Lesion evolution and neurodegeneration in RVCL-S, a monogenic microvasculopathy

Objective: To characterize lesion evolution and neurodegeneration in
retinal vasculopathy with cerebral leukoencephalopathy and systemic
manifestations (RVCL-S) using multimodal MRI.  Methods: We
prospectively performed MRI and cognitive testing in RVCL-S and healthy
control cohorts. Gray and white matter volume and disruption of white
matter microstructure were quantified. Asymmetric spin echo acquisition
permitted voxel-wise oxygen extraction fraction (OEF) calculation as an in
vivo marker of microvascular ischemia. The RVCL-S cohort was included in a
longitudinal analysis of lesion subtypes in which hyperintense lesions on
FLAIR, T1-post-gadolinium, and diffusion-weighted imaging were delineated
and quantified volumetrically. Results: Twenty individuals with RVCL-S and
26 controls were enrolled. White matter volume and microstructure declined
faster in RVCL–S compared to controls. White matter atrophy in RVCL-S was
highly linear (ρ=-0.908, p<0.0001). Normalized OEF was elevated in
RVCL-S, and increased with disease duration. Multiple cognitive domains,
specifically those measuring working memory and processing speed, were
impaired in RVCL-S. Lesion volumes, regardless of subtype,
progressed/regressed with high variability as a function of age, while
FLAIR lesion burden increased near time-to-death (p<0.001).
Conclusion: RVCL-S is a monogenic microvasculopathy predominantly
affecting the white matter with regard to atrophy and cognitive
impairment. White matter volumes in RVCL-S declined linearly, providing a
potential metric against which to test efficacy of future therapies.
Progressive elevation of white matter OEF suggests microvascular ischemia
may underlie neurodegeneration in RVCL-S.