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Brain image (Photo/Courtesy of USC Stevens Institute for Neuroimaging and Informatics)

Brain image (Photo/Courtesy of USC Stevens Institute for Neuroimaging and Informatics)

Researchers Create Maps of the Brain After Traumatic Brain Injury

Anne Warde, UC Irvine, June 17, 2022

 
Scientists from the University of California, Irvine have discovered that an injury to one part of the brain changes the connections between nerve cells across the entire brain.

The new research was published this week in Nature Communications.

Every year in the United States, nearly two million Americans sustain a traumatic brain injury (TBI). Survivors can live with lifelong physical, cognitive and emotional disabilities. Currently, there are no treatments.

One of the biggest challenges for neuroscientists has been to fully understand how a TBI alters the cross-talk between different cells and brain regions.

In the new study, researchers improved upon a process called iDISCO, which uses solvents to make biological samples transparent. The process leaves behind a fully intact brain that can be illuminated with lasers and imaged in 3D with specialized microscopes.

With the enhanced brain clearing processes, the UCI team mapped neural connections throughout the entire brain. The researchers focused on connections to inhibitory neurons, because these neurons are extremely vulnerable to dying after a brain injury. The team first looked at the hippocampus, a brain region responsible for learning and memory.

Then, they investigated the prefrontal cortex, a brain region that works together with hippocampus. In both cases, the imaging showed that inhibitory neurons gain many more connections from neighboring nerve cells after TBI, but they become disconnected from the rest of the brain.

“We’ve known for a long time that the communication between different brain cells can change very dramatically after an injury,” said Robert Hunt, PhD, associate professor of anatomy and neurobiology and director of the Epilepsy Research Center at UCI School of Medicine whose lab conducted the study, “But, we haven’t been able to see what happens in the whole brain until now.”

To get a closer look at the damaged brain connections, Hunt and his team devised a technique for reversing the clearing procedure and probing the brain with traditional anatomical approaches.

The findings surprisingly showed that the long projections of distant nerve cells were still present in the damaged brain, but they no longer formed connections with inhibitory neurons.

“It looks like the entire brain is being carefully rewired to accommodate for the damage, regardless of whether there was direct injury to the region or not,” explained Alexa Tierno, a graduate student and co-first author of the study. “But different parts of the brain probably aren’t working together quite as well as they did before the injury.”

The researchers then wanted to determine if it was possible for inhibitory neurons to be reconnected with distant brain regions.

To find out, Hunt and his team transplanted new interneurons into the damaged hippocampus and mapped their connections, based on the team’s earlier research demonstrating interneuron transplantation can improve memory and stop seizures in mice with TBI.

The new neurons received appropriate connections from all over the brain. While this may mean it could be possible to entice the injured brain to repair these lost connections on its own, Hunt said learning how transplanted interneurons integrate into damaged brain circuits is essential for any future attempt to use these cells for brain repair.

One of the biggest challenges for neuroscientists has been to fully understand how a TBI alters the cross-talk between different cells and brain regions. Image is in the public domain One of the biggest challenges for neuroscientists has been to fully understand how a TBI alters the cross-talk between different cells and brain regions. Image is in the public domain

“Our study is a very important addition to our understanding of how inhibitory progenitors can one day be used therapeutically for the treatment of TBI, epilepsy or other brain disorders,” said Hunt.

“Some people have proposed interneuron transplantation might rejuvenate the brain by releasing unknown substances to boost innate regenerative capacity, but we’re finding the new neurons are really being hard wired into the brain.”

Hunt hopes to eventually develop cell therapy for people with TBI and epilepsy. The UCI team is now repeating the experiments using inhibitory neurons produced from human stem cells.

“This work takes us one step closer to a future cell-based therapy for people,” Hunt said, “Understanding the kinds of plasticity that exists after an injury will help us rebuild the injured brain with a very high degree of precision. However, it is very important that we proceed step wise toward this goal, and that takes time.”

Jan C. Frankowski, PhD; Shreya Pavani; Quincy Cao and David C. Lyon, PhD also contributed to this study.

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Doctors Discuss Knowing the Signs of Concussion in Young Athletes

By Adria Goins and Alex Onken, KSLA

 
Thousands of students in the Arkansas/Louisiana/Texas (and across the nation) began fall sports over the last few weeks.

However, with the new season here, comes a risk of injury. Football is the leading sport when it comes to concussions.

The signs of a concussion are headache, fatigue and nausea. Parents are advised to then bring their child to a doctor right away if suspecting a possible concussion.

“First diagnose it early and then after you diagnose it early make sure you avoid the triggers. So avoid extra screen time, over-exercising and just basically have 24 to 48 hours of cognitive physical rest,” said Dr. Kenneth Aguirre of Oschner-LSU Health Shreveport, who specializes in sports medicine.

According to Dr. Charles Webb, also with Oschner-LSU Health and a sports medicine specialist, the topic of concussions and the potential risks of football comes up often.

“I get that question a lot from parents. They want to know is it safe for my child to play high school or junior high, or even pee wee or popcorn football. and the question comes up because parents are worried about concussions. So my answer to them is if it were my child I wouldn’t let them play until they had an organized professional coach teaching them both how to hit and receive a hit.”

Young athletes are usually taught how to hit and receive a hit around junior high. Dr. Webb said parents should put their children in club soccer or flag football in contrast to popcorn or pee wee football.

“It’s much safer and you’re less likely to get hit in the head,” he said. “And you still get all the conditioning you need to play football later on in life.”

In addition, doctors say keeping children awake when they have a concussion is a common misconception. Sleep is actually very good for the healing process.
 

