Biomarkers

Background: Glymphatic system dysfunction as characterized by increased MRI-visible Perivascular Spaces (PVS) is speculated to play a role in the acceleration of amyloid accumulation in Alzheimer's Disease (AD). However, while PVS is also prevalent amongst Vascular Dementia (VD), the pathological distinctions between regional PVS in AD- and VD-driven cohorts remain largely unknown. Through a mixed dementia cohort, we examined these pathology-driven localization patterns via automated PVS segmentations from T2-weighted MRI.

Method: 99 cognitively unimpaired (CU) and 190 cognitively impaired (CI) patients' data were collected from the Seoul National University Dementia cohort. Through visual assessments of individual's ¹⁸F-Florbetaben PET, FLAIR and SWI images, expert radiologists classified CI patients into 4 groups based on both amyloid and vascular-damage burden (26 A-VB-, 63 A-VB+, 26 A+VB-, and 75 A+VB+). PVS segmentation involved masking and thresholding hyperintense vessel structures using slice-wise Frangi filters applied to T2-weighted MRIs at the basal ganglia (BG) and cerebral white matter (WM), segmented into 4 major lobes (frontal, parietal, temporal, and occipital). We calculated PVS volume fractions (PVS-VF) as voxel counts normalized by intracranial volumes. Automated segmentations were validated against manually segmented PVS volumes at BG and whole WM (rank correlation coefficients: 0.634, 0.539). Groupwise differences were calculated through two-sample t-tests corrected for multiple comparisons.

Result: For A+ groups, significant increases in PVS-VF were observed at the temporal and occipital lobes as compared to CU, a finding that agree well with prior visual rating studies. However, VB+ groups showed significant PVS-VF increases across all lobes as compared to CU. Particularly, BG represented the most pronounced VD-related PVS, with a significantly greater PVS-VF in the VB+ groups compared to their VB- counterparts. Interestingly, PVS volume ratios of lobar regions and BG showed no significant increases for A-VB+, while all A+ groups showed significant increases in temporal and occipital regions as compared to CU.

Conclusion: Full utilization of PVS as a core biomarker in discerning glymphatic dysfunctions of AD requires full understanding of their properties in those contexts. Cross-sectional differentiation of regional PVS localization in AD can become a steppingstone into elucidating those associations within the AD continuum.