Multi-omic and multi-modal MRI signatures to unravel the role of glymphatic pathways in cerebral small vessel disease – Multi-SVD-glyph

Cerebral small vessel disease (cSVD) is a heterogeneous group of pathologies affecting small blood vessels of the brain, and a leading cause of stroke and dementia. Numerous genetic risk loci have been identified for several magnetic resonance imaging (MRI) markers of cSVD, especially white matter hyperintensities (WMH) and perivascular spaces (PVS). In parallel, recent research has identified the key role of the glymphatic system in maintaining brain health by mediating brain waste clearance through a perivascular network of fluid transport. Involvement of the glymphatic system in the development of cSVD is hypothesized. A better understanding of the relationship between small vessel pathologies and glymphatic dysfunction, particularly at the molecular level, may yield critical insights into early pathophysiology and progression of cSVD.
The present project aims to reveal molecular underpinnings of established structural MRI markers of cSVD and novel diffusion and resting state functional MRI (rsfMRI) markers of glymphatic function through integrative multi-omic analyses. First, we will evaluate the novel imaging markers of glymphatic function across the adult lifespan, and characterize their associations with traditional cSVD markers. Building on strong pre-existing collaborations, including joint optimization of deep-learning based quantification of PVS we will leverage data from three complementary population-based cohort studies spanning the adult life spectrum (i-Share, Rhineland Study, UK Biobank), with very similar brain imaging protocols. Second, we will leverage genomic and epigenetic data available in these cohorts to identify molecular pathways underlying the relation between glymphatic function and cSVD pathological processes, and explore causality and directionality.
In secondary analyses we will assess the clinical significance of identified molecular signatures by examining their relation with stroke, cognition and dementia.