Brain autopsies of four former football players reveal not all get chronic traumatic encephalopathy

ScienceDaily (July 26, 2011) — Preliminary results from the first four brains donated to the Canadian Sports Concussion Project at the Krembil Neuroscience Centre, TorontoWesternHospital, reveal that two of the four former Canadian Football League (CFL) players suffered from a brain disease known as Chronic Traumatic Encephalopathy (CTE), while two did not show signs of CTE.See Also:Health & MedicineChronic IllnessHealthy AgingDiseases and ConditionsMind & BrainBrain InjuryDisorders and SyndromesIntelligenceReferenceDementia with Lewy bodiesDementiaHead injuryNeurology

Bobby Kuntz, a former Toronto Argonaut and Hamilton Tiger-Cat and Jay Roberts, an Ottawa Roughrider both had a history of repeated concussions during their careers and showed the characteristic signs of CTE, an abnormal build-up of a protein called Tau in the brain, and other degenerative changes.

CTE can result in memory impairment, emotional instability, erratic behavior, depression, and problems with impulse control. CTE may eventually progress to full-blown dementia. Dr. Hazrati is very clear, however, to emphasize that the precise relationship between concussions and neurodegeneration remains to be demonstrated by future research.

Peter Ribbins, a former Winnipeg Blue Bomber, passed away in December 2010, at age 63 of Parkinson's disease. Autopsy results show he did not have signs of CTE. Tony Proudfoot, anall-star defensive back for the Montreal Alouettes, died at age 61 in 2011 of Lou Gehrig's disease (a neurodegenerative condition also known as ALS). Although a connection between ALS and repeated head trauma is being researched, Proudfoot did not have signs of CTE. Both of these players were in the league at a time when it was common to spear tackle with the crown of the head. According to the Canadian Football League Alumni Association (CFLAA), Proudfoot experienced repeated head trauma as a hard-hitting defensive back throughout his 12 seasons in the league.

Kuntz passed away in February 2011 at age 79 after a long battle with Parkinson's Disease and diffuse Lewy body disease, a condition that overlaps with Parkinson's and Alzheimer's. Roberts, 67, who died in October 2010, suffered from dementia and lung cancer. The autopsies were performed by Dr. Lili-Naz Hazrati, a neuropathologist in the Laboratory Medicine Program at the University Health Network.

"While both of these men appeared to have pathological signs of CTE, they also suffered from other serious neurological and vascular related diseases," said Dr. Hazrati. "Right now we have more questions than answers about the relationship between repeated concussions and late brain degeneration. For example, we are still trying to understand why these two players acquired CTE and the other two did not."

Mary Kuntz, wife of the late Bobby Kuntz, donated his brain to the Canadian Sports Concussion Project at the Krembil Neuroscience Centre and believes the more players who donate their brains, the better the chances of helping future athletes.

"We've always had questions about Bob's health, because there were so many conflicting medical opinions," said Mary Kuntz. "We knew there must have been some effect from all of the concussions over the years, and this was an affirmation that concussions did have a part in his health problems.

"Young players should know the risks of concussions. When you are young, you can't believe what can happen to you when you are older, but we have lived though it. What is good about this study is that there will be more evidence and information for players."

"We were very happy to be involved in this and it has brought us a sense of closure."

The Canadian Sports Concussion Project at the Krembil Neuroscience Centre is organized by a team of concussion experts including Dr. Charles Tator and Dr. Richard Wennberg and scientists from several other Canadian institutions. The focus of the project is to further our understanding of how concussions affect the brain.

"There are still so many unanswered questions surrounding concussion and the long-term consequences of repeated head injuries," said Dr. Tator. "We are trying to determine why some athletes in contact sports develop CTE and others don't, as well as how many concussions lead to the onset of this degenerative brain disease. Also, we need to develop tests to detect this condition at an early stage and to discover treatments."

According to Jed Roberts, son of Jay Roberts, he and his sisters began noticing early signs of their father's memory decline when he starting repeating stories, but insisting he had never told them. "My dad had numerous concussions, although they were undocumented, and I think he knew there was something was wrong, which is why he wanted to help find answers that would hopefully protect future football players," said Jed, a former CFL player with the Edmonton Eskimos. "I think it is really important that we create awareness around this issue, so that players can live healthy, productive lives beyond the game."

Leo Ezerins, former CFL player and current Executive Director of the CFLAA is a member of the Project Team. It has been through the joint efforts of the CFLAA and the research team that these four donations were made possible.

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Bioengineers identify the cellular mechanisms of traumatic brain injury; New hope for treatment of TBI in veterans wounded by explosions

ScienceDaily (July 22, 2011) — Bioengineers at Harvard have identified, for the very first time, the mechanism for diffuse axonal injury and explained why cerebral vasospasm is more common in blast-induced brain injuries than in brain injuries typically suffered by civilians.See Also:Health & MedicineNervous SystemBrain TumorPsychology ResearchMind & BrainBrain InjuryNeuroscienceDisorders and SyndromesReferenceCerebral contusionHead injuryBrain damageTraumatic brain injury

The research addresses two major aspects of traumatic brain injury (TBI), with significant implications for the medical treatment of soldiers wounded by explosions.

Two papers, published in the journals Proceedings of the National Academy of Sciences (PNAS) and PLoS ONE, provide the most comprehensive explanation to date of how mechanical forces can be translated into subtly disastrous physiological changes within the brain's neurons and vasculature.