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ISRIB molecule—image by the Adam Frost lab at UCSF

Drug Reverses Age-Related Mental Decline Within Days, Suggesting Lost Cognitive Ability is Not Permanent

By Good News Network, December 27, 2020

 
Just a few doses of an experimental drug that reboots protein production in cells can reverse age-related declines in memory and mental flexibility in mice, according to a new study by UC San Francisco scientists.

The drug, called ISRIB, has already been shown in laboratory studies to restore memory function months after traumatic brain injury (TBI), reverse cognitive impairments in Down Syndrome, prevent noise-related hearing loss, fight certain types of prostate cancer, and even enhance cognition in healthy animals.

In the new study, published Dec. 1 in the open-access journal eLife, researchers showed rapid restoration of youthful cognitive abilities in aged mice, accompanied by a rejuvenation of brain and immune cells that could help explain improvements in brain function—and with no side effects observed.

“ISRIB’s extremely rapid effects show for the first time that a significant component of age-related cognitive losses may be caused by a kind of reversible physiological “blockage” rather than more permanent degradation,” said Susanna Rosi, PhD, Lewis and Ruth Cozen Chair II and professor in the departments of Neurological Surgery and of Physical Therapy and Rehabilitation Science.

“The data suggest that the aged brain has not permanently lost essential cognitive capacities, as was commonly assumed, but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress,” added Peter Walter, PhD, a professor in the UCSF Department of Biochemistry and Biophysics and a Howard Hughes Medical Institute investigator. “Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time.”

Rebooting cellular protein production holds key to aging

Walter has won numerous scientific awards, including the Breakthrough, Lasker and Shaw prizes, for his decades-long studies of cellular stress responses. ISRIB, discovered in 2013 in Walter’s lab, works by rebooting cells’ protein production machinery after it gets throttled by one of these stress responses—a cellular quality control mechanism called the integrated stress response (ISR; ISRIB stands for ISR InhiBitor).

The ISR normally detects problems with protein production in a cell—a potential sign of viral infection or cancer-promoting gene mutations—and responds by putting the brakes on cell’s protein-synthesis machinery. This safety mechanism is critical for weeding out misbehaving cells, but if stuck in the ‘on’ position in a tissue like the brain, it can lead to serious problems, as cells lose the ability to perform their normal activities, according to Walter and colleagues.

In particular, their recent animal studies have implicated chronic ISR activation in the persistent cognitive and behavioral deficits seen in patients after TBI, by showing that, in mice, brief ISRIB treatment can reboot the ISR and restore normal brain function almost overnight.

The cognitive deficits in TBI patients are often likened to premature aging, which led Rosi and Walter to wonder if the ISR could also underlie purely age-related cognitive decline. Aging is well known to compromise cellular protein production across the body, as life’s many insults pile up and stressors like chronic inflammation wear away at cells, potentially leading to widespread activation of the ISR.

“We’ve seen how ISRIB restores cognition in animals with traumatic brain injury, which in many ways is like a sped-up version of age-related cognitive decline,” said Rosi, who is director of neurocognitive research in the UCSF Brain and Spinal Injury Center and a member of the UCSF Weill Institute for Neurosciences. “It may seem like a crazy idea, but asking whether the drug could reverse symptoms of aging itself was just a logical next step.”

Signature effects of aging disappeared literally overnight

In the new study, researchers led by Rosi lab postdoc Karen Krukowski, PhD, trained aged animals to escape from a watery maze by finding a hidden platform, a task that is typically hard for older animals to learn. But animals who received small daily doses of ISRIB during the three-day training process were able to accomplish the task as well as youthful mice—and much better than animals of the same age who didn’t receive the drug.

The researchers then tested how long this cognitive rejuvenation lasted and whether it could generalize to other cognitive skills. Several weeks after the initial ISRIB treatment, they trained the same mice to find their way out of a maze whose exit changed daily—a test of mental flexibility for aged mice who, like humans, tend to get increasingly stuck in their ways. The mice who had received brief ISRIB treatment three weeks before still performed at youthful levels, while untreated mice continued to struggle.

To understand how ISRIB might be improving brain function, the researchers studied the activity and anatomy of cells in the hippocampus, a brain region with a key role in learning and memory, just one day after giving animals a single dose of ISRIB. They found that common signatures of neuronal aging disappeared literally overnight: neurons’ electrical activity became more sprightly and responsive to stimulation, and cells showed more robust connectivity with cells around them while also showing an ability to form stable connections with one another usually only seen in younger mice.

The researchers are continuing to study exactly how the ISR disrupts cognition in aging and other conditions and to understand how long ISRIB’s cognitive benefits may last. Among other puzzles raised by the new findings is the discovery that ISRIB also alters the function of the immune system’s T cells, which also are prone to age-related dysfunction. The findings suggest another path by which the drug could be improving cognition in aged animals, and could have implications for diseases from Alzheimer’s to diabetes that have been linked to heightened inflammation caused by an aging immune system.

“This was very exciting to me because we know that aging has a profound and persistent effect on T cells and that these changes can affect brain function in the hippocampus,” said Rosi. “At the moment, this is just an interesting observation, but it gives us a very exciting set of biological puzzles to solve.”

Success shows the ‘serendipity’ of basic research

Rosi and Walter were introduced by neuroscientist Regis Kelly, PhD, executive director of the University of California’s QB3 biotech innovation hub, following Walter’s 2013 study showing that the drug seemed to instantly enhance cognitive abilities in healthy mice. To Rosi, the results from that study implied some walled-off cognitive potential in the brain that the molecule was somehow unlocking, and she wondered if this extra cognitive boost might benefit patients with neurological damage from traumatic brain injury.

