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Friday, February 03, 2012

Alzheimer's Disease Analogies - Part One

So often patients and families ask about the how and why Alzheimer’s disease develops. As clinicians, we provide the best answers available based on the most current research. However, we will also use analogies to help explain things more clearly. In this blog, I want to talk about three of the most common analogies that we use in clinic to explain the ideas of 1) Symptomatic versus disease modifying treatments; 2) Prodromal Alzheimer’s disease versus Alzheimer’s disease dementia and 3) The idea that the most common forms of AD may be due to ‘underexcretion’ rather than ‘overproduction’ of beta-amyloid.

Symptomatic versus Disease Modifying Treatments

1. Symptomatic treatments simply relieve symptoms associate with a disease. They do not affect the underlying cause of the disease, and therefore do not affect the duration of the illness. Examples of symptomatic treatments include ‘cold remedies.’ If a patient is suffering from the common cold, and its associated symptoms such as sneezing, coughing, runny nose, and sore throat, physicians will often prescribe medications to reduce these symptoms. However, the patient still has the cold, and the cold will run its usual course. The medications will reduce some of the symptoms, but the patient still has the cold. The natural progression of the common cold is such that the body’s immune system usually clears the virus, and the patient recovers.

The medications that are currently FDA approved for AD, reduce the symptoms associated with AD, such as forgetfulness, confusion, and difficulty performing activities, but these medications do not affect the course of AD, which in time progresses to more severe deficits that do not respond to these medications. A disease modifying drug actually affects the course of the disease, and makes its duration less, or even stops its progression. Antibiotics are a good example of disease modifying medications. They stop an infection in its tracks. In the field of AD, we are actively testing drugs that are thought to be disease modifying, as they target the underlying cause of the disease, toxic beta-amyloid.

Prodromal AD versus AD dementia

2. Another analogy is used to convey the idea that, decades before Alzheimer’s disease dementia becomes apparent in a patient, there is an underlying pathological process that is affecting the brain. High cholesterol levels are associated with a higher incidence of heart attacks. However, a patient does not present to their doctor with any symptom associated with high cholesterol. In fact, until 25 years ago when cholesterol levels started to be routinely checked, many patients would present with a heart attack as the first symptom of their long standing high cholesterol levels. The same is thought to be true about AD.

The symptoms of dementia are to the brain much like a heart attack is to the heart. By the time the symptoms of dementia have developed, there have been years of an underlying pathological process affecting the brain, namely the accumulation of beta-amyloid and the loss of synapses and neurons. And, much the same way, if a patient presents to the emergency with a heart attack, prescribing a cholesterol lowering medication for the first time may be too late. Specifically, 15-20 years too late. Now that we can check cholesterol levels earlier in life with a simple blood test, in the absence of any symptoms, we can start patients on cholesterol lowering medications to reduce their risk of have the heart attack in the first place.

The same is believed to be true about treatment of Alzheimer’s disease dementia. By treating Alzheimer’s disease early, by lowering beta-amyloid levels, we may be able to prevent the dementia phase from ever developing. One of the biggest hurdles in the field has been how best to predict which individuals are ‘on their way’ to developing Alzheimer’s disease dementia. So far, measuring spinal fluid levels of beta-amyloid seems to be one of the most accurate methods. Other techniques being studied include amyloid PET scans, volumetric MRIs and cognitive testing.

To be continued......



By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
 
Author: Michael Rafii MD, PhD at 10:34 AM 0 Comments

Friday, February 03, 2012

Alzheimer's Disease Analogies - Part Two

Overproduction versus Underexcretion

3. Gout is a kind of arthritis that occurs when uric acid builds up in blood and causes joint inflammation. Gout is caused by having higher-than-normal levels of uric acid in the body. This may occur if a) the body makes too much uric acid or b) the body has a hard time getting rid of uric acid. The exact cause is unknown. And interestingly, not everyone with high uric acid levels in the blood has gout. The diagnosis is made when the disease becomes clinically apparent and the patient has symptoms, or by the visualization of the characteristic crystals in joint fluid. Some inherited causes of gout are solely due to overproduction of uric acids. Underexcretion of uric acid by the kidney is the primary cause of 90% of gout cases, while overproduction is the cause in less than 10% of cases.

