Neuropathological and Clinical Consequences of Repetitive Concussion in Athletes.

Principle Investigators: Ann C. McKee, M.D. and Robert A. Stern, Ph.D.

Institution: Trustees of Boston University, BUMC

Title: Neuropathological and Clinical Consequences of Repetitive Concussion in Athletes

The profoundly destructive effects of repetitive concussion on athletes are becoming increasingly recognized. Although chronic traumatic encephalopathy (CTE; dementia pugilistica) has been known to affect boxers since the 1920’s, there have been several reports of CTE occurring in retired professional football players and a professional wrestler. A wide variety of sports and sports-related activities are associated with repetitive concussion, including football, boxing, wrestling, rugby, hockey, lacrosse, soccer, horse-riding, karate and skiing, suggesting that with increased surveillance and recognition, a wider scope of athletes is likely involved.  Repetitive concussion triggers a progressive neurodegeneration clinically associated with the development of memory loss, confusion, impaired judgment, paranoid and aggressive behavior, dementia and parkinsonism. Neuropathologically, repetitive concussion produces striking changes of cortical atrophy, ventricular dilation, cavum septi pellucidii, and microscopic evidence of severe neuronal loss with dense tau immunoreactive neurofibrillary degeneration. These devastating neurodegenerative effects are found throughout the cerebral hemispheres, medial temporal lobe, subcortical white matter, diencephalon, brainstem, cerebellum, and spinal cord. Our own observations on the brains of two retired boxers and a retired professional football player have demonstrated that these changes are neuropathologically distinctive from other conditions. Although CTE shares many features of other neurodegenerative conditions, such as Alzheimer’s disease and progressive supranuclear palsy, the tau immunoreactive neurofibrillary degeneration associated with repetitive sublethal concussion is unique. Furthermore, what is perhaps most disturbing about CTE is that the clinical effects are substantially delayed. The progressive neurodegeneration set off by concussive events suffered during an individuals late teens and early twenties usually does not become clinically apparent until decades after the individual has retired from the sport. Most often, it is not until the retired athlete reaches his mid-40’s that family members notice unpredictable behavioral and personality changes, aggressive tendencies, depression, memory loss and confusion. Clearly, there is an immediate need to expand our knowledge of the effects of repetitive concussion on athletes, by

  1. analyzing the brains of athletes that come to autopsy and
  2. providing a sophisticated longitudinal surveillance system to access subtle neuropsychological, behavioral, and biomarker alterations in athletes.

Only with improved awareness of this vastly under-recognized condition and enhanced knowledge of its ultimate effects on the brain, can we hope to develop and utilize headgear to prevent its development and therapies to arrest or reverse its progression once established.

Specific Aim 1a:
To create the infrastructure, procedures, and necessary materials to establish an outreach/recruitment program and brain donation registry for living athletes (active and retired) who wish to donate brain tissue after death. The Registry will be modeled after the Patient/Control Registry of the Boston University of Alzheimer’s Disease Center (BUADC), but will involve a national recruitment and outreach program.

Specific Aim 1b:
To collect preliminary data on the neuropsychological, neurological, neuropsychiatric, and genetic characteristics of retired athletes with and without histories of concussion. In addition, cerebrospinal fluid (CSF) will be collected for analyses of various biomarkers, and structural brain MRI’s will be conducted.

Specific Aim 2a:
To determine the neuropathological characteristics of CTE in athletes and compare the severity of the neuropathological changes to the number of years of participation in different sports and history of concussion.

Specific Aim 2b:
To develop and coordinate a brain bank of tissue harvested from donors in the registry, as well as from donors whose families agree to brain donation after death in cases where the athlete was not part of the registry. The brain bank will build on the resources and 12 years of experience acquired from directing the brain banks for the BUADC and Framingham Heart Study.

Specific Aim 3:
To determine the clinico-pathological correlations of CTE by comparing post-mortem “cognitive/psychiatric” autopsies and concussion histories of athletes with the severity and distribution of the neuropathological findings.