DOI: 10.5061/dryad.stqjq2c0j
title: Lesion evolution and neurodegeneration in RVCL-S, a monogenic microvasculopathy

description: 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&lt;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&lt;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.  
description: <i>Lesion
 Subtype Segmentation.  </i>Five lesion subtypes were evaluated for
 hyperintensity including: (1) FLAIR lesions, (2) FLAIR lesions excluding
 pseudotumors, (3) FLAIR lesions including only pseudotumors, (4) T1
 post-gadolinium lesions, and (5) diffusion weighted imaging (DWI)
 lesions.  Hyperintense lesions were manually outlined by a vascular
 neurology fellow and board-certified neurologist (V.B.) and medical
 student (V.C.), then reviewed and edited by a board-certified vascular
 neurologist (A.F.) using Medical Image Processing, Analysis, and
 Visualization software (https://mipav.cit.nih.gov/). Pseudotumors,
 including both the central lesion and surrounding vasogenic edema, were
 outlined on FLAIR and defined as a FLAIR hyperintense lesion aligning with
 a central T1 ring-enhancing lesion located near the lateral ventricles.
  For “T1 post-gadolinium lesions” also referred to as “nodular
 contrast-enhancing lesions”, all lesions with contrast-enhancement,
 whether or not, they were associated with a pseudotumor (as judged by
 periventricular and surrounding FLAIR signal), were included. 
 Only the RVCL-S
 participants with at least three scan time-points over at least 30 months
 were included for the lesion subtype analysis. Of these seven patients,
 five had known age of death and two were still alive with age of death
 imputed as the median value from all RVCL-S patients who had died. 
 Repeated patient data was included as a random effect in all models.  For
 models not meeting normality assumptions, data underwent transformation
 prior to regression, using the natural logarithmic function or non-linear
 fits, as needed.  Across all study analyses, results were presented only
 if valid without collinearity and with normal residuals.
description: This is supplemental data that did not fit into the
 manuscript. Clayco Foundation, Energy 4 A
 Cure Foundation, Cure CRV Research, National Institutes of Health:
 National Heart, Lung, and
 Blood Institute (R01HL129241, A.L.F); Washington University
 St. Louis CTSA (UL1 TR000448, A.L.F.).