Perspective on Funding for AD Research

Contributed by: Dennis Fortier, President, Medical Care Corporation
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Amidst all the news stories about the science of Alzheimer's disease, there are also stories about it's economic toll on our health care system and stories about the allocation of research dollars aimed explaining the disease and developing treatments. This week, the NIH released a statement about the American Recovery and Reinvestment Act and how some of its funds are directed at the Alzheimer's problem.

Overall, it is an encouraging piece of news citing the fact that more than 100 Alzheimer's related grants, aimed at identifying risk factors, improving diagnostics, isolating bio-markers, conducting trials, and developing new therapeutic agents, were funded through the act. Specific details were provided for the Alzheimer's Disease Neuroimaging Initiative (ADNI) which will receive $24 million in funds, and the Alzheimer’ Disease Genetics Consortium (ADGC) which will receive about $5.4 million in funds. Certainly these are large grants and represent opportunities to advance the science.

However, this news should be considered against the larger funding context that is also discussed frequently in the news. The big picture is painted clearly by Harry Johns, CEO of the National Alzheimer's Association, through his daily comments to constituents across the country.

A summary in The Detroit News on Monday makes his point. The NIH awarded $6B to cancer research last year. They awarded a further $4 billion for cardiovascular disease and $3 billion for HIV/AIDS. In comparison, the NIH funds for Alzheimer research was $428 million.

With this perspective, it is clear that the potentially devastating impact of Alzheimer's disease on the boomer generation is not reflected in the funding support of the federal government.

Is Memory Screening a Good Idea?

Contributed by: Dennis Fortier, President, Medical Care Corporation
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Is Memory Screening a Good Idea?

Yesterday was National Memory Screening Day and, as usual, there were many editorials in print and online discussing the pros and cons of memory screening. As is often the case, the answer to the question that headlines this article varies greatly depending on whom you ask. When discussed in the press, I rarely see a balanced view of pros and cons but rather a biased presentation of the "facts" aimed at supporting the author's opinion. Here's a summary of what I consider to be the most important considerations.

First, the term "screening" is open to interpretation and is generally used inconsistently from author to author depending on their respective attitudes toward screening.

For those who tend to be against memory screening, they usually adopt the traditional definition of screening which suggests that programs are perpetrated on large populations of symptom free subjects, perhaps even against the will of the subjects. I would agree that a comprehensive, population-based approach is probably not a good idea for many pragmatic reasons related to educating and further evaluating the multitudes of people whose screening results would warrant further attention.

Those who support memory screening tend to adopt a definition consistent with "case finding". This essentially means performing a memory assessment on those with concerns about their memory or evidence that it is declining. With this definition, I would support the general argument that, for people who have a memory concern, some type of evaluation (a screening if you will) should be available to them. This makes sense and would greatly improve our ability to intervene against problems in their earliest stages.

It strikes me that if we could all adopt a common understanding of what is meant by "memory screening", most of the controversy and debate would likely vanish. Having said that, there are three other prominent themes in the argument against memory screening that are not related to the definition of “screening”. Here are my comments on those themes.

Type I Errors – False Positives

This pertains to the possibility of inflicting unnecessary angst in healthy people who could be improperly assessed and mistakenly told that their memory is impaired. Those against memory screening speculate that this could lead to undue anxiety, depression, and even suicide. While that may be plausible, there is really no supporting evidence and it is probably off base. The few studies that have been conducted on attitudes toward screening have shown that people seeking memory assessment are often anxious from the outset and learning the result of an assessment, be it positive or negative, tends to reduce their anxiety.

Type II Errors – False Negatives

This pertains to the possibility that unsophisticated screening instruments or untrained screeners could miss signs of impairment and mistakenly tell symptomatic subjects that they are healthy. This of course might reduce the likelihood of that person seeing a physician and getting good care. That’s a reasonable argument and is likely to be true because we know that patients may seek second opinions when they get “bad medical news” but they are far less likely to do so after receiving “good medical news”. I think it is reasonable to insist that a beneficial memory assessment program would require both the use of a well-validated assessment instrument and well trained administrators.

