Blood test for a dementia protein

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The Dementia Caregiver's Little Book of Hope [Kindle Edition]

Nature

Scientists in Japan and Australia have developed a blood test that can identify people who have high levels of a protein associated with Alzheimer's disease. If confirmed by further research, this long-sought test could help in the increasingly desperate search for therapies that halt the progression of dementia, which affects tens of millions of people worldwide.

The test identifies people whose brains have high levels of amyloid-β, a protein that is a key player in Alzheimer’s disease, and which may either cause dementia or be a symptom of it. The researchers hope that drug developers could use the test to recruit individuals with dementia into clinical trials before irreversible damage to their brains has occurred — thus making the trials more reliable.

Molecular biologist Katsuhiko Yanagisawa at the Center for Development of Advanced Medicine for Dementia in Obu, Japan, and his colleagues developed the prototype biomarker test. They published their work online on 31 January in Nature1.

Scientists around the world have been searching for a simple blood test for dementia for the past 15 years. “At first it wasn’t obvious that it would be possible for brain pathology to be measurable in the blood, but we have been getting ever closer,” says neuroscientist Simon Lovestone at the University of Oxford, UK, who has led other studies to find blood biomarkers for Alzheimer’s disease. “This paper provides the best results I’ve seen so far.”

High failure rate

All candidate drugs designed to halt Alzheimer’s disease have failed in clinical trials so far, and many pharmaceutical companies have abandoned the field. Scientists suspect that the design of such trials might be the problem, rather than the drugs being tested. Until now, there has been no reliable way to identify people with the early stages of dementia, so most clinical trials have recruited people whose clinical symptoms are already apparent. At this point, brain damage associated with amyloid-β has already occurred and it may be too late to reverse it, says Yanagisawa.

Until now, the only way to identify amyloid-β in the brain — short of an autopsy — has been to image the brain using positron-emission tomography, or to measure levels of the protein directly in cerebrospinal fluid from the spinal cord. Both of these procedures have been used to help recruit patients into recent trials, but the tests are expensive and uncomfortable.

To measure the levels of several amyloid-β fragments in blood samples, as well as a fragment of a larger protein from which amyloid-β derives, Yanagisawa and his colleagues combined two existing techniques — immunoprecipitation and mass spectroscopy. Their results matched those achieved through brain imaging and the analysis of spinal-cord fluid in two separate cohorts involving 121 people in Japan and 252 people in Australia. Each cohort included individuals aged between 60 and 90. Some of the participants were healthy; some showed mild impairment in their cognitive skills; and some had Alzheimer’s disease.

The authors say that larger and more long-term studies are needed to confirm how accurate the blood test is at identifying high levels of amyloid-β in human brains. If it is highly accurate, then the test could help recruitment for clinical trials, because it is relatively easy and cheap to do.

LED flickering lights reduce placques in Alzheimer's

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The Dementia Caregiver's Little Book of Hope [Kindle Edition]

MIT News

Using LED lights flickering at a specific frequency, MIT researchers have shown that they can substantially reduce the beta amyloid plaques seen in Alzheimer’s disease, in the visual cortex of mice. 

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This treatment appears to work by inducing brain waves known as gamma oscillations, which the researchers discovered help the brain suppress beta amyloid production and invigorate cells responsible for destroying the plaques.

Further research will be needed to determine if a similar approach could help Alzheimer’s patients, says Li-Huei Tsai, the Picower Professor of Neuroscience, director of MIT’s Picower Institute for Learning and Memory, and senior author of the study, which appears in the online edition of Nature.

Researchers in Li-Huei Tsai's laboratory at the Picower Institute for Learning and Memory have shown that disrupted gamma waves in the brains of mice with Alzheimer’s disease can be corrected by a unique non-invasive technique using flickering light.


“It’s a big ‘if,’ because so many things have been shown to work in mice, only to fail in humans,” Tsai says. “But if humans behave similarly to mice in response to this treatment, I would say the potential is just enormous, because it’s so noninvasive, and it’s so accessible.”

Tsai and Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at the MIT Media Lab and the McGovern Institute for Brain Research, who is also an author of the Nature paper, have started a company called Cognito Therapeutics to pursue tests in humans. The paper’s lead authors are graduate student Hannah Iaccarino and Media Lab research affiliate Annabelle Singer.

“This important announcement may herald a breakthrough in the understanding and treatment of Alzheimer's disease, a terrible affliction affecting millions of people and their families around the world,” says Michael Sipser, dean of MIT’s School of Science. “Our MIT scientists have opened the door to an entirely new direction of research on this brain disorder and the mechanisms that may cause or prevent it. I find it extremely exciting.”

Brain wave stimulation

Alzheimer’s disease, which affects more than 5 million people in the United States, is characterized by beta amyloid plaques that are suspected to be harmful to brain cells and to interfere with normal brain function. Previous studies have hinted that Alzheimer’s patients also have impaired gamma oscillations. These brain waves, which range from 25 to 80 hertz (cycles per second), are believed to contribute to normal brain functions such as attention, perception, and memory.

In a study of mice that were genetically programmed to develop Alzheimer’s but did not yet show any plaque accumulation or behavioral symptoms, Tsai and her colleagues found impaired gamma oscillations during patterns of activity that are essential for learning and memory while running a maze.

