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Tuesday, December 31, 2013

Does Overall Diet in Mid-Life Predict Future Aging Phenotypes?

Dear Readers,

There is an abundant amount of literature about diet and its impact on individual age related diseases – cognitive decline, dementia, cardiovascular disease, stroke and metabolic conditions such as diabetes. However, little has been reported on the effect of diet on overall health - considering the incidence of all of these conditions simultaneously. A recent paper by Akbaraly and colleagues in the American Journal of Medicine sought to examine diet from a “holistic approach” examining data from a well established longitudinal study of persons in the United Kingdom, often noted as the Whitehall group.
The Whitehall group, based in the United Kingdom, is a cohort study of persons aged 35-55 years who worked in 20 civil service departments at the baseline evaluation. A screening phase occurred between 1985-1988 with over 10 000 persons, and comprised a clinical examination and a self administered questionnaire. In Phase 3 of the study (1991-1993, n = 8000) a nutrition survey was given to participants. For this paper, only those 60 years of age by the end of the following period (2007-2009) and with no history of stroke, myocardial infarction, or cancer were included. The final groups of people studied were 5350 persons (3775 men and 1575 women).
The food questionnaire administered during the study, consisted of 127 food items and the selected food items/category was converted to a daily intake. The groups were then categorized into western type diet (fried food, processed food and red meat, pies, high fat dairy products) and healthy foods (high intake of vegetables, fruits and fish).
Cardiometabolic functioning was assessed by blood pressures; respiratory functioning was assessed by forced expiratory volume in 1 second/height squared; musculoskeletal functioning was assessed by walking speed over a 8 foot walking course and good cognitive functioning was assessed using a sum of cognitive scores from 5 cognitive tests. Five aging outcomes were considered for this study (1) ideal aging, (2) non fatal cardiovascular disease at follow up (3) cardiovascular death and (4) non cardiovascular death. Criteria for ideal aging, starting at age 60 years or older, at the last follow up examination included: being alive, having no chronic diseases (such as coronary heart disease), stroke, cancer or diabetes, absence of mental health problems, and good cardio-metabolic, respiratory, musculoskeletal and cognitive functioning.
Over the 16 years period, 12.7 % of the cohort developed non fatal cardiovascular disease, 2.8% died from cardiovascular disease and 7.3% died from non cardiovascular causes. The remaining 73.2% followed a natural aging course. Diet data was examined based on two types of patterns – “healthy foods” and ‘western type”. Higher scores on the Western diet were associated with higher odds of cardiovascular and non cardiovascular mortality (OR= 1.53 and 1.36) in adjusted models. Persons in the highest tertile of the Western dietary pattern, compared to the lowest tertile, were more likely to have poorer musculoskeletal and cognitive functioning. There was no association noted between the Western Diet and indicators of cardio-metabolic and respiratory functioning and mental health.
Interestingly, the health food dietary pattern did not demonstrate any significant associations with the 4 aging outcomes contrary to the literature which has demonstrated a protective effect of vegetarian diet or low meat to health outcomes. This result however should be interpreted cautiously, as in this cohort there were very low numbers of meat non eaters and the study did not attempt to classify whether participants were vegetarians.
Nevertheless, this study did provide a model for examining how multiple aging phenotypes could be analyzed simultaneously in a cohort to inform patterns associated with dietary intake and habits. In addition, it also reinforced that recommendations of other studies, that an avoidance of the Western diet could improve the possibility of achieving older ages free of chronic disease in addition to remaining highly functional.

Want to read more? Here are 3 articles you can refer to, to learn about the diet, nutrition and overall health.

Akbaraly T, Sabia S, Johnson G et al. Does Overall Diet in Midlife Predict Future Aging Phenotypes? A Cohort Study. The American Journal of Medicine (2013) 126, 411 419

Sofi F, Cesari F, Abbate R et al. Adherence to Mediterranean diet and health status: meta analysis. BMJ 2008:337: a1344.

Sundstrom J, Riserus U, Byberg al. Clinical value of the metabolic syndrome for long term prediction of total and cardiovascular mortality: prospective, population based cohort study. BMJ 2006: 332 (7546): 878-882

Thanks for reading.
Author: Neelum Aggarwal MD at 2:34 PM 0 Comments

Saturday, December 21, 2013

2013 Year in Review

Dear Readers,

In this final blog of 2013, I would like to review some of the highlights of what has happened in the world of Alzheimer’s disease research, as well as the new directions that we will likely be heading in 2014.

