Posts Tagged Genetic

[WEB SITE] Study uncovers genetic trigger that may help the brain to recover from stroke, other injuries

Scientists have found a genetic trigger that may improve the brain’s ability to heal from a range of debilitating conditions, from strokes to concussions and spinal cord injuries.

A new study in mice from UT Southwestern’s O’Donnell Brain Institute shows that turning on a gene inside cells called astrocytes results in a smaller scar and – potentially – a more effective recovery from injury.

The research examined spinal injuries but likely has implications for treating a number of brain conditions through gene therapy targeting astrocytes, said Dr. Mark Goldberg, Chairman of Neurology & Neurotherapeutics at UT Southwestern.

“We’ve known that astrocytes can help the brain and spinal cord recover from injury, but we didn’t fully understand the trigger that activates these cells,” Dr. Goldberg said. “Now we’ll be able to look at whether turning on the switch we identified can help in the healing process.”

The study published in Cell Reports found that the LZK gene of astrocytes can be turned on to prompt a recovery response called astrogliosis, in which these star-shaped cells proliferate around injured neurons and form a scar.

Scientists deleted the LZK gene in astrocytes of one group of injured mice, which decreased the cells’ injury response and resulted in a larger wound on the spinal cord. They overexpressed the gene in other injured mice, which stimulated the cells’ injury response and resulted in a smaller scar. Overexpressing the gene in uninjured mice also activated the astrocytes, confirming LZK as a trigger for astrogliosis.

Dr. Goldberg said a smaller scar likely aids the healing process by isolating the injured neurons, similar to how isolating a spreading infection can improve recovery. “But we don’t know under what circumstances this hypothesis is true because until now we didn’t have an easy way to turn the astrocyte reactivity on and off,” he said.

Further study is needed to analyze whether a compact scar tissue indeed improves recovery and how this process affects the neurons’ ability to reform connections with each other.

Dr. Goldberg’s lab will conduct more research to examine the effects of astrogliosis in stroke and spinal cord injuries. The researchers will determine whether turning up LZK in mice in advance of an injury affects its severity. They will then measure how the formation of the compact scar helps or hinders recovery.

“It has been a big mystery whether increasing astrocyte reactivity would be beneficial,” said Dr. Meifan Amy Chen, the study’s lead author and Instructor of Neurology at the Peter O’Donnell Jr. Brain Institute. “The discovery of LZK as an on switch now offers a molecular tool to answer this question.”

 

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[WEB SITE] Largest-ever study to examine anatomical alterations in the brains of epilepsy patients

Largest-ever study to examine anatomical alterations in the brains of epilepsy patients 

An international research consortium used neuroimaging techniques to analyze the brains of more than 3,800 volunteers in different countries. The largest study of its kind ever conducted set out to investigate anatomical similarities and differences in the brains of individuals with different types of epilepsy and to seek markers that could help with prognosis and treatment.

Epilepsy’s seizure frequency and severity, as well as the patient’s response to drug therapy, vary with the part of the brain affected and other poorly understood factors. Data from the scientific literature suggests that roughly one-third of patients do not respond well to anti-epileptic drugs. Research has shown that these individuals are more likely to develop cognitive and behavioral impairments over the years.

The new study was conducted by a specific working group within an international consortium called ENIGMA, short for Enhancing NeuroImaging Genetics through Meta-Analysis, established to investigate several neurological and psychiatric diseases. Twenty-four cross-sectional samples from 14 countries were included in the epilepsy study.

Altogether, the study included data for 2,149 people with epilepsy and 1,727 healthy control subjects (with no neurological or psychiatric disorders). The Brazilian Research Institute for Neuroscience and Neurotechnology (BRAINN), which participated in the multicenter study, was the center with the largest sample, comprising 291 patients and 398 controls. Hosted in Brazil, at the State University of Campinas (UNICAMP), BRAINN is a Research, Innovation and Dissemination Center (RIDC http://cepid.fapesp.br/en/home/) supported by the Sao Paulo Research Foundation – FAPESP.

