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- Title
Substantia Nigra Pathology, Contact Sports Play, and Parkinsonism in Chronic Traumatic Encephalopathy.
- Authors
Adams, Jason W.; Kirsch, Daniel; Calderazzo, Samantha M.; Tuz-Zahra, Fatima; Tripodis, Yorghos; Mez, Jesse; Alosco, Michael L.; Alvarez, Victor E.; Huber, Bertrand R.; Kubilus, Caroline; Cormier, Kerry A.; Nicks, Raymond; Uretsky, Madeline; Nair, Evan; Kuzyk, Eva; Aytan, Nurgul; Cherry, Jonathan D.; Crary, John F.; Daneshvar, Daniel H.; Nowinski, Christopher J.
- Abstract
This cross-sectional study examines the frequency of parkinsonism among patients with chronic traumatic encephalopathy (CTE) and the association of neuropathologic substrates with parkinsonism in this population. Key Points: Question: What are the key clinical and neuropathologic measures associated with parkinsonism in individuals with chronic traumatic encephalopathy (CTE)? Findings: In this cross-sectional study of 481 brain donors with neuropathologically diagnosed CTE, parkinsonism was common (24.7%). Substantia nigra Lewy bodies, neurofibrillary tangles, dopaminergic neuronal loss, and age at death were significantly associated with parkinsonism. Meaning: The findings suggest that multiple abnormal protein accumulations and neuronal loss are associated with parkinsonism in individuals with CTE in an age-dependent manner. Importance: Parkinsonism is associated with traumatic brain injury and chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head impact (RHI) exposure, but the neuropathologic substrates that underlie parkinsonism in individuals with CTE are yet to be defined. Objective: To evaluate the frequency of parkinsonism in individuals with CTE and the association of RHI and neuropathologic substrates with parkinsonism in these individuals. Design, Setting, and Participants: This cross-sectional study included brain donors with neuropathologically diagnosed CTE without other significant neurodegenerative disease and with information on parkinsonism from the Understanding Neurologic Injury and Traumatic Encephalopathy brain bank between July 2015 and May 2022. Exposure: Years of contact sports participation as a proxy for RHI. Main Outcomes and Measures: The main outcomes were frequency of parkinsonism in individuals with CTE and associations between (1) RHI with substantia nigra (SN) Lewy bodies (LBs) and neurofibrillary tangles (NFTs); (2) LBs, NFTs, and arteriolosclerosis with SN neuronal loss; and (3) SN neuronal loss, LBs, NFTs, and arteriolosclerosis with parkinsonism, tested by age-adjusted logistic regressions. Results: Of 481 male brain donors with neuropathologically diagnosed CTE, parkinsonism occurred frequently in individuals with CTE (119 [24.7%]; 362 [75.3%] did not have parkinsonism). Participants with parkinsonism had a higher mean (SD) age at death (71.5 [13.0] years) than participants without parkinsonism (54.1 [19.3] years) (P <.001) and higher rates of dementia (104 [87.4%] vs 105 [29.0%]), visual hallucinations (45 [37.8%] vs 51 [14.1%]), and probable rapid eye movement sleep behavior disorder (52 [43.7%] vs 58 [16.0%]) (P <.001 for all). Participants with parkinsonism had a more severe CTE stage (eg, stage IV: 35 [29.4%] vs 39 [10.8%]) and nigral pathology than those without parkinsonism (NFTs: 50 of 117 [42.7%] vs 103 of 344 [29.9%]; P =.01; neuronal loss: 61 of 117 [52.1%] vs 59 of 344 [17.1%]; P <.001; and LBs: 28 of 116 [24.1%] vs 20 of 342 [5.8%]; P <.001). Years of contact sports participation were associated with SN NFTs (adjusted odds ratio [AOR], 1.04; 95% CI, 1.00-1.07; P =.03) and neuronal loss (AOR, 1.05; 95% CI, 1.01-1.08; P =.02). Nigral neuronal loss (AOR, 2.61; 95% CI, 1.52-4.47; P <.001) and LBs (AOR, 2.29; 95% CI, 1.15-4.57; P =.02) were associated with parkinsonism. However, SN neuronal loss was associated with SN LBs (AOR, 4.48; 95% CI, 2.25-8.92; P <.001), SN NFTs (AOR, 2.51; 95% CI, 1.52-4.15; P <.001), and arteriolosclerosis (AOR, 2.27; 95% CI, 1.33-3.85; P =.002). In American football players, regression analysis demonstrated that SN NFTs and neuronal loss mediated the association between years of play and parkinsonism in the context of CTE (β, 0.012; 95% CI, 0.001-0.038). Conclusions and Relevance: In this cross-sectional study of contact sports athletes with CTE, years of contact sports participation were associated with SN tau pathology and neuronal loss, and these pathologies were associated with parkinsonism. Repetitive head impacts may incite neuropathologic processes that lead to symptoms of parkinsonism in individuals with CTE.
- Publication
JAMA Neurology, 2024, Vol 81, Issue 9, p916
- ISSN
2168-6149
- Publication type
Article
- DOI
10.1001/jamaneurol.2024.2166