By Rivka Sachdev, MD
Repeated head injury from years of contact sports play in men with confirmed chronic traumatic encephalopathy (CTE) may cause pathological changes in the substantia nigra that lead to parkinsonism in a subset of patients with CTE.
Adams JW, Kirsch D, Calderazzo SM, et al. Substantia nigra pathology, contact sports play, and parkinsonism in chronic traumatic encephalopathy. JAMA Neurol. 2024;81(9):916-924.
Parkinsonism in individuals with a history of repeated head trauma has been reported in isolated cases. Repetitive head impact also is accepted as the cause for individuals who develop chronic traumatic encephalopathy (CTE) that has been confirmed by autopsy. CTE is categorized as a tauopathy, and the anatomy and neuropathology demonstrate perivascular deposition of hyperphosphorylated tau protein as neurofibrillary tangles in the depths of cortical sulci and in brainstem areas.
Although idiopathic Parkinson’s disease is a synucleinopathy characterized by aggregates of alpha-synuclein and loss of dopaminergic cells in the substantia nigra, the pathological mechanism for parkinsonism after repeated head injuries has not yet been defined. We do know that clinical parkinsonism can result from non-Lewy body pathology. Examples are progressive supranuclear palsy, which is a tauopathy, and parkinsonism attributed to cerebrovascular disorders with multiple, small-vessel infarcts in the basal ganglia.
The investigators in this study examined the link between repeated head impact (using contact sports, particularly American football, as a proxy for repeated head injury) and the development of parkinsonism in patients with CTE. The data suggest that substantia nigra pathology other than Lewy body inclusions may be the cause for parkinsonism in some patients with CTE.
This was a cross-sectional study that included 481 donor brains from the “UNITE” autopsy brain bank in Boston. All brain specimens were from males who had participated in years of contact sports (without significant comorbid disease) and were confirmed to have CTE.
Researchers examined the frequency of parkinsonism in individuals with CTE; the associations between repeated head impact and the presence of nigral Lewy bodies and neurofibrillary tangles; associations between Lewy bodies, neurofibrillary tangles, and arteriosclerosis with substantia nigra neuronal loss; and the association of substantia nigra neuronal loss, Lewy bodies, neurofibrillary tangles, and arteriosclerosis with parkinsonism.
Results revealed that the presence of clinical parkinsonism in this group was common (24.7% of the 481 individuals). Study participants with parkinsonism had increased frequencies of dementia, visual hallucinations, and probable rapid eye movement (REM) sleep behavior disorder compared to participants who did not have parkinsonism.
Pathologically, participants with parkinsonism had a more severe CTE stage and more substantia nigra pathology (neurofibrillary tangles, neuronal loss, and Lewy bodies) than those without parkinsonism. Moderate to severe neuronal loss was more frequent in individuals with parkinsonism (52.1%) than in those without parkinsonism (17.1%). There was an association between years of contact sports play and nigral neurofibrillary tangles and dopaminergic neuronal loss. Nigral neuronal loss and Lewy bodies were associated with parkinsonism. Nigral neuronal loss was associated with nigral Lewy bodies, neurofibrillary tangles, and arteriosclerosis.
However, although substantia nigra Lewy bodies were more common in those who had parkinsonism, they were absent in most of the study participants with parkinsonism (88 of 116 [75.9%]), suggesting that non alpha-synuclein pathology may be associated with parkinsonism in some individuals with CTE. The leading candidate was neurofibrillary tangles with hyperphosphorylated tau.
Researchers analyzed a subset of participants who played American football (418 out of the 481 study participants), finding that years of American football play were associated with substantia nigra neurofibrillary tangles. For this subset, age was associated with nigral neurofibrillary tangles, nigral Lewy bodies, and arteriosclerosis. Nigral neuronal loss was associated with nigral neurofibrillary tangles, nigral Lewy bodies, and arteriosclerosis. Nigral Lewy bodies and neuronal loss were associated with parkinsonism.
Years of American football play revealed a small indirect association with parkinsonism through nigral neurofibrillary tangles and neuronal loss. The analysis suggests the relationship between repeated head injury and parkinsonism in CTE patients may be mediated by tau pathology in the substantia nigra, leading to neuronal loss.
Commentary
As the authors acknowledge, there are limitations to this study. The study focused on a limited group of athletes, all male, and mostly American football players, limiting the generalizability of the findings. There also is the possibility of recall bias because information about participant symptoms was obtained by informant-based retrospective reviews.
There were no documented neurological examinations or standardized clinical assessments for most study participants. Finally, the study did not account for variables, such as genetic predisposition, environmental exposures, or medication exposures, that could have explained parkinsonism in these patients.
Still, this important study adds to our knowledge of links between repeated head injury and the development of neurodegenerative disease, including movement disorders.
Rivka Sachdev, MD, is Assistant Professor of Clinical Neurology, Weill Cornell Medicine.
