第一部分 脑淀粉样血管病影像学改变空间分布模式

研究背景与目的：脑淀粉样血管病（Cerebral amyloid angiopathy，CAA）与小动脉硬化性脑小血管病（Cerebral small vessel disease，CSVD）是老年人常见的脑小血管病亚型，二者临床表现和影像学特征存在重叠，但病理机制不同。CAA与小动脉硬化性CSVD的脑萎缩、脑白质高信号（White matter hyperintensity，WMH）分布模式差异尚不明确。本研究旨在通过高分辨率5T磁共振，定量分析两种疾病脑萎缩及WMH的空间分布特征，为临床鉴别诊断和机制研究提供依据。

研究方法：本研究为回顾性病例对照研究，纳入北京协和医院2022年8月至2025年4月完成5T磁共振检查的42例CAA患者和71例小动脉硬化性CSVD患者。收集人口学特征、血管危险因素、影像学检查。采用CAT12（Computational Anatomy Toolbox 12）工具对3D-T1序列进行脑体积分割，采用LST（Lesion Segmentation Tool）工具对Flair序列进行WMH分割，通过基于体素的形态学分析比较组间灰质及白质体积、WMH差异。统计方法包括广义线性模型（校正年龄、性别等协变量）和多重比较校正（False discovery rate，FDR）等。

研究结果：结果显示，尽管两组在整体脑体积（灰质、白质及颅内总体积）上无显著差异，但基于体素的分析发现小动脉硬化性CSVD组在双侧小脑半球、左侧中央后回的灰质萎缩较CAA组更明显，且小动脉硬化性CSVD组的脑桥及桥臂白质萎缩更为显著（p_FDR＜0.05）。小脑体积分析进一步表明，小动脉硬化性CSVD组的小脑皮层体积占比低于CAA组。WMH负荷在两组间无统计学差异，但其与年龄增长显著相关。

结论：CAA与小动脉硬化性CSVD患者的脑萎缩空间分布模式存在显著差异，小动脉硬化性CSVD患者的小脑皮层和脑桥桥臂白质区域萎缩更突出。这些发现为两种疾病的影像鉴别和机制探索提供了新证据。

第二部分 脑淀粉样血管病影像学改变模式与临床相关性

研究背景与目的：脑淀粉样血管病（Cerebral amyloid angiopathy，CAA）和小动脉硬化性脑小血管病（Cerebral small vessel disease，CSVD）临床表现相似但病理机制不同。目前关于这两种疾病脑萎缩和脑白质高信号（White matter hyperintensity，WMH）的空间分布特征与认知、步态障碍的关联尚不明确。本研究旨在通过5T高场强磁共振定量、体素化分析影像学改变及其临床相关性，帮助理解CAA及小动脉硬化性CSVD患者临床与影像标记物之间关联的差异。

研究方法：本回顾性病例对照研究纳入2022年8月至2025年4月北京协和医院42例CAA患者和71例小动脉硬化性CSVD患者的5T磁共振数据。采用CAT12（Computational Anatomy Toolbox 12）和LST（Lesion Segmentation Tool）工具分别进行脑体积和WMH分割分析。认知功能评估采用简易智力状态量表（Mini Mental State Examination，MMSE）和蒙特利尔认知评估量表（Montreal Cognitive Assessment，MoCA），步态参数通过ReadyGo™定量运动分析系统获取。分别通过定量、基于体素的形态学分析及感兴趣区域分析明确脑体积、WMH与认知水平及步态的相关性。

研究结果：CAA患者双侧海马、左侧颞叶及小脑等区域的灰质体积与MMSE评分呈正相关（p_FDR＜0.05），小动脉硬化性CSVD患者双侧颞顶叶、左枕叶及双侧胼胝体白质体积与MoCA评分正相关（p_FDR＜0.05）。CAA组左侧顶枕叶及双侧额叶皮层下、侧脑室旁的WMH与MMSE评分负相关（p_FDR＜0.05），但定量分析在两组患者中均未发现WMH与认知水平的相关性。CAA患者的小脑皮层体积占比与步幅、步高相关，小脑皮层下体积占比与步宽相关，而WMH体积与步幅呈负相关（p＜0.05）。

结论：CAA和小动脉硬化性CSVD的患者整体在认知及步态表现上没有差异，但脑结构-功能关系特征不同：CAA患者的认知功能依赖于灰质（尤其是海马、颞叶）完整性，小动脉硬化性CSVD患者则依赖白质结构完整性。与CAA认知相关的WMH主要分布于后部皮层下、侧脑室旁。小脑、WMH体积对步态的调控亦呈现疾病特异性模式。这些发现有助于理解不同类型CSVD的临床表现的病理生理机制。

