By Nitin K. Sethi, MD
Associate Professor of Neurology, Weill Cornell Medical College; Director, Weill Cornell Concussion and Brain Injury Center
Dr. Sethi reports no financial disclosures relevant to this field of study.
The authors of a cross-sectional study involving analysis of data from the ongoing Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) study found that dementia is likely a result of neuropathologic changes associated with repetitive head injury as well as non-head trauma-associated vascular pathologic changes in patients with chronic traumatic encephalopathy.
Alosco ML, Stein TD, Tripodis Y, et al. Association of white matter rarefaction, arteriolosclerosis, and tau with dementia in chronic traumatic encephalopathy. JAMA Neurol 2019; Aug 5. doi: 10.1001/jamaneurol.2019.2244. [Epub ahead of print].
There is increasing evidence that repetitive concussive and subconcussive brain trauma (repetitive head injury) leads to chronic traumatic encephalopathy (CTE) in U.S. football players. CTE presents with cognitive and neuropsychiatric disturbances that can progress to dementia. The pathways that lead to dementia remain to be elucidated scientifically, and it is suggested that tau and non-tau pathologies are involved.
Alosco et al conducted a cross-sectional study involving analyses of data from the ongoing Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) study, which includes brain donors from the Veterans Affairs–Boston University–Concussion Legacy Foundation brain bank between 2008 and 2017. The study included 180 men who had played football and were neuropathologically diagnosed with CTE. Men younger than 40 years of age and those with missing data were excluded. The mean age at death was 67.9 years. The number of years of football play acted as a proxy for repetitive head impacts.
The investigators conducted neuropathological assessment of white matter rarefaction and arteriolosclerosis severity; number of infarcts, microinfarcts, microbleeds, and phosphorylated tau accumulation determined by CTE stage; and semiquantitative rating of dorsolateral frontal cortex (DLFC) neurofibrillary tangles (NFT). Informant-based retrospective clinical interviews determined dementia diagnoses via diagnostic consensus conferences. Of the 180 patients, 120 (66.7%) were found to have dementia prior to death. Moderate to severe white matter rarefaction (84 of 180 [46.6%]) and arteriolosclerosis (85 of 180 [47.2%]) were common, but infarcts, microinfarcts, and microbleeds were not common. Using a simultaneous equations regression model that controlled for age and race, they found that more years of play was associated with more severe white matter rarefaction and greater phosphorylated tau accumulation. White matter rarefaction and DLFC NFTs were associated with dementia. Arteriolosclerosis and years of play were not associated with dementia, but arteriolosclerosis was independently associated with dementia.
COMMENTARY
Physicians evaluating and treating athletes, especially those involved in contact sports such as U.S. football, are concerned by the increasing evidence that repetitive concussive and subconcussive brain trauma leads to CTE. Patients with CTE present with cognitive and neuropsychiatric disturbances that can progress to dementia in some cases.1 It is unclear whether dementia in CTE patients is the result of neuropathologic changes associated with repetitive head injury or if other non-head trauma-associated pathologic changes also contribute. To confound matters, post-traumatic proteinopathies have similarities to dementias such as Alzheimer’s disease (AD). So, while it is difficult to disentangle the neuropathological changes induced by repetitive head trauma from those induced by a progressive neurodegenerative disorder such as AD, the mechanism by which head trauma can trigger neurodegeneration increasingly is understood. Diffuse axonal injury disrupts microtubule function, providing the potential framework for pathologies of tau and amyloid to develop. While CTE only can be identified confidently at postmortem, imaging biomarkers, such as magnetic resonance imaging and positron emission tomography, and fluid biomarkers, such as neurofilament light, can be used to characterize endophenotypes associated with distinct types of post-traumatic neurodegeneration. It is likely that football players who suffer repetitive head trauma and also have multiple vascular risk factors for cerebrovascular disease are most at risk for developing dementia in association with CTE. Clinical trials addressing some of these factors with neuroprotective and disease-modifying treatments are needed.
REFERENCE
- Graham NS, Sharp DJ. Understanding neurodegeneration after traumatic brain injury: From mechanisms to clinical trials in dementia. J Neurol Neurosurg Psychiatry 2019;90:1221-1233.
