第一部分 IL33与可溶性ST2在烟雾病中的表达特征以及预后价值分析

【目的】烟雾病（moyamoya disease, MMD）是一种以进行性颅内动脉狭窄和异常血管网络形成为特征的脑血管疾病，但目前针对术后远期预后的有效预测因子仍较为有限。白细胞介素-33（interleukin-33, IL-33）及其可溶性受体生长刺激表达基因2蛋白（growth stimulation expressed gene 2 protein, ST2）在炎症反应和血管重塑中发挥关键作用，但其在烟雾病中的预后价值尚不明确。本研究旨在探讨IL-33及ST2在烟雾病患者外周血中的表达特征，分析其与疾病预后的相关性，并评估IL33和ST2在烟雾病预后预测模型中的增益价值，为优化临床风险分层及诊疗决策提供循证依据。

【方法】采用前瞻性单中心队列研究设计，连续纳入2022年9月至2024年9月我院神经外科确诊的201例烟雾病患者及49例健康对照。通过酶联免疫吸附法（enzyme-linked immunosorbnent assay，ELISA）检测血清IL-33和ST2水平，收集基线临床资料及脑血运重建术后随访数据。预后不良定义为随访改良Rankin量表（modified Rankin Scale，mRS）评分升高。运用单因素及多因素Logistic回归分析IL-33/ST2与烟雾病预后的关联。应用受试者工作曲线（receiver operating characteristic，ROC）、曲线下面积（area under curve，AUC）、布里尔分数（Brier score）、赤池信息准则（Akaike information criterion，AIC）、贝叶斯信息准则（Bayesian information criterion，BIC）、净重分类改善指数（net reclassification index，NRI）及综合判别改善指数（integrated discrimination improvement，IDI）评估在烟雾病基础预后模型（包括高血压、糖尿病、高脂血症、吸烟史、饮酒史、BMI、白细胞计数、血红蛋白、甘油三酯、总胆固醇、同型半胱氨酸、临床表型、Suzuki分期、手术方式）的基础上，IL-33与ST2的预后增益。运用决策曲线分析（decision curve analysis，DCA）评估IL-33、ST2以及联合应用的临床效能。

【结果】烟雾病患者血清IL-33和ST2水平显著高于健康对照组（P均＜0.001）。患者中位随访时间15.24个月，其中预后不良的患者23例（11.4%）。预后不良组IL-33水平显著低于预后良好组（15.43vs12.13pg/ml，P＜0.001），而ST2水平显著升高（3783.09vs8431.94pg/ml，P＜0.001）。多因素回归显示，IL-33升高可降低烟雾病患者预后不良风险（OR：0.812，95%CI：0.732-0.938），ST2升高则增加预后不良风险（OR：1.584，95%CI：1.132-2.365）。在既有预测模型的基础上，IL-33和ST2能显著改善模型区分度、校准度、再分类度（P均＜0.05）。联合IL-33和ST2不仅可以改善烟雾病基础预测模型的预测效能（AUC：0.868vs0.719；布里尔分数：0.125vs0.166；AIC：331.87vs408.91；BIC：417.37vs486.63；IDI：20.3%，95%CI：15.3%-25.1%；NRI：10.9%，95%CI：8.9%-12.8%，P均＜0.05），也可进一步提升IL-33和ST2带来的预后增益，并在阈值概率在9.0%-71.5%范围时，有良好的临床效能。亚组分析表明，IL-33的保护效应在合并高脂血症及Suzuki分期晚期患者中更显著，而ST2的风险效应在出血型烟雾病患者中尤为突出。

【结论】IL-33是烟雾病远期预后不良的保护因素，其可溶性受体ST2是烟雾病远期预后不良的危险因素。联合IL-33和ST2可显著优化预后预测模型效能，提升个体化风险分层能力。IL-33/ST2炎症信号通路可能在烟雾病的发展过程中发挥作用，为烟雾病的未来研究和治疗确定了一个潜在的炎症靶点。