“Each center was responsible for collecting and analyzing data on its own patients. All the material was then sent to the University of Southern California’s Imaging Genetics Center in the US, which consolidated the results and performed a meta-analysis,” said Fernando Cendes, a professor at UNICAMP and coordinator of BRAINN.

A differential study

All volunteers were subjected to MRI scans. According to Cendes, a specific protocol was used to acquire three-dimensional images. “This permitted image post-processing with the aid of computer software, which segmented the images into thousands of anatomical points for individual assessment and comparison,” he said.

According to the researcher, advances in neuroimaging techniques have enabled the detection of structural alterations in the brains of people with epilepsy that hadn’t been noticed previously.

Cendes also highlighted that this is the first epilepsy study built on a really large number of patients, which allowed researchers to obtain more robust data. “There were many discrepancies in earlier studies, which comprised a few dozen or hundred volunteers.”

The patients included in the study were divided into four subgroups: mesial temporal lobe epilepsy (MTLE) with left hippocampal sclerosis, MTLE with right hippocampal sclerosis, idiopathic (genetic) generalized epilepsy, and a fourth group comprising various less common subtypes of the disease.

The analysis covered both patients who had had epilepsy for years and patients who had been diagnosed recently. According to Cendes, the analysis – whose results were published in the international journal Brain – aimed at the identification of atrophied brain regions in which the cortical thickness was smaller than in the control group.

First analysis

The researchers first analyzed data from the four patient subgroups as a whole and compared them with the controls to determine whether there were anatomical alterations common to all forms of epilepsy. “We found that all four subgroups displayed atrophy in areas of the sensitive-motor cortex and also in some parts of the frontal lobe,” Cendes said.

“Ordinary MRI scans don’t show anatomical alterations in cases of genetic generalized epilepsy,” Cendes said. “One of the goals of this study was to confirm whether areas of atrophy also occur in these patients. We found that they do.”

This finding, he added, shows that in the case of MTLE, there are alterations in regions other than those in which seizures are produced (the hippocampus, parahippocampus, and amygdala). Brain impairment is, therefore, more extensive than previously thought.

Cendes also noted that a larger proportion of the brain was compromised in patients who had had the disease for longer. “This reinforces the hypothesis that more brain regions atrophy and more cognitive impairment occurs as the disease progresses.”

The next step was a separate analysis of each patient subgroup in search of alterations that characterize each form of the disease. The findings confirmed, for example, that MTLE with left hippocampal sclerosis is associated with alterations in different neuronal circuits from those associated with MTLE with right hippocampal sclerosis.

“Temporal lobe epilepsy occurs in a specific brain region and is therefore termed a focal form of the disease. It’s also the most common treatment-refractory subtype of epilepsy in adults,” Cendes said. “We know it has different and more severe effects when it involves the left hemisphere than the right. They’re different diseases.”

“These two forms of the disease are not mere mirror-images of each other,” he said. “When the left hemisphere is involved, the seizures are more intense and diffuse. It used to be thought that this happened because the left hemisphere is dominant for language, but this doesn’t appear to be the only reason. Somehow, it’s more vulnerable than the right hemisphere.”

In the GGE group, the researchers observed atrophy in the thalamus, a central deep-lying brain region above the hypothalamus, and in the motor cortex. “These are subtle alterations but were observed in patients with epilepsy and not in the controls,” Cendes said.

Genetic generalized epilepsies (GGEs) may involve all brain regions but can usually be controlled by drugs and are less damaging to patients.

Future developments

From the vantage point of the coordinator for the FAPESP-funded center, the findings published in the article will benefit research in the area and will also have future implications for the diagnosis of the disease. In parallel with their anatomical analysis, the group is also evaluating genetic alterations that may explain certain hereditary patterns in brain atrophy. The results of this genetic analysis will be published soon.

“If we know there are more or less specific signatures of the different epileptic subtypes, instead of looking for alterations everywhere in the brain, we can focus on suspect regions, reducing cost, saving time and bolstering the statistical power of the analysis. Next, we’ll be able to correlate these alterations with cognitive and behavioral dysfunction,” Cendes said.