As Amyloid Imaging Moves to the Clinic, Tau Tracers Come of Age

Advances in brain imaging, specifically amyloid PET scans, have led the way towards earlier identification of AD. Their widespread use in larger studies has made it possible to visualize the presence of beta-amyloid deposition in individuals with no symptoms.

We began 2013 with the publication of additional data showing that amyloid deposition in the brain leads to atrophy, or shrinkage, of specific brain areas, even before patients develop memory loss. Research groups in France, Australia and the United States reported longitudinal studies of amyloid deposition in the brain, demonstrating that its presence predicts subsequent brain atrophy and cognitive decline.

Additional developments in brain imaging were made with results of Avid’s Tau tracers, both of which allow for visualization of the abnormal Tau protein that contributes to the formation of the neurofibrillary tangles of AD. Tau PET scans will undoubtedly become a critical tool in AD research over the next few years, much like amyloid imaging has been so important since the first papers were published on its use 9 years ago.

Understanding AD in People with Down Syndrome

- Every person with Down syndrome (DS) will develop AD pathology by age 40
- Half of the DS population develops dementia by age 60

In the spring of 2013, the NIH held a meeting focusing on Alzheimer’s disease among people with Down syndrome, bringing researchers together to discuss ways to develop a consortium with an aim to understand AD in this highly susceptible population.

The Down Syndrome Biomarker Initiative (DSBI) pilot study was launched this year as a feasibility study of a planned large-scale study to discover indicators of Alzheimer’s disease in Down syndrome, with the ultimate goal of better understanding brain aging and AD in adults with Down syndrome.

Rand Weighs in on the Economic Impact of Dementia

A major publication in the New England Journal of Medicine by the RAND Corporation estimated the economic cost of dementia to the United States was approximately $203 billion in 2010. This paper garnered major attention, as it was a well conducted analysis of the economic impact of dementia. The sheer dollar amount is greater than the cost of any other disease faced by our society, and is expected to rapidly increase in the next decade.

Trials and Tribulations

2013 was also the year when the long awaited results of the phase III IGIV study were presented, which were unfortunately, negative. Additionally, researchers who were studying the drug Bexarotene were able to replicate some, but not all of the previously reported effects of this drug on memory and beta-amyloid in mouse models of AD. Nonetheless, a placebo controlled clinical trial of Bexarotene was launched this year for the treatment of AD with results expected in mid 2014.

Prevention and Early Intervention

Perhaps one of the biggest events in the AD world this year was the launch of the first clinical trial to prevent AD dementia in the general population. The trial, Anti-Amyloid in Asymptomatic Alzheimer’s Disease, or A4, is a three year long study looking at the effectiveness of a drug given to subjects who have absolutely no outward symptoms of memory loss, but have positive amyloid scans of the brain. Much will be learned when this study is completed about how soon intervention can be offered in efforts to prevent AD.

New Resource from HHS

Also in this year, the U.S. Department of Health and Human Services (HHS) successfully launched a new website, to increase public awareness, provide resources for individuals with a diagnosis, and connect their caregivers with important resources.

G8 on Dementia

And finally, global focus on dementia was raised at this year’s G8 summit. All G8 nations made commitments to develop an international action plan for research, share information and data across the G8 countries and to provide unprecedented collaboration. The G8 plan includes open access to all publically-funded dementia research, the introduction of a new global envoy for dementia innovation, and the ambitious aim to "find a cure or disease-altering therapy by 2025.” This plan parallels the US National Alzheimer’s Project Act (NAPA), with a goal of ‘preventing or effectively treating AD’ by 2025.

AD Research: What’s on the Horizon in 2014?

There are an unprecedented number of clinical trials now running with the aim of preventing AD. Another 3 are being conducted in prodromal AD, where patients have mild cognitive impairment rather than dementia. As data from recent studies suggest, it may only be through early intervention, before the symptomatic stage, that we can truly affect the course of AD and even consider preventing its dementia stage.

