White matter hyperintensities: A long‐term consequence of repetitive head impacts?

Abstract Background Repetitive head impacts (RHI) from American football can lead to tau and non‐tau pathologies that might present as white matter hyperintensities (WMH) on FLAIR MRI. In 2022, we published a study in Alzheimer’s & Dementia that examined WMH and their association with risk factors and clinical function in former elite football players. That study will be presented during this symposium along with new unpublished data that used imaging and fluid biomarkers to examine etiological correlates (tau, amyloid, neurodegeneration, axonal injury, neuroinflammation) of WMH in the same cohort. Methods The multi‐site DIAGNOSE CTE Research Project recruited 180 football players and 60 asymptomatic males without RHI (“controls”), all 45‐74 years (Table 1). Participants completed MRI, lumbar puncture, and neuropsychological testing. Lesion Segmentation Toolbox estimated FLAIR WMH, FreeSurfer derived total cortical thickness, and a diffusion pipeline derived average global FA. CSF was analyzed for p‐tau181, Aβ1‐42, NfL, and sTREM2. Tobit regressions compared football players (n = 149) and controls (n = 53) on total and regional log‐WMH and estimated the effects of years of football and age of first exposure (AFE) to football on log‐WMH. Linear regressions evaluated log‐WMH and clinical associations in football players. Structural equation modeling (SEM) examined effects between log‐WMH and cortical thickness, FA, and the CSF biomarkers. Analyses accounted for age, race, revised Framingham Stroke Risk Profile (rFSRP), body mass index, APOE ε4, and evaluation site. Results Alosco et al. (2022) found older (i.e., 60+) but not younger football players had greater total, frontal, temporal and parietal log‐WMH compared to controls (FDR‐adjusted p‐values<0.05; Table 2). Among older football players, younger AFE was associated with greater log‐WMH (beta = ‐0.13, 95% CI = ‐0.23,‐0.02). Greater log‐WMH corresponded to worse Trails A‐B (beta = ‐4.32, 95% CI = ‐8.59,‐0.05) and List Learning Long Delay scores (beta = ‐0.56, 95% CI = ‐0.93,‐0.19). Subsequent unpublished SEM analyses in football players (Figure 1) showed the following direct effects on log‐WMH: higher rFSRP, higher CSF p‐tau181, lower FA, and reduced cortical thickness. There were no indirect effects. Compared to controls, SEM associations were stronger in football players exception for cortical thickness. Conclusions FLAIR WMH might have unique imaging characteristics, risk factors, and pathological underpinnings in people exposed to RHI.

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