Thank you so much for signing NAPA and putting creation of our first National Plan to Address Alzheimer's Disease on the fast track.
I preface my comments with brief personal history.
I joined the national Alzheimer's Association early in 1980, co-founded both the Chicago and Detroit area chapters as I moved around the country, joined the National Board of Directors circa 1981 and rose to become a national Vice Chair and Chair of the Public Policy Committee. In 1984 I co-founded the Alzheimer's Disease International. I am also proud to have single-handedly suggested the idea of what became the federally funded program to states to create innovative Alzheimer's programs with special emphasis on serving minority populations. While Chair of the Public Policy Committee for the national Alzheimer's Association I was also successful in getting our board to hire full time professional public policy staff, create our annual spring "Public Policy Forum" to bring our citizen advocates to Washington DC to be educated and meet with their Congressional representatives. We also developed our first coalition efforts, e.g. with the then Long Term Care campaign, and the National Citizen's Coalition for Nursing Home Reform and helped support the nursing home reform bill that became law (OBRA 1987). We also held our first meetings with members of the CBO and Medicare/Medicaid administration officials to examine what information was needed to start developing a plan for how to meet the service and funding needs of people with dementia and their families. Later, in the 1990's while at Wellesley Centers for Women we looked at the scary prospects of the diminished numbers of people available (the baby bust era e.g. my children's birth cohort) to serve as care partners to those baby boomers who would be developing Alzheimer's and other brain/body diseases in 2040-2050. I then was asked to join Boston University's NIH funded Alzheimer's Disease Center and Department of Neurology to continue my clinical intervention studies; I currently have a small phase I trial of nutritional supplements underway, funded by the U.S. Alzheimer's Association.
My work over the past 30 plus years on behalf of Alzheimer's disease and now the broader field of brain health, is all inspired by my mother Frances Fink Emerson who developed Alzheimer's disease in her early 50's, lived 25 years and died in 1990 with no ability for willed action or movement of any sort, and a brain shrunk to half its original size. She received great care both at home -9 years-and in a nursing home -- 16 years- (and thus lived a long time despite her disabilities....no other health issues) in an era when we knew only a fraction of what we know now, thanks primarily to the work of the Alzheimer's Association, and research funding by NIH, Alzheimer's Association and WHO and other organizations and caring people around the world.
Today I am an Alzheimer's researcher connected with Boston University School of Medicine, actively serve on my local chapter board (Alz. Assn of Massachusetts and New Hampshire) as member of the Medical Scientific Advisory Committee, serve as a Board Member Emeritus of the national Alzheimer's Association (an inactive role), and actively attend and present scientific papers or posters at the Alzheimer's Disease International. I also have a small business that brings evidence-based knowledge about brain healthy lifestyles to organizations and individuals and families. My centerpiece is the evidence-based Memory Preservation Nutrition program, which I am proud to be bringing to 6 Boston area Assisted Living communities to help them improve the healthfulness of the foods their residents are served and eating. I am also a popular speaker, mainly on the topic of "Healthy Eating for a Healthy Brain and Body." And was featured as part of a Medical Journal TV news report on Boston Channel 5's Chronicle on March 20, 2012 and November 18, 2011.
I am excited by the breadth and content of the draft national Alzheimer's plan and want to make just a few pointed comments about moving forward. I am also attaching a couple documents that might be of interest in summarizing some of the recent work related to brain healthy lifestyles and reducing risk of Alzheimer's and other brain diseases. Here also is the direct link to the article I wrote for Sage Encyclopedia 'Alzheimer's Disease: Encyclopedia of Lifestyle Medicine and Health' See it at: http://www.sage-ereference.com/abstract/lifestylemedicinehealth/n18.xml
First, I am gratified that the draft plan calls for research and program development in the realm of healthy lifestyles, not just innovations in the realm of pharmaceutical and medical research, which of course is needed as we would all like to find the magic bullet(s) to prevent and cure this disease. But given the complexity of this mysterious disease and the delicacy and intricacy of the brain, such magic bullets may not exist. Alzheimer's may be as challenging to reduce risk as has been heart disease, stroke and diabetes, since they are all interrelated in ways we are still seeking to understand. Thus major public health initiatives based on evidence uncovered in the fields of nutrition, physical exercise, sleep, stress reduction and much more may be what works to help our society avoid the catastrophe of doubling, then quadrupling the numbers of Americans with Alzheimer's disease as the numbers of people who could serve as care partners and paid professional providers shrinks in relative numbers.
Second, as an active member of the international Alzheimer's research and practice communities I strongly urge that the HHS Administrative offices charged with designing, refining and implementing the plan be in close liaison with international efforts to combat Alzheimer's disease. People in the US are often very parochial and have no idea of the great strides being made elsewhere. Also, because our healthcare system is presently dominated by for-profit organizations and pharmaceutical companies, it is harder for us to see clearly public health priorities that might be the best use of resources. The international community faces graver restraints in resources but at the same time has the power of being able to find collective solutions that benefit the most people. For instance at our most recent conference of ADI, held in London, the closing debate was whether enough evidence now exists to mount a major public health initiative targeting improvements in healthy lifestyles for middle-aged adults....vs. an even broader public health initiative to improve the health and wellbeing, especially nutrition, of babies and pregnant women and through that route decrease the numbers of future adults with brain diseases. Meanwhile we are all gearing up to try to be ready to serve the millions of adults who already have Alzheimer's, who will develop it if we don't find a way to slow down the progression and delay the age of onset.
Alzheimer's Disease International's small but very competent staff (Mark Wortman is the CEO, based at the UK Alzheimer's offices in London) and with several groups of collaborative research groups who are keyed in on finding practical solutions to this world wide crisis we are all facing together.
One of these research groups is called "10-66" which receives both NIH and WHO funding to conduct important cross-cultural studies in the developing world to establish true and comparable prevalence/incidence rates of both Alzheimer's disease and Mild Cognitive Impairment, has conducted international clinical trials of caregiver interventions to determine usefulness and costs in a variety of different countries and financial settings, and is now looking at some broader public policy and public health issues. Their annual reports can be found on the ADI website:
In addition, there is a collaborative effort of several country based large research projects examining whether certain lifestyle interventions could help reduce the incidence and prevalence of Alzheimer's disease, or delay the age of initial symptoms. Each initiative has different founding sources and different specific research objectives and methods, but by combining and collaborating they hope to increase the robustness of their findings. One of the three studies is taking place in Finland, led by Miia Kivipelto with major funding from Finland's Health Department, and some additional funding from the U.S. Alzheimer's Association and perhaps other sources as well. I touch on that study in one of the two papers I have attached to this email.
