Posts tagged white matter

A chromosomal deletion is associated with changes in the brain’s white matter and delayed language acquisition in youngsters from Southeast Asia or with ancestral connections to the region, said an international consortium led by researchers at Baylor College of Medicine. However, many such children who can be described as late-talkers may overcome early speech and language difficulties as they grow.

The finding involved both cutting edge technology and two physicians with an eye for unusual clinical findings. Dr. Seema R. Lalani, a physician-scientist at BCM and Dr. Jill V. Hunter, professor of radiology at BCM and Texas Children’s Hospital, worked together to identify this genetic change responsible for expressive language delay and brain changes in children, predominantly from Southeast Asia.

Lalani, assistant professor of molecular and human genetics at BCM, is a clinical geneticist and also signs out diagnostic studies called chromosomal microarray analysis, a gene chip that helps identify abnormalities in specific genes and chromosomes, as part of her work at BCM’s Medical Genetics Laboratory.

"I got intrigued when I kept seeing this small (genomic) change in children from a large sample of more than 15,000 children referred for chromosomal microarray analysis at Baylor College of Medicine. These children were predominantly Burmese refugees or of Vietnamese ancestry living in the United States. It started with two children whom I evaluated at Texas Children’s Hospital and soon realized that there was a pattern of early language delay and brain imaging abnormalities in these individuals carrying this deletion from this part of the world. Within a period of two to three years, we found 13 more families with similar problems, having the same genetic change. There were some children who obviously were more affected than the others and had cognitive and neurological problems, but many of them were identified as late-talkers who had better non-verbal skills compared to verbal performance," said Lalani. Hunter, helped in determining the specific pattern of white matter abnormalities in the MRI (magnetic resonance imaging) scans in children and their parents carrying this deletion. Most of the children either came from Southeast Asia or were the offspring of people from that area. (White matter is the paler material in the brain that consists of nerve fibers covered with myelin sheaths.)

Now, in a report that appears online in the American Journal of Human Genetics, Lalani, Hunter and an international group of collaborators identify a genomic deletion on chromosome 2 that is associated with bright white spots that show up in an MRI in the white matter of the brain . The chromosomal deletion removes a portion of a gene known as TM4SF20 that encodes a protein that spans the cellular membrane. They do not know yet what the function of the protein is. They found this genetic change in children from 15 unrelated families mainly from Southeast Asia.

"This deletion could be responsible for early childhood language delay in a large number of children from this part of the world," says Lalani.

She credits Dr. Wojciech Wiszniewski, an assistant professor of molecular and human genetics at BCM with doing much of the work. Wiszniewski has an interest in genomic disorders and is working under the mentorship of Dr. James R. Lupski, vice chair of the department of molecular and human genetics.

Lupski said, “Professor Lalani has made a stunning discovery in that she provides evidence that population-specific intragenic CNV (copy number variation – a deletion or duplication of the chromosome) can contribute to genetic susceptibility of even common complex disease such as speech delay in children.”

"In a way, this is a good news story," said Hunter. There is evidence from family studies that some of these children may do quite well in the future, said Lalani.

Lalani elaborates. “This is a genetic change that is present in 2 percent of Vietnamese Kinh population (an ethnic group that makes up 90 percent of the population in that country),” she said. “In the 15 families we have identified, all children have early language delay. Some are diagnosed with autism spectrum disorder, and if you do a brain MRI study, you find white matter changes in about 70 percent of them. We have found this change in children who are Vietnamese, Burmese, Thai, Indonesian, Filipino and and Micronesian. It is very likely that children from other Southeast Asian countries within this geographical distribution also carry this genetic change.”

Because these are all within a geographic location, she suspects that there is an ancient founder effect, meaning that at some point in the distant past, the gene deletion occurred spontaneously in an individual, who then passed it on to his or her children and to succeeding generations.

"It is important to follow these children longitudinally to see how these late-talkers develop as they grow," said Lalani. "We have also seen this deletion in children whose parents clearly were late-talkers themselves, but overcame the earlier problems to become doctors and professionals. The variability within the deletion carriers is fascinating and brings into question genetic and environmental modifiers that contribute to the extent of disease in these children.