"These results have been a long time coming," says principal investigator Kevin Kit Parker, a Professor of Bioengineering at Harvard's School of Engineering and Applied Sciences (SEAS) and a major in the U.S. Army. "So many young men and women are returning from military service with brain injuries, and we just don't know how to help them."

When the brain encounters a jarring force, such as an exploding roadside bomb, the delicate tissue slams against the skull. The result, if the patient survives, can be a temporary concussion, a more dangerous hemorrhage, or long-term TBI, which can even lead to the early onset of Parkinson's or Alzheimer's diseases.

Inspired by Parker's own military experience, the Disease Biophysics Group (based at SEAS and at the Wyss Institute for Biologically Inspired Engineering at Harvard) has taken up the cause. Using cutting-edge tissue engineering techniques -- essentially creating a living brain on a chip -- biologists, physicists, engineers, and materials scientists collaborate to study brain injury and potential targets for treatment.

Now, researchers in his group have identified the cellular mechanism that initiates diffuse axonal injury, offering urgently needed direction for research in therapeutic treatments.

Their studies show that integrins, receptor proteins embedded in the cell membrane, provide the crucial link between external forces and internal physiological changes.

Integrins connect the structural components within the cell (such as actin and other cytoskeletal proteins) with the extracellular matrix that binds cells together into tissue. Collectively, this network of structural and signaling components is referred to as the focal adhesion complex.

Parker's research has demonstrated that the forces unleashed by an explosion physically disrupt the structure of the focal adhesion complex, setting off a chain reaction of destructive molecular signals within the nerve cells of the brain.

Inside the neuron, integrins normally mediate the activation of the proteins RhoA and Rho kinase (ROCK). When the focal adhesion complex is disturbed, the Rho-ROCK signaling pathway goes haywire: it directs the motor protein actin to retract the cell's arm-like axons, disconnecting the neurons from each other and collapsing the cellular networks that constitute the brain.

"Our research has shown that abrupt mechanical forces, such as those from a blast wave and transduced by integrins, can result in neural injury," says Matthew A. Hemphill, who with Borna Dabiri (S.B. '07) and Sylvain Gabriele, is a lead author of the paper in PLoS One. Dabiri and Hemphill are currently graduate students at SEAS, and Gabriele is a former postdoctoral fellow in Parker's lab.

Adds Dabiri: "Encouragingly, we also found that treating the neural tissue with HA-1077, which is a ROCK inhibitor, within the first 10 minutes of injury, reduced the number of focal swellings. We think that further study of ROCK inhibition could lead to viable treatments within the near future."

A second direction of research in Parker's lab has solved another mystery in TBI, explaining why cerebral vasospasm, a dangerous remodeling of the brain's blood vessels, occurs more commonly in TBI caused by explosions than in other types of brain trauma.

"Until now, other researchers looking at TBI focused on ion channels and membrane poration, and it was generally accepted that cerebralvasospasm was only caused by hemorrhaging. It turns out that it's much morecomplicated than that," says Patrick W. Alford, a former postdoctoral fellow in Parker's lab and lead author of the paper in PNAS. "Integrins and Rho-ROCK signaling appear to be players in both diffuse axonal injury and cerebral vasospasm."

As reported in PNAS, the forces exerted on arteries are different during an explosive blast than during blunt force trauma. Subarachnoid hemorrhage, which can occur in very severe head injuries, is known to cause vasospasm, but Parker's new research shows that the unique force of an explosion can also cause vasospasm by itself.

The blast from an explosion creates a surge in blood pressure, which stretches the walls of the blood vessels in the brain. To study this, Parker's team of bioengineers built artificial arteries, made of living vascular cells, and used a specialized machine to rapidly stretch them, simulating an explosion. While this stretching did not overtly damage the cellular structure, it did cause an immediate hypersensitivity to the protein endothelin-1.

Endothelin-1 is known to stimulate vascular cells to absorb calcium ions, which affect actin -- the same protein involved in the retraction of axons.

In the 24 hours following the simulated blast, the vascular tissues hypercontract and undergo a complete phenotypic switch, disrupting the overall function of the tissue. Both of these behaviors are characteristic of cerebral vasospasm.

Most importantly, as in the neural tissue, the Rho-ROCK signaling pathway plays an important role in the behavior of actin and the cells' contraction. Parker's team found that inhibition of Rho soon after the injury can mitigate the harmful effects of the blast on the brain's vascular system.

"We have established a toe-hold as we try to climb up on top of this problem," says Parker. "In many ways, this work is just the beginning."

Parker's coauthors on the paper in PLoS One are Hemphill, currently at the University of Mons in Belgium; Dabiri, who beganworking in Parker's lab as an undergraduate; Gabriele, who is now at the University of Mons; Lucas Kerscher, a visiting student; Christian Franck, formerly a postdoctoral fellow at SEAS and now at Brown University; Josue A. Goss, a staff engineer at SEAS; and Alford, who is now at the University ofMinnesota.

Parker's coauthors on the paper in PNAS are Alford; Dabiri; Goss; Hemphill; and Mark D. Brigham, a graduate student at SEAS.

The Disease Biophysics Group received financial support from the Defense Advanced Research Projects Agency (DARPA) Preventing Violent Explosive Neurologic Trauma (PREVENT) Program, the Department of Defense, and the Harvard School of Engineering and Applied Sciences (SEAS).

The researchers also gratefully acknowledge the use of facilities at the Harvard Center for Nanoscale Systems, a member of the National Nanotechnology Infrastructure Network (NNIN), which is funded by the National Science Foundation (NSF).

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