 

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[WEB SITE] Findings reveal how seizures can have lasting detrimental effects on memory

October 16, 2017

Although it’s been clear that seizures are linked to memory loss and other cognitive deficits in patients with Alzheimer’s disease, how this happens has been puzzling. In a study published in the journal Nature Medicine, a team of researchers reveals a mechanism that can explain how even relatively infrequent seizures can lead to long-lasting cognitive deficits in animal models. A better understanding of this new mechanism may lead to future strategies to reduce cognitive deficits in Alzheimer’s disease and other conditions associated with seizures, such as epilepsy.

“It’s been hard to reconcile how infrequent seizures can lead to persistent changes in memory in patients with Alzheimer’s disease,” said corresponding author Dr. Jeannie Chin, assistant professor of neuroscience at Baylor College of Medicine. “To solve this puzzle, we worked with a mouse model of Alzheimer’s disease focusing on the genetic changes that seizures might trigger in the memory center of the brain, the hippocampus, that could lead to loss of memory or other cognitive deficits.”

The researchers measured the levels of a number of proteins involved in memory and learning and found that levels of the protein deltaFosB strikingly increase in the hippocampus of Alzheimer’s disease mice that had seizures. DeltaFosB already is well known for its association with other neurological conditions linked to persistent brain activity of specific brain regions, such as addiction. In this study, the researchers found that after a seizure, the deltaFosB protein remains in the hippocampus for an unusually long time; its half-life – the time it takes for the amount of protein to decrease by half – is eight days. Most proteins have a half-life that is between hours and a day or two.

“Interestingly, because deltaFosB is a transcription factor, meaning that its job is to regulate the expression of other proteins, these findings led us to predict that the increased deltaFosB levels might be responsible for suppressing the production of proteins that are necessary for learning and memory,” Chin said. “In fact, we found that when the levels of deltaFosB increase, those of other proteins, such as calbindin, decrease. Calbindin also has been known for a long time to be involved in Alzheimer’s disease and epilepsy, but its mechanism of regulation was not known. We then hypothesized that deltaFosB might be regulating the production of calbindin.”

Further investigations supported the researchers’ hypothesis. The scientists showed that deltaFosB can bind to the gene calbindin suppressing the expression of the protein. When they either prevented deltaFosB activity or experimentally increased calbindin expression in the mice, calbindin levels were restored and the mice improved their memory. And when researchers experimentally increased deltaFosB levels in normal mice, calbindin expression was suppressed and the animals’ memory deteriorated, demonstrating that deltaFosB and calbindin are key regulators of memory.

Connecting pieces of the puzzle

“Our findings have helped us answer the question of how even infrequent seizures can have such lasting detrimental effects on memory,” Chin said. “We found that seizures can increase the levels of deltaFosB in the hippocampus, which results in a decrease in the levels of calbindin, a regulator of memory processes. DeltaFosB has a relatively long half-life, therefore even when seizures are infrequent, deltaFosB remains in the hippocampus for weeks acting like a brake, reducing the production of calbindin and other proteins, and disrupting the consequent brain activity involved in memory. The regulation of gene expression far outlasts the actual seizure event that triggered it.”

The scientists found the same changes in deltaFosB and calbindin levels in the hippocampus of Alzheimer’s disease patients and in the temporal lobe of epilepsy patients. However, they underscore that it is too soon to know whether regulating deltaFosB or calbindin could improve or prevent memory problems or other cognitive deficits in people with Alzheimer’s disease. However, “now that we know that the levels of deltaFosB and calbindin are effective markers of brain activity in the hippocampus and memory function, we propose that these markers could potentially help assess clinical therapies for Alzheimer’s and other diseases with seizures,” Chin said.