The labs joined forces to study the question in mice, and were astounded by what they found. ISRIB didn’t just make up for some of the cognitive deficits in mice with traumatic brain injury—it erased them. “This had never been seen before,” Rosi said. “The mantra in the field was that brain damage is permanent—irreversible. How could a single treatment with a small molecule make them disappear overnight?”

Further studies demonstrated that neurons throughout the brains of animals with traumatic brain injury are thoroughly jammed up by the ISR. Using ISRIB to release those brakes lets brain cells immediately get back to their normal business. More recently, studies in animals with very mild repetitive brain injury—akin to pro athletes who experience many mild concussions over many years—showed that ISRIB could reverse increased risk-taking behavior associated with damage to self-control circuits in the frontal cortex.

“It’s not often that you find a drug candidate that shows so much potential and promise,” Walter says, calling it “just amazing”.

No side effects

One might think that interfering with the ISR, a critical cellular safety mechanism, would be sure to have serious side effects, but so far in all their studies, the researchers have observed none. This is likely due to two factors. First, it takes just a few doses of ISRIB to reset unhealthy, chronic ISR activation back to a healthier state. Second, ISRIB has virtually no effect when applied to cells actively employing the ISR in its most powerful form—against an aggressive viral infection, for example.

ISRIB has been licensed by Calico, a South San Francisco, Calif. company exploring the biology of aging, and the idea of targeting the ISR to treat disease has been picked up by many other pharmaceutical companies, Walter says.

“It almost seems too good to be true, but with ISRIB we seem to have hit a sweet spot for manipulating the ISR with an ideal therapeutic window,” Walter said.

Get more links to background studies from original article from UCSF News.
 

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Ayn al Asad Air Base in western Iraq after an Iranian missile attack on Jan. 8. The number of service members experiencing symptoms associated with brain injuries has since topped 100. Photo Credit…Sergey Ponomarev for The New York Times

 

Brain Injuries Are Common in Battle.
The Military Has No Reliable Test for Them.

Traumatic brain injury is a signature wound of the wars in Iraq and Afghanistan. But the military still has no objective way of diagnosing it in the field.

By Dave Philipps and Thomas Gibbons-Neff for nytimes.com, February 15, 2020

 
U.S. troops at Ayn al Asad Air Base in western Iraq hunkered down in concrete bunkers last month as Iranian missile strikes rocked the runway, destroying guard towers, hangars and buildings used to fly drones.
When the dust settled, President Trump and military officials declared that no one had been killed or wounded during the attack. That would soon change.

A week after the blast, Defense Department officials acknowledged that 11 service members had tested positive for traumatic brain injury, or TBI, and had been evacuated to Kuwait and Germany for more screening. Two weeks after the blast, the Pentagon announced that 34 service members were experiencing symptoms associated with brain injuries, and that an additional seven had been evacuated. By the end of January the number of potential brain injuries had climbed to 50. This week it grew to 109.

The Defense Department says the numbers are driven by an abundance of caution. It noted that 70 percent of those who tested positive for a TBI had since returned to duty. But experts in the brain injury field said the delayed response and confusion were primarily caused by a problem both the military and civilian world have struggled with for more than a decade: There is no reliable way to determine who has a brain injury and who does not.

Top military leaders have for years called traumatic brain injury one of the signature wounds of the wars in Iraq and Afghanistan; at the height of the Iraq war in 2008, they started pouring hundreds of millions of dollars into research on detection and treatment. But the military still has no objective tool for diagnosing brain injury in the field. Instead, medical personnel continue to use a paper questionnaire that relies on answers from patients — patients who may have reasons to hide or exaggerate symptoms, or who may be too shaken to answer questions accurately.

The military has long struggled with how to address so-called invisible war wounds, including traumatic brain injury and post-traumatic stress disorder. Despite big investments in research that have yielded advances in the laboratory, troops on the ground are still being assessed with the same blunt tools that have been in use for generations.

The problem is not unique to the military. Civilian doctors struggle to accurately assess brain injuries, and still rely on a process that grades the severity of a head injury in part by asking patients a series of questions: Did they black out? Do they have memory problems or dizziness? Are they experiencing irritability or difficulty concentrating?

“It’s bad, bad, bad. You would never diagnose a heart attack or even a broken bone that way,” said Dr. Jeff Bazarian a professor of emergency medicine at the University of Rochester Medical Center. “And yet we are doing it for an injury to the most complex organ in the body. Here’s how crazy it gets: You are relying on people to report what happened. But the part of the brain most often affected by a traumatic brain injury is memory. We get a lot of false positives and false negatives.”

Without a good diagnosis, he said, doctors often don’t know whether a patient has a minor concussion that might require a day’s rest, or a life-threatening brain bleed, let alone potential long-term effects like depression and personality disorder.

At Ayn al Asad, personnel used the same paper questionnaires that field medics used in remote infantry platoons in 2010. Aaron Hepps, who was a Navy corpsman in a Marines infantry company in Afghanistan at that time, said it did not work well then for lesser cases, and the injuries of many Marines may have been missed. During and after his deployment, he counted brain injuries in roughly 350 Marines — about a third of the battalion.

After the January missile attack, Maj. Robert Hales, one of the top medical providers at the air base, said that the initial tests were “a good start,” but that it took numerous screenings and awareness among the troops to realize that repeated exposure to blast waves during the hourlong missile strikes had affected dozens.

Traumatic brain injuries are among the most common injuries of the wars in Iraq and Afghanistan, in part because armor to protect from bullet and shrapnel wounds has gotten better, but they offer little protection from the shock waves of explosions. More than 350,000 brain injuries have been reported in the military since 2001.

