第一部分 颅内动脉闭塞的病因分型及长期预后

背景：颅内动脉闭塞常见于中国人群，但是其病因分型以及预后研究的数据严重缺乏。高分辨率磁共振血管壁成像（high-resolution magnetic resonance vessel wall imaging, HRMR-VWI）可以通过同时观察管壁及管腔的病变，对颅内动脉闭塞的病因进行精准分型。本研究应用HRMR-VWI技术探索颅内动脉闭塞患者的病因分型与长期预后的关系。

方法：基于北京协和医院建立的前瞻性HRMR-VWI影像学数据库及随访数据，筛选颅内动脉闭塞患者，通过HRMR-VWI评估病因分型（动脉粥样硬化，烟雾病和其他病因），计算不同分型长期卒中发生率及功能预后。采用 Kaplan-Meier 生存分析评估动脉粥样硬化以及烟雾病亚组卒中发生率，并绘制生存曲线。使用 log-rank 检验比较各组之间的生存差异。利用单/多因素COX回归研究症状性动脉粥样硬化性颅内动脉闭塞亚组卒中复发高危因素，其余亚组由于主要终点事件数限制，仅对有无终点患者的基线临床及核磁特征进行组间比较，探讨不同病因分型卒中发生的潜在影响因素。

结果：本研究共纳入594名患者，总体发病年龄48.9±15.0岁，总体随访中位时间为31个月（11-60，月）。病因为动脉粥样硬化患者占比最高（62.8%），其次为烟雾病（28.1%）。颅内动脉粥样硬化闭塞患者：无症状闭塞患者143人，一年卒中发生率为2.1% [95% CI: 0-4.5]，每1000人年卒中发生率为8.3 [95% CI: 2.3-21.2]；共2人死亡，每1000人年的死亡率为4.18 [95% CI: 0.51-15.1]；6个月及以上mRS评分，7.0%的患者>1分，4.9%的患者>2分。症状性闭塞患者230人，一年卒中发生率为4.1% [95% CI 1.4-6.6]，每1000人年卒中发生率为36.5 [95% CI: 23.6-53.8]；共4人死亡，每1000人年的死亡率为5.43 [95% CI: 1.48-13.9]；6个月及以上mRS评分，16.1%的患者>1分，8.3%的患者>2分。烟雾病的患者：无症状闭塞患者106人，一年卒中发生率为1.9% [95% CI: 0-4.5]，每1000人年卒中发生率为9.9 [95% CI: 2.7-25.4]；共3人死亡，每1000人年的死亡率为7.37 [95% CI: 1.52-21.5]；6个月及以上的mRS评分，4.7%的患者>1分，0.9%的患者>2分。症状性闭塞患者61人，一年卒中发生率为8.3% [95% CI: 11.0-15.0]，每1000人年卒中发生率为43.8 [95% CI: 17.6-90.3]，无死亡事件发生，6个月及以上的mRS评分，14.8%的患者>1分，1.64%的患者>2分。Kaplan-Meier生存分析示，症状性动脉粥样硬化亚组与烟雾病亚组之间的卒中复发率没有显著差异（log-rank, p=0.738）。同时，无症状性动脉粥样硬化亚组与烟雾病亚组之间的卒中发生率也未达到统计学显著性差异（log-rank, p=0.738）。其他病因闭塞：无症状闭塞组无卒中及死亡发生，6个月及以上的mRS评分，5%的患者>1分，0名患者>2分。症状性闭塞组中第一年卒中发生率均为2.9% [95% CI: 0-8.5]，每1000人年卒中发生率为19 [95% CI: 2.3-68.8]，每1000人年死亡率为8.99 [95% CI: 0.23-50.1]，6个月及以上的mRS评分，14.7%的患者>1分，8.8%的患者>2分。多因素COX分析发现，多组颅内动脉闭塞、合并≥50%颅内动脉狭窄是症状性动脉粥样硬化性颅内动脉闭塞患者卒中复发高危因素。

结论：动脉粥样硬化是颅内动脉闭塞的最多见病因，烟雾病次之。这两个病因亚型的卒中复发风险无显著差异。多组颅内动脉闭塞、合并≥50%颅内动脉狭窄是症状性颅内动脉粥样硬化闭塞患者卒中复发的高危因素。