Another perspective that was discussed at this last London meeting was, how best to proceed in planning CARE in the depressing scenario that we can't prevent most of the cases of Alzheimer's. What public policy is best. One that is disease specific, or that is based on disabilities, across diseases and health conditions. This was very interesting to me arising among a group of people who has fought hard for over 25 years to get their home countries to give proper recognition to Alzheimer's disease and other dementias, and to develop national plans. But once one has raised awareness, achieved sufficient specific research dollars and developed specific care programs, then one is freer to look at the broader public policy perspectives and see what is the best use of resources for a country, and what is most likely to be politicall feasible.
As you could gather from my resume, I stand ready to volunteer my time and attention to helping you in your efforts should you see a way I could be helpful.
In the meantime I applaud all the work you are doing and say THANK YOU. You all are fulfilling a dream I've held since the 1980's of a true national effort to combat Alzheimer's disease, both through research, public health and programmatic efforts at the local, state and federal levels.
Alzheimer's Disease & Lifestyle
Lombardo, N.B. Emerson. "Alzheimer's Disease." Encyclopedia of Lifestyle Medicine and Health. Ed. James M. Rippe, MD. Thousand Oaks, CA: SAGE, 2012. 120-42. SAGE Reference Online. Web. 29 Feb. 2012. 6000 words on-line accessed 2 29 2012
This entry (a) describes the evolving definition of Alzheimer's disease (AD) and its prevalence; (b) summarizes evidence for nutrition, physical exercise, and other healthy lifestyle interventions that may delay onset, prevent occurrence, or slow the progression of AD and other dementias and maintain the emotional and physical health of both the person with dementia and his or her care partners; (c) identifies key lifestyle strategies for preserving brain health--both cognitive and emotional--and how they may be related to body health strategies; and (d) highlights some clinical trial results and introduces a groundbreaking multi-domain study under way in Finland and the body of evidence leading to this seminal trial.
Readers may take away confirmation of the importance of some of the things they are already doing and gain ideas and motivation to adopt brain-healthy nutrition and lifestyles.
The World Alzheimer Report 2010: The Global Economic Impact of Dementia, published by Alzheimer's Disease International, reported that around 0.5% of the world's total population live with dementia, predominantly AD, and that the total estimated worldwide costs of dementia were US$604 billion in 2010, equivalent to around 1% of the world's gross domestic product. The Alzheimer's Association reports that there are nearly 15 million caregivers for Alzheimer's and dementia patients in the United States. AD is currently the sixth leading cause of death in the United States and the one growing most rapidly (by 50% from 2000 to 2007). The growth rate of this epidemic is expected to further accelerate with the aging of the baby boomer generation, increasing personal costs to families, which provide the bulk of care, and rapidly escalating economic costs from $172 billion today to more than $1 trillion by 2050. The U.S. National Alzheimer's Project Act was enacted into law in January 2011 to create a coordinated national strategy to address this national public health emergency with widespread social and economic consequences.
Definition of AD and Diagnostic Criteria
AD is the most common form of dementia, causing multiple impairments in thinking and cognition, including planning and organization (executive function), attention, short-term episodic memory (especially the recording of events and experiences), and sometimes visual-spatial function. The pathological hallmarks of AD are extracellular plaques composed of a protein called beta-amyloid (also called "A-beta") and the intracellular accumulations of neurofibrillary tangles, the insoluble paired helical filaments of an abnormally phosphorylated tau protein, and a cytoskeletal protein critical to the brain cell structure. Studies suggest that the soluble forms of A-beta, not the more visible plaques, are the toxic form. The normal function of A-beta is to kill microbes, as part of the innate immune system. It is the large amount of A-beta present in AD that is abnormal. Moreover, plaques and tangles appear to be late-stage developments and may or may not reflect the initiating biological sequelae, which may include injury, inflammation, disruptions of cell signaling pathways, oxidative stress, and disruptions in glucose and/or lipid metabolic processes.
New Criteria for Diagnosing and Redefining AD
National Institutes of Health/Alzheimer's Association working groups in 2010-2011 updated the criteria for diagnosing Alzheimer's dementia, added criteria for diagnosing mild cognitive impairment (MCI) due to underlying Alzheimer's pathology, and set the framework for identifying and testing biomarkers that in the near future could be used to diagnose "preclinical AD." Thus, the definition of AD has expanded beyond dementia and cognitive impairment to include a presymptomatic stage of the disease.
Biomarkers may improve the accuracy of diagnoses of both Alzheimer's dementia and MCI due to Alzheimer's pathology during life and serve as clinical trial end points. Prominent among the new biomarkers are neuroimaging (e.g., of A-beta levels, glucose processing, and the size and shape of brain structures) and measuring the presence of A-beta and tau in cerebrospinal fluid. These criteria will replace those established in 1984 as the "NINCDS-ADRDA" criteria. These criteria, developed by the National Institute of Neurological Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA), were universally adopted and have been in use, without modification, for more than 25 years. One of the challenges of prevention and treatment trials, both with preclinical AD and in MCI, is the inadequacy of cognitive tests to catch early changes reliably. The emergence of other outcome markers, namely brain imaging, and other biomarkers, is revolutionizing the field.
Scientists participating in the work groups formulating the new guidelines note that the updates were urgently needed for establishing the next generation of clinical trials for possible pharmaceutical and nonpharmaceutical interventions. In medical practice, the proposed changes represent refinements of existing criteria for the diagnosis of Alzheimer's dementia. The guidelines suggest, for example, that physicians recognize that complaints of loss of memory may not always be the first or most prominent presenting symptom. A decline in other aspects of cognition (e.g., word finding, vision/spatial issues, and impaired reasoning, judgment, and problem solving) may be the first presenting or the most prominent symptoms. Many research scientists in the field are concerned that current biomarker criteria give too much emphasis to A-beta and tau (especially A-beta) and too little to the role that oxidative stress, inflammation, vascular pathology, white matter, and other lesions or injuries may play in cognitive decline, in clinical symptoms of dementia, and in the development of abnormal levels of A-beta and tau. Ignoring a large body of evidence could hinder identifying proper treatments and preventive interventions, particularly lifestyle interventions. It is also important to guard against reductionist AD theories because what is now called "Alzheimer's disease" may be one or more multifactorial disorders and thus may require "multitherapies."