The Importance of Medical Expertise

This argument suggests that, regardless of mistakes in either direction, people learning that they have a memory problem may fear Alzheimer’s disease as the underlying cause and these people should be counseled and educated immediately to assuage their anxiety. If the structure of a screening program is “high volume” and “public” in nature, then it may be conducted in an environment lacking the medical expertise that some patients will require. I would agree that there may be some real costs associated with screening programs that are not conducted within a framework capable of providing proper follow-up attention to subjects who learn of memory impairments. These costs must be considered in the evaluation of any program's merit.

A Commonly Neglected Perspective

In general, the discussions I see in the media tend to consistently neglect one important aspect of the anxiety consideration. A high percentage of the people that seek to participate in self-selecting memory assessment programs (that is, programs for which one may voluntarily seek to have their memory assessed), are already somewhat anxious about a perceived decline in their memory. We know that such anxiety is often unfounded and that many worries are merely a slowing of name recall or diminished concentration associated with normal aging. As such, voluntary memory screening programs may reassure and relieve anxiety in a high number of normally aging individuals who have been needlessly worrying about their cognitive health. This is a real benefit that should be weighed against other costs when evaluating the value of a given program.

To summarize, we may not be ready for widespread memory screening but we are certainly ready for programs that provide accurate assessment and expert follow-up for those individuals who perceive a decline in their memory. Doing so is one of the best approaches available for promoting early intervention and effective treatment for many aging people with medical conditions that impair cognitive function.

What Causes Dementia?

Contributed by: Dennis Fortier, President, Medical Care Corporation
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Because the general media commonly interchanges the terms "Alzheimer's" and "dementia", there is much confusion about the definition of each and the difference between the two. As such, I like to offer a clarifying viewpoint on a regular basis.

Alzheimer's is a disease. We don't completely understand it but the development of amyloid plaques and neurofibrillary tangles in the brain seem to play a role.

Dementia is a descriptive term for the symptoms caused by disorders that impair cognition. Specifically, if memory and at least one other realm of cognition (judgment, executive function, verbal fluency, etc.) decline to the point where they interfere with daily life, then the condition is dementia.

A key point is that there are many causes of dementia; Alzheimer's is merely one of them. Vascuclar disease, Parkinson's disease, and Normal Pressure Hydrocephalus and others are also on the list. The conditions and disorders that cause memory loss are worth learning about.

The distinction between memory loss and dementia, and the causes of each are well developed in a recent article on examiner.com by Patricia Grace. This perspective and other good views are presented regularly at the blog: AgingwithGrace.net.

Stigma and Dementia

Contributed by: Dennis Fortier, President, Medical Care Corporation
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Here's the definition of "stigma": a mark of disgrace associated with a particular circumstance, quality, or person.

It's really a shame that so often, stigma is a pure social construction based on poor understanding of a circumstance. Having an illness, for example, should never be stigmatizing and in a more informed world, it never would be.

Readers of this blog know how strongly I feel about the importance of awareness and education as parts of a solution to the growing dementia problem, specifically as it pertains to dementia caused by Alzheimer's disease. The greater the understanding and the more prevalent the discourse, the more we can reduce the stigma that holds many back from seeking help while they are still quite healthy and more likely to respond to treatment.

I recently read a great entry at one of the blogs I follow, ElderCareTalk, written by Laura Bramly. She tells an inspiring story about the strength of elders who rise above the stigma and help the rest of us see them for all that they are. I encourage you all to read it.

The Brain Healthy Lifestyle

The “Brain Healthy” Lifestyle Contributed by: Dr. Bernard Croisile, MD (Neurology), Ph.D, Chief Science Officer, HAPPYneuron
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We are all eager to learn how best to keep our brains healthy as we age and much research is underway in that regard. While evidence is still building in many areas, it is clear that certain aspects of a “brain healthy” life style have no downside and should be considered as potential, immediate additions to our regular routines.

Among the approaches with meaningful evidence of benefit are the following six:

1. Physical Exercise
2. Balanced Diet
3. Socialization
4. Stress Reduction
5. Adequate Sleep
6. Cognitive Stimulation

While the most well researched avenues to brain health are balanced diet and physical exercise, there is mounting support that these other four areas should be seriously considered in anyone’s strategy to age with cognitive vitality. Among the public, there is particularly strong interest in learning more about the benefits of cognitive stimulation.

