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Report on the Brain Trauma-Related Neurodegeneration: Strategies to Define, Detect, and Predict Workshop

Report on the Brain Trauma-Related Neurodegeneration: Strategies to Define, Detect, and Predict Workshop
July 22-23, 2013
National Institutes of Health, Bethesda, Maryland
Sports and Health Research Program

The Brain Trauma-Related Neurodegeneration: Strategies to Define, Detect, and Predict Workshop was hosted by the Foundation for the National Institutes of Health (FNIH) as part of the Sports and Health Research Program in partnership with the NIH and the National Football League (NFL).  Approximately 70 scientists, clinicians, and government officials convened July 22-23, 2013 in Bethesda, Maryland to discuss strategies and next steps for future research aimed at better understanding the relationship between brain trauma and progressive neurodegeneration.  Building on the concepts developed at the Neuropathology of Chronic Traumatic Encephalopathy Workshop held in December 2012, sessions focused on the scientific questions in the field, studies that are currently underway, critical tools and resources, and elements of study design.

Traumatic brain injury (TBI) and repetitive subconcussive blows have been linked to delayed changes in cognition and behavior as well as to long-term neurodegeneration, including chronic traumatic encephalopathy (CTE).  However, the clinical manifestations of these progressive brain changes are not well characterized, and diagnostic criteria are lacking.  A key theme of the workshop was to identify the critical scientific questions important for understanding the delayed effects of head trauma. 

Suggestions from participants included:

  • Among those exposed to head impacts, who is at risk to develop brain trauma-related neurodegeneration?  What are the risk factors that determine symptom onset and progression?  How does brain trauma exposure “load” correlate with neurodegeneration?
  • What is the incidence and prevalence of progressive neurological impairment after brain trauma? 
  • By what mechanism does brain trauma cause degeneration?  What biomarkers indicate progression?  Is there a mechanistic link between acute recovery and delayed outcomes?
  • What is the clinical presentation of CTE and how can it be diagnosed in a living person?  What distinguishes CTE from other neurodegenerative diseases?  
  • How can the chronic effects of trauma be prevented or treated?

Identifying feasible strategies to answer these questions was another major theme of the workshop.  The group agreed that clinical studies are essential to define, detect, and predict delayed outcomes of head trauma.  Some scientists advocated for a large prospective study of many individuals over many years – a powerful approach that would identify the population incidence and prevalence of neurological deficits caused by brain trauma.  Alternatively, a subpopulation of individuals with significant brain trauma exposure could be studied beginning in mid- or late-life.  This approach would accelerate knowledge about the effects of brain trauma on neurological impairment, and neurodegeneration findings later in life. Imaging technique validation and biomarker identification would also be enriched by a study of an at-risk population.  A major challenge would be to control for the variability among individuals in terms of their propensity to develop neurodegenerative disease after head trauma.  Some of this variation may be a function of genetic endowment, age, overall health or other factors, of which the impact on outcome is not well understood.  Another challenge would be estimating brain trauma exposure retrospectively, as concussive and subconcussive impacts vary substantially even in relatively homogenous populations.  In addition, self-reported data obtained from patients about their history of concussions may not be accurate.  A number of panelists also highlighted the importance of relevant control groups for all study designs.  Some suggested control groups included uninjured siblings of athletes (to parse out the injury effect from genetic effects) and uninjured soldiers or athletes (to control for psychological effects related to participation in the military or sports).

A discussion of tools and resources important for study of head trauma highlighted the advantages of standardized data collection and data sharing, which will allow researchers to replicate and validate results, as well as encourage collaboration.  Lessons from established data sharing projects, such as the Alzheimer’s Disease Neuroimaging Initiative (which was launched 10 years ago), suggest that inclusiveness is essential for building research capacity and that an open-source research model – despite its challenges – dramatically accelerates the progress of research.  Discussion also focused on lessons learned and resources available from ongoing natural history studies that are being conducted at NIH, as well as studies conducted by the Department of Veterans Affairs and the Walter Reed Defense and Veterans Brain Injury Center on targeted populations of people who have suffered head injuries during military service.

Exciting advances in imaging techniques and the importance of quantitative measures for both acute exposure and chronic neurological impairment were also presented.  There was considerable excitement that positron emission tomography (PET) tracers to detect aggregates of the tau protein may soon be available for studies of individuals suspected of having CTE.  Although neuropathological changes, including tau deposits, have been confirmed in athletes after death, there is some evidence that neurobehavioral measures show a dose response to head trauma.  During the discussion, the importance of conducting dose-response studies was emphasized.  These studies may help establish a link between the number and the intensity of impacts — the “dose” of injury — and severity of neurodegenerative changes.  Validated sensors, such as helmet-based systems, may be useful to measure the magnitude of impact.

To establish an in vivo diagnosis, additional neuropsychological measures, fluid biomarkers, and imaging strategies are needed to distinguish between the effects of normal aging and trauma-related outcomes.  Many workshop participants highlighted the expediency of this problem.   Answers are needed to inform us about the long-term health consequences of both multiple subconcussive impacts and more severe single TBIs that occur in contact sports, military service, and daily life. 

Last Modified August 5, 2013