研究背景 青年缺血性卒中（以下简称“青年卒中”）通常定义为 18-50 岁期间首次 起病的缺血性卒中。相比于老年卒中，青年卒中病因更为复杂，给疾病诊断及预防 复发带来挑战，给个人、家庭及社会造成了严重的疾病负担。相比于传统脑血管成 像技术，高分辨率磁共振血管壁成像（high-resolution magnetic resonance vessel wall imaging, HRMR-VWI）可以提供更多管壁及管腔内信息，在识别动脉粥样硬化斑块 与非动脉粥样硬化性血管病方面发挥重要作用。然而，目前国内外有关使用 HRMR-VWI 方法进行的青年卒中病因学研究数量十分有限，且结果存在差异，需要开展进 一步研究以深入探索 HRMR-VWI 在青年卒中病因诊断中的作用。同时，卒中为一 种受遗传、环境及生活方式等多种因素共同影响的异质性疾病，遗传因素在卒中的 发生发展中起着重要作用，而目前针对青年卒中患者开展的遗传学研究（尤其是罕 见变异的研究）仍较为缺乏。罕见变异关联分析为一种专门用于检测罕见变异与复 杂性状之间关联的遗传学研究方法，目前尚缺乏针对青年卒中的罕见变异关联分析， 需要开展相关研究以填补空白。 研究方法 本研究为一项单中心、前瞻性研究，入组 2017 年 3 月-2024 年 8 月期间 就诊于北京协和医院、近 6 个月内发生急性缺血性卒中的 18-50 岁患者。收集患者 临床信息、实验室辅助检查、影像学检查及随访结果。比较患者 HRMR-VWI 检查 前后病因分型差异，深入分析青年卒中患者的影像学特征，并探索影像学特征与预 后的关系；同时，对患者进行全外显子基因测序和罕见变异关联分析，以及基于通 路的富集分析和表型分析，以深入探索青年卒中患者潜在的遗传学病因和发病机制。 结果 共入组青年卒中患者 353 人，行 HRMR-VWI 检查者 189 人，中位年龄 35 岁，男性占 58.73%。经 HRMR-VWI 检查后，16.93%的患者病因分型发生改变，大 动脉粥样硬化型增加 7.41%，其他明确病因型增加 9.00%，病因不明型患者比例降 低 16.41%，检查前后病因分型构成比差异具有统计学意义（P<0.0001）。存在颅内 动脉粥样硬化病变者占 33.33%，其中年轻患者（<35 岁）中易损斑块更常见（40.62% vs 16.67%, P=0.0378）。相比于经 HRMR-VWI 检查未发现颅内动脉病变的患者，发 现颅内动脉病变的患者复发风险更低（HR=0.38, 95% CI 0.03-0.90, P=0.0276）。青年 卒中队列中，纳入罕见变异关联分析者 221 人，中位年龄为 35 岁，男性占 58.37%。 设定全基因组显著性阈值为 P<2.78×10-6 ，未在全基因组水平上检测到显著关联基 因；对基因进行功能富集和通路分析的结果显示，在与血小板活化相关的通路中， 罕见有害变异携带组与非携带组在临床表型上存在差异，变异携带组大动脉粥样硬 化型卒中的比例高于未携带组（23.16% vs 6.82%, P=0.0265），且血白细胞水平更高 （6.51 [IQR: 5.17,7.72] vs 6.24 [IQR: 4.97,7.04], P=0.0477）。 结论 HRMR-VWI 能够显著改善青年卒中病因分型，病因不明型卒中占比明显下 降。在青年卒中（尤其是隐源性卒中）患者中推广 HRMR-VWI 有望提高病因诊断 率，从而指导后续精准治疗，改善患者预后。同时，应重视深入探索青年卒中患者 早发动脉粥样硬化的发病机制，尤其是遗传因素等内在异质性病因。本次研究结果 提示，血小板活化相关生物学通路在青年卒中及早发动脉粥样硬化的发生中可能起 到重要作用，针对该通路及其关键基因的进一步深入探索和靶向基因药物的研发有 望为疾病的早期干预和精准治疗提供新的方向。

Background Ischemic stroke in young adults is usually defined as ischemic stroke occurring between the ages of 18 and 50 for the first time. Compared to stroke in the elderly, the etiology of young ischemic stroke is more complex, posing challenges to diagnosis and recurrence prevention and imposing a significant disease burden on patients, families, and society. High-resolution magnetic resonance vessel wall imaging (HRMR-VWI) offers superior vessel wall visualization compared to conventional cerebrovascular imaging techniques, playing a crucial role in distinguishing atherosclerotic and non-atherosclerotic vascular diseases. However, studies using HRMR-VWI on etiology of ischemic stroke in young adults remain limited, with inconsistent findings, necessitating further research to clarify its diagnostic utility. Moreover, stroke is a heterogeneous disease influenced by genetic, environmental, and lifestyle factors. Genetic factors play a critical role in its pathogenesis, particularly in early-onset stroke. However, genetic studies focusing on young ischemic stroke, especially on rare variants, remain scarce. Rare variant association studies (RVAS) are specialized genetic research methods designed to detect associations between rare variants and complex