarier.

The report estimates that the annual cost of care for demented patients at over $600B or about 1% of the world's gross domestic product. Astoundingly that figure is dwarfed by the projected rise in costs over the next few decades. In fact, the report estimates that costs could reach nearly $2 trillion by the year 2050.

While a cure is the goal that everyone seeks, a cold economic look at the disease makes it clear that the crippling expense of care comes primarily from patients in the moderate to severely demented stages of illness, when they cannot administer their own lives. While simply delaying progression to those stages might seem to be an uninspiring health care goal, it is a very attractive economic goal. Simply delaying progression by two years would have a tremendous impact in costs.

In the UK, the national body that reviews drugs for the National Health Service in terms of effectiveness and value for money (NICE) decides if a drug should be recommended. NICE has completed a re-assessment of the cholinesterase inhibitors and decided they should now be prescribed more routinely than under the fairly restricted clinical circumstances they proposed in 2007.

Global figures don't mean much if you or a loved one is battling dementia — nor should they. But governments and policymakers are paid to take the longer view, and this report should be a wake-up call. To that end, earlier intervention and robust treatment, including a balanced diet, physical exercise, pharmaceutical therapy, and tight control of diabetes and any present cardiovascular risks, should be a high priority in the primary care setting.

Michael S. Rafii, MD, PhD
Associate Medical Director, Alzheimer's Disease Cooperative Study
 
Author: Michael Rafii MD, PhD at 8:51 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.