Posts tagged brain tissue
Articles and news from the latest research reports.
New Effort to Identify Parkinson’s Biomarkers
Last month, the National Institutes of Health announced a new collaborative initiative that aims to accelerate the search for biomarkers — changes in the body that can be used to predict, diagnose or monitor a disease — in Parkinson’s disease, in part by improving collaboration among researchers and helping patients get involved in clinical studies. As part of this program, launched by the National Institute of Neurological Disorders and Stroke (NINDS), part of the NIH, Clemens Scherzer, MD, a neurologist and researcher at Brigham and Women’s Hospital (BWH), was awarded $2.6 million over five years to work on the development of biomarkers and facilitate NINDS-wide access to one of the largest data and biospecimens bank in the world for Parkinson’s available at BWH. This NINIDS initiative is highlighted in an editorial in the March issue of Lancet Neurology.
"There is a critical gap in the research that leads to lack of treatment for diseases like Parkinson’s," said Scherzer. "Biomarkers are desperately needed to make clinical trials more efficient, less expensive and to monitor disease and treatment response. We are hopeful that this initiative will fast track new discoveries in this area."
According to Scherzer, most of our knowledge of the human brain is based on the analysis of just 1.5 percent of the human genome that encodes proteins. The first part of Scherzer’s project will examine the function of the remaining 98.5 percent of the genome that, so far, has been unexplored in the human brain. While this remainder had been previously dismissed as “junk”, it is now becoming clearer that parts of it actively regulate cell biology. Scherzer and colleagues believe that “dark matter” RNA transcribed from stretches of so called “junk” DNA is active in brain cells and contributes to the complexity of normal dopamine neurons and, when corrupted, Parkinson’s disease.
"This offers a potentially ground breaking opportunity for biomarker development. Initially, the team will search for these RNAs associated in brain tissue of individuals at earliest stages of the disease. Then, this team will look for related biomarkers in the bloodstream and cerebrospinal fluid in both healthy brains and those with Parkinson’s," Scherzer said.
Scherzer’s lab has been spearheading biomarker research in this field since 2004 and the team already has 2,000 patients enrolled and being followed in a longitudinal study with rich clinical data and one of the largest biobanks in the world for Parkinson’s tissue with support from the Harvard NeuroDiscovery Center. The biobank was designed as an incubator for Parkinson’s research and until now was chiefly available for research collaborations within the Harvard-affiliated community. As part of this new project, this vast resource will be open to all NIH-funded investigators.
"Our ultimate goal is to personalize treatment for our patients with Parkinson’s." said Scherzer. "By opening up this vast collection of specimens, we are exploding the resources that are available to NIH-funded investigators looking at this disease. We hope to harness the power of collaboration to speed up biomarkers discovery."
(Source: brighamandwomens.org)
A proposed link between aging, autism, and oxidation
Like any factory, the body burns oxygen to get energy for its various needs. As a result, detrimental byproducts are released and our cells try to clean up shop with antioxidants. But as we age, this process becomes a losing battle.
“Oxidation inexorably moves us along toward an oxidized state,” said pharmaceutical sciences professor Richard Deth. “You have to deal with it progressively.”
One option is to slow down the synthesis of new proteins, a process that requires energy. Indeed, as we age, we produce fewer new proteins, which explains why our capacity for learning and healing suffer as we grow old.
Since every protein originates from instructions in the DNA, protein synthesis can be slowed down by turning off particular genes. A process called epigenetic regulation accomplishes the task by adding molecular tags on top of the genome. The protein methionine synthase regulates this process. But what regulates methionine synthase? Oxidation.
“This enzyme is the most easily oxidized molecule in the body,” said Deth, whose research on the subject was recently published in the journal PLOS ONE. The senior author for the study, Christina Muratore, received her doctorate in pharmaceutical sciences from Northeastern in 2010.
Whenever the body is under oxidative stress, Deth explained, methionine synthase, or MS, stops working. He and his team hypothesized that MS plays an important regulatory role in aging and that it might be impaired in autism, which Deth has connected to unchecked oxidative stress in previous research.
