Family-Based Moyamoya Susceptibility and Early Detection

Overview

This single-center, prospective, family-based observational cohort study aims to investigate susceptibility to moyamoya disease (MMD) and to develop strategies for early screening in individuals at increased familial risk. The study will enroll three groups: patients with MMD, their first-degree relatives, and healthy controls without a family history of MMD. The rationale for this study is that MMD has an important genetic component, but genetic susceptibility alone does not fully explain disease onset. Current diagnosis often relies on angiographic evaluation after symptoms have already appeared. This study seeks to identify earlier, less invasive biological and imaging markers that may help detect individuals at high risk before overt clinical disease develops. At baseline, participants will undergo collection of demographic and clinical data, vascular risk factors, neurological assessments, routine laboratory testing, and 5T high-resolution magnetic resonance imaging. Biospecimens including blood, urine, stool, saliva, and nasal swabs will be collected for multi-omics and biomarker analyses; surgically obtained tissue specimens may also be collected from patients undergoing clinically indicated surgery. Participants in the patient and first-degree relative groups will be followed annually for 3 years, primarily by telephone or online questionnaire, with optional repeat 5T MRI during follow-up. The primary objective is to identify baseline biological and imaging features associated with incident MMD in first-degree relatives and to establish an interpretable early-screening framework for high-risk populations.

Moyamoya disease (MMD) is a chronic, progressive cerebrovascular disorder characterized by progressive stenosis or occlusion of the terminal internal carotid arteries and their major branches, accompanied by the development of abnormal collateral vessels. Although genetic susceptibility plays an important role in MMD, incomplete penetrance suggests that non-genetic factors, including immune, inflammatory, metabolic, microbial, and environmental influences, may also contribute to disease onset and progression. Earlier identification of high-risk individuals remains challenging because definitive diagnosis is often made only after clinical symptoms appear. This study is an investigator-initiated, single-center, prospective, non-randomized, non-interventional observational cohort study conducted at Beijing Hospital. A total of 700 participants are planned for enrollment, including 400 patients with MMD, 200 first-degree relatives of patients with MMD, and 100 healthy controls without a family history of MMD. The overall study duration is 5 years, and the expected participation time for each participant is approximately 3 years. The main objective is to identify early biological and imaging markers of MMD and to evaluate susceptibility in individuals with familial risk. By comparing patients, unaffected first-degree relatives, and healthy controls at baseline, and by prospectively following the relative group, the study aims to determine which baseline features are associated with future disease development and to define risk factors that may support early screening strategies. The study also seeks to generate a multimodal panel of candidate markers and to build an interpretable early warning framework for high-risk populations. At baseline, the study will collect demographic data, family history, medical history, medication use, vascular risk factors, smoking and alcohol exposure, neurological status, physiological measures, and lifestyle information. All groups will undergo routine laboratory testing and 5T high-resolution MRI at enrollment. Biospecimens will include blood, urine, stool, saliva, and nasal swabs for analyses such as inflammatory markers, metabolomics, and microbiome profiling. For patients who undergo clinically indicated surgery, operative tissue specimens may also be collected without adding surgical risk. Follow-up will be performed once yearly for 3 years, mainly by telephone or online questionnaire, in the patient and first-degree relative groups. Participants who are willing may return for optional repeat 5T MRI. Follow-up assessments will include new diagnosis of MMD or suspected cerebrovascular events in the relative group, disease progression in the patient group, functional outcome by modified Rankin Scale, changes in symptoms and daily activity, medication changes, and control of major risk factors. If new MMD or stroke-related events are suspected, relevant medical records and imaging data will be collected for outcome adjudication. The primary outcomes are: (1) incident MMD during follow-up in first-degree relatives, confirmed by clinical diagnosis and imaging findings; and (2) disease progression and prognosis in patients with MMD, including recurrent stroke or transient ischemic attack, rehospitalization, repeat surgery or intervention, and functional outcome. Secondary outcomes include imaging progression, cardiovascular or cerebrovascular death and all-cause mortality, and post-stroke disability defined as modified Rankin Scale score greater than 3. The analytical strategy will include baseline cross-sectional comparisons across the three groups and longitudinal analysis of first-degree relatives according to whether MMD develops during follow-up. Candidate biomarkers and imaging features associated with future disease onset will be evaluated and integrated into prediction models using regression-based and/or machine-learning approaches, with assessment of discrimination, calibration, and potential clinical utility for early screening.