From trauma to tau - Researchers tie brain injury to toxic form of protein

University of Texas Medical Branch at Galveston researchers have uncovered what may be a key molecular mechanism behind the lasting damage done by traumatic brain injury.

The discovery centers on a particular form of a protein that neuroscientists call tau, which has also been associated with Alzheimer’s disease and other neurodegenerative conditions. Under ordinary conditions, tau is essential to neuron health, but in Alzheimer’s the protein aggregates into two abnormal forms: so-called “neurofibrillary tangles,” and collections of two, three, or four or more tau units known as “oligomers.”

Neurofibrillary tangles are not believed to be harmful, but tau oligomers are toxic to nerve cells. They are also are thought to have an additional damaging property — when they come into contact with healthy tau proteins, they cause them to also clump together into oligomers, and so spread toxic tau oligomers to other parts of the brain.

Now, in experiments with laboratory rats, using novel antibodies developed at UTMB, scientists have found that traumatic brain injuries also generate tau oligomers. The destructive protein assemblages formed within four hours after injury and persisted for at least two weeks — long enough to suggest that they might contribute to lasting brain damage.

Significantly, the rats used in the experiments were normal, unlike the genetically modified animals used in most tau research. The findings are thus likely to be more relevant to human traumatic brain injuries.

“Although people have given some attention to the formation of neurofibrillary tangles after traumatic brain injury, we were the first to look at tau oligomers, because we have an antibody that allows us to separate them out and see how much of the total tau is the toxic species,” said Bridget Hawkins, lead author of a paper on the research now online in the Journal of Biological Chemistry. “We saw that it’s a substantial amount — enough to play an important role in the effects of traumatic brain injury.”

Those effects can include memory deficits, which have been recently shown by UTMB researchers to be induced by tau oligomers. Other long-term ramifications of TBI include seizures, and disruptions in the sleep-wake cycle. The UTMB scientists hypothesize that these problems could be avoided if physicians had a way to stop the process of tau oligomerization.

One possibility is a treatment based on the antibodies used to label tau oligomers in this project, which were developed as part of an effort to develop a vaccine against different neurodegenerative disorders.

“We have antibodies that can specifically target these tau oligomers without interfering with the function of healthy tau,” said UTMB associate professor Rakez Kayed, the senior author on the paper. “This is a new approach — we’re starting by targeting them in animals — but we hope to eventually humanize these antibodies for clinical trials.”

Repeat Brain Injury Raises Soldiers’ Suicide Risk

People in the military who suffer more than one mild traumatic brain injury face a significantly higher risk of suicide, according to research by the National Center for Veterans Studies at the University of Utah.

A survey of 161 military personnel who were stationed in Iraq and evaluated for a possible traumatic brain injury – also known as TBI – showed that the risk for suicidal thoughts or behaviors increased not only in the short term, as measured during the past 12 months, but during the individual’s lifetime.

The risk of suicidal thoughts increased significantly with the number of TBIs, even when controlling for other psychological factors, the researchers say in a paper published online Wednesday, May 15 in JAMA Psychiatry, a specialty journal of the American Medical Association.

“Up to now, no one has been able to say if multiple TBIs, which are common among combat veterans, are associated with higher suicide risk or not,” says the study’s lead author, Craig J. Bryan, assistant professor of psychology at the University of Utah and associate director of the National Center for Veterans Studies. “This study suggests they are, and it provides valuable information for professionals treating wounded combat servicemen and women to help manage the risk of suicide.”

Results showed that one in five patients (21.7 percent) who had ever sustained more than one TBI reported suicidal ideation – thoughts about or preoccupation with suicide – at any time in the past. For patients who had received one TBI, 6.9 percent reported having suicidal thoughts, and zero percent for those with no TBIs. In evaluating the lifetime risk, patients were asked if they had ever experienced suicidal thoughts and behaviors up to the point they were assessed.

The increases were similar for suicidal thoughts during the previous year rather than at any time: 12 percent of those with multiple TBIs had entertained suicidal ideas during the past year, compared with 3.4 percent with one TBI and zero percent for no TBIs.

In this study, suicidal ideation was used as the indicator of suicide risk because too few patients reported a history of suicide plan or had made a suicide attempt for statistically valid conclusions to be made.

Researchers found that multiple TBIs also were associated with a significant increase in other psychological symptoms already tied to single traumatic head injuries, including depression, post-traumatic stress disorder or PTSD, and the severity of the concussive symptoms. However, only the increase in depression severity predicted an increased suicide risk.

