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Monday, April 30, 2012

Why Berries May Delay Memory Decline


Dear Readers,

Berries, they’re not just for breakfast anymore.

Researchers recently reported in the April 26, 2012 issue of the Annals of Neurology that consumption of berries and flavonoids showed a slower rate of cognitive decline in women aged 70 and over.* Using data from the long-running Nurses’ Health Study of 122,000 registered nurses the researchers conducted assessments on 16,010 women.

The Nurses Health Study began in 1976. Every four years they were questioned on their eating habits. Between 1995 and 2001, over 16,000 women aged 70 and over underwent memory testing. The researchers at Brigham Women’s Hospital/Harvard Medical School in Boston and the German Center for Neurodegenerative Diseases in Bonn, Germany found that greater ingestion of blueberries and strawberries correlated with slower rates of cognitive decline for up to 2.5 years. The women who showed the most improvement consumed two or more servings of the berries each week.

Berries contain a particularly high amount of flavonoids called anthocyanidins that are capable of crossing the blood brain barrier and localizing themselves in the hippocampus, an area of the brain known for memory and learning. Investigational drugs and other alternative therapies often fail because they cannot cross the blood brain barrier or reach the hippocampus.

Flavonoids are known to have antioxidant and anti-inflammatory characteristics which can benefit the brain. The study’s authors acknowledge that previous small trials of berry supplementation have shown positive results as well. In some earlier non-related studies inflammation and stress have been shown to contribute to a reduction in brain functioning. Increasing flavonoid consumption might slow these harmful effects but more study is needed to test this hypothesis.

The authors acknowledge that this was an observational study that relied on accurate dietary reporting from the nurses. In addition they do not know if the results would apply equally to men since all of the people they studied were female. For the future the authors recommend that men be part of the cohort. Finally they encourage older adults to consume berries as they offer an easy dietary modification that may delay memory decline and will not cause harm.

*Devore, E. E., Kang, J. H., Breteler, M. M. B. and Grodstein, F. (2012), Dietary intakes of berries and flavonoids in relation to cognitive decline. Ann Neurol.. doi: 10.1002/ana.23594


Jeffree Itrich, M.S.W., M.J.
Sr. Clinical Trials Communications & Recruitment Specialist
Alzheimer's Disease Cooperative Study
University of California San Diego

 
Author: Jeffree Itrich at 12:03 PM 0 Comments

Wednesday, April 25, 2012

Genes Determine Hippocampal Volume


Dear Readers,

As many of you are aware, one of the key biomarkers of Alzheimer’s disease (AD) is shrinkage or atrophy of the hippocampus, which is thought to explain the memory difficulties associated with the disease. By measuring the size of the hippocampus and correcting for total brain size and age, we have a useful tool for identifying one of the key hallmarks of AD.

Now, a very large research study*, conducted by an international team that included more than 80 scientists at 71 institutions in eight countries, has been published in the April 15 edition of the journal Nature Genetics looking at genes and hippocampal size.

The study is based on a genetic analysis of more than 9,000 people, and has found that certain versions of four genes may speed shrinkage of the hippocampus and possibly increase vulnerability to AD. The researchers calculated that hippocampus shrinkage in people with these gene variants accelerates by about four years on average. The risk of AD doubles every five years beginning at age 65, so a person of that age would face almost twice the AD risk if he or she had these versions of the gene.

The genes most strongly linked to shrinkage are involved in maturation of the hippocampus and in apoptosis, or programmed cell death - a continual process by which older cells are removed. The genetic analysis draws on what is known as a genome-wide association study -- research aimed at finding the common genetic variants associated with specific diseases or other conditions. Different versions of a gene usually come down to changes in just one of the tens of thousands of DNA "letters" that make up genes. These one-letter differences are known as single-nucleotide polymorphisms, or SNPs. This new evidence shows that brain aging, the hippocampus and memory are influenced by specific genes, and this may translate into increased risk for showing symptoms of AD.


*Common variants at 12q14 and 12q24 are associated with hippocampal volume. Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium, Nat Genet. 2012 Apr 15. Bis JC, Decarli C etc.