The concrete bunkers scattered around bases like Ain al Assad protect from flying shrapnel and debris, but the small quarters can amplify shock waves and lead to head trauma.

The blasts on Jan. 8, one military official said, were hundreds of times more powerful than the rocket and mortar attacks regularly aimed at U.S. bases, causing at least one concrete wall to collapse atop a bunker with people inside.

Capt. Geoff Hansen was in a Humvee at Ayn al Asad when the first missile hit, blowing open a door. Then a second missile hit.

“That kind of blew me back in,” he said. “Blew debris in my face so I went and sat back down a little confused.”

A tangle of factors make diagnosing head injuries in the military particularly tricky, experts say. Some troops try to hide symptoms so they can stay on duty, or avoid being perceived as weak. Others may play up or even invent symptoms that can make them eligible for the Purple Heart medal or valuable veteran’s education and medical benefits.

And sometimes commanders suspect troops with legitimate injuries of malingering and force them to return to duty. Pentagon officials said privately this week that some of the injuries from the Jan. 8 incident had probably been exaggerated. Mr. Trump seemed to dismiss the injuries at a news conference in Davos, Switzerland, last month. “I heard they had headaches,” he said. “I don’t consider them very serious injuries relative to other injuries I have seen.”

In the early years of the war in Iraq, troops with concussions were often given little medical treatment and were not eligible for the Purple Heart. It was only after clearly wounded troops began complaining of poor treatment that Congress got involved and military leaders began pressing for better diagnostic technology.

Damir Janigro, who directed cerebrovascular research at the Cleveland Clinic for more than a decade, said relying on the questionnaire makes accurate diagnosing extremely difficult.

“You have the problem of the cheaters, and the problem of the ones who don’t want to be counted,” he said. “But you have a third problem, which is that even if people are being completely honest, you still don’t know who is really injured.”

In civilian emergency rooms, the uncertainty leads doctors to approve unnecessary CT scans, which can detect bleeding and other damage to the brain, but are expensive and expose patients to radiation. At the same time doctors miss other patients who may need care. In a war zone, bad calls can endanger lives, as troops are either needlessly airlifted or kept in the field when they cannot think straight.

Mr. Janigro is at work on a possible solution. He and his team have developed a test that uses proteins found in a patient’s saliva to diagnose brain injuries. Other groups are developing a blood test.

Both tests work on a similar principle. When the brain is hit by a blast wave or a blow to the head, brain cells are stretched and damaged. Those cells then dispose of the damaged parts, which are composed of distinctive proteins. Abnormal levels of those proteins are dumped into the bloodstream, where for several hours they can be detected in both the blood and saliva. Both tests, and another test being developed that measures electrical activity in the brain, were funded in part by federal grants, and have shown strong results in clinical trials. Researchers say they could be approved for use by the F.D.A. in the next few years.

The saliva test being developed by Mr. Janigro will look a bit like an over-the-counter pregnancy test. Patients with suspected brain injuries would put sensors in their mouths, and within minutes get a message that says that their brain protein levels are normal, or that they should see a doctor.

But the new generation of testing tools may fall short, said Dr. Gerald Grant, a professor of neurosurgery at Stanford University and a former Air Force lieutenant colonel who frequently treated head injuries while deployed to Iraq in 2005.

Even sophisticated devices had trouble picking up injuries from roadside bombs, he said.

“You’d get kids coming in with blast injuries,” he said, “and they clearly had symptoms, but the CT scans would be negative.”

He was part of an earlier effort to find a definitive blood test, which he said in an interview was “the holy grail.” But progress was slow. The grail was never found, he said, and the tests currently being developed are helpful for triaging cases, but too vague to be revolutionary.

“Battlefield injuries are complex,” he said. “We still haven’t found the magic biomarker.”

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What’s the difference between all the different head scans (X-Ray, CT, MRI, MRA, PET scan)? And what do they show in the head?

Michael S. Tehrani, M.D.Follow Founder & CEO at MedWell Medical

 
Ever wonder what’s the difference between all the different head scans (xray, CT, MRI, MRA, PET scan) and what they show in the head. Well wonder no more. The Dr. T easy to understand version…

X-Ray: shows bone/skull only. Does not show the brain. Best used to detect if there are bone fractures.

CT: a quick test. Shows brain but detail not great. Shows if any larger bleed, stroke, lesions, or masses.

MRI: a long test. Shows brain and detail is great. Shows smaller bleeds, stroke, lesions, or masses.

MRA:
shows the flow of blood in the vasculature system of the brain. If there is vessel narrowing or blockage this test would show it.

PET scan: shows how active different parts of the brain is. An active brain uses sugar as energy and pet scan detects how much sugar is being used by lighting up and turning different colors. The more sugar being used the more that area will light up and be different in colors. Cancer cells use the most sugar so cancer cells light up the most. PET scan is used to see if there are cancer cells. (Cancer cells replicate at a very fast and uncontrolled rate hence use a lot of sugar to allow that replication hence why they light up so much).

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Libby and Tom Bates // CBS News

A brain disease best known for impacting football players who suffered concussions is now being found in soldiers

By Sharyn Alfonsi, September 16, 2018, CBS News

Until a few years ago, NFL players who struggled with severe depression, bouts of rage and memory loss in their retirement were often told they were just having a hard time adjusting to life away from the game. Doctors have since learned these changes can be symptoms of the degenerative brain disease CTE – chronic traumatic encephalopathy, caused by blows to the head.

