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Thursday, March 27, 2014

What is Gender Medicine and why is it important to Alzheimer’s disease?

By Neelum Aggarwal, M.D.
Rush Alzheimer’s Disease Center

Prior to the mid-1900s, there was very little discussion about gender medicine. However, with the establishment of the Partnership for Gender Specific Medicine at Columbia University (1997), the Karolinska Institute (2002), and the Charité -Universitätsmedizin Berlin (2003), studies began to systematically examine comparisons between women and men. Over the last 20 years research has slowly but steadily begun to demonstrate the extent of these sex differences, but have also produced advancements in treatment, prevention and diagnosis. The result of this progress led to the 2010 Institute of Medicine declaration that being a woman or a man significantly affects disease course and should be considered in both diagnosis and therapy.

What is the difference between sex and gender and how is it related to medicine?
Gender medicine aims to improve treatment for women as well as for men, and differs from women’s health, because it also focuses on men’s health.

Gender medicine deals with the effects of sex, including biological differences between females and males. Examples of sex differences can include different concentrations of sex hormones, different expression of genes on X and Y chromosomes, or simply reporting a higher percentage and deposition of body fat in women.

Gender however, is the result of socio-cultural processes. Associated with behavior, stress, and lifestyle-related diseases, gender has been shown to determine access to health care, help-seeking behavior, and even individual use of the health care system. Recent studies have shown that gender largely determines one’s compliance with preventative measures, and whether one follows up on referrals or accepts invasive strategies like a pacemaker implant, heart transplant, or other surgeries.

Although the definitions of sex and gender appear straightforward, in medicine, it isn't always that easy to separate the influence of sex and gender on disease. For example, clinical manifestations of prevalent diseases have been shown to differ in women and men; with the question remaining, how much of these differences are due to sex differences in disease mechanisms? One area of medicine that has made great strides in this area is in cardiovascular diseases. Cardiovascular disease risk factors, disease and symptoms of atrial fibrillation, myocardial infarction, and heart failure all have been shown to have sex and gender differences, and have resulted in separately developed suggested treatment plans for men and women.

Alzheimer’s disease ( AD) is the latest medical condition to be put front and center in the sex and gender discussion. Data suggests that the risk for AD and memory decline appear to increase in women after menopause.

Reports have noted that a woman’s overall lifetime risk of developing AD is almost twice that of a man – a statistic not solely due to the fact that women live longer than men. Other areas of study are demonstrating notable sex and gender differences in basic brain structure and function between men and women. In addition, specific AD related risk factors that include cardiovascular disease, genetics (APOE 4 genotype) and depression all have shown to have sex and gender differences and could account for these observations.

Dr. Aggarwal is a cognitive neurologist at the Rush Alzheimer’s Disease Center in Chicago and a Steering Committee member of the Alzheimer’s Disease Cooperative Study.

Author: Neelum Aggarwal MD at 2:33 PM 0 Comments

Thursday, March 20, 2014

New Protein Implicated as Central to Alzheimer’s Disease

Dear Readers,

As many of you are aware, a major puzzle in the Alzheimer’s field has been the issue of how it is possible that some patients can have amyloid plaques and neurofibrillary tangles in the brain, but not show symptoms of dementia, while other patients are fully symptomatic. For years, researchers have explained that this observation is a result of ‘cognitive reserve,’ that is, some protective ability in certain individuals that provides resilience despite the presence of brain pathology.

Now, we have another possible explanation as to why some individuals are protected while others are not. Researchers at Harvard Medical School have published a monumental effort in the journal Nature, showing that a protein called RE1-Silencing Transcription factor (REST), that functions as a gene regulator during fetal brain development, switches back on later in life to protect aging neurons from various stressors, including the toxic effects of abnormally accumulating proteins such as beta-amyloid.

To understand REST's functions, the team genetically engineered mice that lacked REST only in their brains and watched what happened as they aged. Intriguingly, as the mice grew older, neurons in their brain started to die in the same places as in Alzheimer's patients. The research team also studied the REST protein in the worm C. elegans and found that it is necessary to protect against toxicity, thereby suggesting REST’s protective function in the aging brain is shared across species.

