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Wednesday, March 28, 2012

Finding a Blood Test for Diagnosing AD


Dear Readers,

Many of you might be familiar with the term “genomics.” The human genome contains the complete set of genes required to build a functional human being, and genomics refers to the study of these genes or DNA codes. However, the genome is only a source of information. In order to function, this DNA code must be expressed to produce proteins. The proteome is the complete set of proteins produced by the genome at any one time.

The proteome is much more complex than the genome. This is because each protein can be chemically modified in different ways after being produced. These chemical modifications can affect the proteins’ functions. The proteome is also very dynamic. Most of our cells contain the same genome regardless of the cell type, developmental stage, environmental conditions, or disease state. The proteome also varies considerably in these differing circumstances due to different patterns of gene expression and different patterns of protein modification. While scientists are still deciphering the function of most of the 30,000 human genes, researchers estimate that each gene can give instructions for as many as 100 different proteins. On top of that, every organ has a different distribution of proteins, and the distribution changes frequently.

In the field of Alzheimer’s, researchers have identified genes that when mutated, will lead to early Alzheimer’s disease. If a patient has such a mutation, then the diagnosis of early onset AD is made. And by measuring levels of proteins, such as beta-amyloid and tau in the cerebrospinal fluid, we can make the diagnosis of late onset AD. However, in order to get cerebrospinal fluid, patients have to undergo a spinal tap, which is rather inconvenient compared to a simple blood sample. Therefore, tremendous effort has been put into finding a blood test, or biomarker for AD. It is believed that this test would revolutionize the ability of physicians to diagnose AD, even in its asymptomatic stages.

The largest study to look at proteomics has just been presented at the Research & Standardization in Alzheimer's Disease Conference in Melbourne, Australia, by Professor Simon Lovestone, Director of the NIHR BRC for Mental Health and Director of Research King’s Health Partners Academic Health Sciences Centre, London.

In collaboration with British biomarker company Proteome Sciences and the pharmaceutical firm Merck, the study focused on the analysis of over forty proteins in a group of 1,000 individuals comprising of patients with a clinical diagnosis of mild to moderate Alzheimer’s disease or Mild Cognitive Impairment and normal individuals. For each individual a single sample of blood was tested.
The levels of each blood protein were compared with over 200 different clinical parameters to determine those proteins most effective at making an early diagnosis of AD, predicting the current duration of disease and predicting the likely future course of cognitive decline. To ensure that the data obtained was free of bias all samples were randomized before testing and the testers had no knowledge of the health status of any of the patients. Combinations of statistical methods were applied to interpret the over 100,000 individual data points and generate the optimum protein panels for each indicated use.

Biomarkers are used elsewhere in medicine for improved diagnosis, for pre-symptomatic diagnosis, for risk evaluation, to monitor disease progression or the results of therapy. One example is LDL cholesterol, which is used to assess risk for cardiovascular and cerebrovascular disease, and is also used to monitor effectiveness of therapies. It is hoped that we will have a blood test for AD in the very near future given the encouraging results from this study.




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 2:28 PM 0 Comments

Friday, March 23, 2012

Is There a Link between Diabetes and Alzheimer's?


Insulin is critical for normal brain function. Several observations including an increased risk of developing AD for diabetic patients, and reduced insulin levels in the brain tissue of AD patients, have suggested a link between the two diseases.

The Rotterdam Study in the Netherlands was one of the first epidemiological surveys to provide convincing evidence of a relationship between diabetes mellitus and AD by demonstrating that diabetes mellitus doubled the risk for AD, particularly in individuals who required insulin.

It has been hypothesized that raising brain levels of insulin to normal might help patients suffering from Mild Cognitive Impairment or AD to maintain cognitive ability. Last year a phase II clinical trial of inhaled insulin demonstrated that participants who took 20 IUs of insulin a day showed some improved memory functioning.

Now, two back-to-back research articles recently published in the Journal of Clinical Investigation – led by Konrad Talbot colleagues at the University of Pennsylvania and by Fernanda De Felice and colleagues at the University of Rio de Janeiro - address the connection between insulin resistance and AD on a molecular level. The University of Pennsylvania team examined insulin signaling and found that the activation of many insulin signaling molecules were highly related to memory and cognitive function, and were directly affected by beta-amyloid. They further confirmed that insulin resistance is a common and early feature of AD.

The Rio de Janeiro group further observed impaired insulin signaling in AD brain tissue in a mouse model of AD as well as from human tissue. They went on to show in the AD mouse model that treatment with a new anti-diabetic drug, Exendin-4, normalized insulin signaling and improved cognitive function. The drug was discovered as a protein in 1992, as a naturally secreted substance in the saliva and concentrated in the tail of the Gila monster. In 2005, the FDA approved the synthetic version called Exenatide for patients whose diabetes was not controlled by oral medications.

