CADASIL Registry in East Asia (CADREA): Protocol for an international prospective cohort study

Abstract

Introduction: Recent advancements in genomic research have revealed that 9 individuals per 1,000 population in East Asia and 3.4 individuals per 1,000 population worldwide carry cysteine-altering NOTCH3 variants in the epidermal growth factor-like repeat domains, which are the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Compared to CADASIL patients in Western countries, Asian patients exhibit several differences, including: (1) different predominant pathogenic NOTCH3 variants, (2) a higher prevalence of hemorrhagic stroke, and (3) a lower prevalence of white matter hyperintensities in the anterior temporal pole. Therefore, it is necessary to conduct large- scale clinical studies in East Asia to establish clinical evidence for CADASIL patients in this region. We here investigate clinical, genetic, and neuroradiological characteristics of CADASIL patients in Japan, Korea, and Taiwan. Methods: The current CADREA (CADASIL Registry in East Asia) study will recruit 1,000 CADASIL patients diagnosed based on the results of NOTCH3 genetic testing. From September, 2023, physicians in participating facilities will register clinical data, including age, gender, race, medical history, social history, medication history, family history, scores of the Montreal Cognitive Assessment and Trail Making Test, and detailed information on stroke events, into an Electronic Data Capture system called Research Electronic Data Capture (REDCap). Brain MRI data will be independently evaluated by the Central Evaluation Committee. Each patient will undergo annual evaluations for two years. The study will examine genotype-phenotype correlations, particularly in the frequency of stroke events and changes in cognitive function and imaging biomarkers. Discussion: The CADREA study will uncover the natural history of CADASIL patients in East Asia, providing basic data for future clinical trials. Additionally, the findings may have implications for understanding the unique characteristics of CADASIL in Asian populations and inform potential interventions and treatments.