The evolving understanding of AD includes the recognition that individuals with a diagnoses of AD and MCI can still learn new information and acquire new habits, using a variety of preserved functions such as other forms of memory (e.g., visual, emotional, procedural). In addition, it is important to realize that while people with Alzheimer's may have lost many brain cells and synapses, they still retain many healthy brain cells, so it is important to work with them to maintain brain health in the hope of slowing progression, maintaining positive emotion, and improving quality of life.
Possible Causes or Etiology of AD as Related to Lifestyle
The exact causes and etiology of AD are still not fully known. As of 2011, there are still no methods of perfect diagnosis during life or ways to cure or completely prevent AD. Age remains the biggest risk factor for AD, with (lower) education levels the only other consistent risk factor across all ethnic groups. However, much has been learned in the past 30 years, lifestyles are at the heart of this new knowledge.
Research now recognizes AD as a complex chronic disease with many environmental and genetic factors, whose pathology may begin to accumulate 10 to 30 or more years before the appearance of noticeable clinical symptoms. With such a long prodromal stage, preventive interventions are needed that can be safely used for decades. While a few families have an autosomnal dominant form of AD, most individuals have what is called the "sporadic" form, without clear genetic patterns. The APOE4 type of allele confers a dose-related risk for persons of European origin but not typically for those of African origin. While other risk-conferring genes have been identified, most scientists have found that environmental factors are probably at least as important as genetic ones. Recognition of the importance of lifestyle flows directly from the multiple studies that have shown that brain and cognitive health is dramatically affected by the rest of the body, especially the cardiovascular, glucose metabolism, and cell energy systems.
Observational and prospective studies have confirmed this logical relationship and spawned numerous animal studies to explore the relationships between particular lifestyle factors, cognition, and the mechanisms of action. For instance, physical exercise as well as many nutrients and food substances with anti-oxidant or anti-inflammatory properties have proven to lower the amount of A-beta in animal models and also lower inflammation. Some nutrients also improve neuronal cell signaling, lipid metabolism, and glucose metabolism and/or decrease oxidative stress.
This sort of evidence, together with numerous observational studies with a variety of human populations in different countries, has established that appropriate nutrition and physical activity are good candidates for helping reduce the risk of dementia, cognitive decline, and AD in humans. In 2010, gold-standard randomized clinical trials for integrated evidence-based nutrition programs had not yet been undertaken, and those for various forms of exercise had just begun. These kinds of lifestyle interventions are very difficult to get funded and then carry out, so scientists cannot yet say with certainty that the various lifestyles indicated by an array of other studies will be sufficient to delay the onset of cognitive symptoms or slow progression. However, scientists have already proven with certainty the link between nutrition, physical exercise, and certain other lifestyle factors to prevent, slow, or even reverse other related chronic diseases such as stroke, other cardiovascular diseases, diabetes, and insulin resistance. Therefore, most researchers and clinicians are ready to recommend lifestyle approaches as these offer probable additional benefits to cognitive health. Lifestyle interventions are also of keen interest since, given the multiple decades of presymptomatic development of AD-related pathology, preventive interventions need to be safe and tolerable.
A growing body of research suggests that a variety of nutritional factors, social engagement, mental stimulation, physical exercise, complex activities incorporating multiple domains, and management of stress and depression all help preserve brain health. Managing both emotional and physical stress is important because heightened cortisol levels have been connected to cognitive decline as well as to faster rates of decline in persons with Alzheimer's dementia. Moreover, research reports an association between cortisol levels, hippocampal shrinkage, and insulin resistance. Adequate sleep is also essential for a healthy brain, neuroplasticity, and memory. Music, art, acupuncture, T'ai Chi, meditation, and certain other spiritual practices, as well as having a meaning and purpose in life, also appear to enhance brain health. Many of these lifestyle factors are related to neuronal plasticity and the generation of new brain cells as well as prevention of deterioration of existing brain cells.
Research indicates some common factors for both cognitive and emotional health. Intervention studies indicate the independent and synergistic efficacy of nutrition, cognitive rehabilitation, physical exercise, and various alternative medicine practices in improving cognition, mood, and quality of life of persons who already live with AD or other memory or brain disorders. The challenge is in actually making behavioral changes to adopt these protective lifestyles.
Why Lifestyle Factors Are Important to Brain Health
Epidemiological studies show that the prevalence of AD doubles every 5 years after the age of 65 (with 13% of individuals over the age of 65 having AD and about 40% over 85 years having AD). If lifestyle interventions can delay the onset of AD by 5 years, the prevalence of the disease would be halved, along with all the attendant human and financial costs.
Evidence suggests that healthy brain tissue is better able to withstand the ravages of age, genetic vulnerabilities, environmental stresses, accidents, toxins, and disease. Further, healthy lifestyles help enhance and strengthen neurons, dendrites, and other body and brain cells.
Many studies, including gold-standard clinical trials in the case of many other chronic diseases, have suggested that a healthy lifestyle, especially with regard to nutrition and exercise, may help prevent and treat most human chronic diseases. Thus, healthy lifestyles are helpful to both the person with dementia and his or her care partners, who are at extra risk of depression and illness because of caregiving.
Cardiovascular health and normal glucose metabolism contribute to brain health, while the rise in obesity and other chronic illnesses has a direct negative impact on brain health. Dozens of studies have established that each vascular risk factor adds to the risk for AD and severity of dementia.
