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Abstract
Background and Objectives Late neuropathologies of repetitive head impacts from contact sports can include chronic traumatic encephalopathy (CTE) and white matter degeneration. White matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) MRI scans are often viewed as microvascular disease from vascular risk, but might have unique underlying pathologies and risk factors in the setting of repetitive head impacts. We investigated the neuropathologic correlates of antemortem WMH in brain donors exposed to repetitive head impacts. The association between WMH and repetitive head impact exposure and informant-reported cognitive and daily function were tested.
Methods This imaging–pathologic correlation study included symptomatic male decedents exposed to repetitive head impacts. Donors had antemortem FLAIR scans from medical records and were without evidence of CNS neoplasm, large vessel infarcts, hemorrhage, or encephalomalacia. WMH were quantified using log-transformed values for total lesion volume (TLV), calculated using the lesion prediction algorithm from the Lesion Segmentation Toolbox. Neuropathologic assessments included semiquantitative ratings of white matter rarefaction, cerebrovascular disease, hyperphosphorylated tau (p-tau) severity (CTE stage, dorsolateral frontal cortex), and β-amyloid (Aβ). Among football players, years of play was a proxy for repetitive head impact exposure. Retrospective informant-reported cognitive and daily function were assessed using the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ). Regression models controlled for demographics, diabetes, hypertension, and MRI resolution. Statistical significance was defined as p ≤ 0.05.
Results The sample included 75 donors: 67 football players and 8 nonfootball contact sport athletes or military veterans. Dementia was the most common MRI indication (64%). Fifty-three (70.7%) had CTE at autopsy. Log TLV was associated with white matter rarefaction (odds ratio [OR] 2.32, 95% confidence interval [CI] 1.03, 5.24; p = 0.04), arteriolosclerosis (OR 2.38, 95% CI 1.02, 5.52; p = 0.04), CTE stage (OR 2.58, 95% CI 1.17, 5.71; p = 0.02), and dorsolateral frontal p-tau severity (OR 3.03, 95% CI 1.32, 6.97; p = 0.01). There was no association with Aβ. More years of football play was associated with log TLV (unstandardized β 0.04, 95% CI 0.01, 0.06; p = 0.01). Greater log TLV correlated with higher FAQ (unstandardized β 4.94, 95% CI 0.42, 8.57; p = 0.03) and CDS scores (unstandardized β 15.35, 95% CI −0.27, 30.97; p = 0.05).
Discussion WMH might capture long-term white matter pathologies from repetitive head impacts, including those from white matter rarefaction and p-tau, in addition to microvascular disease. Prospective imaging–pathologic correlation studies are needed.
Classification of Evidence This study provides Class IV evidence of associations between FLAIR white matter hyperintensities and neuropathologic changes (white matter rarefaction, arteriolosclerosis, p-tau accumulation), years of American football play, and reported cognitive symptoms in symptomatic brain donors exposed to repetitive head impacts.
Glossary
- Aβ=
- β-amyloid;
- AD=
- Alzheimer disease;
- BU=
- Boston University;
- bvFTD=
- behavioral variant frontotemporal dementia;
- CAA=
- cerebral amyloid angiopathy;
- CDS=
- Cognitive Difficulties Scale;
- CERAD=
- Consortium to Establish a Registry for Alzheimer's Disease;
- CI=
- confidence interval;
- CTE=
- chronic traumatic encephalopathy;
- FAQ=
- Functional Activities Questionnaire;
- FLAIR=
- fluid-attenuated inversion recovery;
- LPA=
- lesion prediction algorithm;
- LST=
- Lesion Segmentation Toolbox;
- NFL=
- National Football League;
- NINDS/NIBIB=
- National Institutes of Neurological Disease and Stroke/National Institute of Brain Imaging and Behavior;
- p-tau=
- hyperphosphorylated tau;
- TBI=
- traumatic brain injury;
- TLN=
- total lesion number;
- TLV=
- total lesion volume;
- UNITE=
- Understanding Neurologic Injury in Traumatic Encephalopathy;
- VRF=
- vascular risk factor;
- WMH=
- white matter hyperintensities
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Class of Evidence: NPub.org/coe
Podcast: NPub.org/Podcast9801
- Received February 4, 2021.
- Accepted in final form September 29, 2021.
- © 2021 American Academy of Neurology
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