To examine their hypothesis, the researchers looked at postmortem human brain samples across the lifespan, with subjects as young as 28 weeks of fetal development to as old as 84 years. They measured the levels of a molecule called MS mRNA, which transcribes the genetic code for methionine synthase into actual protein.
As the subjects aged, their brain tissue showed lower levels of MS mRNA. But, surprisingly, the levels of the protein itself remained constant across the lifespan.
Deth and his colleagues suspect that this observed decrease in MS mRNA over our lives may act as a check in the system to save energy that we no longer have in plentiful supply and to slow down oxidative stress. “One way that the system can guard against too much protein synthesis is to restrict the amount of mRNA,” Deth said.
The team also compared MS protein and mRNA levels between brain tissue samples from autistic and normally developing subjects. Autistic brains had markedly less MS mRNA than the control samples but similar protein levels. Additionally, the age-dependent trend seen in normally developing brains was not mimicked among the autistic sample.
If decreased MS mRNA does mean decreased protein production, it’s no big deal for adults who don’t need to make new proteins as often. But for the developing brain, new proteins are critical. “Your capacity for learning might be prematurely reduced because metabolically you can’t afford it,” Deth suggested.
While the results are preliminary and will benefit from repeated studies and more investigation, Deth’s findings add to a growing body of evidence linking both aging and autism to oxidative stress.
Mouse brain cells live long and prosper
Mouse brain cells scamper close to eternal life: They can actually outlive their bodies. Mouse neurons transplanted into rat brains lived as long as the rats did, surviving twice as long as the mouse’s average life span, researchers report online February 25 in the Proceedings of the National Academy of Sciences.
The findings suggest that long lives might not mean deteriorating brains. “This could absolutely be true in other mammals — humans too,” says study author Lorenzo Magrassi, a neurosurgeon at the University of Pavia in Italy.
The findings are “very promising,” says Carmela Abraham, a neuroscientist at Boston University. “The question is: Can neurons live longer if we prolong our life span?” Magrassi’s experiment, she says, suggests the answer is yes.
One theory about aging, Magrassi says, is that every species has a genetically determined life span and that all the cells in the body wear out and die at roughly the same time. For the neurons his team studied, he says, “We have shown that this simple idea is certainly not true.”
Magrassi’s team surgically transplanted neurons from embryonic mice with an average life span of 18 months into rats. To do so, the researchers slipped a glass microneedle through the abdomens of anesthetized pregnant mice. Then, using a dissecting microscope and a tool to illuminate the corn-kernel-sized mouse embryos, the researchers scraped out tiny bits of brain tissue and injected the neurons into fetal rat brains. After the rat pups were born, Magrassi and colleagues waited as long as three years, until the animals were near death, to euthanize the rats and dissect their brains.
The transplanted mouse cells had linked up with the rat brain cells and developed into mature, working neurons, though they did retain their characteristic small size. Also, because Magrassi’s team had tagged the mouse cells to glow green, the researchers could distinguish between mouse and rat neurons. The mouse cells lived twice as long as they would have in a mouse brain, and they showed signs of aging similar to those of neighboring rat neurons.
Figuring out what’s helping the neurons survive could lead researchers to treatments for human neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, Magrassi says.
First signals from brain nerve cells with ultrathin nanowires
Electrodes operated into the brain are today used in research and to treat diseases such as Parkinson’s. However, their use has been limited by their size. At Lund University in Sweden, researchers have, for the first time, succeeded in implanting an ultrathin nanowire-based electrode and capturing signals from the nerve cells in the brain of a laboratory animal.
The researchers work at Lund University’s Neuronano Research Centre in an interdisciplinary collaboration between experts in subjects including neurophysiology, biomaterials, electrical measurements and nanotechnology. Their electrode is composed of a group of nanowires, each of which measures only 200 nanometres (billionths of a metre) in diameter.
Such thin electrodes have previously only been used in experiments with cell cultures.
“Carrying out experiments on a living animal is much more difficult. We are pleased that we have succeeded in developing a functioning nano-electrode, getting it into place and capturing signals from nerve cells”, says Professor Jens Schouenborg, who is head of the Neuronano Research Centre.