Source: Findings reveal how seizures can have lasting detrimental effects on memory

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[WEB SITE] Doctors appear to have reached unexpected consensus in prescribing pediatric anti-seizure medications

July 19, 2017

The number of available anti-seizure medications has exploded in the past two decades, going from just a handful of medicines available in the 1990s to more than 20 now. Once the Food and Drug Administration (FDA) approves each new medicine based on trials in adults, it’s available for clinicians to prescribe off-label to all age groups. However, says William D. Gaillard, M.D., division chief of Child Neurology and Epilepsy, Neurophysiology and Critical Care Neurology at Children’s National Health System, trials that lead to FDA approval for adults do not provide any information about which medications are best for children.

“With so many medications and so little data,” Dr. Gaillard says, “one might think doctors would choose a wider variety of medicines when they prescribe to children with epilepsy.”

However, the results from a recent study by Dr. Gaillard and colleagues, published online in Pediatric Neurology on June 27, 2017, show otherwise. The study indicates that doctors in the United States appear to have reached an unexpected consensus about which medication to prescribe for their pediatric patients.

The study is part of a broader effort to collect data on the youngest epilepsy patients — those younger than 3 years old, the age at which epilepsy most often becomes evident. As part of this endeavor, researchers from 17 U.S. pediatric epilepsy centers enrolled in the study 495 children younger than 36 months old who had been newly diagnosed with non-syndromic epilepsy (a condition not linked to any of the commonly recognized genetic epilepsy syndromes).

The researchers mined these patients’ electronic medical records for information about their demographics, disease and treatments. About half of the study participants were younger than 1 year old when they were diagnosed with epilepsy. About half had disease marked by focal features, meaning that their epilepsy appeared to originate from a particular place in the brain. Nearly all were treated with a single medication, as opposed to a cocktail of multiple medicines.

Of those treated with a single medication, nearly all were treated with one of five medicines: Levetiracetam, oxcarbazepine, phenobarbital, topiramate and zonisamide. However, the data showed a clear prescribing preference. About 63 percent of the patients were prescribed levetiracetam as a first choice. By contrast, oxcarbazepine and phenobarbital, the next most frequently prescribed medicines, were taken by patients as a first choice by a mere 14 percent and 13 percent respectively.

Even more striking, of the children who were not prescribed levetiracetam initially but required a second medication due to inadequate efficacy or unacceptable side effects, 62 percent also received this medication. That made levetiracetam the first or second choice for about 74 percent of all the children in the study, despite the availability of more than 20 anti-seizure medications.

It’s not clear why levetiracetam is such a frequent choice in the United States, says Dr. Gaillard. However, in its favor, the drug is available in a liquid formulation, causes no ill effects medically and can be started intravenously if necessary. Studies have shown that it appears to be effective in controlling seizures in about 40 percent of infants.

Yet, levetiracetam’s market dominance appears to be a North American phenomenon, the study authors write. A recent international survey that Dr. Gaillard also participated in suggests that outside of this continent, carbazepine and oxcarbazepine were the most frequently prescribed medications to treat focal seizures.

What’s really necessary, Dr. Gaillard says, is real data on efficacy for each of the medications commonly prescribed to pediatric epilepsy patients–a marked vacuum in research that prevents doctors from using evidence-based reasoning when making medication choices.

“This study identifies current practices, but whether those practices are correct is a separate question,” he explains. “Just because a medication is used commonly doesn’t mean it is the best medication we should be using.”

To answer that question, he says, researchers will need to perform a head-to-head clinical trial comparing the top available epilepsy medications in children. This study sets the stage for such a trial by identifying which medications should be included.

“Uncontrolled pediatric epilepsy can have serious consequences, from potential problems in development to a higher risk of death,” Dr. Gaillard says. “You want to use the optimal medicine to treat the disease.”

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[WEB SITE] First-ever neuroscience conference to explore ultra-personal approach to brain health

For three days this week, Roanoke, Virginia, is the capital of the precision neuroscience world.

The first-ever scientific meeting to explore an ultra-personal approach to brain health — the Virginia-Nordic Precision Neuroscience Conference — opened this week at the Virginia Tech Carilion Research Institute.