Language delays mean that they may speak only two or three words at age 2, in comparison to other children who would generally have between 75-100 word vocabulary by this age. While there is evidence that children with this deletion may catch up, it is unclear if they continue to have better non-verbal skills than verbal skills. It is also unclear how the specific brain changes correlate with communication disorders in these children.

In fact, when doctors check the parents of these children, they often find similar white matter changes in the parent carrying the deletion. “Young parents in their 30s should not have age-related white matter changes in the brain and these changes should definitely not be present in healthy children,” said Lalani. Hunter said they are not sure how the gene variation relates to the changes in brain white matter and how all of these result in delay in language.

(Source: eurekalert.org)

The distribution of white matter brain abnormalities in some patients after mild traumatic brain injury (MTBI) closely resembles that found in early Alzheimer’s dementia, according to a new study published online in the journal Radiology.

“Findings of MTBI bear a striking resemblance to those seen in early Alzheimer’s dementia,” said the study’s lead author, Saeed Fakhran, M.D., assistant professor of radiology in the Division of Neuroradiology at the University of Pittsburgh School of Medicine. “Additional research may help further elucidate a link between these two disease processes.”

MTBI, or concussion, affects more than 1.7 million people in the United States annually. Despite the name, these injuries are by no means mild, with approximately 15 percent of concussion patients suffering persistent neurological symptoms.

“Sleep-wake disturbances are among the earliest findings of Alzheimer’s patients, and are also seen in a subset of MTBI patients,” Dr. Fakhran said. “Furthermore, after concussion, many patients have difficulty filtering out white noise and concentrating on the important sounds, making it hard for them to understand the world around them. Hearing problems are not only an independent risk factor for developing Alzheimer’s disease, but the same type of hearing problem seen in MTBI patients has been found to predict which patients with memory problems will go on to develop Alzheimer’s disease.”

For the study, Dr. Fakhran and colleagues set out to determine if there was a relationship between white matter injury patterns and severity of post-concussion symptoms in MTBI patients with normal findings on conventional magnetic resonance imaging (MRI) exams. The researchers studied data from imaging exams performed on 64 MTBI patients and 15 control patients, using an advanced MRI technique called diffusion tensor imaging, which identifies microscopic changes in the brain’s white matter.

The brain’s white matter is composed of millions of nerve fibers called axons that act like communication cables connecting various regions of the brain. Diffusion tensor imaging produces a measurement, called fractional anisotropy, of the movement of water molecules along axons. In healthy white matter, the direction of water movement is fairly uniform and measures high in fractional anisotropy. When water movement is more random, fractional anisotropy values decrease.

Of the MTBI patients, 42 (65.6 percent) were men, and the mean age was 17. Sports injury was the reason for concussion in two-thirds of the patients. All patients underwent neurocognitive evaluation with Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT). The researchers analyzed correlation between fractional anisotropy values, the ImPACT total symptom score, and findings of sleep-wake disturbances.

Sleep-wake disturbances are among the most disabling post-concussive symptoms, directly decreasing quality of life and productivity and magnifying post-concussion memory and social dysfunction.

The results showed a significant correlation between high ImPACT total symptom score and reduced fractional anisotropy at the gray-white junction, most prominently in the auditory cortex. Significantly decreased fractional anisotropy was found in patients with sleep-wake disturbances in the parahippocampal gyri relative to patients without sleep-wake disturbances.

“When we sleep, the brain organizes our experiences into memories, storing them so that we can later find them,” Dr. Fakhran said. “The parahippocampus is important for this process, and involvement of the parahippocampus may, in part, explain the memory problems that occur in many patients after concussion.”

According to Dr. Fakhran, the results suggest that the true problem facing concussion patients may not be the injury itself, but rather the brain’s response to that injury.