Diabetes and prediabetes increase the risk of cognitive decline, MCI and dementia, and, according to some scientists, AD in particular. Studies using imaging techniques in adults and teenagers show that diabetes, prediabetes, or abnormally high insulin resistance as measured by glycosylated hemoglobin (HbA1c) shrinks the hippocampus, the major site for short-term memory and spatial memory, encoding of new information and experiences, as well as some aspects of emotional function. These findings should raise serious public health concerns because study results show that the hippocampi are already shrinking in obese teenagers with type 2 diabetes mellitus as well as in middle-aged nondiabetic adults with insulin resistance. Cognitive impairments in nondiabetic adults were found to be associated with the degree of insulin resistance. Related memory impairments and related white-matter changes were observed in adults with type 2 diabetes mellitus and brain-derived neurotropic factor (BDNF) levels were reduced in adults with insulin resistance.
Inflammation is believed to play a key role in the etiology of AD and has been associated with an increased risk of AD. Existing inflammation, as well as inflammatory events such as infections, surgery, or heart attacks, hastens progression in people with AD. Oxidative stress also plays a key role in AD etiology, including increasing inflammation and oxidation of brain lipids. In addition, mitochondrial dysfunction is part of AD etiology and relates to the energy systems within the brain cells.
In summary, whatever hurts the heart and blood vessels harms the brain. Problems with glucose metabolism and insulin levels also threaten the brain. The organ and disease silos are disintegrating, with increasingly similar clinical recommendations for better nutrition and exercise and for managing stress to treat or prevent a wide range of chronic diseases affecting nearly every organ in the body.
Recommended Lifestyle Approaches for Cognitive Health
Many leaders in the field of brain health believe that the evidence is already sufficient to suggest that regardless of personal risk factors, and with or without pharmacologic intervention, a healthful lifestyle is likely to reduce risk, delay onset, and slow the progression of AD and vascular dementia. Some of these researchers and clinicians conclude that the evidence suggests that it is the combination of vascular lesions (e.g., microstrokes or white-matter lesions) with Alzheimer's pathology that together result in symptoms of MCI and dementia. If these hypotheses are correct, then they offer another argument in favor of practicing healthy lifestyles to reduce cognitive decline.
Nutrition, physical exercise, and other lifestyle interventions work on multiple pathways to improve overall health in multiple organs with minimal or no side effects, even over many decades, which is important since scientists now believe that the pathology of AD--that is, the development of excess A-beta and abnormal phosphorylated tau--begins several decades before the appearance of cognitive symptoms.
Multiple lifestyle factors can have synergistic or additive effects. One of the most interesting trials involved the 2-year study of aged beagle dogs conducted by Carl Cotman's group at the University of California, Irvine, which showed that an enriched diet alone improved performance on a cognitive task from 25% in the control group to 67% of the experimental animals. A third group, with increased physical activity and social play, improved performance to 80%, while combining enriched diet and exercise-play interventions resulted in 100% of a fourth group of dogs being able to perform the difficult learning task.
Given the well-established connection between cardiovascular disease, insulin resistance, and diabetes and cognitive function and cognitive decline, and the evidence-based certainty that good nutrition, physical activity, and certain other lifestyle changes help treat or prevent these diseases, more and more people in the AD field have concluded that it is good clinical practice to recommend these healthy lifestyles to persons concerned about their brain health or who already have a diagnosis of MCI or dementia, including AD.
Multidomain Lifestyle Study Under Way in Finland
Many people in the field agree that the preventive intervention most likely to be effective will be multifaceted to be potent enough to delay the onset of AD or slow it down. There is one such multicenter randomized clinical trial under way in Finland, called the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) Trial, under the leadership of Miia Kivipelto and funded by the Finnish government, the U.S. National Institutes of Health, and the national Alzheimer's Association (clinicaltrials.gov/ct2/show/NCT01041989). Persons between 60 and 77 years of age who are determined to be at increased risk of cognitive decline and dementia are randomized to a control group (standard health counseling at baseline) or to a preventive intervention for 2 years. The latter receive multidisciplinary treatment that includes nutritional guidance, physical exercise, cognitive training and social activity, and intensive monitoring and management of metabolic (e.g., diabetes) and vascular risk factors. Importantly, each intervention includes a coach to guide and encourage the implementation of each lifestyle change. In addition to cognitive end points, a variety of potential biomarkers are monitored in relationship to any cognitive change, including biochemical markers of inflammation or oxidation, hormones controlling blood sugars and fats, as well as brain imaging.
Dr. Kivipelto's study reflects the combined wisdom of many leaders in the field, including the International Academy of Nutrition and Aging. The FINGER study builds on more than a decade of research, suggesting the importance of each domain of this combined program. The collective findings of some of these studies are summarized in the next section.
Selected Findings of Lifestyle Studies
Observational studies have established that each of the following lifestyle behaviors may be independently related to a lower risk of dementia: (a) nutrition, (b) physical fitness, (c) social activities and social engagement, (d) organization memberships, (e) productive (meaningful) activities, (f) mental activities (e.g., reading, word spelling/recognition, numbers, and other games), and (g) management of stress. Several researchers, using meta-analyses, have concluded that the most potent activities are complex activities that involve multiple domains, especially activities that include physical activity and social interaction as well as cognitive challenge, such as dancing and golf. Examples of activities involving 2 domains are board or card games, knitting, gardening, T'ai Chi, chi gong or yoga, and doing exercise in a group. Complex and novel activities such as learning a new language, especially sign language, traveling to new places, and playing a musical instrument, especially a new one, are also particularly recommended.
A 2010 Institute of Medicine Consensus conference and a Cochrane review of certain lifestyle interventions for preserving cognitive health concluded that there was insufficient evidence on which to base clinical recommendations. The Cochrane reviews and the Institute of Medicine, however, used very strict criteria for acceptable clinical trials, and for physical exercise, they reviewed only a few clinical trials of very small size or pilot in nature, which were underpowered. Both panels tended to be overly conservative and looking backward rather than forward in a brand new research field where rigorous clinical trials were just beginning to be designed, funded, and reviewed and where, logically, these interventions might have their biggest impact in the preclinical or MCI stage of AD, where outcome measures are still under development. Most reviews also do not integrate the combined weight of observational studies with clinical trials in animal models of AD, which are the first phase of testing some of the factors observed in human longitudinal studies and of researching mechanisms of action. Nutritional trials, especially those with integrated complex nutritional programs, are difficult to design and gain adherence to, and physical exercise programs to some extent suffer the same challenges. Published randomized controlled trials in the nutrition field as of 2011 were limited to single substances or small groups of vitamins.
