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Tuesday, April 23, 2013

Seeing the Brain with CLARITY


Dear Readers,

A team of engineers has developed a way to turn organs from mammals, such as lab mice or human bodies donated to science, transparent. Once transparent, scientists can add chemicals to the organs that attach to and highlight specific features, such as different cell types. The result is an intact organ that scientists can see inside and study.

The techniques, called CLARITY, involves a series of chemical treatments that replaces the fatty lipid membranes surrounding cells with a chemical mesh that keeps microscopic details intact without scattering light like lipid does. Neurotransmitters and other important molecules remain in place and can be visualized with a rainbow palette of fluorescent dyes.

Until now, neuroscientists typically had to cut a brain into ultra-thin slices to visualize such features. But that destroys one of the things they’re most interested in studying: the cable-like axons that carry signals from one part of the brain to another. The new method makes it possible to visualize these long-range connections as well as the fine-scale anatomy and molecular make up of neurons, the scientists reported last week in the journal Nature. This is probably one of the most important advances for understanding the structure of the brain in decades.

Although they developed the method in mouse brains, the team shows that it works on human post-mortem brain tissue too. In the Nature paper, they describe abnormal neural connections in an autistic boy whose brain had been stored in formalin for more than six years.

With this breakthrough, researchers plan to compare circuitry in banked tissue from people with other neurological diseases, including Alzheimer’s disease, and from controls whose brains were healthy. Such studies in living people are impossible, because most neuron-tracing methods require genetic engineering or injection of dye in living animals. Scientists might also revisit the many specimens in repositories that have been difficult to analyze because human brains are so large.

Chung et al, Structural and Molecular Interrogation of Intact Biological Systems, Nature 2013



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 2:34 PM 0 Comments

Thursday, April 11, 2013

Better Model of Alzheimer’s disease: From mice to rats


Dear Readers,

As you will recall, beta-amyloid is a fragment of a larger protein, known as APP, and is produced by enzymes that cut APP at two places as it secretes from neurons. Its deleterious effects on the brain and in plaques have been written about in previous blogs. Researchers often use rodents to study diseases. However, previous studies on transgenic mice and rats that have the mutations only partially reproduce the problems caused by Alzheimer’s. The animals have memory problems and many plaques, but none of the other hallmarks,especially neurofibrillary tangles and neuron loss.

Now, researchers led by Dr. Terrence Town at Cedars-Sinai Medical Center and UCLA, have engineered rats by mutating a combination of genes, which are known to play a role in the rare, early-onset form of Alzheimer’s. Behavioral studies showed that the rats indeed developed memory and learning problems with age, similar to AD. And, as predicted, the presence of beta-amyloid in the brains of the rats increased with age. However, unlike previous rodent studies, the rats also developed neurofibrillary tangles. That is, these rats manifest a complete repertoire of AD pathological features.

The researchers performed a variety of experiments confirming the presence of neurofibrillary tangles in brain regions most affected by Alzheimer’s such as the hippocampus and the cingulate cortex, which are involved in learning and memory. Further experiments showed that about 30 percent of neurons in these regions died with age, the largest amount of cell death seen in an Alzheimer’s rodent model. The researchers also found that there are increasing levels of beta-amyloid oligomers in the brain, before the neurofibrillary tangles develop.

The results of this work are two-fold. First, it further validates the idea that excessive production of beta-amyloid in the brain drives the development of neurofibrillary tangles inside of neurons that ultimately leads to their demise. In addition, it provides us with a new animal model to test drugs that may be effective in slowing down the progression of the underlying mechanisms seen in AD.
This new animal model of AD will undoubtedly serve as a critical tool to enable future drug studies in AD.


A Transgenic Alzheimer Rat with Plaques, Tau Pathology, Behavioral Impairment, Oligomeric Aß, and Frank Neuronal Loss, The Journal of Neuroscience, 10 April 2013


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 2:01 PM 0 Comments

Friday, April 05, 2013

Costs of Dementia in the United States


Dear Readers,

This week, the non-profit RAND corporation, published a study in the prestigious New England Journal of Medicine that represents the most accurate estimate of the financial costs associated with Alzheimer’s disease dementia. The study was funded by the National Institute on Aging and looked at costs for the disease in 2010.

These costs are, of course, in addition to the incalculable emotional losses caused by the disease, but are quite astonishing in themselves.

The new study is based on findings from the Health and Retirement Study, an ongoing survey of individuals in the United States age 51 and older that began in 1992, and is supported by the National Institute on Aging, as well as the Social Security Administration. A subset of that study group received a detailed in-home clinical assessment for dementia as part of the Aging, Demographics and Memory Study, a nationally representative examination of dementia in the United States.

The survey included an assessment of whether people could perform daily activities such as dressing themselves and preparing their own meals. Participants were also asked about their out-of-pocket health care expenses for services such as nursing home stays, home health care and other medical services. Other questions asked whether they received help from others for their daily living activities. Medicare spending information was linked to medical claims for most participants.

The estimated prevalence of dementia among persons older than 70 years of age in the United States in 2010 was 14.7%. The yearly monetary cost per person that was attributable to dementia was about $50,000. These individual costs suggest that the total monetary cost of dementia in 2010 was approximately $200 billion. Medicare paid approximately $11 billion of this cost.

The main component of the costs attributable to dementia is the cost for institutional and home-based, long-term care rather than the costs of medical services.

As readers of this blog will recall, if we could delay the dementia phase of AD by 5 years, we can cut the incidence by half. The fiscal imperative for finding a cure remains blindingly clear.


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 8:44 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.