“Traditionally, it has been believed that patients with MTBI have symptoms because of abnormalities secondary to direct injury,” he said. “Simply put, they hit their head, damaged their brain at the point of trauma and thus have symptoms from that direct damage. Our preliminary findings suggest that the initial traumatic event that caused the concussion acts as a trigger for a sequence of degenerative changes in the brain that results in patient symptoms and that may be potentially prevented. Furthermore, these neurodegenerative changes are very similar to those seen in early Alzheimer’s dementia.”

The researchers hope that these findings may lead to improved treatments in the future.

“The first step in developing a treatment for any disease is understanding what causes it,” Dr. Fakhran said. “If we can prove a link, or even a common pathway, between MTBI and Alzheimer’s, this could potentially lead to treatment strategies that would be potentially efficacious in treating both diseases.”

(Source: prweb.com)

For many older adults, the aging process seems to go hand-in-hand with an annoying increase in clumsiness — difficulties dialing a phone, fumbling with keys in a lock or knocking over the occasional wine glass while reaching for a salt shaker.

While it’s easy to see these failings as a normal consequence of age-related breakdowns in agility, vision and other physical abilities, new research from Washington University in St. Louis suggests that some of these day-to-day reaching-and-grasping difficulties may be be caused by changes in the mental frame of reference that older adults use to visualize nearby objects.

“Reference frames help determine what in our environment we will pay attention to and they can affect how we interact with objects, such as controls for a car or dishes on a table,” said study co-author Richard Abrams, PhD, professor of psychology in Arts & Sciences.

“Our study shows that in addition to physical and perceptual changes, difficulties in interaction may also be caused by changes in how older adults mentally represent the objects near them.”

The study, published in the journal Psychological Science, is co-authored by two recent graduates of the psychology graduate program at Washington University. The lead author, Emily K. Bloesch, PhD, is now a postdoctoral teaching associate at Central Michigan University. The third co-author, Christopher C. Davoli, PhD, is a postdoctoral psychology researcher at the University of Notre Dame.

When tested on a series of simple tasks involving hand movements, young people in this study adopted an attentional reference frame centered on the hand, while older study participants adopted a reference frame centered on the body.

Young adults, the researchers explain, have been shown to use an “action-centered” reference frame that is sensitive to the movements they are making. So, when young people move their hands to pick up an object, they remain aware of and sensitive to potential obstacles along the movement path. Older adults, on the other hand, tend to devote more attention to objects that are closer to their bodies — whether they are on the action path or not.

“We showed in our paper that older adults do not use an “action centered” reference frame. Instead they use a “body centered” one,” Bloesch said. “As a result, they might be less able to effectively adjust their reaching movements to avoid obstacles — and that’s why they might knock over the wine glass after reaching for the salt shaker.”

These findings mesh well with other research that has documented age-related physical declines in several areas of the brain that are responsible for hand-eye coordination. Older adults exhibit volumetric declines in the parietal cortex and intraparietal sulcus, as well as white-matter loss in the parietal lobe and precuneus. These declines may make the use of an action-centered reference frame difficult or impossible.

“These three areas are highly involved in visually guided hand actions like reaching and grasping and in creating attentional reference frames that are used to guide such actions. These neurological changes in older adults suggest that their representations of the space around them may be compromised relative to those of young adults and that, consequently, young and older adults might encode and attend to near-body space in fundamentally different ways,” the study finds.

As the U.S. population ages, research on these issues is becoming increasingly important. An estimated 60-to-70 percent of the elderly population reports difficulty with activities of daily living, such as eating and bathing and many show deficiencies in performing goal-directed hand movements. Knowing more about these aging-related changes in spatial representation, the researchers suggest, may eventually inspire options for skills training and other therapies to help seniors compensate for the cognitive declines that influence hand-eye coordination

(Source: news.wustl.edu)

Working with lab mice models of multiple sclerosis (MS), UC Davis scientists have detected a novel molecular target for the design of drugs that could be safer and more effective than current FDA-approved medications against MS.

