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Wednesday, February 27, 2013

Researchers Now Able to See Molecular Mechanisms Inside Living Neurons with Genetic AD Mutation


Dear Readers,

As you might recall, about 5 percent of all cases of AD are familial. That is, the disease occurs because of an inherited mutation in the gene for either the amyloid precursor protein (APP) or in genes for the enzymes that cleave APP. The end result is that the mutation causes an over production of beta-amyloid that is toxic to synapses and neurons, and patients develop dementia sometime around the age of 50. In addition, beta-amyloid builds up as the tell-tale amyloid plaques. Some researchers believe the plaques are a way that the brain sequesters toxic beta-amyloid.

Interestingly, in 2008, a paper was published describing a family with an inherited form of AD due to an unusual mutation in APP that results in dementia at a young age, but who have no amyloid plaques in the brain. The beta-amyloid is present, yet it cannot deposit into plaques, and exists only as a free-floating form.

Since then, researchers have genetically engineered mice that have the same exact mutation in APP. These mice also develop the signs of dementia, but also lack the plaques just as their human counterparts do. The explanation for this curious absence of plaques came a few years later by carefully examining the structure of beta-amyloid produced from the mutated APP. The mutation caused the beta-amyloid molecules to chemically repel each other, rather than stick to one another, and therefore could not form plaques. It was this finding, among others, that raised the possibility that plaques may be protective. This should not be too surprising, given that cholesterol plaques in arteries, are in essence, sequestering excessive, free-floating cholesterol and isolating it from depositing in other tissues.

Now, in a study published in the journal Cell - Stem Cell, researchers in Japan have generated neurons from stem cells derived from patients with this curious form of familial AD. They also generated such cells from two patients with the non-inherited form of AD for comparison. The accomplishment of this feat means that we can now look at the molecular mechanisms as they occur inside a living neuron that harbors a genetic mutation that affects the beta-amyloid pathway. The neural cells from one of the familial and one of the non-familial AD patients showed extensive cellular damage from beta-amyloid INSIDE neurons. This internal form of beta-amyloid has not been as extensively studied, and only by this type of experiment, can we hope to better understand how it is involved in AD. The team also found that the injuries were lessened with docosahexaenoic acid (DHA) treatment. Certainly this finding is very important, and needs to be better studied, but more importantly, this stem cell technique may one day allow us to test drugs for AD on neurons derived from patients with AD to efficiently obtain answers about mechanism of action and perhaps chance of success before launching larger scale studies.


Kondo et al. Modeling Alzheimer’s Disease with iPSCs Reveals Stress Phenotypes Associated with Intracellular Aß and Differential Drug Responsiveness.




Thanks for reading,

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 2:45 PM 0 Comments

Wednesday, February 20, 2013

FDA offers New Guidance on Developing Drugs for Alzheimer’s Disease


Dear Readers,

Medications can be categorized in one of two ways: symptomatic or disease-modifying. Symptomatic treatments reduce symptoms associated with a disease, but do not affect its course. For example, over the counter cold medications reduce the symptoms associated with a common cold, such as sneezing, coughing, runny nose, but they do not affect the duration of the cold. Patients can take those medications to feel a bit better, but they will still have the cold.

Disease-modifying drugs actually shorten the duration, or even stop the illness. Antibiotics are a great example. Taking an antibiotic will stop an infection, such as pneumonia. If an antibiotic is not taken, the pneumonia can progressively get worse, and even become fatal. There are other disease modifying drugs, especially in the fields on oncology and infectious disease, but also in neurology.

Current drugs that are FDA approved for dementia due to Alzheimer’s disease (AD) fall into the symptomatic category. They certainly reduce symptoms associated with the disease, but they do not affect the course of the disease. And eventually, in some patients, the dementia becomes so severe, that the medications have less effect.

Last week, the FDA issued a proposed guidance designed to assist companies developing new disease-modifying treatments for patients in the early stages of Alzheimer’s disease, before the onset of the dementia stage of AD. At present, for drugs designed to treat patients with dementia, the FDA requires that treatments not only show an effect on abnormal thinking, but also how well patients function. The goal for existing clinical trials is to ensure that any beneficial effect on thinking is associated with a clinically meaningful outcome for the patient. The new proposal suggests that a biomarker may be used to assess the drug as well.

Because patients in the earliest stages of Alzheimer’s disease, so called prodromal AD , have little, to no impairment of functioning, it is difficult to assess changes in function in these patients. This can make it difficult to determine if a given treatment’s effect is clinically important. The FDA is aware of this, and is proposing a possible change to measuring outcomes in drugs being evaluated in patients with prodromal AD. A biomarker will be needed to show whether the drug is doing what it is supposed to be doing. For example, LDL cholesterol is a biomarker that can be measured and followed over time, to assess whether a statin drug is working. The critical point is that lowering LDL cholesterol is known to lower risk of heart disease.