第二部分 侧枝循环与症状性前循环颅内动脉闭塞卒中复发的关系

背景：症状性颅内动脉闭塞是卒中复发的主要原因之一。良好的侧枝循环可能是保护性因素，但研究不足。高分辨率磁共振血管壁成像（high-resolution magnetic resonance vessel wall imaging, HRMR-VWI）与MRA的联合影像，可以无创评估各级侧枝循环。本研究通过HRMR-VWI/MRA的侧枝循环评估，判断其与症状性前循环颅内动脉闭塞卒中复发风险的关系。

方法：利用北京协和医院建立的前瞻性HRMR-VWI影像学数据库及随访数据，筛选症状性单侧前循环颅内动脉闭塞患者。通过HRMR-VWI联合MRA对每位患者的三级侧枝循环进行评估，包括Willis环完整性、软脑膜侧枝循环评分、深部微小侧枝循环（deep tiny flow voids, DTFVs）以及闭塞后残余血流。软脑膜侧枝循环评分应用HRMR-VWI最小密度投影，闭塞侧侧枝循环与对侧对比，评分范围0-3分。考虑到多种因素会影响卒中的发生风险，我们利用单因素以及两个多因素COX回归分析模型研究基线期三级侧枝循环状态与长期卒中复发风险的关系，模型一为单因素COX回归分析，模型二调整了单因素COX回归分析中p<0.1的变量，模型三对年龄、性别、高血压、高血脂、糖尿病、吸烟、降脂治疗、抗血小板聚集治疗、手术及再灌注治疗、多组颅内血管闭塞、合并≥50%狭窄的颅内动脉进行了调整。

结果：本研究共纳入199名患者，平均年龄48.3±14.4岁，男性患者占56.8%。中位随访时间为27个月（四分位数间距：6-107，月），共15例患者发生卒中,其中6例为同侧缺血性卒中。卒中复发患者中软脑膜侧枝评分≤1分的比例更高（66.7% vs 34.8%, p=0.014），Willis不完整且软脑膜侧枝≤1分的比例更高（66.7% vs 25.0%, p=0.001），Willis环不完整的比例更高（93.3% vs 74.5%, p=0.124），有远端残余血流的比例更低（53.3% vs 69.0%, p=0.211），DTFVs在两组中比例相当（71.4% vs 71.6%, p=1.000）。模型一为单因素COX分析，结果示软脑膜侧枝循环评分≤1分（HR 3.37, 95% CI: 1.15-9.88, p=0.027）与卒中复发显著相关。Willis环不完整并且软脑膜侧枝循环评分≤1分的患者卒中复发风险是Willis环完整和/或软脑膜侧枝循环评分>1分的患者的5.14倍（95% CI: 1.61-16.45, p=0.006）。模型二调整了单因素COX分析中p<0.1的变量，软脑膜侧枝循环评分≤1分（HR 4.68, 95% CI: 1.44-15.19, p=0.010）及Willis环不完整并且软脑膜侧枝循环评分≤1分（HR 6.43, 95% CI: 1.90-21.74, p=0.003）仍与卒中复发显著相关。多因素COX回归模型三对年龄、性别、高血压、高血脂、糖尿病、吸烟、降脂治疗、抗血小板聚集治疗、手术及再灌注治疗、多组颅内血管闭塞、合并≥50%狭窄的颅内动脉进行了调整，结果表明软脑膜侧枝循环评分≤1分（HR 4.59, 95% CI: 1.26-16.79, p=0.021）及Willis环不完整并且软脑膜侧枝循环评分≤1分（HR 8.76, 95% CI: 1.94-39.67, p=0.005）仍与卒中复发显著相关。在单因素及多因素COX回归中，Willis环完整性、DTFVs以及闭塞远端残余血流均与卒中复发无关。次要结局中，共6名患者出现同侧缺血性卒中复发，Willis环均不完整并且软脑膜侧枝循环评分≤1。

结论：基于联合HRMR-VWI与MRA的影像分析，软脑膜侧枝循环评分≤1，联合软脑膜侧枝循环评分≤1并且Willis环不完整与卒中复发风险升高显著相关。我们的结果为颅内动脉闭塞性疾病的危险分层提供了新的方法。