The team further showed that the REST protein was abundant in normal aging human brains. The brains of people who developed mild cognitive impairment, by contrast, showed an early decline in levels of REST. The affected brain regions of people with Alzheimer's were nearly devoid of the REST protein. The findings were also noted in the brains of patients with other neurodegenerative diseases that cause dementia, including frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB). It appears that the toxic protein in each circumstance, beta-amyloid in AD, Tau in FTD and alpha-synuclein in DLB, bind to and inactivate REST, prohibiting its ability to perform its normal functions.

Getting back to the question about cognitive reserve and why some patients don’t exhibit dementia symptoms despite pathology, the researchers examined brain tissue gathered as part of the Religious Orders Study. Participants in the study were clergy who had detailed annual cognitive assessments performed and donated their brains for study after death. The team sorted the samples into two groups. One group had Alzheimer's pathology and experienced symptoms of dementia. The second group had the same amount of Alzheimer's pathology but did not have dementia. The researchers found that the group with no dementia had at least three times more REST protein within key brain areas. Furthermore, REST levels were highest in the brains of people who lived into their 90s and 100s and who remained cognitively intact. And, the levels were high specifically in the brain areas that are most vulnerable to Alzheimer's disease.

So what do all of these findings mean?

The human body has an incredible capacity for healing, and aging is, in essence a balance between damage and repair. In the liver, cells contain various proteins that process compounds and other molecules, including toxins to maintain health. And so it appears that the brain has its own detoxification system, one that involves the REST protein, a gene regulatory protein that turns on a host of other proteins to help protect neurons from age-related toxicities, including the accumulation of beta-amyloid.

The identification of REST as an endogenous neuroprotection system, so intimately involved in AD, identifies it as a prime target for intervention and drug development. One can imagine that by somehow increasing REST levels in the brain, we could increase resilience and reduce the occurrence of the brain dysfunction we call dementia that results from neurodegenerative disease. Undoubtedly, we will see more research following up on this important discovery.

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 12:18 PM 0 Comments

Thursday, March 13, 2014

A Possible New Blood Test for AD?

Dear Readers,

According to a study published last week in the journal, Nature Medicine, a team of researchers has identified 10 lipids in the blood that may be able to detect the early signs of Alzheimer’s disease (AD).

The study included 525 healthy participants aged 70 and older who gave blood samples upon enrolling at various points in the study. Over the course of the five-year study, 74 participants met the criteria for either mild AD or mild cognitive impairment (MCI). Of these, 46 were diagnosed upon enrollment and 28 developed MCI or mild AD during the study (the latter group called converters.

In the study's third year, the researchers selected 53 participants who developed aMCI/AD (including 18 converters) and 53 cognitively-normal matched controls for the lipid biomarker discovery phase of the study. The lipids were not targeted before the start of the study, but rather, were an outcome of the study.

They discovered a panel of 10 lipids, which researchers say appears to reveal the breakdown of neural cell membranes in participants who developed symptoms of cognitive impairment or AD. The panel was subsequently validated using the remaining 21 MCI/AD participants (including 10 converters), and 20 controls. The lipid panel was able to distinguish with 90 per cent accuracy these two distinct groups – cognitively normal participants who would progress to mild cognitive impairment or Alzheimer’s disease within two to three years, and those who would remain normal over the same time interval.

The study has garnered a significant amount of attention, as the need for an easy, inexpensive, and accurate test for AD cannot be found soon enough. However, it should be kept in mind that the findings of the paper are part of a long standing effort by researchers who have been working for at least a decade on a blood test for AD. For this finding to be truly stand apart from the rest, the lipid panel’s predictive power will need to be confirmed in a larger sample of participants.

As readers will recall, the accumulation of beta-amyloid seems to be the driving force behind brain cell injury in AD, leading to a cascade of events that further damage brain cells and compromise cognitive function. As the disease worsens and more neurons die off, atrophy or shrinkage of brain tissue occurs. Some of the most reliable tests in the field include measurements of brain atrophy with volumetric MRI, measures of beta-amyloid in the spinal fluid and detection of amyloid with amyloid PET scans. The premise behind a blood test would be to find a surrogate in the blood for these brain changes. Many have looked at beta-amyloid itself, as well as markers of inflammation. This most recent paper raises the possibility that we may be closer to finally having a blood-based test for AD.