There are some parallels with AD. Although it has been known for the past 20 years that all of the inherited forms of Alzheimer’s disease (5% of all cases) affect the processing of beta-amyloid in the brain, leading to its ‘overproduction’, it was not until last year that it was shown that the non-inherited forms of AD (95% of all cases) are due to ‘underexcretion’ of beta-amyloid from the brain. That is, most cases of AD seem to be due to an impaired ability of the body to remove beta-amyloid from the brain and into the blood stream, where it is rapidly cleared by the liver. The longer beta-amyloid stays within the confines of the brain, the more damage it causes to synapses and neurons, and eventually deposits into plaques. It is believed that different forms of the protein ApoE (2, 3 and 4) appear to regulate the removal of beta-amyloid from the brain, and they do so with different efficiencies. It has also been shown that ApoE4 seems to be the slowest in removing beta-amyloid from the brain, which may be why it confers the most genetic risk for the late-onset form of AD.




By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, Sa
 
Author: Michael Rafii MD, PhD at 10:33 AM 0 Comments

Thursday, January 26, 2012

Exercise and Brain Amyloid Deposition

A sedentary lifestyle is associated with greater brain amyloid deposition among cognitively normal individuals with the E4 version of the apolipoprotein E (APOE) gene, according to a report published last week in the Archives of Neurology.

To examine the association between exercise and brain amyloid deposition among patients with and without the APOE4 allele, Denise Head, Ph.D., and colleagues from Washington University in St. Louis, tested for the APOE gene and administered a questionnaire on physical exercise engagement over the last decade to 201 cognitively normal adults (135 women) age 45 to 88 years. Samples of cerebrospinal fluid were collected from 165 participants and brain amyloid imaging was performed on 163 patients. Fifty-six of the volunteers, of various ages and both sexes, turned out to be positive for APOE4.

Patients who reported higher amounts of exercise had lower average levels of brain amyloid than did patients who reported lower amounts of exercise. Participants who were positive for the APOE4 gene had higher levels of brain amyloid compared with individuals negative for APOE4 gene.

The authors observed a novel interaction, such that a more sedentary lifestyle was associated with an even greater brain amyloid level in APOE4 carriers than for noncarriers. That is, those subjects with the APOE4 variant who rarely or never exercised had the most plaques, putting them at heightened risk for the memory loss of Alzheimer’s disease. Interestingly, the carriers of the APOE4 gene who reported walking or jogging for at least 30 minutes five times a week had plaque accumulation similar to that of subjects who were APOE4-negative. In essence, the APOE4 gene carriers mitigated their inherited risk for developing Alzheimer’s with frequent aerobic exercise.

From previous studies that I have written about in this blog, we know that APOE4 status is associated with an increased risk of cognitive decline and elevated amyloid deposition. In contrast, exercise engagement has been associated with reduced risk of cognitive decline and lower levels of amyloid deposition. This data suggests that exercise at levels recommended by the American Heart Association may be particularly beneficial in reducing the risk of brain amyloid deposition in cognitively normal APOE4-positive individuals. This study is yet another example of how genetics interact with environmental influences to affect risk of manifesting a particular disease. A randomized clinical trial of exercise in cognitively normal individuals will help answer this question more fully, and lead to an intervention that can potentially alter disease progression.

Head D, Bugg JM, Goate AM, Fagan AM, Mintun MA, Benzinger T, Holtzman DM, Morris JC. Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid Deposition. Arch Neurol. 2012 Jan 9.




By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
 
Author: Michael Rafii MD, PhD at 10:05 AM 0 Comments

Tuesday, January 17, 2012

Recent Controversy Involving Resveratrol

Resveratrol was originally isolated from the roots of hellebore plant in 1940, but it attracted wider attention in 1992, when its presence was discovered in wine and was suggested as the explanation for the cardioprotective effects of wine, particularly red wine. Red wine contains more resveratrol than white wine because red wine is fermented with the skins, which contains resveratrol, whereas white wine is fermented after the skin has been removed.

