Report on the Neuropathology of Chronic Traumatic Encephalopathy Workshop
December 5-6, 2012
National Institutes of Health, Bethesda, Maryland
Sports and Health Research Program
What do we know about the neuropathology of CTE?
In 1928, it was recognized that boxers with repetitive head injury developed dementia due to a unique brain degeneration characterized by neurons filled with tangles of a protein called tau as well as widespread loss of brain cells. More recently this disorder, initially termed “dementia pugilistica”, has occurred in non-boxers exposed to varying degrees of repetitive head injury. Chronic traumatic encephalopathy (CTE) is the term currently used to describe this condition. CTE can only be confirmed by pathologic examination of brains from individuals who have died. Ann McKee, M.D., Co-Director of the Center for the Study of Traumatic Encephalopathy at Boston University School of Medicine, autopsied the brains of 85 men with a history of repetitive mild traumatic brain injury (Brain 2012; doi: 10.1093/brain/aws307). Her group described a spectrum of abnormalities in these brains, with the signature finding being the deposition of tau in neurons. Abnormal tau accumulation has been identified in brain tissue in several other neurodegenerative diseases, including Alzheimer’s disease. Dr. Dickson noted that none of the individual pathologic features (such as tau pathology) are unique to CTE, but what confers uniqueness is their peculiar distribution within the brain. Dr. McKee proposed four clinically distinct stages of CTE pathology based on the location, pattern and extent of tau accumulation. Advanced stages of the brain pathology were generally observed in older individuals with a history of a progressive dementia and brain atrophy. In the more mildly affected brains, tau pathology was clustered around small blood vessels in the depths of the brain’s folds (sulci) and in the brain’s superficial layers and atrophy was absent.
The symptoms of CTE appear to fall into at least two clearly distinguishable patterns, according to Robert Stern, Ph.D., Co-Director of the Center for the Study of Traumatic Encephalopathy at Boston University School of Medicine. His study found that younger people (ages 20-40) tended to have a rapid course of disease progression primarily involving behavioral and mood changes, whereas older people (ages 50-70) had a slower course of disease progression involving primarily cognitive difficulties leading to dementia. This raises the question as to whether there are two distinct pathological processes or a single process whose expression changes over time.
There also was discussion of brain alterations that occur over many years in persons who suffered a single, severe TBI. Postmortem brain studies in such individuals who survive for years after the injury suggest that pathological processes, including tau accumulation, continue long after the injury itself, according to William Stewart, Ph.D., Neuropathologist for the National Health Service of Greater Glasgow and Clyde.
What neuroimaging tools and biomarkers show promise in diagnosing CTE?
A major focus of the conference was how the pathological features of CTE identified at autopsy could be correlated with imaging studies of autopsied brains. If correlations could be determined, the neuroimaging techniques could then be tested for their ability to diagnose CTE in living persons. Diffusion tensor imaging (DTI), a type of magnetic resonance imaging (MRI) that reveals white matter tracts, shows promise for detecting CTE. Substantial technological improvements are needed before DTI is ready for routine clinical use, according to David Brody, M.D., Ph.D., Associate Professor of Neurology at Washington University School of Medicine. MRI studies also are complicated by the enormous amount of data collected, said Susumu Mori, Ph.D., Assistant Professor at Johns Hopkins University School of Medicine. Before DTI and other MRI techniques are applicable for assessing CTE in a living person, their accuracy and precision need to improve. Positron emission tomography, or PET scanning, is another imaging tool that shows promise for detecting CTE. PET scanning can map the location of particular molecules in the brain. Novel PET markers now are being validated to detect tau abnormalities associated with neurodegenerative disease, according to Hartmuth Kolb, Ph.D., Vice President of Biomarker Research at Siemens Healthcare. A PET marker that identifies the tau pathology of CTE in living individuals would constitute a major breakthrough in the field.
Who is at risk and what are the symptoms?
Currently a definitive diagnosis of CTE is only possible after death and the brains studied to date come from a highly selected population of mostly professional athletes. As a result, no data indicating the frequency of CTE are available. Similarly, we do not understand which individuals with multiple impacts to the head, as those that occur commonly in children and adults engaged in contact sports, are at risk for CTE. Athletes playing competitive football over the course of high school and college, for example, are estimated to suffer upwards of 8,000 hits to the head according to Thomas McAllister, M.D., Vice Chair for Neuroscience Research at the Geisel School of Medicine at Dartmouth. To gain a better understanding of the relationship between the number and intensity of these hits on brain function, Dr. McAllister’s research team placed force-sensors inside the helmets of college football players. They discovered that while some athletes develop concussions following very low-impact hits, others do not, even after sustaining harder hits. They also discovered that as a group the players were not found to have cognitive differences before and after one football season.