MRI markers of brain fluid dynamics link reduced blood-brain barrier water exchange rate to disease severity in CADASIL.

BACKGROUND

Reduced water exchange rate (kw) across the blood-brain barrier has been linked to disease severity in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), but the mechanisms underlying this association remain unclear. We investigated whether kw is associated with indirect MRI-based markers of brain fluid dynamics and whether these markers statistically explain the relationship between kw and disease severity.

PATIENTS AND

METHODS

Seventy genetically confirmed CADASIL patients underwent clinical, cognitive and multimodal MRI assessments. Whole-brain kw was measured using diffusion-prepared pseudo-continuous arterial spin labelling. Brain fluid dynamics were assessed using indirect MRI-derived markers, including white matter free water (WM FW) fraction, diffusion tensor imaging along the perivascular space (DTI-ALPS) index, choroid plexus (CP) volume and enlarged perivascular space burden.

RESULTS

Lower whole-brain kw was associated with higher WM FW fraction (β = -0.419, P-corrected = .012), lower DTI-ALPS index (β = 0.431, P-corrected = .028) and larger CP volume (β = -0.510, corrected P < .001). Lower kw was also associated with smaller brain volume and slower processing speed. Magnetic resonance imaging markers of brain fluid dynamics were related to lacune count, cerebral microbleed count, WM hyperintensity volume and brain volume. Exploratory mediation analyses identified significant indirect associations between kw and brain volume through WM FW fraction, DTI-ALPS index and CP volume.

CONCLUSIONS

These cross-sectional findings indicate that lower kw is associated with MRI measures consistent with altered brain fluid dynamics and with greater disease burden in CADASIL. Longitudinal and mechanistic studies are needed to determine the temporal and biological relationships among these measures.