We anticipate more discoveries this upcoming year with Tau imaging, as well as the use of biomarkers in asymptomatic individuals. New data is also expected from large-scale whole-genome studies, which are revealing other AD susceptibility genes. We also look forward to data from some of the new mouse models created with these newly discovered mutations to understand how they contribute to the development of AD, and perhaps represent therapeutic targets.

We look forward to keeping you updated on what is happening in the world of AD research in the upcoming year, and are optimistic that there will be great developments in the field of AD in 2014.

Stay tuned.

Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
Author: Michael Rafii MD,PhD at 11:26 AM 0 Comments

Thursday, December 12, 2013

ApoE Exerts Effects on Brain in Infancy

Dear Readers,

In a paper published last week in the journal JAMA Neurology, researchers at Brown University show in a magnetic resonance imaging (MRI) study of 162 babies up to 25 months of age, that those who inherited the ApoE4 allele develop myelin, the insulating material around nerve cells, later than people who do not have ApoE4. In addition, the volume of brain areas typically affected in AD was smaller in E4 infants, and frontal areas were larger.

Readers of this blog will recall that ApoE4 status is associated with an increased risk of Alzheimer’s disease and elevated amyloid deposition. It is believed that the different forms of ApoE (2, 3 and 4) appear to regulate the removal of beta-amyloid from the brain, and they do so with different efficiencies. It has been shown that ApoE4 seems to be the slowest in removing beta-amyloid from the brain, which may be why it confers the most genetic risk. This paper shows an effect on brain structure that is observable starting in infancy.

It is well known that glucose metabolism of brain areas affected by AD decreases years before dementia develops in people carrying the ApoE4 allele. In fact, the brain’s circuitry becomes disrupted in young adults and older E4 carriers prior to amyloid depositing into plaques. MRIs have shown brain thinning and reduced volumes in AD-vulnerable brain regions among ApoE4 carriers in childhood.

It is thought that the ApoE transports in addition to beta-amyloid two components of myelin—cholesterol and lipids. If AD damages myelin, people who have the E4 version of the ApoE protein may be slower at repairing the damage, thus making them more likely to develop AD.

Although ApoE4’s effects on myelination in AD-related areas during infancy are intriguing, a longitudinal study following patients over time would help further clarify this relationship.

Dean et al. Brain Differences in Infants at Differential Genetic Risk for Late-Onset Alzheimer Disease: A Cross-sectional Imaging Study. JAMA Neurol. 2013 Nov 25;

Thanks for reading.

Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
Author: Michael Rafii MD,PhD at 8:46 AM 0 Comments

Thursday, December 05, 2013

Imaging Neurofibrillary Tangles - A new tool to visualize dementia

Dear Readers,

The significance of amyloid imaging in accurately identifying patients with AD cannot be overstated. Rather than having to wait until autopsy, we are now able to visualize amyloid plaques in living patients. As readers of this blog will recall, about 30% of people over age 65, who have no memory problems, will indeed have amyloid plaques in the brain. This leads to the ability to predict, in normal individuals, who will develop dementia due to AD. Of course there are some caveats, the most important one being the fact that we cannot yet predict exactly when the person with a positive scan will develop dementia. We only know that they are at a much higher risk for developing dementia.

However, amyloid imaging is only one part of the story. It is well known that although amyloid plaques are a defining feature of AD brain pathology, it is the neurofibrillary tangles inside of neurons that reflect neuronal disease. And, the amount of neurofibrillary tangles correlates with the level of dementia in patients better than does the amount of amyloid plaques in the brain.

We now have a Tau tracer that is being used to visualize neurofibrillary tangles in patients. Dr. Keith Johnson at Massachusetts General Hospital presented data a few weeks ago at the Clinical Trials in AD (CTAD) meeting from Tau imaging studies on patients with AD, as well as MCI. The same patients had also undergone amyloid imaging, so a direct comparison of the distribution of amyloid and neurofibrillary tangles could be made. This is a major breakthrough in the field because we will soon have the capability of imaging both of the key pathological features of AD, amyloid plaques and neurofibrillary tangles over time, and literally see how they develop in conjunction with each other, from the earliest, least symptomatic stages of AD through the full dementia stage. These tools will be invaluable, not only in diagnosing and staging patients, but also in assessing drug effect.

Thanks for reading.

Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
Author: Michael Rafii MD,PhD at 4:14 PM 0 Comments

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About Us

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.