Abstract 129: Cerebral Oxygen Extraction Fraction Predicts White Matter Lesion Progression In Patients With A Monogenic Cerebral Small Vessel Disease

Background: A rare, monogenic cerebral small vessel disease (cSVD), retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S), is associated with progressive cerebral ischemia and accelerated vascular cognitive impairment, resulting in premature death. We hypothesized that low cerebral blood flow (CBF) and elevated oxygen extraction fraction (OEF), as metrics of microvascular ischemia, would predict growth of white matter lesions (WML) and other neuroimaging manifestations of cSVD. Methods: We prospectively performed sequential brain MRI in a cohort of RVCL-S participants. Pseudocontinuous arterial spin labeling and asymmetric spin echo quantified CBF and OEF in normal appearing white matter (NAWM), respectively. WMLs were manually delineated on FLAIR. WM volumes were segmented and quantified. Diffusion tensor imaging (DTI) was used to measure NAWM mean diffusivity (MD). Results: Each of 14 RVCL-S participants underwent a median of 4.5 scans (IQR 3 - 6.75) with a median of 6.5 months (IQR 5.8 - 8.6) between scans performed over 2.9 years (IQR 2.0 - 4.2). Elevated NAWM OEF from the previous MRI, but not CBF, was associated with WML growth (ρ = 0.672, p < 0.0001), WM atrophy (ρ = 0.654, p < 0.0001), and increased MD (ρ = 0.714, p < 0.0001, Figure). After adjusting for age, sex, previous WML volume, and participant, previous OEF remained an independent predictor of WML growth (β = 7.04 (1.08, 13.01), p = 0.021). NAWM OEF was not retained in the mixed models predicting WM atrophy and MD. Conclusion: We found evidence that hypoxic-ischemic physiology, as measured by elevated OEF in NAWM, independently predicted WML growth. Previous OEF was associated with WM atrophy and decrease in microstructural integrity on follow-up. This work suggests that ischemia in normal brain regions may be a harbinger of disease progression in patients with RVCL-S, an inherited cSVD. Additionally, OEF may serve as a potential predictive biomarker in sporadic cSVD.