There is a great need for such a biomarker in AD. However, as the FDA states, “no reliable evidence exists at the present time that any observed treatment effect on such a biomarker is reasonably likely to predict ultimate clinical benefit.” This means that more work is needed to define such a biomarker for AD. But, the FDA is willing to consider using changes in a biomarker in conjunction with cognitive improvement by the drug. In essence, a positive biomarker result in combination with a positive finding on measure of cognition may support a drug’s claim of disease modification in AD.

The question will be which biomarker should be used. And this question will need to be answered soon in order for such clinical trials to move forward. But the FDA proposal is very encouraging and reflects the knowledge we now have that we need to treat patients with AD in the earliest stages, before dementia sets in.

Thanks for reading,

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 8:54 AM 0 Comments

Tuesday, February 12, 2013

Sex differences in grey matter atrophy patterns among AD and aMCI patients


Dear Readers,

In my last post, I discussed the increasing importance of sex and gender studies in medicine. Recent data suggests that dementia, specifically Alzheimer’s disease may be more prevalent in women than in men, and the basis for this may be in specific biochemical or neuro-anatomical changes in the brain. As I reviewed articles on this topic, I re-read an interesting paper by Skup et al. that examined multiple neuroimaging changes associated with specific diagnoses of cognitive function in men and women who were participating in the Alzheimer’s Disease Neuroimaging Initiative(ADNI).

In this paper, a total of 687 persons (224 healthy controls, 266 amnestic MCI, and 197 probable Alzheimer’s disease) were evaluated for structural brain changes over a 2-3 year period, while remaining “stable” with regards to disease classification. The findings from this study were interesting in that sex/gender differences regarding global and local volume measurements were noted in each of the diagnostic states (healthy control versus amnestic MCI versus probable AD). Females with AD and amnestic MCI differed from controls in the regions of the basal ganglia, specifically the right caudate nucleus – a finding not seen in males. Further, amnestic MCI females and males differed from AD males and females with regards to atrophy in the basal ganglia- thalamus - amygdale and precuneus. Lastly, sex differences were noted in the Alzheimer’s disease participants, in multiple areas such as the caudate, thalamus and bilateral middle temporal gyrus.

What do these findings potentially mean? First, they strongly suggest that not only are differences noted in brain anatomy between the two sexes for varying disease states (aMCI and AD), but that these differences can be seen in the deep structures of the brain – the basal ganglia- in addition to the cortex. Thus the relation of the basal ganglia to cognitive function may be a stronger predictor of risk or vulnerability of developing dementia and AD than previously thought. Second, sex and gender brain changes and how they relate to cognitive function, may have larger implications, as they have the potential to inform clinicians and researchers, how symptoms and long term consequences of disease differ among men and women.

Want to read more? Here are 3 articles that you should read to learn about this particular study or other research in this area.

Skup M, Ahu H, Wang Y et al. Sex Differences in Grey Matter Atrophy Patterns among AD and aMCI Patients: Results from ADNI. Neuroimage: 2011 June 1: 56
Sowell E, Peterson B, Kan E., et al. Sex differences in cortical thickness mapped in 176 healthy individuals between 7 and 87 years of age. Cerebral Cortex. 2007; 17: 1550-1560.

Sullivan E, Rosenblom M, Serventi K. et al. Effects of age and sex on volumes of the thalamus, pons, and cortex. Neurobiology of aging. 2004: 25 (2): 185-192.

Witte A, Savli M, Holik A. Et al. Regional sex differences in grey matter volume are associated with sex hormones in the young adult human brain. NeuroImage 2010; 49 (2): 1205-1212.

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 3:34 PM 0 Comments

Wednesday, February 06, 2013

Gender Differences in Beliefs & Knowledge about AD



Dear Readers,

Studies examining sex and gender differences and how they relate to medical diseases is a growing area of interest among clinicians and researchers alike. Data from many countries, suggest that men die younger than women, while women experience a heavier burden of chronic illness. In addition studies also suggest that there may be differences in how men and women behave with regards to various aspects of their health including the utilization of health services, or thoughts and beliefs about disease or risk of developing a disease. This latter theme – gender differences in perceived risk of developing a disease - was examined by Werner et al in a recent issue of Archives of Gerontology and Geriatrics.

In this study a telephone survey of a national representative sample was conducted in persons 18 years or older to assess gender differences in worries and concerns about developing AD. A total of 1292 phone calls were made using a random digit dialing method, 74 phone numbers were disconnected, and 182 phone calls were deemed unusable due to a language barriers. A total of 404 persons refused to participate, leaving 632 persons that provided complete interviews (67.5%). The majority of persons who responded were female (52.5%), with a mean age of 45 years (range 18y-88y) and an average education of 14 years (range 0-28y). Most were married (70%) and a quarter of the participants (25%) reported having a relative with AD.