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 12:37 PM 0 Comments

Tuesday, April 17, 2012

New Gene for Early-Onset Alzheimer’s Discovered


Dear Readers,

As you will recall, about 5% of all cases of AD are called Early-Onset, because patients develop dementia in their 40’s and 50’s. These patients inherit a mutated gene from one of their parents, who also had AD early in life. In the mid-1990’s researchers led by Dr. Rudi Tanzi at Harvard Medical School, discovered that the mutated genes are APP, with codes for Amyloid Precursor Protein; PS1 which is presenilin1 (PS1) or presenilin 2 (PS2). The PS1 and PS2 genes code for proteins called secretases, whose function is to cleave APP as it is secreted by neurons. When either APP, PS1 or PS2 are mutated, APP is cleaved improperly from birth onwards and a small fragment of APP called beta-amyloid is produced. This neurotoxic beta-amyloid initiates a cascade of brain cell damage that, over decades, leads to dementia.

Now, researchers have discovered a new gene that causes Early-Onset Alzheimer’s disease. A research team led Dr. Dominique Campion at the University of Rouen, France studied the genes from 130 families suffering from early-onset forms of Alzheimer's disease. These families were identified by 23 French hospital teams within the framework of the French National ‘Alzheimer Plan’. Of these families, 116 presented mutations on the already known genes. But in the 14 remaining families, there was no mutation at all observed on these genes.

A study of the genetic makeup of the 14 families using new DNA analysis technique showed evidence of mutations of the SORL1 gene. Two of the identified mutations are responsible for an under-production of SORL1, resulting in an increase in the production of the beta-amyloid peptide. Specifically, SORL1 protein acts as a ‘sorting receptor’ for APP, regulating APP’s trafficking inside of cells, such that it is less likely to be cleaved abnormally to form beta-amyloid. When SORL1 is mutated, and hence dysfunctional, APP passes through a series of steps that lead to an increased production of beta-amyloid.

Certainly the discovery of a new gene that is involved in the beta-amyloid pathway is even further confirmation that beta-amyloid is indeed the most likely causative agent of AD. Further, it adds another potential therapeutic target for AD drug development. And finally, this paper affirms the program set forth by French President Sarkozy in 2008, who started the far-reaching “French Alzheimer Plan” of 1.6 billion euros (2.1 billion dollars) for a five-year national program to ‘improve the quality of life for people with dementia and their caregivers; to develop better understanding of the disease for future action and; to mobilize society for the fight against dementia’.

In January of this year, president Obama signed the American National Alzheimer's Plan, a congressional-ordered strategy that will combine research toward better dementia treatments with steps to help overwhelmed families to better cope today.


Pottier, D Hannequin, S Coutant, A Rovelet-Lecrux, D Wallon, S Rousseau, S Legallic, C Paquet, S Bombois, J Pariente, C Thomas-Anterion, A Michon, B Croisile, F Etcharry-Bouyx, C Berr, J-F Dartigues, P Amouyel, H Dauchel, C Boutoleau-Bretonnière, C Thauvin, T Frebourg, J-C Lambert, D Campion. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Molecular Psychiatry, 2012; DOI: 10.1038/mp.2012.15



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 9:30 AM 0 Comments

Tuesday, April 10, 2012

Can a Pattern of Protein Abnormalities Predict Prodromal AD?


Dear Readers,

Three weeks ago, I wrote about proteomics and a recent paper utilizing this technique to measure protein levels in blood to diagnose Alzheimer’s disease, as well as prodromal Alzheimer’s disease, sometimes called Mild Cognitive Impairment (MCI). This type of research has focused on finding biomarkers to identify AD at the pre-clinical stage of MCI, allowing treatment to be initiated before irreversible damage occurs.

Now researchers from the UK have looked at blood samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and generated data on 190 blood proteins in 566 individuals with MCI, AD or normal cognition. They have identified a pattern of protein abnormalities that seem to be the molecular signature predicting prodromal AD. Readers of this blog will recall that ADNI is the most comprehensive collection of longitudinal Alzheimer’s data in the world.