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 11:09 AM 0 Comments

Thursday, February 20, 2014

Citalopram May Help Reduce Agitation in AD Patients

Dear Readers,

Data from the the Citalopram for Agitation in Alzheimer Disease(CitAD)study was recently published in the Journal of the American Medical Association. The study enrolled 186 patients with probable AD, with an average age of 78, and followed them for nine weeks. None of the participants had major depression or psychosis requiring treatment. Researchers randomly assigned the participants to citalopram or placebo. All participants also received psychosocial interventions that included education materials, crisis management, and individual counseling sessions. At the conclusion of the nine week study, researchers found a statistically significant improvement in the citalopram group compared with the placebo group on the Neurobehavioral Rating Scale-Agitation, which assesses symptoms such as agitation, hostility, and disinhibition, with higher scores indicating more severe symptoms.

Moreover, 40% of the patients receiving citalopram had moderate or marked improvement from baseline severity on the modified Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change score, which assesses items specific to agitation in AD. This compared to 26% of the patients taking placebo. The fact that 26% of patients on placebo improved is important to note, and resulted from the benefits associated with the psychosocial interventions offered as part of the study.

Interestingly, the effect of citalopram on agitation is about the same as that reported for the atypical anti-psychotic drugs, such as olanzapine and risperidon.

What do the results of this study mean? Citalopram is one of many selective serotonin reuptake inhibitors, which are primarily used as anti-depressants. However, in patients with AD, where multiple neurotransmitter systems are becoming disrupted and leading to behavioral symptoms, the use of anti-depressants may provide some benefit. Additional studies should determine the duration of benefits beyond nine weeks of treatment. And, physicians should also continue to emphasize non-pharmacologic strategies to manage agitation. However, this study is a very important first step in looking at new therapies for a very challenging aspect of AD.

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 11:50 AM 0 Comments

Tuesday, February 11, 2014

Increasing Diversity in Clinical Trial Participation in Upcoming ADCS Trials

Over the last few years, increased attention has focused on disparities in health that exist between white Americans and other racial and ethnic minorities. Data from national health surveys has consistently shown that racial and ethnic minorities have higher rates and greater severity of disease than whites, for most, if not all leading causes of morbidity and mortality in the US. These include heart disease, cancer, stroke, diabetes and dementia. Yet, the majority of persons who continue to participate in medical research (including both prevention and treatment trials), often represent the well educated, middle class, married, white population.

Major reasons given for under-representation of minorities in clinical trials include mistrust of researchers and health insitutions, lack of awareness of clinical trials by minorities, inadequate involvement of minority investigators in the recruitment process, cultural differences, economic limitations, less access to both health care and to research facilities. Existing data has shown that minority participation in clinical trials is especially low among older persons.

The major barriers to recruitment and and participation in clinical trials, has traditionally centered around the physician’s concern for the patient, concerns about the conduct of studies, and concerns about the role as both physician care manager and trial researcher. In surveys conducted with physicians, they have often expressed that there a is intellectual and emotional tension between the role they have defined as a physician, which places the health interests of the individual patient first, and the role they define as a researcher, which places the benefit to humanity in general, second. As physicians have not received formal training in either medical school or residency regarding the roles and duties that are associated with that of a Principal Investigator/ Trial Researcher, many are unclear and uneasy about recommending participation in trials to their patients.

Since the ultimate goal of any clinical trial is to recruit and retain study participants, barriers to subject participation must also be understood and minimized. Patient concerns have often related to time commitments needed for participation, negative personal and family attitude regarding trials and their safety, and inadequate evidence of benefits from trial participation.

