Increased neurodegenerative pathology associated with chronic traumatic encephalopathy severity

1. In this retrospective study of post-mortem tissue from former American football players, pathological markers of neurodegeneration were frequent in both mild and severe chronic traumatic encephalopathy (CTE) cases but not in those without symptomatic CTE.

2. Increased distributions and quantities of neuropathological markers were associated with increasing CTE severity and broader symptoms.

Evidence Rating Level: 3 (Average)

Study Rundown: Repeated mild traumatic brain injury often leads to a heterogeneous disorder known as chronic traumatic encephalopathy (CTE), typified by a progressive neurodegenerative disease affecting mood, cognition, and motor deficits. In particular, professional American football players are at very high risk of developing this disease, though little is known about the underlying neuropathological mechanisms. In this retrospective study of post-mortem tissue from former American football players, common neuropathological markers of neurodegenerative disease, such as a p-tau, pTDP43, a-synuclein, and amyloid-b aggregations, were highly prevalent and increased with CTE severity. The distribution of these markers in mild CTE were mostly restricted to select cortical areas whereas those with more severe CTE demonstrated multiple cortical and subcortical areas of pathology. Of the 17% of post-mortem tissues without CTE, neuropathology was rare and generally non-specific, and most of these tissues were derived from players who did not reach the professional level. Retrospective, secondary clinical information from standardized informant reports suggest that all CTE cases determined pathologically resulted in mood or cognitive symptoms regardless of disease severity. Motor impairment was apparent in over half of severe CTE patients, and development of both mood and cognitive symptoms was typical as the disease progressed. The most common primary cause of death was neurodegeneration in this cohort.

Though this study suggests a high degree of specific neuropathologies in CTE cases, numerous limitations should be noted. First, lack of a standardized control cohorts makes interpreting the degree neuropathology difficult, and few conclusions should be drawn about impact of these biomarkers on CTE symptoms. Second, the degree of head-trauma could not be calculated, though time spent playing football generally correlated with disease severity, though no strictly quantitative measure was reported. Third, as clinical reports were given second hand, the reliability of these reports is unlikely to be as strong and may overestimate the development of certain symptoms. As this project continues to collect tissue, it will be important to note future results from more controlled studies.

Click to read the study, published in JAMA

Relevant Reading: The spectrum of disease in chronic traumatic encephalopathy

In-Depth [retrospective cohort]: 202 former American football players donated post-mortem tissue to the Concussion Legacy Foundation (CLF) and clinical data from secondary sources were compiled into a Federal Interagency Traumatic Brain Injury Research-compliant database. Of the participants, 0% of those with only pre-high school experience developed CTE (0/2 players), 21% with high-school experience (3/14), 91% with college experience (48/53), 64% of semiprofessional (9/14), 88% with Canadian Football League experience (7/8), and 99% with NFL experience (110/111). The median age for those with mild CTE was 44 years (IQR 29-64 years), and the median age for those with severe CTE was 71 years (IQR 64-79 years). The most common cause of death in mild CTE cases was suicide (27%), while the most common cause of death in severe CTE cases was neurodegenerative (47%). Cortical perivascular tau inclusions were detected in all CTE cases mainly in distinct frontal cortical areas with some deposition in the lateral temporal and inferior parietal. By contrast, those with severe CTE also had multiple inclusions in the medial temporal lobe, including in most limbic structures, as well as certain subcortical areas, such as the basal ganglia and thalamus. TDP43 and a-synuclein were common in all CTE cases, while only severe CTE cases tended to have noticeable amyloid-b plaques and angiopathy. Of the 25 participants (17%) without CTE, 9 had no pathology, 7 had nonspecific findings of hemosiderin-laden macrophages or axonal injury, 4 had vascular pathology, 3 had unspecified tauopathy inconsistent with CTE, 2 had Alzheimer’s Disease, 1 had argyrophillic brain disease, and 1 with Lewy Body Disease. Mood symptoms occurred in 96% of mild cases and 89% of severe cases, while cognitive symptoms manifested in 85% of mild and 95% of severe cases. No CTE cases were symptomatic, and 75% of those with severe CTE developed motor impairments.

Image: PD

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