He sees this as a real breakthrough, but also as only a step on the way. The research group has already worked for several years to develop electrodes that are thin and flexible enough not to disturb the brain tissue, and with material that does not irritate the cells nearby. They now have the first evidence that it is possible to obtain useful nerve signals from nanometre-sized electrodes.
The research will now take a number of directions. The researchers want to try and reduce the size of the base to which the nanowires are attached, improve the connection between the electrode and the electronics that receive the signals from the nerve cells, and experiment with the surface structure of the electrodes to see what produces the best signals without damaging the brain cells.
“In the future, we hope to be able to make electrodes with nanostructured surfaces that are adapted to the various parts of the nerve cells – parts that are no bigger than a few billionths of a metre. Then we could tailor-make each electrode based on where it is going to be placed and what signals it is to capture or emit”, says Jens Schouenborg.
When an electrode is inserted into the brain of a patient or a laboratory animal, it is generally anchored to the skull. This means that it doesn’t move smoothly with the brain, which floats inside the skull, but rather rubs against the surrounding tissue, which in the long term causes the signals to deteriorate. The Lund group’s electrodes will instead be anchored by their surface structure.
“With the right pattern on the surface, they will stay in place yet still move with the body – and the brain – thereby opening up for long-term monitoring of neurones”, explains Jens Schouenborg.
He praises the collaboration between medics, physicists and others at the Neuronano Research Centre, and mentions physicist Dmitry B. Suyatin in particular. He is the principal author of the article which the researchers have now published in the international journal PLOS ONE.
The overall goal of the Neuronano Research Centre is to develop electrodes that can be inserted into the brain to study learning, pain and other mechanisms, and, in the long term, to treat conditions such as chronic pain, depression and Parkinson’s disease.
(Source: lunduniversity.lu.se)
Genome-wide imaging study identifies new gene associated with Alzheimer’s plaques
A study combining genetic data with brain imaging, designed to identify genes associated with the amyloid plaque deposits found in Alzheimer’s disease patients, has not only identified the APOE gene — long associated with development of Alzheimer’s — but has uncovered an association with a second gene, called BCHE.
A national research team, led by scientists at the Indiana University School of Medicine, reported the results of the study in an article in Molecular Psychiatry posted online Tuesday. The study is believed to be the first genome-wide association study of plaque deposits using a specialized PET scan tracer that binds to amyloid.
The research also is believed to be the first to implicate variations in the BCHE gene in plaque deposits visualized in living individuals who have been diagnosed with Alzheimer’s disease or are at-risk for developing the disease. The enzyme coded by the BCHE gene has previously been studied in post-mortem brain tissue and is known to be found in plaques.
“The findings could recharge research efforts studying the molecular pathways contributing to amyloid deposits in the brain as Alzheimer’s disease develops and affects learning and memory,” said Vijay K. Ramanan, the paper’s first author and an M.D./Ph.D. student at the IU School of Medicine.
The BCHE gene finding “brings together two of the major hypotheses about the development of Alzheimer’s disease,” said Andrew J. Saykin, Psy.D., Raymond C. Beeler Professor of Radiology and Imaging Sciences at IU and principal investigator for the genetics core of the Alzheimer’s Disease Neuroimaging Initiative.
Scientists have long pointed to the loss of an important brain neurotransmitter, acetylcholine, which is depleted early in the development of the disease, as a key aspect of the loss of memory related neurons. The BCHE gene is responsible for an enzyme that breaks down acetylcholine in the brain. The other major Alzheimer’s hypothesis holds that the development of the amyloid plaques is the primary cause of the disease’s debilitating symptoms. As it turns out, the enzyme for which the BCHE gene codes is also found in significant quantities in those plaques.
“This study is connecting two of the biggest Alzheimer’s dots,” said Dr. Saykin, director of the Indiana Alzheimer Disease Center and the IU Center for Neuroimaging at the IU Health Neuroscience Center.
“The finding that BCHE gene variant predicts the extent of plaque deposit in PET scans among people at risk for Alzheimer’s disease is likely to reinvigorate research into drugs that could modify the disease by affecting the BCHE enzyme or its metabolic pathway,” he said. Some existing drugs inhibit this enzyme, but it is unclear whether this influences plaque deposits.