Since the early 1990’s, resveratrol has been shown to have health benefits on multiple fronts, including cancer, inflammatory disease, cardiovascular, and even thought to affect longevity. Resveratrol is believed to be a strong antioxidant and, therefore, to contribute to the cardioprotective, anti-inflammatory, and neuroprotective properties of red wine intake.

Several epidemiological studies indicate that moderate consumption of red wine is associated with a lower incidence of dementia and Alzheimer's disease. The first study, published in 1997, reported that moderate to mild wine consumption was associated with a low risk of AD. Later, a study of individuals aged 65 years and older confirmed that intake of wine, but not other alcoholic drinks, was associated with a low risk of dementia, including AD. Furthermore, a prospective analysis of risk factors for AD in the Canadian population determined that wine consumption was the most protective variable against AD by reducing the risk of AD by 50%.

In the field of AD, recent work indicates that resveratrol reduces beta-amyloid accumulation in cell cultures. Resveratrol does not inhibit beta-amyloid production, since it has no effect on the beta-amyloid -producing enzymes beta- and gamma-secretases, but instead promotes the clearance of beta-amyloid from the brain.

Nearly 4,500 scientific articles have been published about functions and effects of Resveratrol in the body and various disease.

This past week, the media reported that a researcher who worked on the effects of resveratrol on cardiovascular health and longevity had fabricated data in many of his research projects. This scientific misconduct occurred only in the lab of this one researcher, who had a modest reputation in his field. The data do not appear to have any major impact at all on the larger body of scientific research involving resveratrol and related areas. Importantly, none of the research involved resveratrol in Alzheimer’s disease. The Alzheimer’s data comes from multiple, independent labs from around the world, and has been validated over the past 10 years. The data from the AD research has been so compelling, that a clinical trial has been funded by the NIH, after rigorous review. In addition, as with any and all clinical trials, the resveratrol in AD data has also been reviewed by the FDA.

Scientific integrity represents the core of the research enterprise, and it is unfortunate that this has occurred with regards to Resveratrol. The field will move on, continuing to strive towards finding a cure for this Alzheimer’s disease with the latest scientific advances.




By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
 
Author: Michael Rafii MD, PhD at 2:04 PM 0 Comments

Thursday, January 12, 2012

Spinal Fluid Abnormalities Predict MCI Conversion to AD Almost 10 years in Advance

In the most recent issue of the Archives of General Psychiatry, Peder Buchhave, M.D., Ph.D, who is affiliated with Lund University and Skane University, Sweden, and colleagues report findings from a study of 137 patients with mild cognitive impairment (MCI) at baseline. The median follow-up was 9.2 years. During the follow-up, 72 patients (53.7 percent) developed AD and 21 (15.7 percent) progressed to other forms of dementia.

At the baseline, cerebrospinal fluid levels of beta-amyloid were reduced and two other biomarkers, total tau and phosphorylated tau protein levels were elevated in patients who converted to AD during follow-up compared with levels in patients who did not develop AD.

The study indicates baseline CSF beta-amyloid levels were equally reduced in patients with MCI who converted to AD within five years (the early converters) compared to those who converted later between five and 10 years. However, Total-tau and Phosphorylated-tau levels were significantly higher in early converters compared to later ones.

Readers of this blog will recall that there has been a lot of recent work focusing on the interplay between beta-amyloid and tau, specifically the dependency of beta-amyloid on phosphorylated tau protein to cause neurodegeneration. The work suggests that about 90 percent of patients with MCI who have these abnormal CSF biomarkers at baseline will develop AD within a period of about nine years.

Greater emphasis is being placed on early diagnosis, and certainly CSF analysis will continue to play an important part in this process.

P. Buchhave, L. Minthon, H. Zetterberg, A. K. Wallin, K. Blennow, O. Hansson. Cerebrospinal Fluid Levels of ß-Amyloid 1-42, but Not of Tau, Are Fully Changed Already 5 to 10 Years Before the Onset of Alzheimer Dementia. Archives of General Psychiatry, 2012; 69 (1): 98



By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
 
Author: Michael Rafii MD, PhD at 3:38 PM 0 Comments

Tuesday, January 03, 2012

Alzheimer's 2011: A Year in Review

In this final blog I would like to review some of the highlights of what has happened in the AD world this past year, and the new directions that we will likely be heading towards in 2012.