To stay sharp and defer brain decline, the scientific evidence shows that the odds of success are significantly increased by living a “brain healthy” lifestyle and that wide and varied cognitive stimulation is a critical element of such a lifestyle. To achieve that, one must engage regularly in brain activity that spans the use of all the major brain functions of language, memory, attention, visual-spatial and logic and reasoning activities. This can be difficult to achieve consistently over time. One way to activate all these brain functions on a consistent and regular basis is to play specially designed brain games and to participate in evidence based brain-training programs.

These games are designed to be engaging and by most accounts they are generally fun and entertaining. You have nothing to lose and a lot to gain, most notably, staying sharp!

High Protein Diet and AD

Contributed by: Michael Rafii, M.D., Ph.D - Director of the Memory Disorders Clinic at the University of California, San Diego. ______________________________________

A research team from the US, Canada, and the UK have concluded a study comparing the relationship between four different diets and Alzheimer's pathology in mice.

For 14 weeks the mice were fed one of four diets: (1) a regular (reference) diet; (2) a high fat/low carbohydrate diet; (3) a high protein/low carbohydrate diet; or (4) a high carbohydrate/low fat diet. After this, the researchers did post mortem analyses on the brains of the mice and measured their weight, plaque build up and structural differences in those regions known to be involved in the memory defects of Alzheimer's disease.

Amyloid Precurser Protein's role in the brain is not fully understood; however it is of great interest to AD researchers because the body uses it to generate the amyloid plaques typical of Alzheimer's. For each diet group, the researchers looked at the brain and body weight of the mice, as well as plaque build up and differences in the structure of several brain regions that are involved in the memory defect underlying AD. Unexpectedly, mice fed a high protein/low carbohydrate diet had brains five percent lighter that all the others, and regions of their hippocampus were less developed.

However, until researchers test for this effect in non-genetically engineered mice, it remains unclear whether the loss of brain mass is linked to the amyloid plaque found in Alzheimer's disease. The only way to verify this in humans would be to do prospective randomized double blind diet trials.


Beta Amyloid: Friend or Foe?

Contributed by: Dennis Fortier, President, Medical Care Corporation
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According to the amyloid hypothesis, an accumulation of this protein in the brain leads to the formation of plaques which eventually kills neurons and causes dementia. It is a popular theory given a fairly high correlation between amyloid load and loss of cognition and given that lowering amyloid load (through a variety of strategies) has been associated with improved cognitive function. This theory is driving a large portion of drug development activity in current FDA trials.

However, there are some troubling aspects to the theory. Notably, there are many well-documented instances of autopsied brains that were full of amyloid plaques but came from the skulls of persons with high cognitive function. Perhaps this can be explained by timing. Perhaps the plaques build, then there is a period of progressive brain damage due to the presence of the amyloid, then cognition declines. It is plausible and would explain why we sometimes find cognitively vital people with lots of amyloid in their brains.

New research from Saint Louis University and published in the online Journal of Alzheimer's Disease suggests a more complex relationship between amyloid and the brain. In a study on mice, researchers demonstrated that amyloid was associated with improved learning and memory, the exact opposite of what might have been expected. This suggests that viewing all amyloid as bad may be too simplistic. Perhaps having either too much or too little is the real problem and therapeutic strategies should be refined to "regulate" amyloid as opposed to "eliminate" this important protein.

Each day we find another answer and pose another question to this complex puzzle but slowly, it is coming together into a more comprehensive understanding of how to treat the disease.

Is Memory Loss a Normal Part of Aging?

Contributed by: Dennis Fortier, President, Medical Care Corporation
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In a recent posting supporting the value of awareness in our collective fight against Alzheimer's disease, I wrote that memory loss is not a normal part of aging. Based on comments left by readers, it became clear to me that, among some portion of the population, that is a difficult fact to accept. In fact, by most readers' accounts, the evidence seems stacked in the other direction with a high percentage of elders complaining of eroding ability to store and retrieve information.

