Factors Influencing Clinical Correlates of Chronic Traumatic Encephalopathy (CTE): a Review

Abstract

Chronic traumatic encephalopathy (CTE) is a neuropathologically defined disease reportedly linked to a history of repetitive brain trauma. As such, retired collision sport athletes are likely at heightened risk for developing CTE. Researchers have described distinct pathological features of CTE as well a wide range of clinical symptom presentations, recently termed traumatic encephalopathy syndrome (TES). These clinical symptoms are highly variable, non-specific to individuals described as having CTE pathology in case reports, and are often associated with many other factors. This review describes the cognitive, emotional, and behavioral changes associated with 1) developmental and demographic factors, 2) neurodevelopmental disorders, 3) normal aging, 4) adjusting to retirement, 5) drug and alcohol abuse, 6) surgeries and anesthesia, and 7) sleep difficulties, as well as the relationship between these factors and risk for developing dementia-related neurodegenerative disease. We discuss why some professional athletes may be particularly susceptible to many of these effects and the importance of choosing appropriate controls groups when designing research protocols. We conclude that these factors should be considered as modifiers predominantly of the clinical outcomes associated with repetitive brain trauma within a broader biopsychosocial framework when interpreting and attributing symptom development, though also note potential effects on neuropathological outcomes. Importantly, this could have significant treatment implications for improving quality of life.

Keywords: Biopsychosocial; Brain injury; CTE; Chronic traumatic encephalopathy; Concussion; Repetitive brain trauma.

Figure

Conceptual framework describing a non-exhaustive list of mediators and moderators of neuropathological and clinical outcomes of collision sport exposure. Evidence suggests repetitive brain trauma is a primary risk factor for developing neuropathology unique to CTE. Arrows between factors (ovals) indicate possible uni- and bidirectional influences amongst these variables. Path A includes the potential neurobiological mediators and moderators of pathological burden. Path B includes psychosocial factors directly influencing clinical/functional outcomes which over time, if untreated, may result in underlying neuronal reorganization or compound neuropathological outcomes (Path D). Path C describes factors that may modify the degree to which neuropathological changes ultimately manifest clinically (i.e. “cognitive reserve”). Possible treatment interventions may mitigate neuropathological outcomes by directly targeting neurobiological factors (Intervention Level A), prevent or minimize negative clinical/functional outcomes by directly targeting psychosocial factors (Intervention Level B), or mitigate the degree to which accumulated neuropathology translates to clinical outcomes (Intervention Level C). Research is essential for early identification of at-risk populations and improved understanding of appropriate intervention timing (e.g. before, during, and/or after playing careers). Abbrev: ApoE – apolipoprotein E, CTE – chronic traumatic encephalopathy, p-tau – phosphorylated tau, b-amyloid – beta amyloid, TES – traumatic encephalopathy syndrome, MCI – mild cognitive impairment *Research linking CTE to repetitive brain trauma, specifically, suggests mediating/moderating factors are not causally responsible for its unique distribution of neurofibrillary tangles