This year we saw the publication of new diagnostic guidelines for AD formulated by committees sponsored by the National Institute on Aging and the Alzheimer’s Association. The NIA/AA also published guidelines for diagnosis of mild cognitive impairment due to Alzheimer’s disease, and for preclinical AD. These guidelines will be important tools for clinicians to diagnose AD in its earliest stages, and represent the first revision in 25 years.

An FDA advisory committee gave preliminary approval of the PET amyloid imaging ligand AV-45, citing work to be done to ensure consistency in reading PET scans. Full approval is expected sometime in 2012, if a uniform training program is implemented for radiologists interpreting the scans.

The European Medicines Agency announced the likely approval of hippocampal atrophy as a marker of early AD for the purpose of clinical trials. Much work has gone into linking hippocampal atrophy visualized by MRI, as an early and specific biomarker of neurodegeneration seen in AD.

IGAP—the International Genomics of Alzheimer’s Project, a transatlantic collaboration to create the most detailed map of genetic variants that link to AD was also launched in 2011. Meta analysis of genome-wide association studies (GWAS) revealed four new genetic risk variants for AD.

In terms of clinical trials, Gantenerumab, an antibody against beta-amyloid, was shown to clear plaques when given intravenously, according to results from a Phase 1 trial. The drug seems to be one of the most potent developed thus far in reducing plaques. A Phase 2 gene therapy trial for Parkinson’s disease was deemed a success. A similar Phase II gene therapy trial for AD, called the Nerve Growth Factor Study, is currently ongoing and recruiting. Multiple clinical trials, including the ADCS Phase III Resveratrol and Roche Phase II Gantenerumab trial are launching in 2012.

A very important paper by the Holtzman group at Washington University further established the relationship between ApoE4 genotype and decreased clearance of beta-amyloid from brain, both in humans and animal models. The idea that ApoE4 is less effective in removing beta-amyloid from the brain is not necessarily novel, per se, and had been previously shown. However, it had never been proven so convincingly and in such a complete manner in humans and animal models of AD. Together, the data suggest that ApoE variants contribute to a person’s risk for AD by affecting the clearance of beta-amyloid from the brain long before amyloid plaque deposition begins. Later in the year, the same group reported that, in mice, lowering the levels of ApoE4 results in fewer amyloid plaques. The results imply that ApoE-lowering treatments have a place among proposed AD therapies, including immunotherapy, gene therapy, as well as beta-, and gamma- secretase inhibitors.

Results published in the Journal of the American Medical Association showed that women with sleep-disordered breathing (SDB)— pauses in breathing or reduced ventilation quality during sleep — are more likely to develop cognitive impairment five years later. The biology behind this finding may include hypoxia, or decreased oxygen delivery to certain parts of the brain, including the hippocampus which is critical in memory function. In addition, sleep fragmentation, which can interfere with memory consolidation, which occurs during certain stages of sleep, may also lead to cognitive problems. This study has really brought much needed attention to the evaluation of sleep as part of the work-up in individuals with Mild Cognitive Impairment.

We anticipate further progress in understanding the progression of the earliest stages of Mild Cognitive Impairment and AD with the Alzheimer’s Disease Neuroimaging Initiative (ADNI2), The Dominantly Inherited Alzheimers Network (DIAN) study and the Alzheimer’s Prevention Initiative (API) during 2012.


By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
 
Author: Michael Rafii MD, PhD at 11:06 AM 0 Comments

Friday, December 23, 2011

Reducing ApoE Lowers Beta-amyloid Levels in Brains of Mice

In a paper published this week in the Journal of Neuroscience, Dr David Holtzman and colleagues at the Washington University School of Medicine provide strong evidence that less ApoE is better, at least with regards to beta-amyloid levels in the brain. They report that, in mice, lowering the levels of ApoE4 results in fewer amyloid plaques. The results imply that ApoE-lowering treatments have a place among proposed AD therapies, including immunotherapy, gene therapy, as well as beta-, and gamma- secretase inhibitors.