“The promise, hope, and opportunity for precision neuroscience is great — with the potential for realizing the brain and mind’s full potential, preventing disorders, and restoring brain health after injury or degenerative disease,” said Virginia Tech President Tim Sands, who welcomed about 200 scientists on behalf of Virginia Tech and Carilion Clinic. “It is also the responsibility of the scientific and medical communities to help define the real possibilities, differentiate hype from reality, and help focus the scientific enterprise and resource allocation on areas where the promise can be realized.”

More than 1,000 disorders of the brain and nervous system result in more hospitalizations than any other disease group, including heart disease and cancer.

“By understanding an individual’s genetics, behavior, education, habits, life experiences such as physical and psychological trauma — all the things that make people who they are — the neuroscientific community may be able to develop individually tailored plans for people to optimize education, health care, diet, exercise, and environments where they are likely to thrive cognitively, socially, and physically,” said Michael J. Friedlander, Virginia Tech’s vice president for health sciences and technology and the founding executive director of the Virginia Tech Carilion Research Institute.

The collaboration grew from an idea developed by Friedlander and Tor S. Haugstad, a neurologist and neuroscience chair at Sunnaas National Rehabilitation Hospital in Oslo, Norway, worked to develop as the Norway/U.S. Neuroscience Collaboration, initially called NUNC. The effort has grown to include multiple universities in Norway as well as in several other Nordic countries, and universities and foundations throughout Virginia.

People respond to brain injuries differently, which is one of the motivations for further development of the precision neuroscience field.

“We may get two people in our department with very similar brain injuries, and one may be rendered with a low level of consciousness while the other can recover and return home to his family and work life,” said Haugstad, who also chairs the traumatic brain rehabilitation program at Sunnaas National Rehabilitation Hospital. “We need to discover at cellular and molecular levels why people respond so differently, and tailor treatment and rehabilitation to the specific person.”

The meeting, which will continue through Friday, is the first to bring the top minds of precision neuroscience from across the globe together in a think-tank setting to explore the challenges and promise of bringing personalized medicine to brain health and brain disorders.

“One individual’s experience with Alzheimer’s disease, Parkinson’s disease, a traumatic brain injury, or various other neurological or psychiatric disorders will not be exactly like anyone else’s,” Friedlander said.

“From a business and health care point of view, clinical trials may fail because they target generic diseases that manifest very differently in different people,” Friedlander said. “If a drug or treatment doesn’t work in 75 percent of the people, it is considered a failure — but it worked in 25 percent. Should we forget about the 25 percent of people it helped and scrap potentially lifesaving therapies that may have cost hundreds of millions of dollars during a decade of development?”

By targeting groups of patients based on their predicted manifestations of a particular brain disorder, the success rate for finding new treatments will improve and the investment risk can be lessened, according to Friedlander.

“Essentially the pharmaceutical industry and investors de-risk their investments by having more precise, targeted therapies and tests that are more likely to be successful,” Friedlander said. “The treatment may be effective for 10 percent of people with a particular brain disease, but we can learn a lot about why those 10 percent may have benefitted based on their genetic composition and expression patterns and their life experiences. Then, we get back to work on a treatment for the next 10 percent, and the next 10 percent. It may not be one size fits all.”

Researchers will discuss innovations ranging from a Nobel prize-winning imaging system that visualizes the action of molecules within the brain, to the work of physician-scientists who are on the frontlines of health care delivery for brain injury, neurodegenerative diseases of aging, and brain developmental disorders.

In many ways, the conference has special meaning for the partner cities in Virginia and in Europe, Haugstad said.

“Roanoke is a city with a history of rail that, through innovation and spirit, is reinventing itself, and it is leading the way in precision neuroscience,” Haugstad said. “In Norway, a country that depends on oil revenue, the cities are changing much like cities in Virginia, by finding new ways to live and move forward. Together, we are very good partners.”

Source: Virginia Tech

Source: First-ever neuroscience conference to explore ultra-personal approach to brain health

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