Next, the researchers stimulated gamma oscillations at 40 hertz in a brain region called the hippocampus, which is critical in memory formation and retrieval. These initial studies relied on a technique known as optogenetics, co-pioneered by Boyden, which allows scientists to control the activity of genetically modified neurons by shining light on them. Using this approach, the researchers stimulated certain brain cells known as interneurons, which then synchronize the gamma activity of excitatory neurons.

After an hour of stimulation at 40 hertz, the researchers found a 40 to 50 percent reduction in the levels of beta amyloid proteins in the hippocampus. Stimulation at other frequencies, ranging from 20 to 80 hertz, did not produce this decline.

Tsai and colleagues then began to wonder if less-invasive techniques might achieve the same effect. Tsai and Emery Brown, the Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience, a member of the Picower Institute, and an author of the paper, came up with the idea of using an external stimulus — in this case, light — to drive gamma oscillations in the brain. The researchers built a simple device consisting of a strip of LEDs that can be programmed to flicker at different frequencies.

Using this device, the researchers found that an hour of exposure to light flickering at 40 hertz enhanced gamma oscillations and reduced beta amyloid levels by half in the visual cortex of mice in the very early stages of Alzheimer’s. However, the proteins returned to their original levels within 24 hours.

The researchers then investigated whether a longer course of treatment could reduce amyloid plaques in mice with more advanced accumulation of amyloid plaques. After treating the mice for an hour a day for seven days, both plaques and free-floating amyloid were markedly reduced. The researchers are now trying to determine how long these effects last.

Furthermore, the researchers found that gamma rhythms also reduced another hallmark of Alzheimer’s disease: the abnormally modified Tau protein, which can form tangles in the brain.

“What this study does, in a very carefully designed and well-executed way, is show that gamma oscillations, which we have known for a long time are linked to cognitive function, play a critical role in the capacity of the brain to clean up deposits,” says Alvaro Pascual-Leone, a professor of neurology at Harvard Medical School who was not involved in the research. “That’s remarkable and surprising, and it opens up the exciting prospect of possible translation to application in humans.”

Tsai’s lab is now studying whether light can drive gamma oscillations in brain regions beyond the visual cortex, and preliminary data suggest that this is possible. They are also investigating whether the reduction in amyloid plaques has any effects on the behavioral symptoms of their Alzheimer’s mouse models, and whether this technique could affect other neurological disorders that involve impaired gamma oscillations.

Two Modes of Action

The researchers also performed studies to try to figure out how gamma oscillations exert their effects. They found that after gamma stimulation, the process for beta amyloid generation is less active. Gamma oscillations also improved the brain’s ability to clear out beta amyloid proteins, which is normally the job of immune cells known as microglia.

“They take up toxic materials and cell debris, clean up the environment, and keep neurons healthy,” Tsai says.

In Alzheimer’s patients, microglia cells become very inflammatory and secrete toxic chemicals that make other brain cells more sick. However, when gamma oscillations were boosted in mice, their microglia underwent morphological changes and became more active in clearing away the beta amyloid proteins.

“The bottom line is, enhancing gamma oscillations in the brain can do at least two things to reduced amyloid load. One is to reduce beta amyloid production from neurons. And second is to enhance the clearance of amyloids by microglia,” Tsai says.

The researchers also sequenced messenger RNA from the brains of the treated mice and found that hundreds of genes were over- or underexpressed, and they are now investigating the possible impact of those variations on Alzheimer’s disease. 

MORE INFORMATION:

• The research was funded by the JPB Foundation, the Cameron Hayden Lord Foundation, a Barbara J. Weedon Fellowship, the New York Stem Cell Foundation Robertson Award, the National Institutes of Health, the Belfer Neurodegeneration Consortium, and the Halis Family Foundation.

MicroRNAs Hold Promise For Treating Diseases In Blood Vessels

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ScienceDaily-- A newly discovered mechanism controls whether muscle cells in blood vessels hasten the development of both atherosclerosis and Alzheimer's disease, according to an article published online July 5 in the journal Nature.

The study was led by the Gladstone Institute of Cardiovascular Disease (GICD) in San Francisco, with key contributions from the Aab Cardiovascular Research Institute at the University of Rochester School of Medicine and Dentistry.

Thanks to stem cells, humans develop from a single cell embryo into a complex being with about 250 unique cell types. As the fetus develops, cells divide and multiply (proliferate) in many generations and specialize (differentiate) with each generation until millions of functional cells result (bone, nerve, blood, skin, muscle, etc.). To serve specific roles in the body, some stem cells also switch back and forth between primitive, rapidly proliferating precursors and their mature, functioning, non-proliferating counterparts, a quality called "plasticity."

Among the most "plastic" of cells are vascular smooth muscle cells (VSMC), which form in layers around blood vessels, and by contracting or relaxing, regulate blood pressure. Because VSMC surround blood vessels that are continually becoming clogged by atherosclerosis, they must be ever ready to grow along with the vessel as it attempts, by growing, to remain open to blood flow despite fatty deposits and inflammation. If these efforts fail, heart attack or stoke may occur. Each time a vessel grows to avoid a clog, the VSMC surrounding it must grow too by reverting to their high-growth precursor form. Once a vessel reaches its growth limit, however, the growth that once kept vessels open begins adding to clogs by thickening vessel walls.

Past studies in Rochester have shown.........read all about MicroRNAs treating blood vessell diseases