The genetically engineered mice had about half the amount of ApoE protein in the brain. They also had less than half the amount of beta-amyloid, and a dramatic reduction in Amyloid plaques. Interestingly, they also had about 95 percent less microglial activation. Readers of this blog will recall that microglia are the immune cells in the brain, and their over-activation is thought to accelerate the damage to brain cells observed in AD. Moreover, a dose-dependent effect was seen with lowering ApoE4, the strongest risk gene for sporadic AD.

It is believed that the different forms of ApoE (2, 3 and 4) appear to regulate the removal of beta-amyloid from the brain, and they do so with different efficiencies. It has been shown that ApoE4 seems to be the slowest in removing beta-amyloid from the brain, which may be why it confers the most genetic risk.

Experiments are planned to increase ApoE levels in the brain and see what happens to beta-amyloid levels. If they go up, then there is good evidence that by modulating ApoE levels with medications, we might be able to modify beta-amyloid levels in the brain.

Kim J, Jiang H, Park S, Eltorai AEM, Stewart FR, Yoon H, Basak JM, Finn MB, Holtzman D. Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-ß Amyloidosis. The Journal of Neuroscience, 2011 December 10; 31(49):18007–12
 
Author: Michael Rafii MD, PhD at 11:43 AM 0 Comments

Wednesday, December 14, 2011

Weight Change & Cognitive Function: Results from the Women’s Health Initiative

Dear Readers,

It is very rare in the course of a community talk on lifestyle factors and their relation to cognitive function, that I don’t discuss the “Big 3” - hypertension, diabetes and obesity. Some studies have suggested that dementia risk is greater in those who are obese. Other studies have suggested central adiposity may be protective against cognitive impairment and dementia in older women while others have suggested that lower weight may be associated with greater cognitive decline. In a recent article from Driscoll and colleagues, the authors attempted to characterize the relationship between changes in weight and waist circumference with cognitive function.

A total of 2238 women participating in the Women’s Health Initiative (WHI) were followed longitudinally, in a sub-study called WHISCA (Women’s Health Initiative Study of Cognitive Aging). The women enrolled in this study underwent detailed cognitive assessments, anthropometric measurements [weight, height, waist circumference, waist/hip ratio] and questionnaires regarding caloric intake using a Food Frequency Questionnaire. Other demographic characteristics that were assessed were level of education, cardiovascular risk factors [hypertension, smoking, history of stroke, heart disease, diabetes, alcohol intake] and depression. Cognitive tests measured global cognitive function, verbal and figural memory, attention and working memory, spatial ability and fine motor speed. Other variables assessed were race, education in yrs (range 0-30), and the history or presence of medical conditions (heart disease, TIA, stroke, hypertension, diabetes, and Parkinson’s disease).

At each WHI visit, staff obtained measurements of height and weight to calculate BMI, and also filled out a food questionnaire. Waist circumference was measured at baseline and year one. The investigators had measurements through the WHI follow and before entry in to WHISCA. Those who gained weight occurred more in younger women, those who were smokers at baseline, those who had lower wait/hip ratios and no hypertension. When the women were grouped according to weight gain, (>5% gain), weight lost (>5% loss) or remaining stable before enrollment, women with prior weight loss had a slightly lower cognitive score compared to women who had stable weight or those who had gained weight. When weight was grouped according to either any weight loss (<10% or >10%) or weight gain (<10% or >10%), women with >10% weight loss performed significantly worse on cognitive tests, than both weight gain groups, and those with 10% weight loss performed significantly worse than women gaining <10%.

At the time of WHI enrollment, 10.6% of women reported that they were currently following a low calorie diet. A low calorie diet was associated with lower cognitive test scores for attention and working memory (p<0.001) and higher scores on fine motor speed. Self report food intake measured by the food frequency questionnaire, revealed that higher caloric intake was associated with better cognitive performance.