第二部分 糖脂代谢异常在烟雾病风险预测及预后评估中的综合研究

第一节 血清ApoB/ApoA1比值与烟雾病风险的相关性及其预测价值

【目的】烟雾病（Moyamoya Disease，MMD）是一种以颅内动脉进行性狭窄和代偿性侧支血管形成为特征的罕见脑血管疾病，其病因尚未完全阐明。脂质代谢异常可能与烟雾病发病机制相关，载脂蛋白B（apolipoprotein B，ApoB）与载脂蛋白A1（apolipoprotein A1，ApoA1）比值（ApoB/ApoA1）是反映脂质代谢与转运异常的重要评估指标，ApoB/ApoA1比值与烟雾病的关系尚不明确，本研究旨在探讨ApoB/ApoA1比值与烟雾病风险的关联及其临床预测价值。

【方法】本研究纳入2022年9月至2024年9月我院神经外科就诊的201例烟雾病患者（缺血型144例，出血型57例）及49例健康对照，收集研究人群的基线资料。通过单因素和多因素Logistic回归模型分析ApoB/ApoA1比值与烟雾病及其亚型风险的关联。采用受试者工作曲线（receiver operating characteristic，ROC）、曲线下面积（area under curve，AUC）净重分类改善指数（net reclassification index，NRI）及综合判别改善指数（integrated discrimination improvement，IDI）评价在烟雾病风险基础预测模型（年龄、性别、心率、收缩压、舒张压、BMI、白细胞计数、淋巴细胞计数、单核细胞计数、中性粒细胞计数、血小板计数、白蛋白、谷丙转氨酶、谷草转氨酶、碱性磷酸酶、空腹血糖、尿素、肌酐、尿素、同型半胱氨酸）的基础上，ApoB/ApoA1比值的风险增益。

【结果】烟雾病患者及其亚型的ApoB/ApoA1比值显著高于健康对照组（P均＜0.05）。在校正传统风险因素后，多因素回归显示，血清ApoB/ApoA1水平与烟雾病及其亚型风险显著相关。ApoB/ApoA1每升高1单位，烟雾病风险增加6.103倍（OR：7.103，95%CI:1.242-15.620，P=0.028）。缺血型与出血型亚型中，风险关联同样显著（OR：6.715，95%CI：2.475-15.528，P=0.002；OR：8.400，95%CI：4.438-22.589，P=0.001）。ROC分析显示，基础模型加入ApoB/ApoA1后预测效能提升（AUC：0.882vs0.871），在缺血型亚型增益同样显著（AUC：0.884vs0.867）。新模型对烟雾病风险的净重分类能力和综合判别能力均显著提升（IDI：5.1%，95%CI：2.8%-12.9%，P=0.041；NRI：14.4%，95%CI：7.9%-36.8%,P=0.020），在缺血型亚型中保持这种趋势（IDI：7.4%，95%CI:4.1%-9.7%，P=0.005；NRI：16.3，95%CI：95%CI:2.9-27.3%，P=0.002）。

【结论】ApoB/ApoA1比值升高是烟雾病的独立危险因素，其作为新型生物标志物可显著提升烟雾病风险预测模型的区分度与再分类能力，尤其在缺血亚型中表现优异。该发现为烟雾病的早期筛查和机制研究提供了重要依据。

第二节 甘油三酯-葡萄糖指数对烟雾病脑血运重建术后远期脑血管不良事件的预测价值

【目的】烟雾病是一种以脑血管进行性狭窄和异常血管网形成为特征的疾病，脑血运重建术可降低卒中风险，但术后远期脑血管事件仍无法完全避免。胰岛素抵抗（insulin resistance，IR）与心脑血管事件密切相关，甘油三酯-葡萄糖指数（triglyceride glucose index，TyG）作为IR的替代标志物，其在烟雾病术后预后中的价值尚不明确。本研究旨在探究TyG指数与烟雾病脑血运重建术后远期脑血管不良事件的关联。