Nonetheless the body of evidence is growing rapidly.
One well-structured prospective study published in 2010 found that persons with the highest levels of all 8 forms of vitamin E (tocopherols and tocotrienols) had half the risk of AD, whereas previous studies and intervention trials, less knowledgeable about the necessity of all forms of vitamin E in the brain and body, had looked at only a-tocopherol. This Karolinska Institutet (Sweden) study concluded that it was the combination of the 8 vitamin E forms that was important to brain health.
Various nutritional studies using animal models have shown the power of various single nutrients to lower A-beta levels, reduce oxidative stress, and improve cognitive function. Clinical trials of persons with MCI or AD have been few in number and show mixed results but some limited promise. A Swedish clinical trial of fish oil capsules using a daily dose of 1.7 mg of docosahexaenoic acid and 0.6 mg of eicosapentaenoic acid (2 long-chain omega-3 fatty acids abundant in the human brain) reported preliminary results suggesting a slowing of cognitive decline in persons with early-stage AD. A larger trial of just algae-derived docosahexaenoic acid had no effect across all AD patients. One study of 3 B vitamins (B6, B12, and folate) had no effect in persons with AD, but another using lower doses of the same 3 B vitamins improved cognition in people with MCI, but only in those with high homocysteine levels. These results suggest that while combination dietary programs may produce stronger effects on cognition than current pharmacological treatments for AD, single nutrients may be insufficient, and nutritional interventions may have more effect in MCI and very early-stage AD. Continued clinical research is needed.
Of greater interest for clinical study is combining multiple nutrients since the most recent observational studies have suggested that it is combinations of whole foods, such as in the Mediterranean or DASH (Dietary Approaches to Stop Hypertension) diets, that really make a difference. A 2006 integrative review presents evidence of how various nutrients appear to work on the multiple different pathways leading to AD and/or dementia, including inflammation, oxidative stress, glucose or insulin abnormalities, levels of A-beta and tau, cell signaling, and mitochondrial dysfunction. A recent animal study showed that a combination of whole foods-based nutrients, including vegetable, fruit, and herb and spice nutrients combined with fish oil, appears to restore mitochondrial dysfunction in triply transgenic AD mice, and a clinical trial is now under way in healthy older adults. A series of pilot studies with both mice and humans conducted by Thomas Shea and colleagues have shown preliminary success in improving short-term memory and attention in both cognitively normal adults and patients with AD, with a novel combination of vitamins and nutrients: namely, vitamin E, folic acid, vitamin B12, N-acetyl-l-cysteine, acetyl-l-carnitine hydrochloride, and S-adenosylmethionine. These preliminary studies suggest an important focus for continued studies in nutrition and brain health.
Most of the meta-analyses of physical activity that had less strict criteria for study inclusion than the Cochrane reviews reported consistently positive results, backing up the observational studies that had linked physical activity to reduced incidence of AD and slower rates of conversion from MCI to AD dementia. An array of intervention studies in healthy older adults, people with MCI, and people with early AD, all found evidence of decrease in the rates of cognitive decline.
Animal studies have established that physical activity increases cognitive function and identified at least 2 newer mechanisms of action beyond the known cardiovascular mechanisms: (1) decrease in levels of A-beta in the brain and (2) increased amount and rates of neurogenesis, especially in the hippocampus. Human studies have established that people who exercise more have higher levels of hippocampal BDNF, a brain chemical related to neurogenesis. Increased serum BDNF levels have been correlated with larger hippocampi and better memory performance.
Kirk I. Erickson's randomized controlled study using magnetic resonance imaging as an outcome measure established that aerobic exercise (specifically 1 year of walking 3 times a week for 40 minutes) can increase the size of critical brain structures. Consistent with the expected 1% to 2% annual hippocampal loss in dementia-free seniors, the control group (which spent an equal amount of time stretching) lost about 1.4% volume in this brain region by the end of the 12-month trial. In contrast, the hippocampi of the walkers grew by roughly 2%. In addition, researchers found that greater elevations in serum BDNF were linked to greater gains in hippocampal volume.
The benefit of walking exercise seemed specific to the anterior part of the hippocampus (including the dentate gyrus). Similar effects did not appear in the thalamus, caudate nucleus, or posterior hippocampus. The dentate gyrus is the most metabolically active part of our brain and is involved in spatial memory, short-term memory, and new learning. Neurogenesis is most prominent in this part of the adult brain; many surmise that it is so because creation of new brain cells and dendritic connections is essential to the production of new memories.
Meditation and Spiritual Practices
Stress management and spiritual practices may also contribute to brain health. For example, a recent study using magnetic resonance imaging of the brain in live human participants reported that persons participating in an 8-week mindfulness meditation program experienced measurable increases in the hippocampus regions associated with memory, sense of self, and empathy while reducing areas of the amygdala associated with stress. Numerous studies demonstrate that other spiritual practices such as forgiveness improve emotional and mental health. By relieving stress and depression and decreasing cortisol levels, such practices may also improve cognitive health.
Cognitive Training, Cognitive Rehabilitation, and Cognitive-Kinetic Interventions
With regard to cognitive training and cognitive rehabilitation strategies to improve and preserve cognition, the evidence is particularly strong. Observational studies suggested that "use it or lose it" applies to keeping one's mind active. The groundbreaking ACTIVE randomized clinical trial study demonstrated that even short-term cognitive skills practice interventions had persistent effects in the healthy elderly. A number of later studies suggest that the most effective interventions combine modalities--for example, cognitive training with physical exercise and support groups.
Multifaceted Relationship Between Physical Activity and Cognition
In population and clinical studies, physical activity and exercise have been shown to have a positive effect on cognitive function in people of all ages. Recent studies have found that physical exercise stimulates a positive increase in executive control processes, including planning, scheduling, working memory, inhibitory processes, and multitasking. The impact of physical activity on cognitive abilities also continues through the entire lifespan. Physical exercise, for example, has been found to be a key facilitator in neurogenesis, particularly in the hippocampus as well as in other areas of the brain. In general, the rate of neurogenesis and other cognitive benefits is related to the intensity, novelty, and dose of physical activity and exercise. Both endurance (aerobic) and strength (resistance training) exercise benefit both cognitively intact and cognitively impaired individuals.