The cumulative results of these two studies should be put into context: Beta-amyloid that has been formed in the brain, but yet to deposit into plaques, is thought to be the main cause of memory loss and brain cell injury in AD. It appears that insulin may activate a defense mechanism that protects brain cells from damage caused by beta-amyloid. And the protective action of insulin requires signals that are transmitted inside of brain cells and block beta-amyloid from binding to neurons. However, beta-amyloid disrupts this very mechanism and leads to further brain cell injury.

Undoubtedly, follow up research is needed to confirm these findings and extend them towards developing anti-diabetes drugs that could potentially treat the symptoms of AD.



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 10:40 AM 0 Comments

Thursday, March 15, 2012

The Effect of Statin Drugs on Memory


The FDA recently reviewed their national database of reported adverse events, published medical literature, and randomized clinical trials to evaluate the effect of statins on cognition. Based on their review, they have decided to add memory-problems to the list of potential side-effects of this class of medications.

The adverse event reports generally described individuals over the age of 50 years who experienced notable, but poorly-defined memory loss that was reversible upon discontinuation of statin therapy. Time to onset of the event was highly variable, ranging from one day to years after taking the statin medication. None of the cases reported were associated with Alzheimer’s disease. The review also did not reveal an association between the adverse event and a specific statin, the statin dose, or any interaction between statins and other medications. Finally, the data did not suggest that statin use leads to clinically significant cognitive decline.

In this blog, I would like to review some data from the scientific literature on the effect of statins on cognition. One of the larger clinical trials to include the effect of statins on memory is the 17,802-patient study of Crestor called JUPITER. This study showed that Crestor reduced the risk of a major cardiovascular or cerebrovascular event by 44%. In these people, the risk of a heart problem during the course of the study was low: 142 of 8,901 patients on Crestor had a major cardiovascular event during the course of the study, compared to 252 of the 8,901 patients taking placebo. This is a statistically significant difference. Of the 8,901 patients taking Crestor, 18 subjects experienced a “confusional state” versus 4 placebo-treated subjects. Thus, 18 patients out of a total of 8,901 reported having a confused state, and this was about four times the number on placebo. Crestor caused this side effect in 0.16% of patients on the medication. With such low percentages, it is indeed difficult to assess an increase in risk of a specific adverse event. Nonetheless, this appears to be part of the data that led the FDA to add memory loss to the list of side-effects from statins.

Another large study that looked at the effect of statins on memory function was the Heart Protection Study, which involved 20,536 patients who were randomized to Zocor or placebo and were followed for 5 years. Primary outcomes measured were mortality and vascular events. In addition, the investigators monitored cognitive function. No differences were found in cognition between patients who received statin therapy and those who received placebo, either overall or in any subgroups.

In the Prospective Study of Pravastatin in the Elderly at Risk of Vascular Diseases, 5,804 patients aged 70-82 years, received Pravachol or placebo, and were followed for an average of 3 years. Pravachol lowered low-density lipoprotein cholesterol (LDL) by 34% and reduced death from heart disease by about 24% as compared to placebo. Pravachol also had no effect on cognition as measured by a battery of cognitive tests throughout the course of that trial.
The brain contains an abundance of cholesterol, much of it in the myelin sheaths that insulate neurons and accelerate nerve conduction. Cholesterol is also required for the proper functioning of synapses, where neurons communicate with each other. It is even needed for the proper release of transmitters inside cholesterol-laden vesicles that transport signals to other neurons. Data from the ongoing Framingham Heart Study demonstrates that older people with low total cholesterol (under 200) are much more likely to perform poorly on tests of mental function than those with high cholesterol (over 240).

What all of this data points to is that there needs to be a balance, where cholesterol levels are not too high and not too low in order to provide for heart health while maintaining normal brain functioning. Awareness of this issue may help physicians better counsel patients and improve monitoring of adverse events. There is no evidence of any cognitive benefits or risks associated with statins. Overall, statins clearly offer substantial cardiovascular benefits, and a small number of case reports of memory loss should not discourage appropriate statin administration. Perhaps, by monitoring memory function prior to and while on statins, we may gain a clearer understanding of any possible relationship between statins and memory loss.


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 11:55 AM 0 Comments

Monday, March 05, 2012

Part One: Prev & Impact of MCI from 10/66 Study


Prevalence and Impact of MCI in Latin America, China and India: Results from the 10/66 Study

Part One


Dear Readers,

I recently read the following statistics from the World Health Organization: (1) Of the 35 million people currently living with dementia worldwide, 58% are estimated to live in low-and middle-income countries, with this number approaching 71% of total by 2050. (2) Both Eastern and Southern Asia will see dementia growth rates more than double in the coming 20 years. (3) Increased dementia growth rates are also expected for Latin America (134% to 146%) and North Africa and the Middle East( 125% increase). Along with these increased rates of dementia, comes a daunting economic burden to these countries. Thus the article from Sosa et al, was especially interesting to review, as it sought to examine amnestic Mild Cognitive Impairment (aMCI) - the prodromal stage before dementia- in these countries and characterize the impact of aMCI on the population.