The findings of the research study, published online today in the journal EMBO Molecular Medicine could have therapeutic applications for MS as well as cerebral palsy and leukodystrophies, all disorders associated with loss of white matter, which is the brain tissue that carries information between nerve cells in the brain and the spinal cord.

The target, a protein referred to as mitochondrial translocator protein (TSPO), had been previously identified but not linked to MS, an autoimmune disease that strips the protective fatty coating off nerve fibers of the brain and spinal cord. The mitrochronical TSPO is located on the outer surface of mitochondria, cellular structures that supply energy to the cells. Damage to the fatty coating, or myelin, slows the transmission of the nerve signals that enable body movement as well as sensory and cognitive functioning.

The scientists identified mitochondrial TSPO as a potential therapeutic target when mice that had symptoms of MS improved after being treated with the anti-anxiety drug etifoxine, which interacts with mitochondrial TSPO. When etifoxine, a drug clinically available in Europe, was administered to the MS mice before they had clinical signs of disease, the severity of the disease was reduced when compared to the untreated lab animals. When treated at the peak of disease severity, the animals’ MS symptoms improved.

“Etifoxine has a novel protective effect against the loss of the sheath that insulates the nerve fibers that transmit the signals from brain cells,” said Wenbin Deng, principal investigator of the study and associate professor of biochemistry and molecular medicine at UC Davis.

“Our discovery of etifoxine’s effects on an MS animal model suggests that mitochondrial TSPO represents a potential therapeutic target for MS drug development,” said Deng.

“Drugs designed to more precisely bind to mitochondrial TSPO may help repair the myelin sheath of MS patients and thereby even help restore the transmission of signals in the central nervous system that enable normal motor, sensory and cognitive functions,” he said.

Deng added that better treatments for MS and other demyelinating diseases are needed, especially since current FDA-approved therapies do not repair the damage of immune attacks on the myelin sheath. 

The UC Davis research team hopes to further investigate the therapeutic applications of mitochondrial TSPO in drug development for MS and other autoimmune diseases. To identify more efficacious and safer drug candidates, they plan to pursue research grants that will enable them to test a variety of pharmacological compounds that bind to mitochondrial TSPO and other molecular targets in experimental models of MS and other myelin diseases.

(Source: ucdmc.ucdavis.edu)

The instability of “white matter” in humans may contribute to greater cognitive decline during the aging of humans compared with chimpanzees, scientists from Yerkes National Primate Research Center, Emory University have found.

Yerkes scientists have discovered that white matter — the wires connecting the computing centers of the brain — begins to deteriorate earlier in the human lifespan than in the lives of aging chimpanzees.

This was the first examination of white matter integrity in aging chimpanzees. The results were published April 24 and are available online before print in the journal Neurobiology of Aging.

"Our study demonstrates that the price we pay for greater longevity than other primates may be the unique vulnerability of humans to neurodegenerative disease," says research associate Xu (Jerry) Chen, first author of the paper. “The breakdown of white matter in later life could be part of that vulnerability.” 

Both humans’ longer life spans and distinctive metabolism could lie behind the differences in the patterns of brain aging, says co-author Todd Preuss, PhD, associate research professor in Yerkes’ Division of Neuropharmacology and Neurologic Diseases.

“White matter integrity actually peaks around the same absolute age in both chimpanzees and humans, but humans may experience more degradation because they live longer. Perhaps the need to retain brain capacity late in life is one reason increased brain size was selected for in human evolution,” Preuss says.  

The senior author is James Rilling, PhD, Yerkes researcher, associate professor of anthropology at Emory and director of the Laboratory for Darwinian Neuroscience. Collaborators at the University of Oslo also contributed to the paper.

In the brain, gray matter represents information processing centers, while white matter represents wires connecting these centers. White matter looks white because it is made up of myelin, a fatty electrical insulator that coats the axons of neurons.

If myelin deteriorates, neurons’ electrical signals are not transmitted as effectively, which contributes to cognitive decline. Myelin breakdown has been linked with cognitive decline both in healthy aging and in the context of Alzheimer’s disease.