This study examined the association of weight gain/loss to cognitive function, in a large group of older women. The results suggest that there were no differences in cognitive performance between women who gained weight or whose weight remained stable over approximately 3.5 years. Worse cognitive performance was associated with weight loss, and this relationship was not modified by initial BMI. The findings from this study are provocative, as they add to the literature that suggests weight loss could potentially signal the beginning of cognitive decline and dementia, and that there is no specific evidence to suggest a relationship between obesity and cognitive decline. The major limitation of this study as suggested by the authors was that it was done in women only, thus not generalizable to a general population of men and women. Unfortunately, this study only included ~10% of minority women in the sample, and thus was not able to comment on any differential findings that may have been influenced by race/ethnicity. Additional longitudinal studies to confirm these associations are needed, and could shed light on potential mechanisms of how body weight is associated with cognitive function.

Here are 3 articles you can refer to, to learn about this study, and other studies examining the oldest old.

Driscoll I, Espeland MA, Wassertheil-Smoller S et al. Weight Change and Cognitive Function: Findings From the Women’s Health Initiative Study of Cognitive Aging. Obesity (2011)19, 1595-1600. Arch Neurol. 2011 68(5): 631-636.

Wolf P, Beiser A, Elias MF et al. Relation of obesity to cognitive function: improtance of central obesity and synergistic influence of concomitant hypertension. The Framingham Heart Study. Curr Alzheimer Res 2007; 4: 111-116.

Kerwin DR, Zhang Y, Kotchen JM et al. The cross sectional relationship between body mass index, waist hip ratio and cognitive performance in post menopausal women enrolled in the Women’s Health Initiative. J Am Geriatr Soc 2010: 58:1427-1432.

Thanks for reading.


Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Rush Alzheimer’s Disease Center
Rush Institute for Aging
Chicago, IL
 
Author: Neelum Aggarwal MD at 1:43 PM 0 Comments

Friday, December 09, 2011

Targeting Tau with a Vaccine

Readers,

AD brains are characterized by the deposition of two hallmark proteins, the amyloid-ß protein and the microtubule-associated protein tau. Beta-amyloid is derived from the Amyloid precursor protein (APP) and is the major constituent of plaques, while abnormally phosphorylated (hyperphosphorylated) tau gives rise to neurofibrillary tangles. Beta-amyloid is closely associated with the onset of AD, but it is the tau pathology that correlates with its severity.

Frontotemporal dementia (FTD) describes a heterogeneous group of neurodegenerative disorders that are characterized by a broad spectrum of clinical symptoms including behavioral changes, language abnormalities and motor dysfunction. FTD is the second most common form of dementia before the age of 65. In FTD, tau pathology occurs in the absence of overt beta-amyloid deposition. In a subset of FTD, pathogenic mutations have been identified in the gene for tau.

Taken together, tau plays a central role in AD and FTD, making it an attractive drug target. I have discussed the relationship between beta-amyloid and tau in previous blogs.

This week, researchers at Sydney University’s Brain and Mind Research Institute have used active immunization against tau in aged mice that have been genetically engineered to have abnormal tau. (You will recall that active vaccination means injecting the abnormal protein into the bloodstream, to illicit and endogenous immune response, as opposed to passive immunization where pre-made antibodies against the abnormal protein are injected).

Three groups of mice were used in the study. Each group was formed according to age – 6 months, 12 months and 18 months. The older group was most similar to the more advanced stage of Alzheimer's disease. The mice were given three injections over 4 weeks and then evaluated 10 months later and assessed at the end of that period for the pathological hallmarks mentioned above.

This active vaccine treatment reduced both tau phosphorylation and neurofibrillary tangles, suggesting that therapeutic immunization against tau may prevent progression of disease, in FTD and perhaps AD as well.

Should this strategy prove to be effective, active vaccination will be a powerful tool in treating not only AD, but other neurodegenerative diseases including Frontotemporal dementia and Dementia with Lewy bodies and Parkinson’s disease, where vaccination would target alpha-synuclein, the main component of Lewy bodies.

Bi et al, Tau-Targeted Immunization Impedes Progression of Neurofibrillary Histopathology in Aged P301L Tau Transgenic Mice, PLoS One, December 8, 2011.