【方法】本研究为单中心回顾性队列研究，纳入2022年9月至2024年9月我院神经外科接受脑血运重建术的烟雾病患者。通过单因素、多因素Cox回归以及Kaplan-Meier生存曲线分析TyG指数与术后脑血管不良事件（TIA、缺血/出血性卒中）的关联，并评估其在基础预测模型（包括年龄、性别、高血压、糖尿病、高脂血症、吸烟史、饮酒史、BMI、同型半胱氨酸、临床表型、Suzuki分期和手术方式）中的增益效能。应用一致性评分（concordance index）、布里尔分数（Brier score）、赤池信息准则（Akaike information criterion，AIC）、贝叶斯信息准则（Bayesian information criterion，BIC）、净重分类改善指数（net reclassification index，NRI）及综合判别改善指数（integrated discrimination improvement，IDI）评估在烟雾病基础预测模型（包括年龄、性别、高血压、糖尿病、高脂血症、吸烟史、饮酒史、BMI、同型半胱氨酸、临床表型、Suzuki分期和手术方式）的基础上，TyG指数的预后增益。运用决策曲线分析（decision curve analysis，DCA）评估应用TyG指数的临床效能。

【结果】最终纳入201例烟雾病患者，中位随访15.24个月，随访期间31例（15.4%）患者发生脑血管不良事件。多因素Cox回归分析显示，基线TyG指数水平升高与烟雾病患者脑血运重建术后随访期间脑血管不良事件发生风险升高相关。TyG指数每升高1个单位，脑血管不良事件风险增加2.487倍（校正后HR=3.487，95%CI:1.981-6.139，P<0.001）。相较于TyG最低三分位组（T1），最高三分位组（T3）风险增加4.086倍（HR=5.086，95%CI:3.161-6.886）。基础模型联合TyG指数后，能显著改善患者脑血管不良事件风险分层和预后能力（C-index：0.776vs0.726；布里尔分数：0.131vs0.136；AIC：341.29vs354.68；BIC：422.89vs432.40；IDI：5.0%，95%CI：2.4%-7.6%；NRI：5.9%,95%CI:3.4%-8.5%，P均<0.05），当事件阈值概率为36.5%-81.5%范围内时，能提高预后模型的临床效能。

【结论】TyG指数升高是烟雾病脑血运重建术后远期脑血管不良事件的独立危险因素。将其纳入现有预测模型可显著提升风险分层效能，为术后管理提供重要参考。

Part 1: Expression Profiles and Prognostic Value of IL-33 and Soluble ST2 in Moyamoya Disease

【Objective】Moyamoya disease (MMD) is a cerebrovascular disorder characterized by progressive intracranial arterial stenosis and the formation of abnormal vascular networks. However, effective predictors for long-term postoperative prognosis remain limited. Interleukin-33 (IL-33) and its soluble receptor suppression of tumorigenicity 2 (ST2) play critical roles in inflammatory responses and vascular remodeling, yet their prognostic value in MMD is unclear. This study aimed to investigate the expression profiles of IL-33 and ST2 in the peripheral blood of MMD patients, analyze their correlation with disease prognosis, and evaluate the incremental value of IL-33 and ST2 in optimizing prognostic prediction models, thereby providing evidence-based insights for clinical risk stratification and treatment decision-making.

【Methods】This study employed a prospective single-center cohort design, consecutively enrolling 201 patients with moyamoya disease diagnosed in the Department of Neurosurgery at our hospital and 49 healthy controls from September 2022 to September 2024. Serum IL-33 and ST2 levels were measured using enzyme-linked immunosorbent assay (ELISA). Baseline clinical data and postoperative follow-up outcomes after cerebral revascularization were collected. Poor prognosis was defined as an increase in the modified Rankin Scale (mRS) score during follow-up. Univariate and multivariate logistic regression analyses were performed to assess the association of IL-33/ST2 with prognosis. Receiver operating characteristic (ROC) curves, area under the curve (AUC), Brier score, Akaike information criterion (AIC), Bayesian information criterion (BIC), net reclassification index (NRI), and integrated discrimination improvement (IDI) were used to evaluate the incremental prognostic value of IL-33 and ST2 when added to a baseline MMD prognostic model (including hypertension, diabetes, hyperlipidemia, smoking, alcohol use, BMI, white blood cell count, hemoglobin, triglycerides, total cholesterol, homocysteine, clinical phenotype, Suzuki stage, and surgical approach). Decision curve analysis (DCA) was applied to assess the clinical utility of IL-33, ST2, and their combination.