As we first reported in January, CTE isn’t just affecting athletes, but also showing up in our nation’s heroes. Since 9/11 over 300,000 soldiers have returned home with brain injuries. Researchers fear the impact of CTE could cripple a generation of warriors.

When Joy Kieffer buried her 34-year old son this past summer, it was the end of a long goodbye.

Kieffer’s son, Sgt. Kevin Ash, enlisted in the Army Reserves at the age of 18. Over three deployments, he was exposed to 12 combat blasts, many of them roadside bombs. He returned home in 2012 a different man.

Joy Kieffer: His whole personality had changed. I thought it was exposure to all of the things that he had seen, and he had just become harder. You know, but he was — he was not happy.

Sharyn Alfonsi: So at this point, you’re thinking this decline, this change in my child is just that he’s been in war and he’s seen too much.

Joy Kieffer: Right.

Sharyn Alfonsi: Did he tell you about blasts that he experienced during that time?

Joy Kieffer: Uh-huh.

Sharyn Alfonsi: What did he–tell you?

Joy Kieffer: That they shook him. And he was having blackouts. And — it frightened him.

Ash withdrew from family and friends. He was angry. Depressed. Doctors prescribed therapy and medication, but his health began to decline quickly. By his 34th birthday, Sgt. Kevin Ash was unable to speak, walk or eat on his own.

Sharyn Alfonsi: Looking back on it now, was there anything you feel like he could’ve done?

Joy Kieffer: Uh-uh.

Sharyn Alfonsi: Because?

Joy Kieffer: Because it was– it– it was his brain. The thing I didn’t know was that his brain was continuing to die. I mean, before he went into the service he said, “you know, I could come back with no legs, or no arms, or even blind, or I could be shot, I could die,” but nobody ever said that he could lose his mind one day at a time.

His final wish was to serve his country one last time by donating his brain to science — a gesture he thought would bring better understanding to the invisible wounds of war.

Joy reached out to the VA-Boston University-Concussion Legacy Foundation Brain Bank where neuropathologist Dr. Ann McKee is leading the charge in researching head trauma and the degenerative brain disease CTE.

McKee has spent fourteen years looking at the postmortem brains of hundreds of athletes who suffered concussions while playing their sport.

Last summer, her findings shook the football world when she discovered CTE in the brains of 110 out of 111 deceased NFL players — raising serious concerns for those in the game today.

And when Dr. McKee autopsied Patriots tight-end Aaron Hernandez who killed himself after being convicted of murder, she found the most severe case of CTE ever, in someone under 30.

Now she’s seeing similar patterns in deceased veterans who experienced a different kind of head trauma — combat blasts. Of the 125 veterans’ brains Dr. Mckee’s examined, 74 had CTE.

Sharyn Alfonsi: I can understand a football player who keeps, you know, hitting his head, and having impact and concussions. But how is it that a combat veteran, who maybe just experienced a blast, has the same type of injury?

Dr. Ann McKee: This blast injury causes a tremendous sort of– ricochet or– or– a whiplash injury to the brain inside the skull and that’s what gives rise to the same changes that we see in football players, as in military veterans.

Blast trauma was first recognized back in World War I. Known as ‘shell shock,’ poorly protected soldiers often died immediately or went on to suffer physical and psychological symptoms. Today, sophisticated armor allows more soldiers to walk away from an explosion but exposure can still damage the brain — an injury that can worsen over time.

Dr. Ann McKee: It’s not a new injury. But what’s been really stumping us, I think, as– as physicians is it’s not easily detectable, right? It’s– you’ve got a lot of psychiatric symptoms– and you can’t see it very well on images of the brain and so it didn’t occur to us. And I think that’s been the gap, really, that this has been what everyone calls an invisible injury.

Dr. Ann McKee: This is the world’s largest CTE brain bank.

The only foolproof way to diagnose CTE is by testing a post-mortem brain.

Sharyn Alfonsi: So these are full of hundreds of brains…

Dr. Ann McKee: Hundreds of brains, thousands really…

Researchers carefully dissect sections of the brain where they look for changes in the folds of the frontal lobes – an area responsible for memory, judgement, emotions, impulse control and personality.

Dr. Ann McKee: Do you see there’s a tiny little hole there? That is an abnormality. And it’s a clear abnormality.

Sharyn Alfonsi: And what would that affect?

Dr. Ann McKee: Well, it’s part of the memory circuit. You can see that clear hole there that shouldn’t be there. It’s connecting the important memory regions of the brain with other regions. So that is a sign of CTE.

Thin slivers of the affected areas are then stained and viewed microscopically. It’s in these final stages where a diagnosis becomes clear as in the case of Sgt. Kevin Ash.

Sharyn Alfonsi: So this is Sergeant Ash’s brain?

Dr. Ann McKee: Right. This is– four sections of his brain. And what you can see is– these lesions. The, and those lesions are CTE And they’re in very characteristic parts of the brain. They’re at the bottom of the crevice. That’s a unique feature of CTE.

Sharyn Alfonsi: And in a healthy brain, you wouldn’t see any of those kind of brown spots?

Dr. Ann McKee: No, no, it would be completely clear. And then when you look microscopically, you can see that the tau, which is staining brown and is inside nerve cells is surrounding these little vessels.

Sharyn Alfonsi: And explain, what is the tau?

Dr. Ann McKee: So tau is a protein that’s normally in the nerve cell. It helps with structure and after trauma, it starts clumping up as a toxin inside the nerve cell. And over time, and even years, gradually that nerve cell dies.

Dr. Lee Goldstein has been building on Dr. McKee’s work with testing on mice.