Given this response, I think it is important to reconcile the two perspectives. There are two important points to consider.

First, what many label as "memory loss" is actually something else; commonly "slow recall" or "distraction". Each of these is described in full in this earlier post. It is clear that the term "memory loss" is interpreted quite widely and many consider all sorts of cognitive deficits to be memory problems when often they are something else. At the end of the day, there are probably far fewer actual "memory complaints" than many of the readers perceive.

Second, because medical conditions that impair memory are prevalent in old age, memory loss is indeed common. People with depression, thyroid disease, vitamin deficiencies, multiple medications, metabolic disorders, vascular disease and early stage Alzheimer's may all complain of memory loss. My earlier posting took the position that having one of these conditions is not normal.

In hindsight, it would have been more clear for me to write that memory loss is not a normal part of healthy aging.

Alzheimer's Awareness: Why Bother?

Contributed by: Dennis Fortier, President, Medical Care Corporation

As you may have read elsewhere, November is National Alzheimer’s Awareness Month. But surely, the public is already well aware of this horrible disease. After all, Alzheimer’s has directly affected approximately 1 in every 2 families and the others must have certainly noted its prominent coverage in the news. We don’t really need more awareness, right?

Wrong.

Some of the information below may surprise you. That is to say, it is information about which you are not presently aware. However, by merely learning the seven facts below you will be helping to reduce the Alzheimer’s problem. That’s right…making you aware of this information and encouraging you to share it with your social networks will facilitate a more informed and more effective approach to combating the threat we face from this disease.

First, here are a few facts and figures that you may already know. Alzheimer’s currently affects more than 5 million Americans and that number is likely to triple by 2050. It is the sixth leading cause of death in the USA and is climbing steadily in the rankings. Also, Alzheimer’s is the leading cause of dementia and accounts for about 65% of all dementia worldwide. These are all sobering facts but perhaps not new to your understanding.

7 Facts You Need To Know
Now, here are some points you may not know but should. It is the following information that I hope will stimulate discussion and promote a better understanding of the disease. With more discourse, we can begin to erode the lingering stigma that currently prevents some people with early symptoms from seeking timely medical attention.

1) We generally detect Alzheimer’s at the end-stage of the disease. On average, Alzheimer’s follows a 14-year course from the onset of the first symptoms until death. There is some variability across patients but 14 years is pretty typical. The more surprising news is that, on average, we diagnose Alzheimer’s in years 8-10 of that disease course. This means that for most patients, symptoms go undiagnosed and untreated for at least seven years, during which time the lesions spread through the brain and cause irreparable damage. Please be aware that we diagnose Alzheimer’s disease far too late to optimize the effects of currently available treatments.

2) Memory loss is not a part of normal aging. The point about end-stage detection raises an obvious question about “why” we diagnose this disease so late. There are many contributing factors but most of them can be reduced through awareness and education. Some patients resist medical attention in the early stages because they fear a stigmatizing label or because they are misinformed to believe that Alzheimer’s cannot be treated. Many people, including a startling number of physicians, incorrectly believe that memory loss is a normal part of aging. Improving the timeliness of diagnoses for Alzheimer’s is, in many ways, a problem that can be addressed through awareness and education. Please be aware that memory loss is not a part of normal aging and, regardless of the cause of the memory loss, timely medical intervention is best.

3) Current Alzheimer’s drugs are probably more effective than you think. Our widespread practice of late detection has many negative consequences. For example, one of the reasons that current treatments are often deemed ineffective is because they are routinely prescribed for patients with end-stage pathology who already have massive brain damage. With earlier intervention, treatment can be administered to patients with healthier brains, many of whom will respond more vigorously to the recommended therapy. Yes, we need better treatments, but a great start would be to intervene earlier with the treatments we already have. Please be aware that currently approved treatments may be more effective than some headlines indicate.

