Distinct spatial patterns of perivascular spaces enlargement for multiple and Co-existing pathologies of cognitive impairment

BACKGROUND: This study examines how amyloid-β and vascular pathology independently and jointly relate to regional perivascular space (PVS) burden on T2-weighted MRI. METHODS: In 307 cognitively impaired participants retrospectively identified from the Seoul National University dementia cohort, PVS were automatically quantified in the basal ganglia (BG) and lobar white matter regions from 2D T2-weighted MRI. Amyloid-β and vascular pathology positivity were defined by [18F]Florbetaben PET and small vessel disease markers. Group differences among pathology-negative (n=36), vascular-only (n=106), amyloid-only (n=48), and mixed (n=117) subgroups, as well as amyloid-vascular interactions, were assessed using analysis of covariance and multivariable linear regression. RESULTS: BG PVS were greater in participants with vascular burden than in pathology-negative participants (F=26.97, p<0.001; Cohen's d=1.28), independent of amyloid-β. Lobar PVS were higher in single-pathology than pathology-negative participants across the parietal, temporal, and occipital regions (F=8.25-18.04, Cohen's d=0.66-0.98, all p≤0.014), with no additional increase in the mixed group. Greater amyloid-β retention was associated with parietal, temporal, and occipital PVS in VB- participants (β [95% CI]=0.55 [0.19, 0.92], 0.69 [0.35, 1.02], 0.40 [0.16, 0.64], respectively). Among AB- participants, vascular burden was associated with BG PVS (β [95% CI]=0.65 [0.40, 0.89]). Multivariable regression demonstrated less-than-additive AB×VB interactions in parietal, temporal, and occipital PVS (β [95% CI]=-0.65 [-1.08, -0.23], -0.74 [-1.13, -0.35], -0.42 [-0.70, -0.14], respectively). CONCLUSIONS: Distinct regional PVS patterns reflect spatially selective and severity-dependent glymphatic-related structural alterations associated with amyloid-β and vascular pathologies, supporting PVS as a quantitative imaging biomarker for disentangling mixed pathways of cognitive impairment.