The 10/66 study consists of a series of cross sectional geographic catchment areas surveyed between January 2003- 2007. The target sample size was 2000 persons from each country, and all community residents aged 65+ were eligible for participation. Each participant completed the standard protocol, with all testing done either in Spanish, Tamil, or Mandarin. Interviews included questions regarding socio-demographic status, education, childhood environment, social networks and support, self report lifestyle measures (diet, smoking, exercise). Participants also underwent physical function tests that included, resting blood pressure, anthropometric measures, and a structured neurological examination. The battery of cognitive assessments included a screening instrument for dementia, and used the Mayo Clinic definition of amnestic MCI (aMCI). Assessing the "impact of amnestic MCI" was quantified by investigating the associations of aMCI with disability and neuropsychiatric symptoms. Disability scales used were the World Health Organization disability assessment schedule (WHODAS-12) which assesses -physical mobility, communication, self care, life and social activities and interpersonal interactions. Neuropsychiatric symptoms were assessed by the Neuropsychiatric Index (NPI) and categories were grouped by: depression, anxiety, apathy and irritability.

To be cont'd in Part Two


Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Rush Alzheimer’s Disease Center
Rush Institute for Aging
Chicago, IL
 
Author: Neelum Aggarwal MD at 12:44 PM 0 Comments

Monday, March 05, 2012

Part Two: Prev & Impact of MCI from 10/66 Study


Part Two of Prevalence and Impact of MCI in Latin America, China and India: Results from the 10/66 Study.



Data were obtained from over 15,000 non demented participants (aged 65yrs+) across the different countries. In the total sample, women participated more than men, and younger ages (65-69yrs) for participation were noted in China, India and Venezuela. Disability was significantly higher in aMCI cases, however there were differences noted in these associations between countries( China being the lowest). After adjustment, aMCI cases were more likely to have informant rated anxiety, irritability, and apathy symptoms with no significant "between- country" differences. The prevalence of aMCI ranged from 0.8 % in China to 4.3% in India and changed very little after controlling for age, gender, and education level.

This study examined the prevalence estimates and impact of aMCI, across a diverse group of countries and the impact of aMCI with regards to physical and behavioral functioning. Rates of prevalent aMCI appeared to be lower than those previously reported from some community samples (i.e. Korea, Italy, Japan, US and Finland) however, were comparable to rates reported by others (Germany, France and Great Britain). The authors rightly conclude that the variability of aMCI prevalence rates across world regions, most likely reflects diagnostic issues arising from a lack of specific operational criteria of aMCI as well as differences and cultural variations relevant to some of the diagnostic components. The specific issue raised, and one that is subject to cultural influences is the necessity of having a "subjective memory complaint" as part of the diagnostic criteria. This specific diagnostic criteria is highly subject to cultural influences ( i.e. Is the memory issue "enough" to warrant a formal complaint?). Another interesting finding was that aMCI associations with disability were relatively more consistent across all regions, thus supporting the use of this measure in cross cultural studies. Lastly, this study did not find an association between aMCI and depressive symptoms, but did find associations between anxiety, irritability and apathy, a finding consistent with other larger studies.

to be cont'd.......

Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Rush Alzheimer’s Disease Center
Rush Institute for Aging
Chicago, IL
 
Author: Neelum Aggarwal MD at 12:42 PM 0 Comments

Monday, March 05, 2012

Part Three: Prev & Impact of MCI from 10/66 Study


Part Three of: Prevalence and Impact of MCI in Latin America, China and India: Results from the 10/66 Study


The major limitation of this study as suggested by the authors was that samples drawn were from specific geographic catchment areas and therefore, cannot be assumed to be representative of the entire nation. Lastly, this was a cross sectional study, and further longitudinal analyses on this data set are needed to clarify the predictive validity of the aMCI diagnosis in this sample. Nevertheless, this study is one of the first to investigate the prevalence of aMCI in low and middle income global communities, and as such could be particularly useful to any initiative that seeks to provide community level interventions to prevent the progression to dementia.

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

Sosa AL, Albanese E, Stephan BCM et al. Prevalence, Distribution, and Impact of Mild Cognitive Impairment in Latin America, China, and India: A 10/66 Population Based Study. PLoS Med. 2012 Feb;9(2):

Prince M, Ferri CP, Acosta D et al. (2007). The protocols for the 10/66 dementia research group population based research programme. BMC Public Health 7: 165.

Bulletin of the World Health Organization 2011;89:166–167.

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 12:38 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.