The challenge facing many large scale trials is to recruit diverse populations to participate in a wide range of prevention and treatment studies. In doing so one must carefully consider how we define diversity in trials. One set of guidelines put forth by the National Institute of Health, was developed to ensure that women and minorities are included in trials, and utilizes purely demographic categories. On the other end of the spectrum are the epidemiologists and social sciences researchers, who define diversity based on descriptors such as age, marital status, sex, race, ethnicity, religious affiliation, education level, socioeconomic status and other socio-cultural attributes. Despite all these efforts for characterization it is very important to recognize that diversity within ethnic and racial group will exist. No group is entirely homogeneous, and as such, many socio-cultural factors can converge and influence the individual’s behavior when a person considers participating in a trial.

Another area that has been shown to impact participation in trials in both minority and non-minority populations is the concept of health and disease. Health and illness concerns vary widely within and across ethnic populations. Chronic illness and disability are not always viewed as problems that are appropriate for intervention. For some groups, illness may be a burden that the individual or family is expected to bear. Such beliefs have shown to alter and affect the probability that people will participate in trials.

With the changes in the healthcare delivery underway, and the emergence of “population health” as a discipline within itself, it is becoming apparent that biomedical research and specifically, clinical trials, can have a prominent role in determining the most effective method of prevention and treatment of chronic conditions for all segments of the population. Encouraging and involving physicians and patients to consider participating in clinical trials should be viewed as opportunities to enhance our understanding of treatment and prevention outcomes.

Dr. Neelum Aggarwal is a cognitive neurologist at the Rush Alzheimer’s Disease Center and Rush University Medical Center, and serves on the clinical trial Steering Committee for the NIH-funded Alzheimer’s Disease Cooperative Study (ADCS).

Author: Neelum Aggarwal MD at 9:31 AM 0 Comments

Thursday, February 06, 2014

Watching Memories Form

Dear Readers,

In a technological tour de force, researchers at Albert Einstein College of Medicine of Yeshiva University have published two studies in the January 24 2014 issue of the journal, Science, that provide an unparalleled window into how the brain makes memories. Such insights into the molecular basis of memory formation have never before been achieved in animals.

Einstein researchers developed a mouse in which they fluorescently tagged all molecules of messenger RNA (mRNA) that code for the beta-actin protein – a key structural protein found in large amounts in neurons and considered a key player in making memories. mRNA is a family of RNA molecules that copy DNA's genetic information and translate it into the proteins that make life possible.

The researchers then stimulated neurons in the mouse's hippocampus, where memories are made and stored, and watched fluorescently glowing beta-actin mRNA molecules form in the nuclei of neurons and travel within dendrites, the neuron's branched projections. They discovered that mRNA in neurons is regulated through a novel process described as "masking" and "unmasking," which allows beta-actin protein to be synthesized from the mRNA.

As readers of this blog will recall, neurons communicate with each other at synapses. Studies over the past 30 years have demonstrated that repeated stimulation increases the strength of synaptic connections by changing the shape of synapses. Beta-actin protein plays an important role in physically strengthening these connections. Memories are thought to be encoded when stable, long-lasting synaptic connections form between neurons in contact with each other.

The relevance of such research in the field of AD cannot be overstated. By seeing the physical nature of memory formation, we can now look at this process in various disease states, including memory robbing diseases such as AD. Further, we can better understand how beta-amyloid may perhaps interfere with the brain’s memory machinery.

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 2:12 PM 0 Comments

Wednesday, January 22, 2014

More Data on DHA and AD

Dear Readers,

As many of you are aware, there is growing evidence that dietary changes can affect the brain’s structure and even functioning. For example, higher adherence to a Mediterranean-type diet has been shown to be associated with decreased cognitive decline. The typical dietary pattern of the Mediterranean-type diet is characterized by a high intake of vegetables, fruits and nuts, legumes, ?sh and monounsaturated fatty acids; relatively low intakes of meat and dairy products; and moderate consumption of alcohol. In fact, higher consumption of olive oil, very rich in monounsaturated fatty, is considered the hallmark of the traditional Mediterranean-type diet.