【Results】Serum IL-33 and ST2 levels in MMD patients were significantly higher than in healthy controls (both P<0.001). The median follow-up was 15.24 months, with 23 patients (11.4%) experiencing poor prognosis. Poor prognosis patients exhibited significantly lower IL-33 levels (15.43 vs 12.13 pg/mL, P<0.001) and higher ST2 levels (3783.09 vs 8431.94 pg/mL, P<0.001). Multivariate regression revealed that elevated IL-33 reduced the risk of poor prognosis (OR: 0.812, 95% CI: 0.732-0.938), while elevated ST2 increased the risk (OR: 1.584, 95% CI: 1.132-2.365). Adding IL-33 and ST2 to the baseline model significantly improved model discrimination, calibration, and reclassification (all P<0.05). The combined IL-33/ST2 model enhanced predictive performance (AUC: 0.868 vs 0.719; Brier score: 0.125 vs 0.166; AIC: 331.87 vs 408.91; BIC: 417.37 vs 486.63; IDI: 20.3%, 95% CI: 15.3%-25.1%; NRI: 10.9%, 95% CI: 8.9%-12.8%; all P<0.05) and demonstrated robust clinical utility at threshold probabilities of 9.0%-71.5%. Subgroup analyses indicated that the protective effect of IL-33 was more pronounced in patients with hyperlipidemia or advanced Suzuki stage, while the risk effect of ST2 was particularly significant in hemorrhagic MMD.

【Conclusion】IL-33 is a protective factor against long-term poor prognosis in MMD, whereas ST2 is a risk factor. Combining IL-33 and ST2 significantly enhances the performance of prognostic models, improving individualized risk stratification. The IL-33/ST2 inflammatory signaling pathway may play a role in MMD progression, highlighting a potential therapeutic target for future research and treatment.

Part II Comprehensive Study on Abnormal Glucose and Lipid Metabolism in Risk Prediction and Prognosis Assessment of Moyamoya Disease
Section 1：Correlation Between Serum ApoB/ApoA1 Ratio and Moyamoya Disease Risk and Its Predictive Value

【Objective】Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by progressive intracranial arterial stenosis and compensatory collateral vessel formation, with its etiology remaining incompletely understood. Abnormal lipid metabolism may contribute to its pathogenesis. The apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) ratio, a key indicator of lipid metabolism and transport dysfunction, has an unclear relationship with MMD. This study aims to explore the association between the ApoB/ApoA1 ratio and MMD risk, as well as its clinical predictive value.

【Methods】This study enrolled 201 patients with moyamoya disease (144 ischemic type, 57 hemorrhagic type) and 49 healthy controls who visited the Department of Neurosurgery at our hospital from September 2022 to September 2024, and baseline data of the study population were collected. Univariate and multivariate logistic regression models were used to analyze the association between the ApoB/ApoA1 ratio and MMD risk, including its subtypes. Receiver operating characteristic (ROC) curves, area under the curve (AUC), net reclassification index (NRI), and integrated discrimination improvement (IDI) were employed to evaluate the incremental predictive value of adding the ApoB/ApoA1 ratio to a baseline risk model (age, sex, heart rate, systolic blood pressure ,diastolic blood pressure, BMI, leukocyte platelet counts, lymphocyte platelet counts, monocyte, platelet counts, neutrophil, platelet counts, platelet counts, albumin, ALT, AST, ALP, fasting glucose, urea, creatinine, homocysteine).