第三部分 深部微小侧枝循环与颅内动脉闭塞性疾病功能预后的研究

背景和目的：深部微小侧枝循环（deep tiny flow voids, DTFVs）最近被确定为一种新的侧支循环形式，与慢性狭窄闭塞性大脑中动脉（MCA）粥样硬化病变有关，可通过高分辨率磁共振血管壁成像（high-resolution magnetic resonance vessel wall imaging, HRMR-VWI）检测到。到目前为止，还没有研究关注DTFVs在急性MCA动脉粥样硬化闭塞中的存在及其临床意义。

材料和方法：本回顾性研究包括来自两个多中心HRMR-VWI队列的急性MCA动脉粥样硬化闭塞患者。分析DTFVs的发生率及其与基线美国国立卫生研究院卒中量表（NIHSS）评分、梗死面积、90天临床预后良好（修正Rankin量表，mRS≤2）的患者比例的关系。

结果：66例患者（平均年龄58.2±9.2岁；71.2%男性）。从中风发作到成像的中位时间为44.5（27.3-67.0）小时。57.6%的急性MCA动脉粥样硬化闭塞患者存在DTFVs。在调整潜在混杂因素后，存在DTFVs与较低的基线NIHSS评分显著相关（β, -3.68; 95% CI: -6.30-1.07; p=0.007），梗死面积较小（β, -40.88; 95% CI: -70.15, -11.60; p=0.007），90天临床预后良好的患者比例更高（OR, 6.03; 95% CI: 1.39-26.19; p=0.017）。

结论：DTFVs的存在与急性MCA动脉粥样硬化闭塞患者的良好预后相关。提高对这一侧枝影像标记物的识别及认知，有助于理解MCA闭塞时梗死的不同演变，有助于更个性化的管理和治疗。

Part Ⅰ. Etiological classification and long-term prognosis of intracranial artery occlusion

Background: Intracranial artery occlusion is commonly observed in the Chinese population; however, data on its etiological classification and prognosis remain significantly limited. High-resolution magnetic resonance vessel wall imaging (HRMR-VWI) enables precise etiological classification of intracranial artery occlusion by simultaneously assessing both vessel wall and luminal pathology. This study employs HRMR-VWI to explore the association between etiological classification and long-term prognosis in patients with intracranial artery occlusion.

Methods: Based on the prospective HRMR-VWI imaging database and follow-up data established at Peking Union Medical College Hospital, patients with intracranial artery occlusion were selected for analysis. Etiological classification (atherosclerosis, moyamoya disease, and other causes) was determined using HRMR-VWI, and the long-term stroke incidence and functional outcomes of different subtypes were calculated. Kaplan-Meier survival analysis was performed to assess stroke recurrence in the atherosclerosis and moyamoya disease subgroups, and survival curves were plotted. The log-rank test was used to compare survival differences among groups. Univariable and multivariable Cox regression analyses were conducted to identify high-risk factors for stroke recurrence in the symptomatic intracranial artery occlusion subgroup. Due to the limited number of primary endpoint events in other subgroups, only baseline clinical and MRI characteristics were compared between patients with and without endpoints to explore potential factors influencing stroke occurrence across different etiological subtypes.