Awareness of Alzheimer’s Disease (AD) was assessed with a single question: “Did you ever hear about AD?” A negative answer was rated as 0 and a positive answer was 1. Questions about susceptibility of developing AD, fear of developing AD or worry about developing AD were assessed with separate questions and answers were based on the Likert type of scale (ranging from 1 = not at all to 5 = very likely). Socio-demographic variables included gender, age, years of education, marital status and ethnicity.

Although no differences were noted between men and women with regards to awareness of Alzheimer’s disease, statistically significant differences were noted for perceived susceptibility, worry and fear regarding AD.

Interestingly, the variables associated with increased rates of susceptibility of disease were familiarity with someone with AD, lower education and higher age. Among all the factors examined, susceptibility of disease rated as moderate to high, was lower overall in both sexes (12% in male, 18% in women); although knowledge of AD was relatively high (39% of men vs. 51% of women).

What do these findings potentially mean for education and awareness campaigns for Alzheimer’s disease? One thought, is that tailoring educational initiatives that focus on the susceptibility of developing the disease may have the most impact on changing behaviors leading to disease prevention and potentially care considerations for those who have the disease. Research in health behaviors have shown the “vulnerability” or “susceptibility” of developing the disease, may influence behaviors more than simply education of the health concern alone.

Further, sex/gender messaging may be more important than previously realized in health behaviors/prevention of AD. Women and men may respond differently to the educational initiatives presented, and focusing on concerns of worry, or fear (both increased in women in this sample) in developing these messages, may not only lead to more realistic perceptions of susceptibility of developing the disease, but also encourage more persons, including caregivers and family members, to gain knowledge of the disease and potential treatment options.

Want to read more? Here are 3 articles you can refer to, to learn about this particular study or the latest research on post traumatic stress disorder:

Werner P, Goldberg S, Mandel S et al. Gender differences in lay persons’ beliefs and knowledge about Alzheimer’s disease (AD): A national representative study of Israeli adults. Am J Geriatr Psychiatry 20:9, September 2012

Carter CL, Resnick EM, Mallampalli M et al. Sex and gender differences in AD: Recommendations for future research. Journal of Women’s Health 21: 1018-1023.

Wang C, O’Neill SM, Rothrock N. et al. Comparison of risk perceptions and beliefs across common chronic diseases. Preventive Medicine,48 197-202.(2009)


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 9:46 AM 0 Comments

Friday, February 01, 2013

Medicare's Decision on Whether to Cover PET Scans


Dear Readers,

Although the FDA approved florbetapir (Amyvid) in April 2012 as a tracer for PET scans in detecting brain amyloid, Medicare has not covered it. The test costs about $3,000 in total and some patients have been paying out of pocket for it.

This past Wednesday, a Medicare advisory panel voted against medicare coverage for amyloid brain PET scans. Although the technology has been around for 8 years, and numerous studies have shown its accuracy in detecting amyloid plaques, the committee felt that it did not improve health outcomes in patients. One major concern has been what to do with a positive result from the scan given that no current therapy exists to alter the progression of the disease.

It is expected that such a test would be used not for patients who have clear-cut Alzheimer’s dementia, but rather to identify those who are at greatest risk for developing the disease. As readers of this blog will recall, there have been many studies that have shown the connection between amyloid and the brain and subsequent development of memory problems and Alzheimer’s dementia. However, the question still remains as to what to do once the scan is found to be positive. I would submit that there is much to be gained, not only from a positive scan, but even more so from a negative scan.

The test may in fact be most useful in patients with Mild Cognitive Impairment (MCI). About 50% of patients will progress to full-blown AD dementia within five years. This scan would help us determine to which group a patient belongs: MCI due to AD or not due to AD. Such early detection would allow patients and families to plan for the future as opposed to the cases I see routinely in clinic where the first manifestation of memory impairment is something such as a medication overdose, financial mistakes, and other functional issues with potentially serious complications. As a clinician, I see great benefits not only in being able to accurately inform my patients about the cause of their cognitive impairment, but also being able to tell a patient with MCI that he or she does not have amyloid in the brain. That is, not on the path towards Alzheimer’s dementia. In these cases, we would initiate other studies as part of the work up to evaluate the cause of the patient’s cognitive impairment. In fact, just one day prior to the medicare advisory panel meeting, the Alzheimer’s Association and the Society for Nuclear Medicine published guidelines specifying in which patients amyloid scans would have greatest impact on outcome.

Until such coverage is available, we will rely on clinical history, neurological and cognitive evaluation, blood tests and volumetric MRI for evaluating patients with cognitive complaints. As disease modifying treatments become available, the coverage of such scans will no longer be in question.




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 3:56 PM 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.