Family-Based Moyamoya Susceptibility and Early Detection

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.

Inclusion criteria

• Participants must belong to 1 of the following 3 cohorts:

Moyamoya disease cohort: diagnosed with primary moyamoya disease according to standard diagnostic criteria, with progressive stenosis or occlusion at the terminal internal carotid arteries and/or their major branches and typical collateral vessels on DSA, CTA, or MRA; newly diagnosed and previously diagnosed cases are both eligible; no age or sex restriction.

First-degree relative cohort: first-degree blood relatives of patients with moyamoya disease, including parents, children, and siblings; no age or sex restriction; no clinical diagnosis of moyamoya disease and no history of stroke or other cerebrovascular events at enrollment; baseline MRI does not show definite moyamoya disease, although mild changes are allowed.

Healthy control cohort: no family history of moyamoya disease; no personal history of cerebrovascular disease; no major abnormalities on physical examination or baseline screening; age and sex distribution matched as closely as possible to the moyamoya disease cohort.

Exclusion criteria

• Major systemic or central nervous system diseases that may interfere with study results or substantially affect survival or adherence, such as advanced malignant tumors, active tuberculosis or other serious infections, active systemic lupus erythematosus, or severe hepatic or renal dysfunction.

Atypical cerebrovascular lesions on baseline imaging, such as widespread atherosclerotic stenosis or congenital vascular malformations.

Inability to complete examinations or follow-up, including MRI contraindications such as non-compatible metal implants or severe claustrophobia, expected difficulty completing follow-up because of long-term relocation, poor communication access, poor adherence, or other situations judged by the investigators to make participation inappropriate.

Pregnant women.