The team’s data show that white matter integrity, as measured through a form of magnetic resonance imaging (MRI), peaks at age 31 in chimpanzees and at age 30 in humans. The average lifespan of chimpanzees is between 40 to 45 years, although in zoos or research facilities some have lived until 60. For comparison, human life expectancy in some developed countries is more than 80 years.

"The human equivalent of a 31 year old chimpanzee is about 47 years," Rilling says. "Extrapolating from chimpanzees, we could expect that human white matter integrity would peak at age 47, but instead it peaks and begins to decline at age 30."

The researchers collected MRI scans from 32 female chimpanzees and 20 female rhesus macaques and compared them with a pre-existing set of scans from human females. They used diffusion-weighted imaging (a form of MRI) to examine age-related changes in white matter integrity.

Diffusion-weighted imaging picks up microscopic changes in white matter by detecting directional differences in the ability of water molecules to diffuse. When the myelin coating of axons breaks down, water molecules in the brain can diffuse more freely, especially in directions perpendicular to axon bundles, Chen says.

(Source: news.emory.edu)

Researchers at Georgetown University Medical Center (GUMC) have found what they say is evidence that veterans who suffer from “Gulf War Illness” have physical changes in their brains not seen in unaffected individuals. Brain scans of 31 veterans with the illness, compared to 20 control subjects, revealed anomalies in the bundles of nerve fibers that connect brain areas involved in the processing and perception of pain and fatigue.

The discovery, published online March 20 in PLOS ONE, could provide insight into the mysterious medical symptoms reported by more than one-fourth of the 697,000 veterans deployed to the 1990-1991 Persian Gulf War, the researchers say. These symptoms, termed Gulf War Illness, range from mild to debilitating and can include widespread pain, fatigue, and headache, as well as cognitive and gastrointestinal dysfunctions.

Although these veterans were exposed to nerve agents, pesticides and herbicides, among other toxic chemicals, no one has definitively linked any single exposure or underlying mechanism to Gulf War Illness according to the scientists.

This is the first study to show veterans, compared to unaffected subjects, have significant axonal damage. Bundles of axons, which form the brain white matter, are akin to telephone wires that carry nerve impulses between different parts of the gray matter in the brain. The researchers found that damage to the right inferior fronto-occipital fasciculus was significantly correlated with the severity of pain, fatigue, and tenderness.

“This tract of axons links cortical gray matter regions involved in fatigue, pain, emotional and reward processing.  This bundle also supports activity in the ventral attention network, which searches for unexpected signals in the surrounding environment that may be inappropriately interpreted as causing pain or being dangerous. Altered function in this tract may explain the increased vigilance and distractibility observed in veterans.” says lead author Rakib Rayhan, MS, a researcher in the lab of the study’s senior investigator, James Baraniuk, MD, a professor of medicine at GUMC.

In this Department of Defense-funded study, the research team used a form of functional magnetic resonance imaging (fMRI) called diffusion tensor imaging. This imaging method examines patterns of water diffusion in the brain to look for changes in the integrity of white matter, which is not seen on regular MRI scans. “This provides a completely new perspective on Gulf War Illness,” says Baraniuk. “While we can’t exactly tell how this tract is affected at the molecular level — the scans tell us these axons are not working in a normal fashion.”

Although preliminary, “the changes appear distinct from multiple sclerosis, major depression, Alzheimer’s disease and other neurodegenerative diseases,” says Rayhan. “These novel findings are really exciting because they provide validation for many veterans who have long said that no one believes them.”

The results must be replicated, say its authors, but for the first time a potential biomarker for Gulf War Illness may be on the horizon as well as a possible target for therapy aimed at regenerating these neurons.

“Pain and fatigue are perceptions, just like other sensory input, and Gulf War Illness could be due to extensive damage to the structures that facilitate them,” says Rayhan. “Some of the veterans we studied feel pain when doing something as simple as putting on a shirt. Now we have something to tell them about why their lives have been so greatly affected.”

(Source: explore.georgetown.edu)