Comparison of Longitudinal Changes of Cerebral Small Vessel Disease Markers and Cognitive Function Between Subcortical Vascular Mild Cognitive Impairment With and Without NOTCH3 Variant: A 5-Year Follow-Up Study.

Cindy W Yoon,Duk L Na,Hee Jin Kim,Chang-Seok Ki,Hyejoo Lee,Young-Eun Kim,Joung-Ho Rha,Sang Won Seo

doi:10.3389/fneur.2021.586366

Abstract

No study yet has compared the longitudinal course and prognosis between subcortical vascular cognitive impairment patients with and without genetic component. In this study, we compared the longitudinal changes in cerebral small vessel disease markers and cognitive function between subcortical vascular mild cognitive impairment (svMCI) patients with and without NOTCH3 variant [NOTCH3(+) svMCI vs. NOTCH3(–) svMCI]. We prospectively recruited patients with svMCI and screened for NOTCH3 variants by sequence analysis for mutational hotspots in the NOTCH3 gene. Patients were annually followed-up for 5 years through clinical interviews, neuropsychological tests, and brain magnetic resonance imaging. Among 63 svMCI patients, 9 (14.3%) had either known mutations or possible pathogenic variants. The linear mixed effect models showed that the NOTCH3(+) svMCI group had much greater increases in the lacune and cerebral microbleed counts than the NOTCH3(–) svMCI group. However, there were no significant differences between the two groups regarding dementia conversion rate and neuropsychological score changes over 5 years.

Highlights

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant disorder of cerebral small vessels caused by mutations in the NOTCH3 gene on chromosome 19 [1]
We compared the longitudinal course of subcortical vascular mild cognitive impairment (svMCI) patients according to the presence of NOTCH3 variant in a well-defined svMCI cohort based on standardized imaging protocols, detailed clinical evaluation, and genetic analysis
We believe this is the first study to compare the longitudinal changes of cerebral small vessel disease (CSVD) markers and cognition between subcortical vascular cognitive impairment (SVCI) patients with and without NOTCH3 variant

Summary

Introduction

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant disorder of cerebral small vessels caused by mutations in the NOTCH3 gene on chromosome 19 [1]. CADASIL is characterized by cerebral small vessel disease (CSVD) and cognitive impairment, and is considered as a genetic form of subcortical vascular cognitive impairment (SVCI). Sporadic SVCI is mostly caused by vascular risk factors. Longitudinal Effect of NOTCH3 Variant vascular risk factors can lead to CSVD characterized by white matter hyperintensities (WMHs), lacunes, and cerebral microbleeds (CMBs) on magnetic resonance imaging (MRI) [2]. We previously reported that approximately 13% of consecutive patients with SVCI had NOTCH3 variants, they were of advanced age and frequently had a history of HTN [4]. Cross-sectional comparison, a snapshot of a single moment in time, has interpretative limitations

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