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Association Between Antemortem FLAIR White Matter Hyperintensities and Neuropathology in Brain Donors Exposed to
Madeline Uretsky1, Sylvain Bouix1, Ronald J Killiany1
1From the Boston University Alzheimer's Disease Research Center and CTE Center, Department of Neurology (M.U., R.J.K., Y.T., D.H.D., B.D., L.G., D.K., C.N., R.C., N.K., B.R.H., R.A.S., V.E.A., T.D.S., A.M., J.M., M.L.A.), Department of Anatomy and Neurobiology (R.J.K., R.A.S.), Center for Biomedical Imaging (R.J.K.), Department of Radiology (A.Z.M., C.F.), Framingham Heart Study (C.F., T.D.S., A.M., J.M.), Department of Pathology and Laboratory Medicine (L.G., N.K., T.D.S., A.M.), Department of Psychiatry (L.G.), Department of Ophthalmology (L.G.), and Department of Neurosurgery (R.C., R.A.S.), Boston University School of Medicine; Department of Psychiatry, Psychiatry Neuroimaging Laboratory (S.B.), Brigham and Women's Hospital, Harvard Medical School; Department of Biostatistics (Y.T.) and Biostatistics and Epidemiology Data Analytics Center (B.M., J.P.), Boston University School of Public Health; Departments of Radiology (K.B.) and Physical Medicine & Rehabilitation (D.H.D.), Massachusetts General Hospital, Boston; Braintree Rehabilitation Hospital (B.D., D.K.); Department of Biomedical, Electrical & Computer Engineering (L.G.), Boston University College of Engineering; Concussion Legacy Foundation (C.N., R.C.), Boston; Department of Neurosurgery (R.C.), Emerson Hospital, Concord; VA Boston Healthcare System (B.R.H., V.E.A., T.D.S., A.M.), US Department of Veterans Affairs, Jamaica Plain; National Center for PTSD (B.R.H., V.E.A.), VA Boston Healthcare, Jamaica Plain; and Department of Veterans Affairs Medical Center (V.E.A., T.D.S., A.M.), Bedford, MA.
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.
Insights
White matter hyperintensities (WMH) on MRI scans may indicate long-term brain damage from repetitive head impacts, including chronic traumatic encephalopathy (CTE). This damage is linked to white matter rarefaction, tau pathology, and cognitive decline in athletes.
Area of Science:
- Neuroscience
- Neuropathology
- Radiology
Background:
- Repetitive head impacts (RHIs) from contact sports are linked to late neuropathologies like chronic traumatic encephalopathy (CTE) and white matter degeneration.
- White matter hyperintensities (WMH) on FLAIR MRI are often attributed to vascular risk but may have unique causes in RHIs.
- This study investigates the neuropathologic basis of WMH in individuals exposed to RHIs.
Purpose of the Study:
- To examine the neuropathologic correlates of antemortem WMH in brain donors with a history of RHIs.
- To assess the association between WMH, RHI exposure, and cognitive/functional decline.
Main Methods:
- An imaging-pathologic correlation study of symptomatic male decedents with RHIs and available FLAIR MRI scans.
- Quantification of WMH using total lesion volume (TLV) and neuropathologic assessment of white matter rarefaction, cerebrovascular disease, and tau/amyloid pathology.
- Correlation analysis with years of football play (as a proxy for RHI exposure) and informant-reported cognitive and functional scores (CDS, FAQ).
Main Results:
- WMH (log TLV) were significantly associated with white matter rarefaction, arteriolosclerosis, CTE stage, and frontal p-tau severity.
- Increased years of football play correlated with higher log TLV.
- Greater WMH burden (log TLV) was associated with poorer cognitive and daily function scores (FAQ and CDS).
Conclusions:
- WMH on FLAIR MRI may reflect long-term white matter pathologies resulting from RHIs, including white matter rarefaction and tau accumulation, beyond typical microvascular disease.
- Further prospective imaging-pathologic studies are warranted to confirm these findings.
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