Inside his Boston University lab, Dr. Goldstein built a 27-foot blast tube where a mouse – and in this demonstration, a model – is exposed to an explosion equivalent to the IEDs used in Iraq and Afghanistan.

Dr. Lee Goldstein: When it reaches about 25 this thing is going to go.

Dr. Goldstein’s model shows what’s going on inside the brain during a blast. The brightly colored waves illustrate stress on the soft tissues of the brain as it ricochets back and forth within the skull.

Dr. Lee Goldstein: What we see after these blast exposures, the animals actually look fine. Which is shocking to us. So they come out of what is a near lethal blast exposure, just like our military service men and women do. And they appear to be fine. But what we know is that that brain is not the same after that exposure as it was microseconds before. And if there is a subsequent exposure, that change will be accelerated. And ultimately, this triggers a neurodegenerative disease. And, in fact, we can see that really after even one of these exposures.

Sharyn Alfonsi: The Department of Defense estimates hundreds of thousands of soldiers have experienced a blast like this. What does that tell you?

Dr. Lee Goldstein: This is a disease and a problem that we’re going to be dealing with for decades. And it’s a huge public health problem. It’s a huge problem for the Veterans Administration. It’s a huge moral responsibility for all of us.

A responsibility owed to soldiers like 34-year-old Sgt. Tom Bates.

Sgt. Tom Bates: We were struck with a large IED. It was a total devastation strike.

Bates miraculously walked away from a mangled humvee — one of four IED blasts he survived during deployments in Iraq and Afghanistan.

Sharyn Alfonsi: Do you remember feeling the impact in your body?

Sgt. Tom Bates: Yes. Yeah.

Sharyn Alfonsi: What does that feel like?

Sgt. Tom Bates: Just basically like getting hit by a train.

Sharyn Alfonsi: And you were put back on the frontlines.

Sgt. Tom Bates: Yes.

Sharyn Alfonsi: And that was it?

Sgt. Tom Bates: Uh-huh

When Bates returned home in 2009, his wife Libby immediately saw a dramatic change.

Libby Bates: I thought, “Something is not absolutely right here. Something’s going on. For him to just lay there and to sob and be so sad. You know, what do you do for that? How do I– how do I help him? He would look at me and say, “If it wasn’t for you, I would end it all right now.” You know, I mean, like, what do you– what do you do– and what do you say to somebody who says that? You know I love this man so much. And —

Sharyn Alfonsi: You’re going to the VA, you’re getting help, but did you feel like you weren’t getting answers?

Sgt. Tom Bates: Yes.

Sharyn Alfonsi: And so you took it into your own hands and started researching?

Sgt. Tom Bates: I knew the way everything had gone and how quick a lot of my neurological issues had progressed that something was wrong. And I just– I wanted answers for it.

That led him to New York’s Mount Sinai Hospital where neurologist Dr. Sam Gandy is trying to move beyond diagnosing CTE only in the dead by using scans that test for the disease in the living.

Dr. Sam Gandy: By having this during life, this now gives us for the first time the possibility of estimating the true prevalence of the disease. It’s important to estimate prevalence so that people can have some sense of what the risk is.

In the past year, 50 veterans and athletes have been tested for the disease here. Tom Bates asked to be a part of it.

That radioactive tracer – known as t807 – clings to those dead clusters of protein known as tau, which are typical markers of the disease.

Through the course of a 20 minute PET scan, high resolution images are taken of the brain and then combined with MRI results to get a 360 degree picture of whether there are potential signs of CTE.

Scan results confirmed what Tom and Libby had long suspected.

On the right, we see a normal brain scan with no signs of CTE next to Tom’s brain where tau deposits, possible markers of CTE, are bright orange.

Dr. Sam Gandy: Here these could be responsible for some of the anxiety and depression he’s suffered and we’re concerned it will progress.

Sgt. Tom Bates: My hope is that this study becomes more prominent, and gets to more veterans, and stuff like that so we can actually get, like, a reflection of what population might actually have this.

There is no cure for CTE.

Dr. Gandy hopes his trial will lead to drug therapies so he can offer some relief to patients like Tom.

Dr. Ann McKee believes some people may be at higher risk of getting the disease than others.

While examining NFL star Aaron Hernandez’s brain she identified a genetic bio-marker she believes may have predisposed him to CTE.

A discovery that could have far-reaching implications on the football field and battlefield.

Sharyn Alfonsi: Do you think you will ever be your old self again?

Sgt. Tom Bates: I don’t ever see me being my old self again. I think it’s just too far gone.

Sharyn Alfonsi: So what’s your hope then?

Sgt. Tom Bates: Just to not become worse than I am now.

Since our story first aired, over 100 veterans have contacted Dr. Gandy to enroll in ongoing trials to identify whether they are living with CTE. And more than 300 have reached out to Dr. Mckee about donating their brains to research.

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Ann C. McKee, chief of neuropathology at the VA Boston Healthcare System, which houses the world’s largest brain bank devoted to CTE research, examines a brain earlier this month.(Photo: Robert Deutsch, USA TODAY)

Researchers close in on CTE diagnosis in living, one brain at a time

By Nancy Armour, August 24, 2018, USA TODAY

BOSTON – Submerged in chemicals in the stainless-steel bowl is the key to life and, researchers hope, death.

It’s a human brain. That of a man who played college football in the 1950s, to be exact. His family donated his brain to get answers for themselves, but what’s found could lead to more answers about chronic traumatic encephalopathy, the devastating neurodegenerative disease linked to concussions and repetitive head trauma from football and other contact sports.

