White matter hyperintensities are associated with glymphatic impairment and antioxidant pathway in healthy aging

Abstract Background White matter hyperintensities (WMHs), a marker of vascular‐brain injury in older adults, constitute an Alzheimer's disease (AD) risk‐factor (Debette et al. , 2019). Recent studies in AD associate WMHs to (a) enlarged choroid plexus (ChP) (Hong et al. , 2024), a structure involved in glymphatic clearance of AD‐related proteins and waste from the brain (Hauglund et al. , 2020), and (b) lower brain levels of glutathione, an antioxidant metabolite (Detcheverry et al. , 2024). However, the interplay between WMHs, ChP, and brain metabolites in healthy aging remains poorly understood, which is essential for unraveling their role in dementia progression. We investigated the relationship between WMH volume, ChP volume, brain metabolites, and plasma proteins. Method 7T‐MRI/MRS and plasma samples were acquired from 83 healthy adults (42W/41M) aged 20‐79. ChP and WMHs were manually segmented on T1‐weighted MP2RAGE and 3D FLAIR images, respectively, and normalized for head size. Metabolites in the posterior cingulate cortex were measured with single‐voxel STEAM MRS. Mass spectrometry‐based proteomics was performed on plasma. GLMs were performed for WMH volume and ChP volume (controlling for age); and MRS‐detected brain metabolites. Exploratory analyses were performed on plasma proteins and (a) WMH volume (controlling for age), followed by functional enrichment analysis on the significant proteins using STRING; and (b) MRS‐detected brain metabolites (Spearman). Result We found significant associations (Figure 1) between WMH volume and (a) ChP volume (all: p <0.001; women: p <0.001), (b) five brain metabolites, including glutathione ( p adjusted < 0.05), and (c) age (all: p <0.001; women: p <0.05; men: p <0.05). WMH volume was also significantly associated with 21/315 plasma proteins ( p unadjusted <0.05: all, N = 9; women, N = 15; men, N = 4), with the majority of biological processes linked to antioxidant activity ( p adjusted < 0.05). Additionally, several of the 21 proteins (e.g., flavin reductase [NADPH], catalase) were significantly associated ( p unadjusted <0.05) with brain levels of the antioxidant glutathione. Conclusion We demonstrated a link between greater WMH and ChP volumes, indicating an interplay between vascular‐brain injury and glymphatic function, with the antioxidant system playing a key role.