MRI markers of cerebrospinal fluid dynamics predict dementia and mediate the impact of cardiovascular risk

INTRODUCTION: Impaired cerebrospinal fluid (CSF) dynamics may contribute to dementia, but human evidence is limited. We examined associations between magnetic resonance imaging-based proxies of CSF dynamics and incident dementia, and whether CSF dysfunction mediates links between cardiovascular risk and dementia. METHODS: Using the UK Biobank, we measured CSF dynamics: perivascular space (PVS) volume, diffusion tensor image analysis along the PVS (DTI-ALPS), blood oxygen level-dependent CSF (BOLD-CSF) coupling, and choroid plexus (CP) volume. We assessed cardiovascular risk factors and their associations with CSF dynamics and dementia based on general practitioner, mortality, and hospital records. Mediation analysis evaluated CSF dysfunction in cardiovascular risk-dementia relationships. RESULTS: Lower DTI-ALPS, lower BOLD-CSF coupling, and higher CP volume predicted dementia, but PVS volume did not. DTI-ALPS and CP volume mediated the effect of white matter hyperintensities and diabetes duration on dementia. DISCUSSION: Impaired CSF dynamics may lead to dementia and partially mediate cardiovascular risk-dementia associations. HIGHLIGHTS: We developed fully automated methods for quantifying diffusion tensor image analysis along the perivascular space (DTI-ALPS) and blood oxygen level-dependent cerebrospinal fluid (BOLD-CSF) coupling. Three CSF dynamics markers-BOLD-CSF coupling, DTI-ALPS, and choroid plexus (CP) volume-were predictive of incident dementia, whereas PVS volume was not. Magnetic resonance imaging proxies of CSF dynamics markers were associated with cardiovascular injury. CP volume and DTI-ALPS mediated the associations of both white matter hyperintensities and diabetes with dementia.