The researchers showed that measuring a panel of 11 proteins in blood can provide a predictive test with more than 85 per cent accuracy. Monitoring the change in blood protein levels over time could increase accuracy above 90 per cent. This is about the same accuracy as more expensive tests such as Neuroimaging, neuropsychological testing and Cerebrospinal fluid (CSF) analysis. The findings of this type of proteomic research may allow for a blood test to become commercially available in the next couple of years to be used in the evaluation of memory loss, searching for signs of Alzheimer's disease as the underlying cause.

The study was funded by the University of Newcastle and the Hunter Medical Research Institute, and its findings are published in the prestigious PLoS ONE journal*.

*Johnstone D, Milward EA, Berretta R, Moscato P, for the Alzheimer's Disease Neuroimaging Initiative (2012) Multivariate Protein Signatures of Pre-Clinical Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI) Plasma Proteome Dataset. PLoS ONE 7(4): e34341



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 11:32 AM 0 Comments

Monday, April 09, 2012

Alzheimer's Scanning Agent Florbetapir Approved by FDA


Dear Readers,

This past Friday, the FDA gave final approval of Amyvid, a diagnostic agent indicated for brain imaging of beta-amyloid plaques in patients with cognitive impairment who are being evaluated for Alzheimer's Disease and other causes of cognitive decline. Readers of this blog will recall that Amyvid is a chemical tracer that allows visualization of beta-amyloid plaques in the brain using a PET scan. Before the development of imaging agents, amyloid plaques could be determined only after death, by examining the brain during an autopsy.

A negative Amyvid scan indicates that no amyloid plaques are currently present, which is inconsistent with a diagnosis of Alzheimer's disease and greatly reduces the likelihood that a patient's cognitive impairment is due to Alzheimer's disease. A positive Amyvid scan indicates moderate to frequent amyloid plaques are present; which is most consistent with Alzheimer's disease, but may also be present in patients with other types of neurologic conditions. So, a positive Amyvid scan does not establish a diagnosis of Alzheimer's disease, but in conjunction with a neurological examination and medical history, may help confirm the diagnosis.

The test will be available starting in June 2012 and will cost somewhere between $1600 and $2000 and, although FDA approved, does not have medicare or insurance coverage at this time. Nonetheless, it is expected to become widely used in the clinical evaluation of individuals presenting with mild cognitive impairment and dementia to see if AD is the underlying cause. Amyloid scans, by the way, have been in use in the research setting, including clinical trials, since 2004.



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 10:17 AM 0 Comments

Tuesday, April 03, 2012

Summary of Recent Bapineuzumab Research


Dear Readers,

Bapineuzumab is an antibody to beta-amyloid, the protein that is believed to underlie Alzheimer's disease neuropathology. A phase III study of bapineuzumab’s efficacy in AD is ongoing, but data from two phase II studies have recently been published in the journal Archives of Neurology.

To evaluate bapineuzumab's effects on cerebrospinal fluid (CSF) biomarkers, Kaj Blennow, MD, PhD, of the University of Gothenburg in Sweden and colleagues conducted an analysis of two separate phase II, randomized, double-blind, placebo-controlled trials, each a year long, involving a total of 46 patients from the U.S., the U.K., and Finland, who had mild to moderate Alzheimer's disease. A total of 27 patients were given bapineuzumab while 19 were given placebo.
Treatment with bapineuzumab significantly lowered levels of phosphorylated tau (P-tau) in the cerebrospinal fluid of Alzheimer's patients as compared with controls.

Interestingly, there were no changes, in CSF levels of beta-amyloid. The findings may indicate that the monoclonal antibody has some downstream effects on the degenerative process.

Patients with Alzheimer's disease typically have lower levels of beta-amyloid in their CSF fluid, while levels of tau proteins are increased in CSF. This is thought to be due to the fact that beta-amyloid is sequestered in the plaques within the brain, and therefore is reduced in its levels in the CSF.

P-tau is thought to be the last step before neurofibrillary tangles form within neurons. It is the chemical change in tau (addition of a phosphate molecule) in the presence of high brain beta-amyloid levels that is thought to lead to a structural change in the tau protein. When this occurs, P-Tau releases from the neurofilament scaffolding that holds neurons together, and leads to degeneration of neurons.

An important question remains whether such changes in CSF biomarkers correlate with clinical benefit. This question will be addressed in the ongoing bapineuzumab Phase III trials.


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 2:27 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.