Results: A total of 594 patients were included in this study, with a mean age of 48.9±15.0 years. The median follow-up time was 31 months (range: 11–60 months). Atherosclerosis was the most common etiology (62.8%), followed by moyamoya disease (28.1%). Among patients with intracranial atherosclerotic occlusion, 143 were asymptomatic. The 1-year stroke incidence was 2.1% [95% CI: 0–4.5], with an incidence rate of 8.3 per 1000 person-years [95% CI: 2.3–21.2]. Two patients died, resulting in a mortality rate of 4.18 per 1000 person-years [95% CI: 0.51–15.1]. At six months or later, 7.0% had an mRS score >1, and 4.9% had an mRS score >2. Among 230 patients with symptomatic intracranial atherosclerotic occlusion, the 1-year stroke incidence was 4.1% [95% CI: 1.4–6.6], with an incidence rate of 36.5 per 1000 person-years [95% CI: 23.6–53.8]. Four patients died, with a mortality rate of 5.43 per 1000 person-years [95% CI: 1.48–13.9]. At six months or later, 16.1% had an mRS score >1, and 8.3% had an mRS score >2. Among patients with moyamoya disease, 106 were asymptomatic. The 1-year stroke incidence was 1.9% [95% CI: 0–4.5], with an incidence rate of 9.9 per 1000 person-years [95% CI: 2.7–25.4]. Three patients died, with a mortality rate of 7.37 per 1000 person-years [95% CI: 1.52–21.5]. At six months or later, 4.7% had an mRS score >1, and 0.9% had an mRS score >2. Among 61 symptomatic occlusion patients, the 1-year stroke incidence was 8.3% [95% CI: 11.0–15.0], with an incidence rate of 43.8 per 1000 person-years [95% CI: 17.6–90.3]. No deaths occurred in this group. At six months or later, 14.8% had an mRS score >1, and 1.64% had an mRS score >2. Kaplan-Meier survival analysis showed no significant difference in stroke recurrence between symptomatic intracranial atherosclerosis and symptomatic moyamoya disease (log-rank, p=0.738). Similarly, no significant difference was observed between asymptomatic intracranial atherosclerosis and asymptomatic moyamoya disease in terms of stroke incidence (log-rank, p=0.738). For patients with occlusion due to other etiologies, no stroke or death occurred in the asymptomatic group. At six months or later, 5% had an mRS score >1, and none had an mRS score >2. In the symptomatic group, the 1-year stroke incidence was 2.9% [95% CI: 0–8.5], with an incidence rate of 19 per 1000 person-years [95% CI: 2.3–68.8]. The mortality rate was 8.99 per 1000 person-years [95% CI: 0.23–50.1]. At six months or later, 14.7% had an mRS score >1, and 8.8% had an mRS score >2. Multivariate Cox regression analysis revealed that multiple intracranial artery occlusions and coexisting ≥50% intracranial artery stenosis were high-risk factors for stroke recurrence in patients with symptomatic atherosclerotic intracranial artery occlusion.

Conclusion: Atherosclerosis is the most common cause of intracranial artery occlusion, followed by moyamoya disease. There is no significant difference in stroke recurrence risk between these two etiological subtypes. Multiple intracranial artery occlusions and concomitant ≥50% intracranial artery stenosis are high-risk factors for stroke recurrence in patients with symptomatic intracranial atherosclerotic occlusion. 

Part ⅠⅠ. Association between collateral circulation and stroke recurrence in symptomatic anterior circulation intracranial artery occlusion

Background: Symptomatic intracranial artery occlusion is one of the leading causes of stroke recurrence. Adequate collateral circulation may serve as a protective factor, but evidence remains limited. The combination of high-resolution magnetic resonance vessel wall imaging (HRMR-VWI) and magnetic resonance angiography (MRA) enables a noninvasive assessment of collateral circulation at different levels. This study aims to evaluate collateral circulation using HRMR-VWI/MRA and investigate its association with the risk of stroke recurrence in symptomatic anterior circulation intracranial artery occlusion.

Methods: Based on the prospective HRMR-VWI imaging database and follow-up data established at Peking Union Medical College Hospital, we identified patients with symptomatic unilateral anterior circulation intracranial artery occlusion. Collateral circulation was assessed at three levels using HRMR-VWI combined with MRA, including the integrity of the circle of Willis, leptomeningeal collateral score, deep tiny flow voids (DTFVs), and residual flow voids beyond occlusion. The leptomeningeal collateral score was evaluated using the minimum intensity projection of HRMR-VWI, comparing the collateral circulation on the occluded side with the contralateral side, with a scoring range of 0–3. Given the potential impact of multiple factors on stroke risk, we employed univariable and multivariable Cox regression models to investigate the association between baseline collateral circulation status and long-term stroke recurrence risk. Model 1 was a univariable Cox regression analysis. Model 2 adjusted for variables with p < 0.1 in the Model 1. Model 3 further adjusted for age, sex, hypertension, hyperlipidemia, diabetes, smoking, lipid-lowering therapy, antiplatelet therapy, surgical or reperfusion treatment, multiple intracranial artery occlusions, and concurrent intracranial artery stenosis of ≥50%.