“That head injury and resulting psychological effects increase the risk of suicide is not new,” says Bryan. “But knowing that repetitive TBIs may make patients even more vulnerable provides new insight for attending to military personnel over the long-term, particularly when they are experiencing added emotional distress in their lives.”

How the Study was Conducted

During a six-month period in 2009, 161 patients who received a suspected brain injury while on duty in Iraq were referred to an outpatient TBI clinic at a combat support hospital there. Patients were predominantly male, average age of 27, with 6.5 years of military service.

Diagnosis of traumatic brain injury was made by a clinical psychologist specifically trained in the assessment, diagnosis and management of the condition. Only patients with mild or no TBI completed all assessments; patients with moderate to severe TBI were immediately evacuated from Iraq.

TBI was confirmed if at least one clinical event was newly presented or worsened following the injury: loss of consciousness or memory, alteration of mental state, some neurological decline or brain damage.

Patients were divided into three groups based the total number of TBIs during their entire lives – zero, single TBI and two or more – the most recent of which was typically within the days immediately preceding their evaluation and inclusion in the study.

Each individual was also given surveys as part of his or her evaluation and treatment. Using standard evaluation tools, patients were surveyed about their symptoms of depression, PTSD and concussions, and their suicidal thoughts and behaviors.

“An important feature of the study is that by being on the ground in Iraq, we were able to compile a unique data set on active military personnel and head injury,” Bryan says. “We collected data on a large number of service members within two days of impact.”

At the same time, because the results of this study are based on a single clinical sample –active military in a war zone within days of the injury – the researchers note that caution is advised before assuming that the results from this particular group will apply to every other group. Studies with larger sample sizes and conducted over longer periods of time will be needed.

Why TBI is of Concern for Military Personnel

As defined by the Centers for Disease Control and Prevention, a traumatic brain injury is caused by a bump, blow or jolt to the head, or a penetrating head injury that disrupts the normal function of the brain. Effects can be mild to severe. The majority of TBIs that occur each year are concussions or other mild forms.

TBI is considered a “signature injury” of the Iraq and Afghanistan conflicts and is of particular concern because of the frequency of concussive injuries from explosions and other combat-related incidents. Estimated prevalence of TBI for those deployed in these two countries ranges from 8 percent to 20 percent, according to a 2008 study.

In addition, according to studies by the RAND Corp., suicide is the second-leading cause of death among U.S. military personnel, and the rate has risen steadily since the conflicts began in Iraq and Afghanistan. Prevalence of PTSD, depression and substance abuse have risen as well, especially among those in combat, and each has been shown to increase risk for suicidal behaviors.

“Being aware of the number of a patient’s head injuries and the interrelation with depression and other psychological symptoms may help us better understand, and thus moderate, the risk of suicide over time,” Bryan says. “Ultimately, we would like to know why people do not kill themselves. Despite facing similar issues and circumstances, some people recover. Understanding that is the real goal.”

Imaging Technique Could Help Traumatic Brain Injury Patients

A new application of an existing medical imaging technology could help predict long-term damage in patients with traumatic brain injury, according to a recent UC San Francisco study.

The authors of the study analyzed brain scans using applied rapid automated resting state magnetoencephalography (MEG) imaging, a technique used to map brain activity by recording magnetic fields produced by natural electrical currents in the brain. They discovered “abnormally decreased functional connectivity” – or possible long-term brain damage – could persist years after a person suffers even a mild form of traumatic brain injury.

“We were hoping that areas of abnormal brain activity would match up with some of the functional measures such as patients’ symptoms after injury, and we saw such correlation,” said senior author Pratik Mukherjee, MD, PhD, associate professor in residence at the UCSF School of Medicine.

In a study published on April 19 in the Journal of Neurosurgery, UCSF researchers analyzed brain connectivity data on 14 male and seven female patients, whose median age was 29. Brain connectivity refers to a pattern of causal interactions between specific parts within a nervous system. Eleven patients had mild, one had moderate, and three had severe forms of traumatic brain injury. Six patients suffered no brain injury.

“Once we have connectivity information, we can create a template of what it looks like in a normal subject. When we have subjects that have had head injuries, we can compare their connectivity pattern to that of the normal subjects with an automated computer algorithm,” Mukherjee said. “And that will automatically detect areas of abnormally low and abnormally high connectivity compared to the normal database.” 

MEG imaging provides much richer information than a typical magnetic resonance imaging (MRI), which uses magnetic field and radio wave energy to give a static image of the brain or other internal structures of the body.