Overall, the results appear to offer scientists new potential targets for drugs to slow, reverse or even prevent the disease. Alzheimer’s disease affects an estimated 5.4 million Americans and has proven resistant to treatments that do more than temporarily slow the worsening of symptoms.
Amyloid plaque deposits build up abnormally in the brains of Alzheimer’s patients and are believed to play an important role in the memory loss and other problems that plague patients.
The study makes use of an imaging agent, florbetapir, now approved for use by the U.S. Food and Drug Administration, that allows physicians to see the level of plaque buildup in a patient’s brain, something that previously could be determined only with an autopsy.
In a genome-wide association study, researchers evaluate alternate versions of many genes to determine whether particular genetic variants are associated with a particular trait — in this case, the amounts of amyloid plaque deposits that the PET scans revealed in the brains of study participants.
Using the imaging agent that enables detection of the plaques in the brain, the researchers conducted PET scans of 555 participants in the Alzheimer’s Disease Neuroimaging Initiative, a long-term public-private research project that includes people at risk for Alzheimer’s disease and patients who have been diagnosed with the disease as well as participants with no symptoms.
With sophisticated statistical analyses, the imaging data was combined with analyses of DNA collected from the 555 participants to determine whether particular gene variants were found more often among patients with higher levels of plaque deposits.
The analysis found that a variant in BCHE was significantly associated with the levels of plaque deposits. As would be expected, the analysis also found a strong association with variants of another gene, APOE, that has long been known to be associated with the development of Alzheimer’s. The effect of BCHE was independent of APOE, however. Moreover, the effects of the two genes were additive — that is, people with the suspect variants of both genes had more plaque deposits than people who had only one of the variants associated with plaque development.
Omega-3 Lipid Emulsions Markedly Protect Brain After Stroke in Mouse Study
Triglyceride lipid emulsions rich in an omega-3 fatty acid injected within a few hours of an ischemic stroke can decrease the amount of damaged brain tissue by 50 percent or more in mice, reports a new study by researchers at Columbia University Medical Center.
The results suggest that the emulsions may be able to reduce some of the long-term neurological and behavioral problems seen in human survivors of neonatal stroke and possibly of adult stroke, as well. The findings were published today in the journal PLoS One.
Currently, clot-busting tPA (recombinant tissue-type plasminogen activator) is the only treatment shown to improve recovery from ischemic stroke. If administered soon after stroke onset, the drug can restore blood flow to the brain but may not prevent injured, but potentially salvageable, neurons from dying.
Drugs with neuroprotective qualities that can prevent the death of brain cells damaged by stroke are needed, but even after 30 years of research and more than 1000 agents tested in animals, no neuroprotectant has been found effective in people.
Omega-3 fatty acids may have more potential as neuroprotectants because they affect multiple biochemical processes in the brain that are disturbed by stroke, said the study’s senior author, Richard Deckelbaum, MD, director of the Institute of Human Nutrition at Columbia’s College of Physicians & Surgeons. “The findings also may be applicable to other causes of ischemic brain injury in newborns and adults,” added co-investigator Vadim S. Ten, MD, PhD, an associate professor of pediatrics from the Department of Pediatrics at Columbia.
The effects of the omega-3 fatty acids include increasing the production of natural neuroprotectants in the brain, reducing inflammation and cell death, and activating genes that may protect brain cells. Omega-3 fatty acids also markedly reduce the release of harmful oxidants into the brain after stroke. “In most clinical trials in the past, the compounds tested affected only one pathway. Omega-3 fatty acids, in contrast, are very bioactive molecules that target multiple mechanisms involved in brain death after stroke,” Dr. Deckelbaum said.
The study revealed that an emulsion containing only DHA (docosahexaenoic acid), but not EPA (eicosapentaenoic acid), in a triglyceride molecule reduced the area of dead brain tissue by about 50 percent or more even when administered up to two hours after the stroke. Dr. Deckelbaum noted, “Since mice have a much faster metabolism than humans, longer windows of time for therapeutic effect after stroke are likely in humans.” Eight weeks after the stroke, much of the “saved” mouse brain tissue was still healthy, and no toxic effects were detected.
