PHILADELPHIA - An international team of investigators led by experts at the Perelman School of Medicine at the University of Pennsylvania has been awarded a nearly $3 million, five-year grant from the National Institute of Neurological Disorders and Stroke (NINDS) to establish diagnostic criteria for chronic traumatic encephalopathy (CTE).
The Penn-led team will search for common pathological changes in the post-mortem brains of over 200 patients with a history of traumatic brain injury and for comparison, over 1,500 postmortem brains from patients with other neurodegenerative diseases who were followed over time as part of other NIH funded grants at Penn. Research activities will include identifying proteins that show evidence of neurodegenerative damage; documenting gross anatomical changes such as brain atrophy; and uncovering underlying biochemical and genetic alterations.
“We want to see which pathological changes consistently occur in CTE and assess whether they are similar to or different than those in other major neurodegenerative diseases,” said co-lead researcher Douglas Smith, MD, the Robert A. Groff Professor of Teaching and Research in Neurosurgery at Penn and director of the Penn Center for Brain Injury and Repair.
CTE is a progressive neurodegenerative disease that afflicts the brains of people who have primarily suffered repeated concussions, such as athletes who take part in contact sports, and in some individuals with a history of a single severe traumatic brain injury. Symptoms of CTE are comparable to other neurodegenerative conditions such as Alzheimer’s disease and include memory loss, confusion, depression and difficulty paying attention and organizing thoughts. However, it remains unknown how the neuropathological changes associated with CTE affect these symptoms. In addition, an authoritative diagnosis of CTE can only be made after death, when an autopsy can determine whether brain changes currently tied to CTE are present.
“Despite strong current interest in CTE, there have been surprisingly few cases reported and there are no validated neuropathological diagnostic criteria to define it as a distinct disease,” Smith said. “Nonetheless, there is a widely held, but to date unsupported, perception that repetitive traumatic brain injury alone culminates in CTE.”
While generally known for decades in the scientific literature as “dementia pugilistica” (or "punch-drunk syndrome") in boxers and later renamed chronic traumatic encephalopathy, the condition has recently reached wider public awareness from studies of retired living athletes said to have CTE, or a small number of postmortem brain studies of deceased athletes.
“In some parts of the CTE-affected brain there is a build-up of tau protein, which normally stabilizes cellular structure in the neurons. But when tangled and twisted, this can cause major malfunctioning of the neurons,” said co-lead researcher John Q. Trojanowski, MD, PhD, William Maul Measey-Truman G. Schnabel, Jr., MD Professor of Geriatric Medicine and Gerontology in the department of Pathology and Laboratory Medicine and director of Penn’s Institute on Aging as well as the NIH funded Alzheimer’s Center. These same tau “tangles” are the hallmark brain lesions implicated in Alzheimer’s disease. “Several other neuropathological features have been described for CTE in addition to tau pathologies, but the scientific community is searching for a better understanding of their prevalence.”
These include brain atrophy, occurrence of beta-amyloid, another protein found in Alzheimer’s patients; pathologies of the TDP-43 protein (which have been found in 97 percent of people with amyotrophic lateral sclerosis or “Lou Gehrig’s disease”); and neuroinflammation. “As traumatic brain injury-associated neurodegeneration has become a major health concern, there is a clear need to develop verifiable neuropathological criteria for diagnosis, which will in turn be crucial to the success of future diagnostic tests and possible screening and treatment efforts,” Trojanowski said.
In addition to an absence of validated clinical or neuropathological diagnostic criteria for CTE, it is not known how its associated neurodegeneration occurs. “Therefore,” said Smith, “we want to outline a potential mechanistic basis of traumatic brain injury-induced neurodegeneration by examining the temporal course and potential contribution of inflammatory changes following traumatic brain injury.”
The Penn-led team comprises international, multidisciplinary experts with extensive experience in studying long-term neurodegeneration after traumatic brain injury and assessing common neuropathological diseases such as Alzheimer’s. The researchers have access to the only comprehensive brain archives in the U.S. and UK that include both single and repetitive traumatic-injury brain samples, as well as approximately 1,500 longitudinally-followed and extensively characterized autopsy-confirmed brains of patients with Alzheimer’s and related disorders for comparison in the Penn Brain Bank.
In addition to Smith and Trojanowski, Penn team members include M. Sean Grady, MD and Victoria Johnson, MBChB, PhD (Neurosurgery) and Virginia Man-Yee Lee, PhD; Eddie Lee, MD, PhD; and Vivianna Van Deerlin MD, PhD (Pathology and Laboratory Medicine). They are joined by neuropathology experts at the University of Washington (Seattle) and Baylor College of Medicine (Houston). William Stewart at the University of Glasgow and adjunct associate professor of Neurosurgery at Penn, will oversee the UK arm of the program, which also includes investigators at the Imperial College London.
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