Neuropathologic and Clinical Findings in Young Contact Sport Athletes Exposed to Repetitive Head Impacts

Abstract

Importance: Young contact sport athletes may be at risk for long-term neuropathologic disorders, including chronic traumatic encephalopathy (CTE).

Objective: To characterize the neuropathologic and clinical symptoms of young brain donors who were contact sport athletes.

Design, setting, and participants: This case series analyzes findings from 152 of 156 brain donors younger than 30 years identified through the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank who donated their brains from February 1, 2008, to September 31, 2022. Neuropathologic evaluations, retrospective telephone clinical assessments, and online questionnaires with informants were performed blinded. Data analysis was conducted between August 2021 and June 2023.

Exposures: Repetitive head impacts from contact sports.

Main outcomes and measures: Gross and microscopic neuropathologic assessment, including diagnosis of CTE, based on defined diagnostic criteria; and informant-reported athletic history and informant-completed scales that assess cognitive symptoms, mood disturbances, and neurobehavioral dysregulation.

Results: Among the 152 deceased contact sports participants (mean [SD] age, 22.97 [4.31] years; 141 [92.8%] male) included in the study, CTE was diagnosed in 63 (41.4%; median [IQR] age, 26 [24-27] years). Of the 63 brain donors diagnosed with CTE, 60 (95.2%) were diagnosed with mild CTE (stages I or II). Brain donors who had CTE were more likely to be older (mean difference, 3.92 years; 95% CI, 2.74-5.10 years) Of the 63 athletes with CTE, 45 (71.4%) were men who played amateur sports, including American football, ice hockey, soccer, rugby, and wrestling; 1 woman with CTE played collegiate soccer. For those who played football, duration of playing career was significantly longer in those with vs without CTE (mean difference, 2.81 years; 95% CI, 1.15-4.48 years). Athletes with CTE had more ventricular dilatation, cavum septum pellucidum, thalamic notching, and perivascular pigment-laden macrophages in the frontal white matter than those without CTE. Cognitive and neurobehavioral symptoms were frequent among all brain donors. Suicide was the most common cause of death, followed by unintentional overdose; there were no differences in cause of death or clinical symptoms based on CTE status.

Conclusions and relevance: This case series found that young brain donors exposed to repetitive head impacts were highly symptomatic regardless of CTE status, and the causes of symptoms in this sample are likely multifactorial. Future studies that include young brain donors unexposed to repetitive head impacts are needed to clarify the association among exposure, white matter and microvascular pathologic findings, CTE, and clinical symptoms.

Figure 1.. Gross Neuropathologic Features Associated With Chronic Traumatic Encephalopathy (CTE) in Young Athletes

A, A 27-year-old control. Coronal brain sections at the level of the caudate, accumbens, and putamen (left); anterior thalamus and mammillary bodies (center); and midthalamus (right). B, Young athletes with CTE. Examples of macroscopic brain abnormalities in CTE. Cavum septum pellucidum (top left; arrowhead), thalamic notch (top center; arrowhead), degeneration of fornix (top right; arrowhead), enlargement of the frontal horns of the lateral ventricles and septal fenestrations (bottom left; asterisk), enlargement of the frontal horns of the lateral ventricles and cavum septum pellucidum (2 bottom center images; arrowheads), and thalamic notch (bottom right; asterisk).

Figure 2.. Stages of Chronic Traumatic Encephalopathy (CTE) Severity in Contact Sport Athletes Younger Than 30 Years

Hemispheric 50-μm tissue sections immunostained with CP-13, directed against phosphoserine 202 of tau (courtesy of Peter Davies, PhD, Feinstein Institute for Medical Research; 1:200); positive hyperphosphorylated tau (p-tau) immunostaining appears dark brown, showing representative images of CTE in the young athlete brain donors using the McKee staging scheme (I-IV).^,

Figure 3.. Microscopic Pathologic Features Associated With Chronic Traumatic Encephalopathy (CTE) in Young Athletes

A, AT8-immunostained sections of 10-μm formalin-fixed, paraffin-embedded sections shows pathognomonic CTE lesions consisting of hyperphosphorylated tau (p-tau) neurofibrillary tangles (NFTs), pretangles, and dotlike neurites around a central vessel (original magnification ×200). B, Dorsolateral frontal cortex of a 28-year-old female soccer player shows a cluster of AT8-positive NFTs and dotlike neurites at the depth of the sulcus surrounding several small vessels (original magnification ×400). The p-tau lesion measured 1.3 × 1.3 × 1.4 mm in total dimension. C, Dense pigment-laden and clear macrophages surround arterioles in the frontal subcortical white matter (Luxol fast blue, hematoxylin-eosin stain; original magnification ×200). D, White matter rarefaction with myelin pallor, astrocytosis, and macrophage infiltration (Luxol fast blue, hematoxylin-eosin stain; original magnification ×200). E, Dense pigment-laden and clear macrophages surround arterioles in the frontal subcortical white matter in the young female soccer player with CTE (Luxol fast blue, hematoxylin-eosin stain; original magnification ×400). F, Conspicuous macrophages (left, arrowheads) and reactive astrocytes (right, arrowheads) in the white matter in the young female soccer player with CTE (Luxol fast blue, hematoxylin-eosin stain; original magnification ×600). G, Clusters of activated microglia in the frontal white matter of the young female soccer player with CTE (IBA1 immunostaining; original magnification ×600). H, Macrophages surrounding arteriole in the frontal white matter of the young female soccer player with CTE (IBA1 immunostaining; original magnification ×400). I, Subpial and interface astrogliosis in the frontal cortex of the young female soccer player with CTE (glial fibrillary acidic protein immunostaining; original magnification ×20). J, Astrogliosis at the interface between the gray and white matter in the frontal cortex of the young female soccer player with CTE (glial fibrillary acidic protein immunostaining; original magnification ×40).