第三部分 神经影像标记物对脑淀粉样血管病认知障碍的中介作用

研究背景与目的：脑淀粉样血管病（Cerebral amyloid angiopathy，CAA）是一种以β-淀粉样蛋白在脑血管壁沉积为特征的疾病，常导致认知功能障碍和脑出血。尽管脑小血管病（Cerebral small vessel disease，CSVD）的影像标记物（如脑微出血[Cerebral microbleed，CMB]、脑白质高信号[White matter hyperintensity，WMH]等）与认知功能下降密切相关，但其在CAA中的中介作用尚未完全阐明。本研究旨在通过中介分析，探讨神经影像标记物在CAA与认知功能障碍关联中的中介作用及其程度。

研究方法：本研究为回顾性观察性研究，纳入北京协和医院2017年3月至2024年6月间的89例CAA患者和87例小动脉硬化性CSVD患者作为对照组。收集患者的人口学特征、血管危险因素、影像学资料（包括CMB、WMH定量、脑体积、腔隙等）及认知评估结果（简易智力状态量表[Mini Mental State Examination，MMSE]和蒙特利尔认知评估量表[Montreal Cognitive Assessment，MoCA]）。采用多元中介分析模型，调整年龄、性别及血管危险因素，评估影像标记物对CAA与认知下降关系的中介效应。

研究结果：CAA组患者的认知功能显著低于小动脉硬化性CSVD组，MMSE分别为24 vs 27（p＜0.001）。脑叶CMB在两组间分布差异显著（p＜0.001），CAA组CMB数量＞50个的比例更高（34.8% vs 1.18%），小动脉硬化性CSVD则有更多腔隙。中介分析显示，脑叶CMB对CAA与认知下降的中介效应显著，解释了总效应的47-54%（p＜0.05），而直接效应不显著。其他影像标记物（如WMH、脑萎缩等）未表现出显著中介作用。

结论：相较于小动脉硬化性CSVD，脑叶CMB是CAA相关认知障碍的重要中介因素，其作用机制可能与微血管损伤导致的神经网络破坏有关，而脑萎缩、WMH对CAA认知的作用不突出。这一发现提示，针对脑叶CMB的干预措施（如优化血压管理）可能有助于延缓CAA患者的认知功能下降。

Part 1 Spatial Patterns of Imaging Changes in Cerebral Amyloid Angiopathy

Background and Purpose: Cerebral amyloid angiopathy (CAA) and arteriolosclerotic cerebral small vessel disease (CSVD) are common subtypes of cerebral small vessel disease in the elderly. While they share overlapping clinical and imaging features, their pathological mechanisms differ. The distinct spatial distribution patterns of brain atrophy and white matter hyperintensity (WMH) between CAA and arteriolosclerotic CSVD remain unclear. This study aims to quantitatively analyze the spatial distribution characteristics of brain atrophy and WMH in these two diseases using high-resolution 5T MRI, providing evidence for clinical differential diagnosis and mechanistic research.

Methods: This retrospective case-control study included 42 CAA patients and 71 arteriolosclerotic CSVD patients who underwent 5T MRI at Peking Union Medical College Hospital between August 2022 and April 2025. Demographic characteristics, vascular risk factors, and imaging data were collected. The Computational Anatomy Toolbox 12 was used for brain volume segmentation based on 3D-T1 sequences, while the Lesion Segmentation Tool was employed for WMH segmentation on FLAIR sequences. Voxel-based morphometry was performed to compare intergroup differences in gray matter volume, white matter volume, and WMH. Statistical methods included generalized linear models (adjusted for covariates such as age and sex) and multiple comparison correction (False discovery rate，FDR).

Results: The results showed no significant differences in overall brain volume (gray matter, white matter, and total intracranial volume) between the two groups. However, voxel-based analysis revealed that the arteriolosclerotic CSVD group exhibited more pronounced gray matter atrophy in the bilateral cerebellar hemispheres and left postcentral gyrus, as well as greater white matter atrophy in the pons and middle cerebellar peduncle compared to the CAA group (FDR-corrected p<0.05). Cerebellar volume analysis further demonstrated that the percentage of cerebellar cortical volume was lower in the arteriolosclerotic CSVD group. No significant difference in WMH burden was observed between the two groups, though WMH was significantly correlated with increasing age.

Conclusion: The spatial patterns of brain atrophy differ significantly between CAA and arteriolosclerotic CSVD, with the latter showing more prominent atrophy in the cerebellar cortex and pontine white matter. These findings provide new evidence for the imaging differentiation and mechanistic exploration of the two diseases.

Part 2 Neuroimaging Patterns and Clinical Correlations in Cerebral Amyloid Angiopathy

Background and Purpose: Cerebral amyloid angiopathy (CAA) and arteriolosclerotic cerebral small vessel disease (CSVD) share similar clinical manifestations but differ in their underlying pathological mechanisms. Currently, the spatial patterns of brain atrophy and white matter hyperintensity (WMH) in these two diseases, as well as their associations with cognitive and gait impairments, remain unclear. This study aims to employ quantitative, voxel-wise analyses based on 5T high-field MRI to characterize neuroimaging changes and their clinical correlations, thereby elucidating the differential relationships between imaging markers and clinical manifestations in CAA versus arteriolosclerotic CSVD patients.