With regard to improvement in individuals with MCI and AD, substantial clinical trial evidence suggests that various cognitive rehabilitation and training strategies may help restore lost function and slow progression of cognitive decline. Different strategies appear to have more or less potent effects in only one area or in multiple areas. For example, a cognitive training strategy targeting episodic memory benefited only episodic memory. A more holistic strategy that combined physical movements based on kinetic/cognitive theory with cognitive training benefitted areas of attention, spatial abilities, language, memory executive functions, and daily functions. Arkin's pioneering study, initially published in 1999, found a combination of simultaneous physical exercise and conversation, and language practice and word games, interspersed with volunteer activity, particularly effective.
Barriers to Adopting Lifestyle Initiatives
There are several barriers to adopting lifestyle changes, including cultural and psychological barriers. Cultural challenges include the overdependence of the American health care system, and therefore of most individuals, on pharmaceuticals and surgery, which have limited preventive roles for many chronic diseases or could be more potent if combined with lifestyle changes. Perhaps the biggest challenge for implementing these interventions as standard clinical practice is financial. Generally, lifestyle interventions are not covered by most current health insurance plans, although the concept of health promotion and prevention of illness is starting to develop. For instance, because research has established that having a "coach" or personal trainer helps individuals make lasting lifestyle changes, some private insurers will supply a free "health coach" even if the actual interventions are not reimbursed.
To promote brain health, prescribed cognitive training and physical activity may be the modalities most likely to be recognized with some incentives. Nutrition for brain health promotion is not currently covered, although individuals with diagnoses may find some limited coverage for counseling with licensed nutritionists. For families working together to provide a healthier home environment for both a patient with brain disease and his or her care partners, one possible source of funding is the National Family Caregiver Support program, which can be accessed online at http://www.aoa.gov/prof/aoaprog/caregiver/caregiver.asp. Individuals who have long-term care policies also may be able to gain coverage for these services. The future major solutions lie in the realm of public health, public education, public policy, and research envisioned with the 2011 passage of the National Alzheimer's Project Act.
Alzheimer's Disease International. World Alzheimer Report 2010. http://preview.alz.org/documents/national/World_Alzheimer_Report_2010.pdf. Accessed July 8, 2011.
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4.2.0. Memory and Cognitive Impact of Foods
Research is proceeding rapidly on the connection between diet, including individual nutrients, on memory and other aspects of our thinking.
Most of the research to date has examined how foods relate to memory and cognition. This research has consisted of either animal studies of specific foods or nutrients, or of epidemiological studies of large groups of people (which can show an association, but not prove a direct cause). These studies have explored the relationship between aspects of what we eat and the likelihood or risk of developing general cognitive problems, mild cognitive impairment (including of the amnestic type i.e. involving memory problems), any kind of dementia (i.e. problems in thinking in multiple areas serious enough to cause problems in daily life or work) or specific diseases such as Alzheimer's disease.
The mechanisms of action (for how specific foods might help or hurt the brain) identified to date appear to vary, and in the case of many whole foods, multiple actions could be working simultaneously (See for example, Emerson Lombardo NB et al. 2006, Sun AY et al 2008. Tian J et al 2010, Howes and Perry 2011, Williams RJ, 2011). Some ways specific foods could enhance brain health include increasing the availability of the memory neurotransmitter acetylcholine in the brain (apple juice, sage, Melissa, saffron) (e.g. by directly increasing production, slowing its metabolic breakdown, similar to the action of the cholinesterase inhibitors currently on the market), anti-oxidant and/or anti-inflammatory action, regulating amount of various forms of Abeta peptides, slowing or preventing oligomerization or fibrilization of the Abeta molecule (Wang 2008, Frydman-Marom, A.,2011), protecting omega-3 fatty acids in brain cell membranes or fatty acids, regulating blood sugar and insulin, and/or cholesterol, estrogenic effects that can be neuro-protective, promoting creation of new brain cells or connective parts, or slowing their destruction, improving neuronal signaling and synapse activity, restoring mitochondrial function (related to energy) of brain cells, and retarding tau pathology (the "other" problem protein in AD) (Green 2007) . This list is only partial!
The number of human clinical trials is still small but growing.
The body of evidence suggests a clear connection between foods, overall diet and our brain health, including memory and other cognitive skills such as attention and executive function (ability to organize and plan), and is growing each year.
This website and our brain healthy newsletters will keep you informed of this growing body of evidence.
Here are some highlights:
Several studies using various mouse models of Alzheimer's disease demonstrated the positive effects of a wide variety of food substances chosen for their believed health benefits such as strong anti-oxidant properties. Each food type may be comprised of thousands of nutrients. Foods tested that improved cognitive behaviors and/or lowered Abeta levels in TG mice include: apple juice, blueberries, spinach, strawberries, green tea, melatonin, DHA, plum juice, Concord grape juice, resveratrol, grape seed extract and others (Chan A et al, 2006, Rogers EJ et al.2004, Joseph JA. Et al. 1999, 2009, Lee JW, et al 2009, Mandel SA et al. 2011, Calon, F et al, 2004 and Green et al, 2007, Shukitt-Hale B et al, 2009, Shukitt-Hale B et al 2006, Lagouge, M., et al, 2006, Wang et al., 2008). Both almonds and walnuts helped Alzheimer transgenic mice perform better in cognitive tests and lowered levels of A-beta (Chauhan N et al. 2004, Muthaiyah B, et al, 2011 - no published citation for almonds- see continued work by Neelima Chauhan, PhD, of the University of Illinois-Chicago, as reported in 2005 by Society for Neuroscience. http://www.sfn.org/index.aspx?pagename=news_111405). An unrelated Indian study in aged rats reported almond paste reversed scopolamine-induced amnesia, reduced cholinesterase activity in the brain, and also significantly reduced cholesterol and triglycerides in these aged rats (Kulkarni KS, et al. 2010).
Epidemiological studies have also identified a long list of brain healthy foods. More recently, innovative studies have begun to identify GROUPS of foods that appear to reduce risk of cognitive decline and onset of dementia, MCI or Alzheimer's disease, such as foods typical of the Mediterranean diet (Féart, C et al 2009, Gu Y, et al 2009, Scarmeas N et al., 2006, 2009a, 2009b, or the DASH (Dietary Approaches to Stop Hypertension) Diet (LINK http://dashdiet.org/dash_diet_book.asp?google&gclid=CMDj8qOMsq0CFUTc4Aodvz0FlQ ) (see unpublished study led by Heidi Wengreen, RD, PhD, Assistant Professor of Nutrition at Utah State University).
