30 Jul 2024

Nearly a century ago, physicians realized that boxers who had sustained many hits to the head often became “punch drunk,” with symptoms such as slurred speech, poor balance, and tremors. The condition is now recognized as a form of parkinsonism, but a new paper hints it is more likely caused by neurofibrillary tangles of tau than the deposits of α-synuclein fibrils typically associated with Parkinson’s disease.

In a study reported in the July 15 JAMA Neurology, scientists led by Ann McKee and Thor Stein at Boston University examined, postmortem, the brains of 481 men who had been diagnosed with chronic traumatic encephalopathy (CTE) based on neuropathology. The men ranged in age from 17 to 97 and had played contact sports—mostly American football—for an average of 15 years. From medical records and interviews with their caregivers, the researchers determined that a quarter of them had had parkinsonism. Of these, 43 percent had tau tangles in the substantia nigra, the small area of the brain that is packed with dopaminergic neurons that coordinate movement. In contrast, only a quarter had nigral Lewy bodies—the α-synuclein protein aggregates found in Parkinson’s disease.

To avoid complications from other tauopathies or movement disorders, the study excluded athletes who had had frontotemporal dementia, motor neuron disease, or Alzheimer’s, although many of the older donors with more severe tau damage did have dementia.

First author Jason Adams and colleagues also found that more years of playing sports increased the risk of neurofibrillary tangles (NFT), neuronal loss, and parkinsonism, but not Lewy bodies. “We think that in CTE it's more the tau pathology that's driving the Parkinson’s symptoms rather than the Lewy bodies,” Stein told Alzforum. In support of this, mediation analysis found that among those with a history of head injury, NFTs caused parkinsonism indirectly through neuronal loss. In contrast, in those without head injury, Lewy bodies and arteriosclerosis did the same as people aged (image below).

“It appears that CTE-associated NFT may represent an additional diagnostic consideration for patients with parkinsonism,” wrote Breton Asken and Stefan Prokop, University of Florida, Gainesville, and Sonja Scholz, National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, in an accompanying editorial. They added that it remains unclear whether parkinsonism associated with head injuries has different features than other kinds of parkinsonism.

It is not known how head injuries repeated over decades lead to neuronal loss later in life. Forces that rattle the brain in the skull can tear axons, dendrites, and blood vessels—especially in areas such as the substantia nigra, which lies deep inside the brain and can’t easily conform to pressure.

Kevin Bieniek, University of Texas Health Science Center, San Antonio, thinks the new study is important in delineating how repeated head injuries cause different pathologies. “It is profound how CTE is a multi-etiology dementia,” he said. He noted that some people with CTE who had extensive tangles in the substantia nigra did not have parkinsonism, suggesting they may be more resilient to tau pathology.

The authors caution that the study is retrospective, and that people who choose to donate their brains to CTE research are likelier to have had severe symptoms and the most severe tau pathology. They, and other groups, including BU’s BANKCTE study and Harvard University’s Football Players Health Study, are tracking living athletes with CTE to find blood-based markers through deep phenotyping, genetic analysis, and neuroimaging. Easily measurable biomarkers could allow researchers to identify those with brain pathology and eventually to test different treatments in the people most likely to benefit.

Gil Rabinovici, University of California, San Francisco, thinks such longitudinal studies will allow researchers to start looking into questions raised by the new study, such as whether different sports create different kinds of head injuries or whether individual symptoms of Parkinsonism, such as sleep disorder or tremors, indicate either α-synuclein or tau pathology. “We need biomarkers to answer these questions because we can't do prospective studies over 15 to 20 years,” he said. “We need the answers much sooner than that.”—Sara Reardon

Sara Reardon is a freelance writer based in Bozeman, Montana.

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References

External Citations

1. BANKCTE 
2. Football Players Health Study

Further Reading

News

1. Transient Filament Yields AD and CTE Tau Fibrils 8 Dec 2023
2. Do 'Headers' Rack Up Brain Damage in Soccer Players? 17 Feb 2017
3. In Football Players With Possible CTE, Tau PET Reveals Subtle Tau Deposition 12 Apr 2019