(Image: Shutterstock)
Identification of abnormal protein may help diagnose, treat ALS and frontotemporal dementia
Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, and frontotemporal dementia (FTD) are devastating neurodegenerative diseases with no effective treatment. Researchers are beginning to recognize ALS and FTD as part of a spectrum disorder with overlapping symptoms. Now investigators reporting online February 12 in the Cell Press journal Neuron have discovered an abnormal protein that first forms as a result of genetic abnormalities and later builds up in the brains of many patients with either disease.
"In identifying the novel protein that abnormally accumulates in the brains of affected patients, we have uncovered a potentially new therapeutic target and biomarker that would allow clinicians to confirm diagnosis of the diseases," says senior author Dr. Leonard Petrucelli, Chair of Neuroscience at Mayo Clinic in Florida.
By analyzing brain tissue from patients with ALS or FTD, Dr. Petrucelli and his team discovered that the abnormal protein, which they call C9RANT, is generated as a result of repeat expansions of nucleotides in the noncoding region of the C9ORF72 gene. These expansions are the most common cause of ALS and FTD. “Simply put, an error in the highly regulated cellular process through which proteins are generated causes the abnormal production of C9RANT,” explains Dr. Petrucelli.
The researchers discovered the protein C9RANT after creating a novel antibody to specifically detect it. The ability to detect C9RANT in individuals’ cerebrospinal fluid may provide a valuable diagnostic and prognostic tool for identifying patients carrying the C9ORF72 repeat expansion and for then tracking the progression of the disease in these at-risk individuals.
"Although it remains to be shown whether C9RANT is causing the cell death or toxicity associated with disease symptoms, our discovery offers a potential target to prevent neuronal loss in patients carrying the C9ORF72 repeat expansion," says Dr. Petrucelli.
The concept that abnormal proteins accumulate and can be toxic to cells is not new. In fact, tau protein forms tangles in Alzheimer’s disease and alpha-synuclein forms clumps in Parkinson’s disease. Just as new therapies are being developed to break down the protein aggregates associated with these diseases, developing a therapeutic strategy to target C9RANT aggregates may also prove beneficial.
Doctors aim to help stroke patients overcome disability by helping rewire their brains
Researchers at the University of Glasgow are hoping to help victims of stroke to overcome physical disabilities by helping their brains to ‘rewire’ themselves.
Doctors and scientists from the Institute of Cardiovascular and Medical Sciences will undertake the world’s first in-human trial of vagus nerve stimulation in stroke patients. Stroke can result in the loss of brain tissue and negatively affect various bodily functions from speech to movement, depending on the location of the stroke.
The study, which will be carried out at the Western Infirmary in Glasgow, will recruit 20 patients who suffered a stroke around six months ago and who have been left with poor arm function as a result.
Each participant will receive three one-hour sessions of intensive physiotherapy each week for six weeks to help improve their arm function.
Half of the group will also receive an implanted Vivistim device, a vagus nerve stimulator, which connects to the vagus nerve in the neck. When they are receiving physiotherapy to help improve their arm, the device will stimulate the nerve.
It is hoped that this will stimulate release of the brain’s own chemicals, called neurotransmitters, that will help the brain form new neural connections which might improve participants ability to use their arm.
Lead researcher Dr Jesse Dawson, a Stroke Specialist and Clinical Senior Lecturer in Medicine, said: “When the brain is damaged by stroke, important neural connections that control different parts of the body can be damaged which impairs function.
“Evidence from animal studies suggests that vagus nerve stimulation could cause the release of neurotransmitters which help facilitate neural plasticity and help people re-learn how to use their arms after stroke; particularly if stimulation is paired with specific tasks. A slightly different type of vagus nerve stimulation is already successfully used to manage conditions such as depression and epilepsy.
“This study is designed to provide evidence to support whether this is the case after stroke but our primary aim is to assess feasibility of vagus nerve stimulation after stroke.
“It remains to be seen how much we can improve function, but if we can help people perform even small actions again, like being able to hold a cup of tea, it would greatly improve their quality of life.”
(Source: gla.ac.uk)
Oxygen Chamber Can Boost Brain Repair
Stroke, traumatic injury, and metabolic disorder are major causes of brain damage and permanent disabilities, including motor dysfunction, psychological disorders, memory loss, and more. Current therapy and rehab programs aim to help patients heal, but they often have limited success.