Methods: This retrospective case-control study included 5T MRI data from 42 CAA patients and 71 arteriolosclerotic CSVD patients at Peking Union Medical College Hospital between August 2022 and April 2025. Brain volume and WMH segmentation were performed using Computational Anatomy Toolbox 12 and Lesion Segmentation Tool, respectively. Cognitive function was assessed using the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), while gait parameters were obtained via the ReadyGo™ quantitative motion analysis system. The correlations between brain volume, WMH, and cognitive levels as well as gait were determined through quantitative voxel-based morphometry analysis and region of interest (ROI) analysis, respectively.

Results: In CAA patients, the gray matter volumes in bilateral hippocampi, left temporal lobe, and cerebellum showed positive correlations with MMSE scores (p_FDR<0.05). In arteriolosclerotic CSVD patients, the white matter volumes in bilateral temporoparietal regions, left occipital lobe, and bilateral corpus callosum were positively correlated with MoCA scores (p_FDR<0.05). WMH in the subcortical/periventricular regions of the left parieto-occipital lobe and bilateral frontal lobe exhibited negative correlations with MMSE scores (p_FDR < 0.05) in the CAA group. However, quantitative analysis revealed no significant association between WMH and cognitive performance in either group. CAA patients demonstrated correlations between cerebellar cortical volume ratio and stride length/step height, while cerebellar subcortical volume ratio was associated with stride width. Additionally, WMH volume was negatively correlated with stride length (p < 0.05).

Conclusion: CAA and arteriolosclerotic CSVD exhibit distinct patterns of brain structural damage: CAA primarily shows associations between gray matter (particularly temporal lobe) damage and cognition, whereas arteriolosclerotic CSVD demonstrates stronger links between white matter damage and cognition. Cerebellar volume displays disease-specific regulatory patterns for gait. These findings provide novel neuroimaging evidence for the differentiation and individualized management of cerebral small vessel disease subtypes.

There was no overall difference in cognitive or gait performance between patients with CAA and arteriolosclerotic CSVD. However, their brain structure-function relationships exhibited distinct characteristics. In CAA patients, cognitive function depended on gray matter integrity (particularly in the hippocampus and temporal lobe). In arteriolosclerotic CSVD patients, cognition relied more on white matter structural integrity. WMH associated with cognitive impairment in CAA were predominantly distributed in posterior subcortical and periventricular regions. Additionally, the cerebellum and WMH volumes influenced gait in a disease-specific manner. These findings contribute to understanding the pathophysiological mechanisms underlying clinical manifestations in different types of CSVD.

Part 3 The Neuroimaging Mediators of Cognitive Impairment in Cerebral Amyloid Angiopathy

Background and Purpose: Cerebral amyloid angiopathy (CAA) is a disease characterized by the deposition of amyloid β in cerebral blood vessel walls, often leading to cognitive impairment and intracerebral hemorrhage. Although neuroimaging markers of cerebral small vessel disease (CSVD), such as cerebral microbleed (CMB) and white matter hyperintensity (WMH), are closely associated with cognitive decline, their mediating role in CAA remains incompletely understood. This study aimed to explore the mediating effects of neuroimaging markers on the association between CAA and cognitive impairment through mediation analysis.

Methods: This retrospective observational study included 89 CAA patients and 87 arteriolosclerotic CSVD patients as controls from Peking Union Medical College Hospital between March 2017 and June 2024. Demographic characteristics, vascular risk factors, neuroimaging data (including lobar CMB, WMH, brain volume, and lacunes), and cognitive assessments (Mini Mental State Examination [MMSE] and Montreal Cognitive Assessment [MoCA]) were collected. A multiple mediation analysis model was used, adjusting for age, sex, and vascular risk factors, to evaluate the mediating effects of imaging markers on the relationship between CAA and cognitive decline.

Results: Cognitive function was significantly lower in the CAA group than in the arteriolosclerotic CSVD group (MMSE scores: 24 vs 27, p < 0.001). The distribution of lobar CMB differed significantly between the two groups (p < 0.001), with a higher proportion of CMB>50 in the CAA group (34.8% vs 1.18%), while arteriolosclerotic CSVD had more lacunes. Mediation analysis revealed that lobar CMB significantly mediated the association between CAA and cognitive decline, accounting for 47–54% of the total effect (p < 0.05), whereas the direct effect was nonsignificant. Other imaging markers (e.g., WMH, brain atrophy) showed no significant mediating effects.

Conclusion: Lobar CMB serves as a critical mediator in CAA-related cognitive impairment when compared with arteriolosclerotic CSVD, likely due to microvascular injury disrupting neural networks, whereas brain atrophy and WMH play a less prominent role. These findings suggest that interventions targeting lobar CMBs (e.g., optimized blood pressure management) may help mitigate cognitive decline in CAA patients.