By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
 
Author: Michael Rafii MD, PhD at 11:19 AM 0 Comments

Tuesday, November 22, 2011

Updates from the International CTAD meeting & the Society for Neuroscience meeting

The 4th annual conference on Clinical Trials in Alzheimer’s Disease in San Diego, California was filled beyond its venue's capacity, drawing over 500 researchers from around the world. For the bulk of the meeting, researchers worked on methodological aspects they hope will improve future trials’ chances of success. Clearly, better drugs are needed to treat AD, and there have been no drugs approved in over a decade. These methodological improvements include using more advanced statistical methods to analyze subject data, and to incorporate biomarkers of disease, including brain amyloid levels and measures of brain atrophy, as part of efficacy measures. In addition, there was much discussion on trial designs that target the disease in the pre-dementia phase of Alzhiemer’s disease, sometimes referred to as Mild Cognitive Impairment (MCI).

There is international consensus that Alzheimer’s disease starts some 15 years before symptoms of dementia, and new trial designs will need to be based on a biomarker-supported diagnosis of prodromal AD. Prodromal AD, which is the cause of cognitive impairment in roughly half of patients diagnosed with MCI, is basically defined as patients who are not demented but are destined to develop dementia within a few years because they have the earliest signs of AD developing in their brain. Several companies have begun using such designs to treat patients with prodromal AD, before dementia sets in.

The Society for Neuroscience meeting in Washington D.C. with 42,000 members is the largest meeting in the world on fundamental research on the nervous system. Many presentations were made with direct relevance to AD. One included the work of Dr. Gene Alexander from the University of Arizona, who found that physically fit seniors show fewer age-related changes in their brains. The findings further previous data in the AD field and underscore the importance of exercise for maintaining brain health throughout life.

As people age, some regions of the brain — including those responsible for attention and memory functions — begin to lose volume or shrink. To see how physical fitness affects brain aging and age-associated declines in cognition, Alexander and colleagues scanned the brains of 58 men and 65 women (ages 50 to 89 years) and evaluated their performance walking on an inclined treadmill.

The more physically fit a participant was, the less age-related brain changes they showed. In particular, exercise endurance and breathing efficiency offered the best combination of fitness measures in predicting patterns of brain aging. Individuals with higher levels of aerobic fitness also outperformed their less physically fit counterparts on tests measuring memory, executive function, and information processing. Identifying the fitness indices that are the best predictors of brain aging and cognitive performance may help improve exercise-based interventions to promote healthy brain aging.

Another interesting presentation was on how short-term estrogen treatment increases the volume of cortical gray matter — brain cells and their uninsulated connections — in postmenopausal women. The research reveals a potential benefit from short-term hormone replacement therapy. Researchers, led by Paul Newhouse, MD, of Vanderbilt University, imaged the brains of 24 healthy postmenopausal women who took either estrogen or a placebo for three months. After treatment, the women who took estrogen had more gray matter in parietal, temporal, and prefrontal areas of the brain. These regions are known to be involved in attention, decision-making, and memory.

The findings suggest the brain remains responsive to estrogen treatment even after menopause, and that this responsiveness or plasticity is important for preserving cognitive functioning, especially in the early postmenopausal period. The findings suggest that long-term hormone treatment, shown to have adverse effects on health in postmenopausal women, may be unnecessary for cognitive benefit. Short-term estrogen treatment in normal postmenopausal women is sufficient to increase gray matter in the brain.






By Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego
 
Author: Michael Rafii MD, PhD at 10:58 AM 0 Comments
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The Alzheimer's Disease Cooperative Study (ADCS) was formed in 1991 as a cooperative agreement between the National Institute on Aging (NIA) and the University of California, San Diego. The ADCS is a major initiative for Alzheimer's disease (AD) clinical studies in the Federal government, addressing treatments for both cognitive and behavioral symptoms. This is part of the NIA Division of Neuroscience's effort to facilitate the discovery, development and testing of new drugs for the treatment of AD and also is part of the Alzheimer's Disease Prevention Initiative.

The ADCS was developed in response to a perceived need to advance research in the development of drugs that might be useful for treating patients with Alzheimer's disease (AD), particularly drugs that might not be developed by industry.


 
 

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