“If you scan someone a couple months after the trauma with an MRI, and you scan them again a couple of years after the trauma, it’s going to look the same,” Mukherjee said. “With MEG, we can characterize simple systems in much more in fine grain detail. It produces the most detailed activity mapping of the brain.”

Although MEG signals were first measured in 1968, the technology has not been widely used for patients with traumatic brain injury until recently. 

“It takes a minute or two to complete an MEG scan and it automatically detects the areas of abnormality using a computer algorithm,” Mukherjee said. “And it seems to be fairly sensitive because it’s showing us areas of abnormality even in people where MRIs missed some abnormalities.”

Every year approximately 1.7 million people in the United States suffer from traumatic brain injury, which costs the U.S. health care system an estimated $60 billion according to the U.S. Centers for Disease Control and Prevention. The most common forms of traumatic brain injury are suffered by athletes, members of the military, and those involved in motor vehicle collisions or occupational injuries.

“This is a preliminary study testing a new technique with a small sample, which makes it difficult to have enough statistical power to make such correlations,” Mukherjee said. “But I think this is an important step in our quest to help people suffering from traumatic brain injuries.”

Brain Anatomy of Dyslexia Is Not the Same in Men and Women, Boys and Girls

Using MRI, neuroscientists at Georgetown University Medical Center found significant differences in brain anatomy when comparing men and women with dyslexia to their non-dyslexic control groups, suggesting that the disorder may have a different brain-based manifestation based on sex.

Their study, investigating dyslexia in both males and females,is the first to directly compare brain anatomy of females with and without dyslexia (in children and adults). Their findings were published online in the journal Brain Structure and Function.

Because dyslexia is two to three times more prevalent in males compared with females, “females have been overlooked,” says senior author Guinevere Eden, PhD, director for the Center for the Study of Learning and past-president of the International Dyslexia Association.

“It has been assumed that results of studies conducted in men are generalizable to both sexes. But our research suggests that researchers need to tackle dyslexia in each sex separately to address questions about its origin and potentially, treatment,” Eden says.

Previous work outside of dyslexia demonstrates that male and female brains are different in general, adds the study’s lead author, Tanya Evans, PhD.

“There is sex-specific variance in brain anatomy and females tend to use both hemispheres for language tasks, while males just the left,” Evans says. “It is also known that sex hormones are related to brain anatomy and that female sex hormones such as estrogen can be protective after brain injury, suggesting another avenue that might lead to the sex-specific findings reported in this study.”

The study of 118 participants compared the brain structure of people with dyslexia to those without and was conducted separately in men, women, boys and girls. In the males, less gray matter volume is found in dyslexics in areas of the brain used to process language, consistent with previous work. In the females, less gray matter volume is found in dyslexics in areas involved in sensory and motor processing.

The results have important implications for understanding the origin of dyslexia and the relationship between language and sensory processing, says Evans.

After Brain Injury, New Astrocytes Play Unexpected Role in Healing

The production of a certain kind of brain cell that had been considered an impediment to healing may actually be needed to staunch bleeding and promote repair after a stroke or head trauma, researchers at Duke Medicine report.

These cells, known as astrocytes, can be produced from stem cells in the brain after injury. They migrate to the site of damage where they are much more effective in promoting recovery than previously thought. This insight from studies in mice, reported online April 24, 2013, in the journal Nature, may help researchers develop treatments that foster brain repair.

“The injury recovery process is complex,” said senior author Chay T. Kuo, M.D., PhD, George W. Brumley Assistant Professor of Cell Biology, Pediatrics and Neurobiology at Duke University. “There is a lot of interest in how new neurons can stimulate functional recovery, but if you make neurons without stopping the bleeding, the neurons don’t even get a chance. The brain somehow knows this, so we believe that’s why it produces these unique astrocytes in response to injury.”

Each year, more than 1.7 million people in the United States suffer a traumatic brain injury, according to the Centers for Disease Control and Prevention. Another 795,000 people a year suffer a stroke. Few therapies are available to treat the damage that often results from such injuries.

Kuo and colleagues at Duke are interested in replacing lost neurons after a brain injury as a way to restore function. Once damaged, mature neurons cannot multiply, so most research efforts have focused on inducing brain stem cells to produce more immature neurons to replace them.

This strategy has proved difficult, because in addition to making neurons, neural stem cells also produce astrocytes and oligodendrocytes, known as glial cells. Although glial cells are important for maintaining the normal function of neurons in the brain, the increased production of astrocytes from neural stem cell has been considered an unwanted byproduct, causing more harm than good. Proliferating astrocytes secrete proteins that can induce tissue inflammation and undergo gene mutations that can lead to aggressive brain tumors.