Result: A total of 199 patients were included in this study, with a mean age of 48.3 ± 14.4 years, and 56.8% were male. The median follow-up duration was 27 months (interquartile range: 6–107 months). Stroke occurred in 15 patients, including 6 cases of ipsilateral ischemic stroke. Among patients with stroke recurrence, a higher proportion had a leptomeningeal collateral score ≤1 (66.7% vs. 34.8%, p = 0.014), a higher proportion had an incomplete Willis circle combined with a leptomeningeal collateral score ≤1 (66.7% vs. 25.0%, p = 0.001), a higher proportion had an incomplete Willis circle (93.3% vs. 74.5%, p = 0.124), a lower proportion had distal residual flow (53.3% vs. 69.0%, p = 0.211), and the proportion of deep tiny flow voids (DTFVs) was similar between the two groups (71.4% vs. 71.6%, p = 1.000). In univariable Cox regression analysis, a leptomeningeal collateral score ≤1 was significantly associated with stroke recurrence (hazard ratio [HR] 3.37, 95% confidence interval [CI]: 1.15–9.88, p = 0.027). Patients with an incomplete Willis circle and a leptomeningeal collateral score ≤1 had a 5.14-fold higher risk of stroke recurrence compared to those with a complete Willis circle and/or a leptomeningeal collateral score >1 (95% CI: 1.61–16.45, p = 0.006). In Model 2, which adjusted for variables with p < 0.1 in the univariable analysis, a leptomeningeal collateral score ≤1 (HR 4.68, 95% CI: 1.44–15.19, p = 0.010) and an incomplete Willis circle combined with a leptomeningeal collateral score ≤1 (HR 6.43, 95% CI: 1.90–21.74, p = 0.003) remained significantly associated with stroke recurrence. In the multivariable Cox regression Model 3, which adjusted for age, gender, hypertension, hyperlipidemia, diabetes, smoking, lipid-lowering treatment, antiplatelet aggregation therapy, surgery and reperfusion treatment, multiple intracranial artery occlusion, and intracranial artery stenosis ≥50%, a leptomeningeal collateral score ≤1 (HR 4.59, 95% CI: 1.26–16.79, p = 0.021) and an incomplete Willis circle combined with a leptomeningeal collateral score ≤1 (HR 8.76, 95% CI: 1.94–39.67, p = 0.005) remained significantly associated with stroke recurrence. In both univariable and multivariable Cox regression analyses, Willis circle integrity, DTFVs, and distal residual flow were not associated with stroke recurrence. In secondary outcomes, 6 patients experienced ipsilateral ischemic stroke recurrence, all of whom had an incomplete Willis circle and a leptomeningeal collateral score ≤1.

Conclusion: Based on the combined imaging analysis of HRMR-VWI and MRA, a leptomeningeal collateral score ≤1, as well as the combination of a leptomeningeal collateral score ≤1 and an incomplete Willis circle, were significantly associated with an increased risk of stroke recurrence. Our results provide a new approach for risk stratification in intracranial arterial occlusive diseases.

Part ⅠⅠⅠ. Study of deep tiny flow voids and functional prognosis in intracranial arterial occlusive disease

Background and purpose: Deep tiny flow voids (DTFVs) have recently been identified as a novel form of collateral circulation linked to chronic steno-occlusive atherosclerotic middle cerebral artery (MCA) lesions, detectable via high-resolution magnetic resonance vessel wall imaging (HRMR-VWI). To date, no study has focused on the presence and clinical significance of DTFVs in acute MCA atherosclerotic occlusion.

Materials and Methods: This retrospective study included patients with acute MCA atherosclerotic occlusion from two multicenter HRMR-VWI cohorts. The incidence of DTFVs and its association with baseline National Institute of Health Stroke Scale (NIHSS) scores, infarct volume, and the proportion of patients with a favorable 90-day clinical outcome defined as a modified Rankin Scale (mRS) ≤ 2 were analyzed.

Results: Sixty-six patients (mean age 58.2±9.2 years; 71.2% men) were included. The median time from stroke onset to image was 44.5 (27.3-67.0) hours. DTFVs were identified in 57.6% of patients with MCA atherosclerotic occlusion. After adjusting the potential confounders, DTFVs were significantly associated with lower baseline NIHSS scores (β, -3.68; 95% CI: -6.30 -1.07; p = 0.007), smaller infarct volume (β, -40.88; 95% CI: -70.15, -11.60; p = 0.007), and a higher proportion of patients with favorable 90-day clinical outcome (OR, 6.03; 95% CI: 1.39-26.19; p = 0.017).

Conclusions: The presence of DTFVs was correlated with a favorable outcome in patients with acute MCA atherosclerotic occlusion. Improved recognition and awareness of this imaging marker of collaterals could help understand the varying infarct evolution seen in MCA occlusion and contribute to more individualized management and treatment.