Now Dr. Shai Efrati of Tel Aviv University’s Sackler Faculty of Medicine has found a way to restore a significant amount of neurological function in brain tissue thought to be chronically damaged — even years after initial injury. Theorizing that high levels of oxygen could reinvigorate dormant neurons, Dr. Efrati and his fellow researchers, including Prof. Eshel Ben-Jacob of TAU’s School of Physics and Astronomy and the Sagol School of Neuroscience, recruited post-stroke patients for hyperbaric oxygen therapy (HBOT) — sessions in high pressure chambers that contain oxygen-rich air — which increases oxygen levels in the body tenfold.
Analysis of brain imaging showed significantly increased neuronal activity after a two-month period of HBOT treatment compared to control periods of non-treatment, reported Dr. Efrati in PLoS ONE. Patients experienced improvements such as a reversal of paralysis, increased sensation, and renewed use of language. These changes can make a world of difference in daily life, helping patients recover their independence and complete tasks such as bathing, cooking, climbing stairs, or reading a book.
Even the Smallest Possible Stroke Can Damage Brain Tissue and Impair Cognitive Function
Blocking a single tiny blood vessel in the brain can harm neural tissue and even alter behavior, a new study from the University of California, San Diego has shown. But these consequences can be mitigated by a drug already in use, suggesting treatment that could slow the progress of dementia associated with cumulative damage to miniscule blood vessels that feed brain cells. The team reports their results in the December 16 advance online edition of Nature Neuroscience.
"The brain is incredibly dense with vasculature. It was surprising that blocking one small vessel could have a discernable impact on the behavior of a rat," said Andy Y. Shih, lead author of the paper who completed this work as a postdoctoral fellow in physics at UC San Diego. Shih is now an assistant professor at the Medical University of South Carolina.
Working with rats, Shih and colleagues used laser light to clot blood at precise points within small blood vessels that dive from the surface of the brain to penetrate neural tissue. When they looked at the brains up to a week later, they saw tiny holes reminiscent of the widespread damage often seen when the brains of patients with dementia are examined as a part of an autopsy.
These micro-lesions are too small to be detected with conventional MRI scans, which have a resolution of about a millimeter. Nearly two dozen of these small vessels enter the brain from a square millimeter area of the surface of the brain.
"It’s controversial whether that sort of damage has consequences, although the tide of evidence has been growing as human diagnostics improve," said David Kleinfeld, professor of physics and neurobiology, who leads the research group.
To see whether such minute damage could change behavior, the scientists trained thirsty rats to leap from one platform to another in the dark to get water.
The rats readily jump if they can reach the second platform with a paw or their snout, or stretch farther to touch it with their whiskers. Many rats can be trained to rely on a single whisker if the others are clipped, but if they can’t feel the far platform, they won’t budge.
"The whiskers line up in rows and each one is linked to a specific spot in the brain," Shih said. "By training them to use just one whisker, we were able to distill a behavior down to a very small part of the brain."
When Shih blocked single microvessels feeding a column of brain cells that respond to signals from the remaining whisker, the rats still crossed to the far platform when the gap was small. But when it widened beyond the reach of their snouts, they quit.
The FDA-approved drug memantine, prescribed to slow one aspect of memory decline associated with Alzheimer’s disease, ameliorated these effects. Rats that received the drug jumped whisker-wide gaps, and their brains showed fewer signs of damage.
"This data shows us, for the first time, that even a tiny stroke can lead to disability," said Patrick D. Lyden, a co-author of the study and chair of the department of neurology at Cedars-Sinai Medical Center in Los Angeles. "I am afraid that tiny strokes in our patients contribute—over the long term—to illness such as dementia and Alzheimer’s disease," he said, adding that "better tools will be required to tell whether human patients suffer memory effects from the smallest strokes."
“We used powerful tools from biological physics, many developed in Kleinfeld’s laboratory at UC San Diego, to link stroke to dementia on the unprecedented small scale of single vessels and cells,” Shih said. “At my new position at MUSC, I plan to work on ways to improve the detection of micro-lesions in human patients with MRI. This way clinicians may be able to diagnose and treat dementia earlier.”