“Our main objective, our overarching goal, is to help the people who are living. To be able to diagnose this disease during life,” says Ann McKee, chief of neuropathology at the VA Boston Healthcare System, which houses the world’s largest brain bank devoted to CTE research.

“If we can diagnose it, we can monitor it and test therapies to see if they’re effective in treating this disease,” says McKee, director of the CTE Center at Boston University’s School of Medicine. “It would really dramatically increase our ability to point out genetic susceptibilities for this. We’d be able to look at how much is too much in certain individuals or certain positions in certain sports.”

As another football season begins, it inevitably leads to questions and fears about head trauma and its long-term damage. How many hits are too many? What can parents do to protect their children or players do to protect themselves? Are athletes in certain sports more susceptible?

Most important, which athletes will develop CTE – or Parkinson’s or ALS (amyotrophic lateral sclerosis) – and why?

The answers will come from brains such as the one McKee dissected this month, when USA TODAY Sports toured the brain bank.

The brain bank has more than 500 brains, most of them donated by former athletes or their families who suspected CTE because of mood swings, behavioral changes, depression or dementia. Of those brains, more than 360 had CTE, McKee says.

SEARCHING FOR CLUES

The arrival of a brain sets two teams in motion. One set of clinicians talks to the family to find out more about the donors. Did they play any sports? If so, what and for how long? When did they start? Did they experience any other kind of head trauma, say from an automobile accident, domestic violence or military service? Did they have drug or alcohol problems? How did their mental health change, and when did that occur?

Separately, and usually without any information about the person whose brain it was, McKee and her researchers study the brain. It is cut in half, and one half is stored in a minus-80-degree freezer, so it will be available for molecular, genetic and biochemical studies.

The other half is then photographed and sectioned. After removing the brain stem, McKee uses what looks like a bread knife to cut slices of the brain about a quarter-inch thick.


Ann C. McKee slices the brain into segments about a quarter-inch thick as part of in-depth, time consuming research on the organ. McKee hopes the work will unlock answers to CTE. (Photo: Robert Deutsch, USA TODAY)
 
Simply by looking at the brain, McKee can tell a few things. The brain of this man, who was in his 80s when he died, has shrunk, noticeably smaller than it should be for a man who once played football. The folds of the brain, normally pressed tightly against one another, are loose and have gaps between them, some large enough that the tip of a finger could be inserted.

She points to the ventricles, chambers in the middle of his brain that are filled with fluid during life. They should be small, but these are “just gigantic.”

“As the brain shrinks, they expand. What this indicates is there’s been enormous shrinkage of the brain,” McKee says. “Those are huge.”

The hippocampus, a section in the middle of the brain that controls memory, is small but not abnormally so for a man in his 80s. If it was, that could be an indication of Alzheimer’s. But a membrane that runs from one side of the brain to the other, normally thick like a rubber band, has shrunk. In some spots, it’s almost invisible.

“This is looking more like frontal predominant atrophy, and that could mean CTE because Alzheimer’s almost always affects the hippocampus,” McKee says. “At this point, I always want to know, ‘What is it? Let’s look under the microscope.’ But you have to wait.”

CTE can’t be seen by the naked eye, and it takes at least three weeks to prepare slides of the brain tissue.


 
CTE is caused by tau, a protein in the brain released as a result of head trauma. When tau clumps together, it damages brain cells and can change the brain’s function. Though tau causes Alzheimer’s, McKee says, the tau that causes CTE looks distinctly different.

Under a microscope, it can be seen in telltale brown spots.

“CTE is very focal. In fact, in its early stages, it’s in the crevices. It just piles up. And that’s around blood vessels,” McKee says. “That’s very different. Alzheimer’s never does that.”

As CTE progresses, those clusters or clumps of tau will spread, and the disease will become more severe. That’s why, in the early stages of disease, stages 1 and 2, the symptoms usually relate to behavioral changes or mood swings. In stages 3 and 4, the disease is exhibited in memory loss.

“We think there may be more pathology in the young players than we’re appreciating just with the tau protein,” McKee says. “We think there’s maybe white matter structural changes or maybe inflammatory changes that are responsible for that loss of control, which is so difficult for the individuals.”

‘EVERY CASE IS A MYSTERY’

Once the slides have been examined, the pathologists and clinicians will come together for a conference. At this point, neither knows what the other does. The clinicians detail what they’ve learned about the brain donor’s history and suggest a diagnosis. The pathologists will then say whether the brain tissue confirms it.

“Every case is a mystery,” McKee says. “It’s not the same way you usually solve a mystery. I solve the pathology first, and then you go back and find out (the history). And then you try and put the two together.”

Some former players and their families once were reluctant to donate their brains, but that stigma largely has disappeared. So much so that McKee said brains arrive at the Boston bank almost every day.

Though that lengthens the time it takes to reach a definitive diagnosis, it will shorten the time before a living diagnosis can be found. In addition to the work done in her lab, McKee shares tissue samples with researchers around the world.

“What we want to do is establish the risk, educate people, educate parents, educate players,” McKee says. “So if they’re unwilling to risk that future self, if they’re unwilling to take that risk because it’s too high for them personally, we want to give them enough data so they can make a very sound and wise decision.”

When that day comes, it will change sports forever.

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Traumatic brain injury causes widespread damage to neurons, leading to deficits in learning and memory. Cypin activators restore neuronal survival and function in mice, allowing for normal learning and memory. Credit: Mihir Patel/Rutgers University-New Brunswick

Traumatic brain injury: Discovery of two molecules could lead to new drug treatments

By Todd B. Bates, July 27, 2018, Rutgers University

After 10 years of research, a Rutgers-led team of scientists has identified two molecules that protect nerve cells after a traumatic brain injury and could lead to new drug treatments.