【Results】The ApoB/ApoA1 ratio was significantly higher in MMD patients and subtypes compared to controls (P<0.05). After adjusting for traditional risk factors, multivariate regression revealed a significant association between serum ApoB/ApoA1 levels and MMD risk. Each 1-unit increase in ApoB/ApoA1 elevated MMD risk by 6.103-fold (OR:7.103,95% CI:1.242-15.620, P=0.028). Similar associations were observed for ischemic (OR: 6.715, 95% CI: 2.475-15.528, P=0.002) and hemorrhagic subtypes (OR: 8.400, 95% CI: 4.438-22.589, P=0.001). ROC analysis showed improved predictive performance after adding ApoB/ApoA1 to the baseline model (AUC: 0.882 vs 0.871), with greater gains in ischemic subtypes (AUC: 0.884 vs 0.867). The new model significantly enhanced net reclassification (NRI: 14.4%, 95%CI: 7.9%–36.8%, P=0.020) and discrimination (IDI: 5.1%, 95%CI: 2.8%-12.9%, P=0.041), particularly in ischemic subtypes (IDI: 7.4%, 95%CI: 4.1%-9.7%, P=0.005; NRI: 16.3%, 95% CI: 2.9%-27.3%, P=0.002).

【Conclusion】Elevated ApoB/ApoA1 ratio is an independent risk factor for MMD. As a novel biomarker, it significantly improves the discrimination and reclassification of MMD risk prediction models, especially in ischemic subtypes. These findings provide critical insights for early screening and mechanistic research of MMD.
 

Section 2：Predictive Value of Triglyceride-Glucose Index for Long-Term Cerebrovascular Adverse Events After Cerebral Revascularization Surgery in Moyamoya Disease

【Objective】Moyamoya disease (MMD) is characterized by progressive cerebrovascular stenosis and abnormal vascular network formation. Cerebral revascularization surgery reduces stroke risk, but long-term postoperative cerebrovascular events remain unavoidable. Insulin resistance (IR) is closely associated with cardiovascular and cerebrovascular events. The triglyceride-glucose index (TyG), a surrogate marker of IR, has unclear prognostic value in MMD. This study aims to explore the association between TyG index and long-term cerebrovascular adverse events after cerebral revascularization surgery in MMD.

【Methods】This study was conducted as a single-center retrospective cohort study, enrolling patients with moyamoya disease who underwent cerebral revascularization surgery in the Department of Neurosurgery at our hospital from September 2022 to September 2024. Univariate and multivariate Cox regression analyses and Kaplan-Meier survival curves were used to evaluate the association between TyG index and postoperative cerebrovascular adverse events (transient ischemic attack [TIA], ischemic/hemorrhagic stroke). The incremental prognostic value of TyG index was assessed over a base prediction model (including age, sex, hypertension, diabetes, hyperlipidemia, smoking history, alcohol use, BMI, homocysteine, clinical phenotype, Suzuki stage, and surgical approach). Model performance was evaluated using the concordance index (C-index), Brier score, Akaike information criterion (AIC), Bayesian information criterion (BIC), net reclassification index (NRI), and integrated discrimination improvement (IDI). Decision curve analysis (DCA) assessed clinical utility.

【Results】A total of 201 MMD patients were included, with a median follow-up of 15.24 months. During follow-up, 31 patients (15.4%) experienced cerebrovascular adverse events. Multivariate Cox regression revealed that elevated baseline TyG index was independently associated with increased risk of adverse events (adjusted HR = 3.487 per 1-unit increase, 95% CI: 1.981-6.139, P<0.001). Compared to the lowest TyG tertile (T1), the highest tertile (T3) had a 4.086-fold higher risk (HR = 5.086, 95% CI: 3.161-6.886). Adding TyG to the base model significantly improved risk stratification and prognostic performance (C-index: 0.776 vs 0.726; Brier score: 0.131 vs 0.136; AIC: 341.29 vs 354.68; BIC: 422.89 vs 432.40; IDI: 5.0%, 95% CI: 2.4%-7.6%; NRI: 5.9%, 95% CI: 3.4%-8.5%; all P<0.05). DCA demonstrated enhanced clinical utility when the event probability threshold ranged from 36.5% to 81.5%.

【Conclusion】Elevated TyG index is an independent risk factor for long-term cerebrovascular adverse events after cerebral revascularization surgery in MMD. Incorporating TyG into existing prediction models improves risk stratification and provides critical guidance for postoperative management.