Combination supplement studies are also gaining interest. Professor Thomas Shea, Ph.D., Director of the Cellular Neurobiology and Neurodegeneration Research Centerat U Mass Lowell (http://www.uml.edu/research_labs/Cellular_Neurobiology/Staff.html ) is examining, first in mice and now in humans with and without memory impairments, a combination of certain B vitamins, amino acids and anti-oxidants, with some encouraging results. Another study led by Jon Valla in Arizona uses a combination of fruit and vegetable powers, anti-inflammatory spices and herbs, and fish oil, yielding some positive results in TG mice. A similar combination with the addition of vitamin D is currently undergoing a pilot Phase I clinical trial with healthy older adults at Boston University. Also, Nutricia, a subsidiary of the French Danone Company, is pursuing human clinical trials in both Europe and the US, of Souvenaid® (http://souvenaid.com/) a combination of neuron building substrates identified (and patented) by Dr. Richard Wurtman at MIT, together with anti-oxidant isolated vitamins (Kamphuis and Scheltens, 2010), featured at a company sponsored symposium at MIT (http://web.mit.edu/newsoffice/2010/fighting-alzheimers.html). The consumer needs to be aware of the differences between medical foods such as Souvenaid, and nutritional supplements such as "Great Mind, as the rules of evidence and FDA regulations are different. The Alzheimer's Forum engaged in an excellent discussion of this topic in 2009, http://www.alzforum.org/new/detail.asp?id=2258
A Swedish placebo-controlled clinical trial using fish oil containing both DHA and EPA reported that fish oil appeared to slow cognitive decline only in a few persons with early stage Alzheimer's disease. In persons with mid stage disease the main positive effect was to reverse weight loss, which can be a serious problem in some people (Freund-Levi Y. et al, 2006). A larger, more recent clinical trial of just DHA derived from algae, in persons with AD, reported no significant effect on cognition; however the trial neglected to include EPA, the more highly anti-inflammatory long chain Omega 3 which, in nature, usually occurs in conjunction with DHA and which humans typically consume (and synthesize) along with DHA. Since other AD research has established that AD has an inflammatory aspect to its etiology, we believe that EPA may prove to be as important as DHA in its treatment and prevention. Also, psychiatric and attention-deficit disorders research has established that EPA rather than DHA appears to be the active long chain Omega 3 in achieving the desired treatment effect. See for example Jazayeri S, 2008 (http://www.ncbi.nlm.nih.gov/pubmed/18247193 ) and work by Andew Stoll, MD (http://www.amazon.com/Omega-3-Connection-Groundbreaking-Anti-depression-Program/dp/0684871386) and Ned Hollowell, MD. (http://www.amazon.com/Delivered-Distraction-Getting-Attention-Disorder/dp/034544230X).
Cinnamon helps lower cholesterol and blood sugar, is a potent anti-oxidant (see ORAC chart...link) and is anti-inflammatory, and thus through these 4 pathways is thought to be positive for brain health. A January 2011 publication of an animal study (transgenic mice and flies) by a group of Israeli scientists suggests that cinnamon may also have a positive direct brain effect - cinnamon helps retard the development of Alzheimer's pathology by preventing the oligomerization ("clumping") of single Abeta molecules, leading to toxic forms that kill brain cells (Frydman-Marom A). To learn more, see our newsletter on the topic (Link to Cinnamon newsletter CHANGE THIS TO NEW WEBSITE POSITION http://healthcareinsights.net/home/newsletter-2011/august-2011-newsletter/). Grape seed extract also prevents or slows oligomerization and fibrilization.
A proof of concept RCT in 12 older adults with MCI found significant improvements in one test of memory (verbal learning) in the 6 randomized to drinking Concord Grape Juice for 12 weeks (Krikorian R et al 2010).
Three small pilot randomized controlled studies of three different spices/herbs in Alzheimer's patients, all led by the same medical researcher in Iran, all published in reputable peer-reviewed journals, suggested positive effects in slowing cognitive decline compared to placebo (sage and lemon balm, also known as melissa) or slowing at same rate as a current prescription drug, without the usual gastro-intestinal side effects (saffron). (See Akhondzadeh, S. et al. 2003a, 2003b, 2010)
Diets high in sugar and/or saturated fats appear to be harmful for the brain. A preclinical study in AD transgenic mice demonstrated that simply spiking water with 10% sugar (while offering same healthy mouse chow to two groups of identical, randomized mice) resulted in speedier cognitive decline of the mice drinking the sugared water, higher levels of Abeta in the brain, and abnormal cholesterol levels. Cao D et al. 2007, Suzanne Craft group's proof of concept randomized clinical trial in 50 older adults for just 1 month demonstrated that a high glycemic index, high saturated/high fat diet, compared to a low glycemic, low saturated fat/low fat diet, resulted in significantly worse cognitive performance (using a visual memory test), and undesirable changes in levels of Abeta in cerebral spinal fluid. (Bayer-Carter JL et al. 2011).
Akhondzadeh S, Shafiee Sabet M, Harirchian MH, Togha M, Cheraghmakani H, et al. A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of mild-to-moderate Alzheimer's disease. Psychopharmacology (Berl). 2010 Jan; 207(4):637-43. Epub 2009 Oct 20.
Akhondzadeh S, Noroozian M, Mohammadi M, Ohadinia S, Jamshidi AH, Khani M. Salvia officinalis extract in the treatment of patients with mild to moderate Alzheimer's disease: a double blind, randomized and placebo-controlled trial. J Clin Pharm Ther. 2003 Feb;28(1):53-9.
Akhondzadeh S, Noroozian M, Mohammadi M, Ohadinia S, Jamshidi A, and Khani M. Melissa officinalis extract in the treatment of patients with mild to moderate Alzheimer's disease: a double blind, randomized, placebo controlled trial J Neurol Neurosurg Psychiatry. 2003 Jul;74(7):863-6.