One particular form of omega-3 fatty acid, called DHA, which is the most abundant fatty acid in the brain, has been of particular interest in regards to AD. In 2006, researchers at the USDA Human Nutrition Research Center on Aging at Tufts University found individuals with the highest DHA levels had a 47% reduction in all-cause dementia and a 39% lower risk of developing AD. In that study, which was a nine-year prospective, follow-up cohort study researchers analyzed completed dietary questionnaires and measured DHA blood levels of 899 study subjects who were participating in the Framingham Heart Study.

Neuropsychological testing revealed that all study participants were dementia-free at baseline. Thereafter, subjects had their cognitive function tested every two years using the Mini-Mental State Examination (MMSE). Those who experienced a decline of three or more points on the MMSE from the most recent exam were called back for a neurological and neuropsychological examination. The study population was 36.5% male and had an average age of 76 years. Plasma samples were measured for plasma DHA. In addition, a subgroup of 488 patients completed dietary questionnaires.

During the study period, 99 of 899 subjects developed dementia, including 71 cases of AD. Researchers divided individuals into quartiles according to their blood DHA levels. Those in the upper quartile experienced a significantly lower risk of all-cause dementia and AD compared with participants with levels in the lower three quartiles.

However, there are two ways to measure blood DHA: to directly measure it in the plasma fraction of blood, or to measure it within the red blood cells. It turns out that red blood cell DHA reflects dietary DHA intake up to 120 days, whereas plasma concentrations reflect intake over only the last few days.

Last year, researchers looked at red blood cell DHA levels and found that lower red blood cell DHA levels are associated with smaller brain volumes even in persons free of clinical dementia. The MRI finding of lower brain volume represents a change equivalent to approximately two years of structural brain aging.

For the latest study, Pottala and colleagues looked at the omega-3 fatty acids levels in the red blood cells of 1,111 women who participated in the Women's Health Initiative Memory Study. The women had MRI scans eight years after the study began to measure their brain volume. They were an average of 78 years old. Those with the highest levels of omega-3 fatty acids in their red blood cells had a 2.7% larger volume in the hippocampus portion of the brain compared with those with the lowest levels of omega-3 fatty acid and those with the highest levels of omega-3 fatty acids in their blood had 0.7% larger overall brain volume compared with those with the lowest levels.

What do these results mean? More data is accumulating that high dietary omega-3 acid levels may reduce the risk of AD in healthy individuals and also reduce the atrophy or shrinkage rate of the brain, including that of the hippocampus. Of course, one must consult with their doctor or pharmacist before purchasing or taking any supplement, as they can interact with medications. But we remain excited about the possibility that diet may influence AD risk.

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 4:17 PM 0 Comments

Wednesday, January 15, 2014

Potential Early Biomarker of AD

Dear Readers,

Many readers are familiar with Apolipoprotein E, and its effects on AD risk. Now, another protein called apolipoprotein J, also called ‘clusterin’ has been implicated in AD. Apolipoprotein J, turns up repeatedly in large genome-wide association studies of Alzheimer’s disease. The protein is known to be involved in the clearance of cellular debris and prior studies have suggested that people who already have Alzheimer's disease have more Apo J in their blood. In fact, Apo J levels in blood correlate with faster cognitive decline in individuals with Alzheimer's disease.

Now, researchers led by Rahul Desikan at the University of California, San Diego, found that a combination of low beta-amyloid and high Apo J in the cerebrospinal fluid (CSF) of people without dementia identifies those who have the earliest signs of brain atrophy as judged by MRI imaging. The specific atrophy seen in AD is shrinkage of the part of the brain called the entorhinal cortex, and this is exactly what was observed.

The entorhinal cortex is a hub in a widespread network for memory and navigation, and connects the hippocampus with the rest of the brain. The entorhinal cortex is the first area of the brain that degenerates in AD, and is the entry way of information into the hippocampus which consolidates short term memory into long term memory. As such, atrophy and dysfunction of the entorhinal cortex, as well as that of the hippocampus, is thought to serve as the basis for the extensive memory loss observed in AD.

What do the findings of this paper mean? Apo J may be a potential early biomarker of AD. It also helps explain the mechanism by which beta-amyloid causes degeneration, by its known interactions with Apo J. More work is needed, but this paper has certainly brought Apo J into the spotlight.

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 2:14 PM 0 Comments

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

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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.