4) Alzheimer’s disease can be treated. Another treatment related concept about which everyone should be aware is this. Preventing or slowing further brain damage is preferable to letting the damage spread without constraint. Yet, many physicians, patients, and caregivers conclude that any treatment short of a cure is not worthwhile. While today it is true that we have no cure for Alzheimer’s, that does not mean there is no treatment. With a good diet, physical exercise, social engagement, and certain drugs, many patients (especially those detected at an early stage) can meaningfully alter the course of Alzheimer’s and preserve their quality of life. Please be aware that “we have no cure” does not mean “there is no treatment”.

5) The Alzheimer’s drug pipeline is full. Here’s another fact of which you should be aware. Through an intense research effort over the past twenty years, scientists have gained a lot of insight about Alzheimer’s disease mechanisms and about other factors that increase the risk for the disease. Much has been learned and some very promising drugs, based on sound theoretical approaches, are in FDA clinical trials right now. While much of the disease remains shrouded in mystery and we may still be a long way from better treatments, it is possible that an effective agent is already in the pipeline. Please be aware that, although we don’t know when, better treatments for Alzheimer’s are certainly on the way.

6) Taking good care of your heart will help your brain stay healthy. Know this; the health of your brain is very closely tied to the health of your body, particularly your heart. Researchers have shown conclusively that high cholesterol, high blood pressure, and obesity all confer greater risk for cognitive decline. The mechanisms that keep oxygen rich blood flowing through your body play a key role in maintaining a healthy brain. Everyone should be aware about the close association between vascular health and cognitive health. Please be aware that maintaining good vascular health will help you age with cognitive vitality.

7) Managing risk factors may delay or prevent cognitive problems later in life. There are well-identified risk factors for Alzheimer’s disease that are within our power to manage. These include diabetes, head injuries, smoking, poor diet, lethargy, and isolation. With greater awareness of these facts, we can imagine a world where diabetics take more care to control their blood sugar, where helmets are more prevalent in recreational activities that are likely to cause head trauma, where people smoke less and eat more fruits and vegetables, and where everyone makes a better effort to exercise and to stay socially engaged on a regular basis. While these facts may not be well known, they are all well proven. Galvanizing an effort to publicize them is one purpose of National Alzheimer’s Awareness Month. Please be aware that many risk factors for Alzheimer’s can be actively managed to reduce the likelihood of cognitive decline.

So why bother with Alzheimer’s awareness? Because it is a terrible disease poised to ravage our aging society and the lack of education and awareness has lead to a stigma that prevents a more proactive approach to early intervention. The result is that we diagnose it too late, which hampers the efficacy of available treatments. A more educated public could manage risk factors to minimize the likelihood of Alzheimer’s, could monitor personal cognitive health with greater vigilance, and could seek medical attention at the earliest sign of decline. Physicians could then diagnose problems earlier and prescribe appropriate treatment including diet, exercise, and drugs to slow disease progression as much as possible. In the end, we could have fewer cases, more effective treatment, slower progression, higher quality of life, and lower healthcare costs. The social, emotional, and fiscal benefits of awareness and education in this area are too large to quantify.

By reading this article, you have increased your understanding of the problem and raised your awareness about what can be done. That is a great step in the right direction but you can do one thing more. You can help to spread this message.

In the spirit of National Alzheimer’s Awareness Month, please share this article with your friends to promote more widespread awareness. Post it to your Facebook page, mark it in Delicious, Tweet it, Digg it, or email it. It doesn’t matter how you do your part, it only matters that you get it done.

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A better understanding and more awareness of Alzheimer's related issues can impact personal health decisions and generate significant impact across a population of aging individuals. Please use the share button below to spread this educational message as widely as possible.

Vision Problems and Variant AD

Contributed by: Michael Rafii, M.D., Ph.D - Director of the Memory Disorders Clinic at the University of California, San Diego. ______________________________________

In a minority of Alzheimer's patients the disease shows up first as problems with vision rather than memory or other cognitive functions. But diagnosis can be difficult because standard eye exams are often inconclusive for these patients.

Neuro-ophthalmologists Pierre-Francois Kaeser, MD, and Francois-Xavier Borruat, MD, Jules Gonin Eye Hospital, Switzerland, examined and followed 10 patients with unexplained vision loss who were ultimately diagnosed with the visual variant of Alzheimer's disease (VVAD). Their study -- presented at the 2009 Joint Meeting of the American Academy of Ophthalmology and the Pan-American Association of Ophthalmology (PAAO) -- describes clinical clues that may improve ophthalmologists' ability to detect VVAD and refer patients for further tests. When patients receive neurological assessment, treatment and family counseling early in the disease, outcomes may be better for all concerned.