Bayer-Carter JL, Green PS, Montine TJ, VanFossen B, Baker LD, Craft S, Diet Intervention and Cerebrospinal Fluid Biomarkers in Amnestic Mild Cognitive Impairment Arch Neurol. 2011;68(6):743-752. doi:10.1001/archneurol.2011.125
Calon, F., Lim, G.P., Yang, F., Morihara, T., Teter, B., Ubeda, O., Rostaing, P., Triller, A., Salem, Jr., N., Ashe, K.H., Frautschy, S.A., Cole, G.M., 2004. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron. 43, 633-645.
Cao D, Lu H, Lewis TL, Li L. Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease. J Biol Chem, (2007) 282(50):36275-82. Epub 2007 Oct 17.
Chan A. Graves V. Shea TB. Apple juice concentrate maintains acetylcholine levels following dietary compromise. J Alz. Dis. 2006 9 (3) :287-91.
Chauhan N, Wang KC, Wegiel J, Malik MN. Walnut extract inhibits the fibrillization of amyloid beta-protein, and also defibrillizes its preformed fibrils. Curr Alzheimer Res. 2004 Aug;1(3):183-8.
Emerson Lombardo, N.B., Volicer L., Martin A., Wu B., Zhang X.W., 2006. Memory preservation diet to reduce risk and slow progression of Alzheimer's disease, in Vellas, B., Grundman, M., Feldman, H., Fitten, L.J., Winblad, B. (Eds.), Research and Practice in Alzheimer's Disease and Cognitive Decline, vol 9, pp. 138-59.
Féart, C., Samieri, C., Barberger-Gateau, P., et al. Or Féart C, Samieri C, Rondeau V, Amieva H, Portet F, Dartigues JF, Scarmeas N, Barberger-Gateau P. Adherence to a Mediterranean diet, cognitive decline, and risk of dementia JAMA 2009;302(6):638-648.
Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T, Basun H, Faxen-Irving G, Palmblad J.et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol 2006 63(10): 1402-8.
Frydman-Marom A, Levin A, Farfara D, Benromano T, Scherzer-Attali R, Peled S, Vassar R, Segal D, Gazit E, Frenkel D, Ovadia M. Orally administrated cinnamon extract reduces ?-amyloid oligomerization and corrects cognitive impairment in Alzheimer's disease animal models. PLoS One. 2011 Jan 28;6(1):e16564
Green, K.N., Martinez-Coria, H., Khashwji, H., Hall, E.B., Yurko-Mauro, K.A., Ellis, L., LaFerla, F.M., 2007. Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-? and tau pathology via a mechanism involving Presenilin 1 levels. J Neurosci. 27(16), 4385-4395.
Gu Y, Luchsinger JA, Stern Y, Scarmeas N. Mediterranean diet, inflammatory and metabolic biomarkers, and risk of Alzheimer's disease. J Alzheimer's Dis. (2010) 22(2):483-92.
Howes MJ, Perry E. The role of phytochemicals in the treatment and prevention of dementia. Drugs Aging. 2011 Jun 1;28(6):439-68. doi: 10.2165/11591310-000000000-00000.
Jazayeri S, Tehrani-Doost M, Keshavarz SA, Hosseini M, Djazayery A, Amini H, Jalali M, Peet M. Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder Aust N Z J Psychiatry. 2008 Mar;42(3):192-8
Joseph JA. Shukitt-Hale B. Casadesus G. Reversing the deleterious effects of aging on neuronal communication and behavior: beneficial properties of fruit polyphenolic compounds. [Review] [62 refs] Am J Clin Nutr. 2005 81(1 Suppl):313S-316S.
Joseph JA, Shukitt-Hale B, Denisova NA, Martin A, et al. Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J-Neurosc:1999 19(18): 8114-8121.
Kamphuis, P.J.G.H., Scheltens, P., 2010. Can nutrients prevent or delay onset of Alzheimer's disease? J Alzheimer's Dis. 20, 765-775.
Krikorian R, Nash TA, Shidler MD, Shukitt-Hale B, Joseph JA. Concord grape juice supplementation improves memory function in older adults with mild cognitive impairment. Br J Nutr. 2010 Mar;103(5):730-4. Epub 2009 Dec 23.
Kulkarni KS, Kasture SB, Mengi SA. Efficacy study of Prunus amygdalus (almond) nuts in scopolamine-induced amnesia in rats. Indian J Pharmacol. 2010 Jun;42(3):168-73.
Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C. Daussin, F., Messadeq, N., Milne, J., Lambert, P., Elliott, P., Geny, B., Laakso, M., Puigserver, P., Auwerx, J., 2006. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1a. Cell. 127, 1109-1122.
Lee JW, Lee YK, Ban JO, Ha TY, Yun YP, Han SB, Oh KW, Hong JT. Green tea (-)-epigallocatechin-3-gallate inhibits beta-amyloid-induced cognitive dysfunction through modification of secretase activity via inhibition of ERK and NF-kappaB pathways in mice. J Nutr. 2009 Oct;139(10):1987-93. Epub 2009 Aug 5.
Mandel SA, Amit T, Weinreb O, Youdim MB. Understanding the broad-spectrum neuroprotective action profile of green tea polyphenols in aging and neurodegenerative diseases. J Alzheimer's Dis. 2011;25(2):187-208.
Muthaiyah B, Essa MM, Chauhan V, Chauhan A. Protective effects of walnut extract against amyloid beta peptide-induced cell death and oxidative stress in PC12 cells. Neurochem Res. 2011 Nov;36(11):2096-103. Epub 2011 Jun 25.
Rogers EJ, Mihalick S, Ortiz D and Shea TB. Apple juice prevents oxidative stress and impaired cognitive performance caused by genetic and dietary deficiencies in mice. J Nutr Health & Aging. 2004 8:92-7.
Scarmeas N, Luchsinger JA, Schupf N, Brickman AM, Cosentino S, Tang MX, Stern Y. Physical activity, diet, and risk of Alzheimer disease. JAMA 2009b;302(6):627-637.
Scarmeas N, Stern Y, Tang MX, Mayeux R, Luchsinger JA. Mediterranean diet and risk for Alzheimer's disease. Ann Neurol Apr 18;2006 59(6):912-921. [PubMed: 16622828]
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