Reconsideration of the DTI-ALPS index as a glymphatic surrogate: disease-specific findings in small vessel disease due to cerebral amyloid angiopathy or arteriolosclerosis

Objectives To explore the disease-specific performance of diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index in cerebral amyloid angiopathy (CAA) and arteriolosclerosis CSVD (aCSVD). Methods We retrospectively enrolled probable CAA or aCSVD patients who underwent 5.0T MRI. Disease-specific DTI-ALPS characteristics and the correlations with clinical, imaging markers, and cognition were evaluated. Regression models were applied according to outcome distributions. Multiple comparisons were controlled using the Benjamini–Hochberg false discovery rate (FDR) procedure. Results A total of 134 participants (56 probable CAA and 78 arteriolosclerosis, mean age 64.9 ± 10.0 years, 64.9% males) were enrolled. DTI-ALPS index was significantly lower in aCSVD than in CAA ( p < 0.001). After adjustment for age and sex and FDR correction, no clinical factors remained significantly associated with DTI-ALPS index. In aCSVD, DTI-ALPS was significantly associated with cognitive performance, whereas these associations did not reach statistical significance in CAA. Across both groups, DTI-ALPS was significantly associated with white matter hyperintensity volume, skeletonized fractional anisotropy, skeletonized mean diffusivity, and peak width of skeletonized mean diffusivity (all FDR-adjusted p < 0.05). Associations with PVS burden and established CAA imaging markers did not reach statistical significance. Conclusion DTI-ALPS index is heterogenous across distinct angiopathies but consistently associated with white matter microstructural damage. These subtype-specific findings question the relevance of DTI-ALPS index and caution against using DTI-ALPS index as a universal glymphatic surrogate.