VVAD patients differ from typical Alzheimer's patients in a number of ways. At the time they report visual problems, many are younger than those for whom memory loss is the tell-tale sign. In Dr. Kaeser's study the median patient age was 65, and only 3 of 10 reported memory loss. In comprehensive neuro-ophthalmic exams even though most patients' visual acuity was adequate, all but one had difficulty with reading, 8 of 10 with writing, and 6 of 10 with basic calculations. The visual field was altered in 8 of 10 patients.

All had trouble identifying colored numbers despite being able to name colors correctly, and, importantly, 8 of 10 patients had difficulty recognizing and interpreting components of a complex image (simultagnosia). This is an early indicator of the brain damage that prevents later-stage Alzheimer's patients from recognizing people they know and navigating familiar surroundings. MRI and PET scans revealed neurological changes consistent with VVAD in all study patients. Though VVAD patients' first symptoms are visual, Alzheimer's memory and personality impairments eventually occur in most.

Interestingly, in the neurology field VVAD is referred to as Posterior Cortical Atrophy (PCA), because the posterior, or back of the brain, shrinks. When pathologists examine the brain tissue from these patients, they see amyloid plaques in the occipital lobe, which is in the posterior part of the brain, and resposible for vision.

New Dimebon Trials Launched

Contributed by: Dennis Fortier, President, Medical Care Corporation
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As we have chronicled in past posts, there are multiple agents for treating Alzheimer's disease in the FDA pipeline. One of the most advanced, and by many measures, most promising, is Dimebon.

The co-developers of this agent (Pfizer and Medivation) have announced two additional trials that are now enrolling subjects. While it is not completely understood, Dimebon appears to have a novel mechanism compared to the currently approved drugs Aricept, Razadyne, and Exelon, all of which are cholinesterase inhibitors and Namenda, which is a glutamate blocker. The mechanism is theorized to be one of improving mitochondrial function to promote ongoing cell health. The new trials will explore poly-therapy with Aricept and with Namenda.

To learn more details and to inquire about enrolling in the studies, please follow these links to the CONTACT study (or email contactstudy@medivation.com) and to the CONSTELLATION study (or call 1-877-377-4476).

Inflammation and AD

Contributed by: Michael Rafii, M.D., Ph.D - Director of the Memory Disorders Clinic at the University of California, San Diego. ______________________________________

Microglia are the housekeepers of the brain, digesting foreign bodies and protecting neurons from damage. In culture, these cells are well known for ingesting amyloid-β, and in Alzheimer disease they surround amyloid deposits.

But in a study published in the October 18 Nature Neuroscience online, researchers in Germany have almost completely removed microglia from the brains of transgenic mice, and to their surprise they found absolutely no change in plaque size or number.

This leads to the hypothesis that the microglia may surround the plaques, but are essentially protecting the rest of the brain and not involved in modifying, depositing, or removing the plaques. The study also raises the possibility that cell-mediated inflammation does not promote more amyloid or more Aβ, which has been a hypothesis for a long time.

The Value of Memory Tests

Contributed by: Dennis Fortier, President, Medical Care Corporation
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In the news today you may read about the value of memory tests for identifying subtle memory loss at an early and more treatable stage. The findings are published in Neurology by a team of researchers at Oxford University.

In the study, the research team followed healthy volunteers for 20 years and assessed their memory at regular intervals. For those whose cognition eventually declined, the scientists were able to look back and identify specific, measurable signs of diminishing memory and language skills.

These findings are consistent with our understanding that many conditions that impair cognition, particularly Alzheimer's disease, follow a long course that slowly damages the brain. The findings are important because they speak to the potential for very accurate tests that detect subtle changes to facilitate much earlier intervention and better treatment results. Currently, most causes of dementia go undiagnosed for many years while unnecessary brain damage accumulates irreversibly.