The molecules promote full recovery after traumatic brain injury (TBI) in mice, according to the study published online in Neurobiology of Disease. Traumatic brain injury is the leading cause of death for people under 45 years old in the United States and is associated with disability, early-onset dementia, cognitive disorders, mental illness and epilepsy.

Nearly all approaches for treating TBI focus on trying to prevent neurons, or nerve cells, from degenerating or on attempting to promote their survival, the study notes. TBI typically alters neural circuits within injured brain regions.

“The big issue with treatment after TBI is that there are no drugs that work well on patients to restore memory, and we’re targeting reconnectivity of neural circuitry,” said Bonnie L. Firestein, senior author of the study and a professor in the Department of Cell Biology and Neuroscience at Rutgers University-New Brunswick. “That means we want our neurons to function properly and connect with other neurons. We want to allow people to retain their cognition and ability to remember and learn, so our angle is novel.”

The researchers studied the protein cypin, an enzyme that breaks down guanine, which is an important building block for DNA and RNA in cells. The scientists previously showed that cypin is involved in promoting the proper shape in neurons and “keeping them happy,” Firestein said. This study found that speeding the breakdown of guanine protects neurons from injury and retains brain functioning.

Scientists at Rutgers-New Brunswick, University of Pennsylvania, Fox Chase Chemical Diversity Center Inc. and Columbia University want to develop drugs from the molecules for further studies.

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CARSON, CA – AUGUST 03: Bronze medal winner Dave Mirra speaks in a press conference after the Rally Car race during the summer X Games 14 at Home Depot Center on August 3, 2008 in Carson, California. (Photo by Christian Petersen/Getty Images)

Months after committing suicide, Dave Mirra has become the first action sports athlete to be diagnosed with CTE

by Robert Silverman, vocativ.com (May 24, 2016)
 
After BMX biking legend Dave Mirra committed suicide on February 4 of this year, his wife had his brain tested for chronic traumatic encephalopathy. Sadly, the result came back positive, rife with tau proteins dotting both his temporal and frontal lobes after years of enduring an unknown amount of concussive and sub-concussive trauma. This makes Mirra the first action sports athlete to be diagnosed with CTE.

The neuropathologist went so far as to equate the condition of his brain to that of NFL players and other contact sport athletes that have been posthumously diagnosed with the disease. “I couldn’t tell the difference,” Dr. Lili-Naz Hazrati said.

In an exclusive interview with ESPN: The Magazine, Mirra’s wife Lauren describes the agonizing final weeks of his life, the transformation of his formerly vibrant personality into something different and darker, prone to wild mood swings and unprovoked crying jags or bouts of exhaustion, his mind clouded and wracked with depression.

“I remember seeing him sitting on our bed one day, in the last month of his life,” she said. “I had just gotten out of the shower and saw him hunched over with the blankest lost look. I sat down next to him and held his hand. I said, ‘What is wrong? Are you OK?’ And he just shrugged his shoulders. He couldn’t even speak. He didn’t know. He couldn’t put it into words. He was lost. He was helpless. It was completely different from who he was.”

“He was gone. I could see straight through him,” she continued. “It was the hardest thing to see, looking at someone you love, and you can’t have a conversation with them, and you can see straight through their eyes.”

Lauren Mirra doesn’t know what her exact plans might be for the future, but her overarching hope is that she’ll be able to find a forum in which to speak out, to encourage best practices and prevention measures, without coming across as an ideologue out to ban action sports altogether.

“Through him we have an opportunity to help and change,” she said. “Beauty from ashes. That’s how I will always choose to see it.”

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The Cohen family partners with USC to serve families in Los Angeles.
 
by Lynn Lipinski, tfm.USC.edu (Autumn 2016) — PEACE AFTER WAR can be elusive for combat veterans who fight painful memories long after they’ve left the battlefield. Of the more than 2.6 million men and women who have served in the U.S. military since 9/11, about 20 percent experience some form of post-traumatic stress or brain injury—but nearly half forego treatment, according to the Cohen Veterans Network.

The Steven A. Cohen Military Family Clinic at USC, made possible by a $15.7 million gift from Steven Cohen and the Cohen Veterans Network, offers veterans and their family members free outpatient mental health services and case management. Recently opened in downtown Los Angeles, the Cohen Military Family Clinic at USC is part of a national network of clinics serving veterans and is a collaboration between the USC School of Social Work and the Keck School of Medicine of USC.

Providers will also be stationed at locations throughout the county in areas that otherwise lack these types of services. The clinic will also serve veterans who are ineligible for Veterans’ Admnistration benefits, such as those who served in the National Guard or the Reserves.

“The wounds of war are serious. It is not easy to serve your country in combat overseas and then come back into society seamlessly, especially if you are suffering,” says Cohen, chairman and CEO of Point72 Asset Management. “Veterans have paid an incredible price. It’s important that this country pays back that debt.”

The Cohen Veterans Network plans to create a system of about two dozen centers across the country by 2020 as part of a $275 million initiative to improve access to behavioral health care for recent veterans. Cohen’s support of services for veterans began in part because of a personal connection: His son, Robert, deployed to Afghanistan with the Marines and is currently in the Reserves.

USC’s strong programs for veterans made it a natural fit to host the clinic. The USC School of Social Work is home to the Center for Innovation and Research on Veterans and Military Families, where researchers conducted the first comprehensive study of veterans in L.A. County. Their findings are already helping to create effective services for veterans. The school has also earned national recognition for its pioneering master’s degree in military social work—the only program of its kind offered by a civilian research university.

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