In their study of mice, the Duke team found an unexpected insight about the astrocytes produced from stem cells after injury. Stem cells live in a special area or “niche” in the postnatal/adult brain called the subventricular zone, and churn out neurons and glia in the right proportions based on cues from the surrounding tissue.

After an injury, however, the subventricular niche pumps out more astrocytes. Significantly, the Duke team found they are different from astrocytes produced in most other regions of the brain. These cells make their way to the injured area to help make an organized scar, which stops the bleeding and allows tissue recovery.

When the generation of these astrocytes in the subventricular niche was experimentally blocked after a brain injury, hemorrhaging occurred around the injured areas and the region did not heal.  Kuo said the finding was made possible by insights about astrocytes from Cagla Eroglu, PhD, whose laboratory next door to Kuo’s conducts research on astrocyte interactions with neurons.

“Cagla and I started at Duke together and have known each other since our postdoctoral days,” Kuo said. “To have these stem cell-made astrocytes express a unique protein that Cagla understands more than anyone else, it’s just a wonderful example of scientific serendipity and collaboration.”

Additionally, Kuo said first author Eric J. Benner, M.D., PhD, a former postdoctoral fellow who now has his own laboratory at Duke, provided key clinical correlations on brain injury as a physician-scientist and practicing neonatologist in the Jean and George Brumley Jr. Neonatal-Perinatal Research Institute.

“We are very excited about this innate flexibility in neural stem cell behavior to know just what to do to help the brain after injury,” Kuo said. “Since bleeding in the brain after injury is a common and serious problem for patients, further research into this area may lead to effective therapies for accelerated brain recovery after injury.”

Engineer helping unravel mystery of traumatic brain injury

The American Academy of Neurology issued new guidelines last week for assessing school-aged athletes with head injuries on the field. The message: if in doubt, sit out.

With more than 3 million sports-related concussions occurring in the U.S. each year, from school children to professional athletes, the issue is a burgeoning health crisis.

While concussions may not be difficult to diagnose initially, the longer one waits, the more difficult treatment can be.

The efforts of a researcher and his colleagues at Washington University in St. Louis’ School of Engineering & Applied Science are helping to unravel the many mysteries of traumatic brain injury.

“There’s and urgent need to understand the problem of traumatic brain injuries, for the sake of athletes, military personnel and accident victims,” says Philip Bayly, PhD, the Lilyan and E. Lisle Hughes Professor of Mechanical Engineering.

“Anyone who has met someone who’s had a head injury knows how scary it is, and how frustrating it is that we know so little about the causal pathways, and thus the best therapeutic opportunities,” he says.

Bayly, chair of the Department of Mechanical Engineering & Materials Science, researches the mechanics of brain injury. He recently received a $2.25 million grant from the National Institutes of Health to better understand traumatic brain injuries.

Head injuries, concussions and the resulting trauma have been in public discussion recently as the National Football League (NFL) deals with a lawsuit regarding head injuries by about one-third of living former NFL players. The league is accused of not providing information connecting football-related head injuries to brain damage, memory loss and other long-term health issues.

Bayly’s team is working on ways to measure 3-D relative motion between in the brain and skull and estimate strain during mild head acceleration. Bayly hopes computer simulation can teach researchers about the basic physics of brain injury and ways to develop new approaches to prevention and therapy.

“Our studies provide experimental data on how the brain actually responds mechanically in response to mild external loads,” Bayly says. “This is especially critical to developing useful computer simulations, to make sure they reflect reality.
These simulations will in turn be used to design new equipment, evaluate rule changes in sports and determine exposure thresholds or diagnostic tests.”

Computer simulation is important in creating animal models that can be used to develop diagnostic and therapeutic approaches, he says.

“Understanding mechanical deformation in traumatic brain injury is also essential to anyone studying brain trauma by exposing cultured brain cells to mechanical stress,” Bayly says. “We need to understand how much stress to apply and in what directions.”

How can athletes minimize their risks?

“From a mechanical standpoint, they should avoid repeated high head accelerations,” Bayly says. “Head-to-head collisions and collisions with head-to-ground are clearly to be avoided.”

Bayly says to truly protect athletes, new rules need to be instated.

“I would actually advocate for eliminating sports like boxing, in which injury-level accelerations are known to occur routinely. More research is needed on sports where the threshold is less clear.”

There is where Bayly and his colleagues come in.

“We need to do the research to find out what kinds of repeated accelerations are responsible for producing the degeneration seen in chronic traumatic encephalopathy,” he says.

(Image: Jupiterimages / Getty Images)