traits. Currently, there is still a lack of RVAS on young ischemic stroke. Methods This study is a single-center, prospective study enrolling patients aged 18–50 who experienced acute ischemic stroke within the past six months and were admitted to Peking Union Medical College Hospital between March 2017 and August 2024. Clinical data, laboratory test results, imaging findings, and follow-up outcomes were collected. The study compared etiological classification before and after HRMR-VWI, analyzed imaging characteristics of young ischemic stroke patients, and conducted survival analysis. Additionally, whole-exome sequencing (WES) and RVAS were conducted, followed by pathway-based enrichment analysis and phenotypic analysis to explore potential genetic etiologies and underlying mechanisms of ischemic stroke in young adults. Results A total of 353 patients were enrolled, among whom 189 underwent HRMR-VWI (median age: 35 years; male: 58.73%). After HRMR-VWI, 16.93% of patients had a reclassified etiology, with an increased proportion of large-artery atherosclerosis and other determined causes, while the proportion of cryptogenic stroke decreased. The change in etiological classification was statistically significant (P<0.0001). Intracranial atherosclerosis was present in 33.33% of patients, with vulnerable plaques being more common in younger patients (<35 years) compared to older patients (40.62% vs. 16.67%, P=0.0378). Patients with intracranial vascular abnormalities detected by HRMR-VWI had a lower risk of recurrence than those without such abnormalities (HR=0.38, 95%CI: 0.03– 0.90, P= 0.0276). And 221 patients underwent WES (median age: 35 years; male: 58.37%). No genome-wide significant association was identified at the threshold of P<2.78×10⁻⁶. Functional enrichment and pathway analyses revealed that rare deleterious variants were associated with pathways related to platelet activation. Clinically, the rare variant carrier group had a higher proportion of large-artery atherosclerosis stroke compared with non-carriers (23.16% vs. 6.82%, P = 0.0380) and exhibited a higher level of white blood cell (6.51 [IQR: 5.17,7.72] vs 6.24 [IQR: 4.97,7.04], P=0.0477). Conclusion HRMR-VWI provides valuable adjunctive information for the etiological diagnosis of ischemic stroke in young adults. The application might enhance diagnostic accuracy, guide targeted treatment strategies, and improve outcomes. Additionally, further research into the mechanisms of premature atherosclerosis in young stroke is warranted, with particular emphasis on genetic factors and other intrinsic heterogeneities. Our findings suggest that the pathway of platelet activation might play a pivotal role in young ischemic stroke and early-onset atherosclerosis. Future research on these pathways and their key genes might lay foundation for early intervention and precision medicine in young ischemic stroke.