Department of Neurology, Radboud Institute for Medical research and Innovation and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 510000 Guangzhou, China.
Brain. 2024 Nov 4;147(11):3804-3816. doi: 10.1093/brain/awae145.
Cerebral small vessel disease (SVD) is known to contribute to cognitive impairment, apathy and gait dysfunction. Although associations between cognitive impairment and either apathy or gait dysfunction have been shown in SVD, the inter-relations among these three clinical features and their potential common neural basis remain unexplored. The dopaminergic meso-cortical and meso-limbic pathways have been known as the important brain circuits for both cognitive control, emotion regulation and motor function. Here, we investigated the potential inter-relations between cognitive impairment, apathy and gait dysfunction, with a specific focus on determining whether these clinical features are associated with damage to the meso-cortical and meso-limbic pathways in SVD. In this cross-sectional study, we included 213 participants with SVD for whom MRI and comprehensive neurobehavioural assessments were performed. These assessments comprised six clinical measures: processing speed, executive function, memory, apathy (based on the Apathy Evaluation Scale) and gait function (based on the time and steps in the Timed Up and Go Test). We reconstructed five tracts connecting the ventral tegmental area (VTA) and dorsolateral prefrontal cortex (PFC), ventral lateral PFC, medial orbitofrontal cortex, anterior cingulate cortex (ACC) and nucleus accumbens within meso-cortical and meso-limbic pathways using diffusion weighted imaging. The damage along the five tracts was quantified using the free water (FW) and FW-corrected mean diffusivity indices. Furthermore, we explored the inter-correlations among the six clinical measures and identified their common components using principal component analysis (PCA). Linear regression analyses showed that higher FW values of tracts within meso-cortical pathways were related to these clinical measures in cognition, apathy, and gait (all P-corrected values < 0.05). The PCA showed strong inter-associations among these clinical measures and identified a common component wherein all six clinical measures loaded on. Higher FW values of tracts within meso-cortical pathways were related to the PCA-derived common component (all P-corrected values < 0.05). Moreover, FW values of the VTA-ACC tract showed the strongest contribution to the PCA-derived common component over all other neuroimaging features. In conclusion, our study showed that the three clinical features (cognitive impairment, apathy, and gait dysfunction) of SVD are strongly inter-related and that the damage in meso-cortical pathway could be the common neural basis underlying the three features in SVD. These findings advance our understanding of the mechanisms behind these clinical features of SVD and have the potential to inform novel management and intervention strategies for SVD.
脑小血管病（SVD）已知会导致认知障碍、淡漠和步态功能障碍。虽然 SVD 中的认知障碍与淡漠或步态功能障碍之间存在关联，但这三种临床特征之间的相互关系及其潜在的共同神经基础仍未得到探索。中脑皮质和中脑边缘多巴胺能通路已被认为是认知控制、情绪调节和运动功能的重要脑回路。在这里，我们研究了认知障碍、淡漠和步态功能障碍之间的潜在相互关系，特别关注这些临床特征是否与 SVD 中中脑皮质和中脑边缘通路的损伤有关。在这项横断面研究中，我们纳入了 213 名 SVD 患者，对其进行了 MRI 和全面的神经行为评估。这些评估包括 6 项临床指标：处理速度、执行功能、记忆、淡漠（基于淡漠评估量表）和步态功能（基于计时起身和行走测试中的时间和步数）。我们使用扩散加权成像重建了中脑皮质和中脑边缘通路内连接腹侧被盖区（VTA）和背外侧前额叶皮层（PFC）、腹外侧前额叶皮层、眶额内侧皮层、前扣带皮层（ACC）和伏隔核的五条通路。使用自由水（FW）和 FW 校正的平均扩散系数指数量化五条通路的损伤。此外，我们探索了这 6 项临床指标之间的相互关联，并使用主成分分析（PCA）确定了它们的共同成分。线性回归分析显示，中脑皮质通路内 FW 值较高与认知、淡漠和步态的这些临床指标有关（所有 P 校正值<0.05）。PCA 显示这些临床指标之间存在强烈的相互关联，并确定了一个共同成分，其中所有 6 项临床指标都有负荷。中脑皮质通路内 FW 值较高与 PCA 得出的共同成分有关（所有 P 校正值<0.05）。此外，VTA-ACC 通路的 FW 值对 PCA 得出的共同成分的贡献最大，超过了所有其他神经影像学特征。总之，我们的研究表明，SVD 的三种临床特征（认知障碍、淡漠和步态功能障碍）之间存在强烈的相互关系，中脑皮质通路的损伤可能是 SVD 这三种特征的共同神经基础。这些发现加深了我们对 SVD 这些临床特征背后机制的理解，并有可能为 SVD 的新的管理和干预策略提供信息。
