Perivascular space enlargement and cerebrovascular and Alzheimer’s diseases

Abstract Background Perivascular spaces (PVS) can become large enough to be visible in magnetic resonance imaging (MRI). The exact aetiology of PVS enlargement in humans remains, however, elusive and under continuous debate [1‐5]. Here, we tracked PVS volumes longitudinally over three years in 525 individuals along AD syndromal cognitive stages, namely cognitively unimpaired (CU), mild cognitive impairment (MCI), and Alzheimer’s disease (AD), to pinpoint conditions related to PVS enlargement. Method We studied centrum semiovale (CSO) and basal ganglia (BG) PVS computationally over three to four annual visits in 525 DELCODE participants (CU/MCI/AD 417/72/36; 49.52% female, mean age 70.85 (SD 5.78)) [6]. We segmented PVS using a multimodal Hessian‐based filtering method [7] leveraging T1w and FLAIR imaging, which we validated against clinical visual ratings. We used linear mixed‐effect modelling to study temporal PVS volume changes. First, we tested whether PVS volumes increased over follow‐ups in CU. Second, we explored whether longitudinal PVS enlargement was associated across ROIs, and predicted by individual white matter hyperintensities (WMH), Amyloid and Tau positivity status at baseline in the entire cohort. We adjusted all analyses by age, sex, years of education, and total intracranial volume. Result We observed PVS volume increase over follow‐ups in healthy ageing with a significant individual difference of change (Figure 1; BG: B=0.06 [95%‐CI 0.04‐0.08], p<0.001; CSO: B=0.06 [95%‐CI 0.04‐0.09], p<0.001). PVS enlargement in BG was associated with that in CSO (ρ=0.17, p FDR <0.001). Participants with greater baseline WMH volumes tended to have faster BG‐PVS enlargement (ρ=0.05, p FDR =0.06). Participants with both Amyloid and Tau positive tended to have faster CSO‐PVS enlargement than those with neither (Figure 2; Χ²(2)=5.07, p=0.079, η²=0.014). Conclusion Given our findings, ageing is a primary driver of PVS enlargement. Associations between PVS and WMH underline shared cerebrovascular mechanisms. Detrimental cycles driven by neurotoxic waste accumulation might also contribute to PVS enlargement. Further research is needed to disentangle pathological cascades, their concurrent dynamics, and their unique contribution to disease progression. References 10.1016/j.neurobiolaging.2022.01.006 10.18632/oncotarget.17724 10.1002/ana.26475 10.1161/STROKEAHA.117.017526 10.1016/j.clineuro.2019.05.002 10.1186/s13195‐017‐0314‐2 10.1007/BFb0056195