From the Department of Anatomy and Neurosciences (I.F., T.A.A.B., C.-P.L., M.M.A.B., I.K., W.D.J.V.D.B., L.D., L.E.J.), and Department of Radiology and Nuclear Medicine (F.B.), Amsterdam UMC location Vrije Universiteit Amsterdam, the Netherlands; Institutes of Neurology and Healthcare Engineering (F.B.), University College London, United Kingdom; and Department of Neurology (H.W.B.), Amsterdam UMC location Vrije Universiteit Amsterdam, the Netherlands.
Neurology. 2024 Aug 27;103(4):e209678. doi: 10.1212/WNL.0000000000209678. Epub 2024 Jul 23.
In Parkinson disease (PD), α-synuclein spreading through connected brain regions leads to neuronal loss and brain network disruptions. With diffusion-weighted imaging (DWI), it is possible to capture conventional measures of brain network organization and more advanced measures of brain network resilience. We aimed to investigate which neuropathologic processes contribute to regional network topologic changes and brain network resilience in PD.
Using a combined postmortem MRI and histopathology approach, PD and control brain donors with available postmortem in situ 3D T1-weighted MRI, DWI, and brain tissue were selected from the Netherlands Brain Bank and Normal Aging Brain Collection Amsterdam. Probabilistic tractography was performed, and conventional network topologic measures of regional eigenvector centrality and clustering coefficient, and brain network resilience (change in global efficiency upon regional node failure) were calculated. PSer129 α-synuclein, phosphorylated-tau, β-amyloid, neurofilament light-chain immunoreactivity, and synaptophysin density were quantified in 8 cortical regions. Group differences and correlations were assessed with rank-based nonparametric tests, with age, sex, and postmortem delay as covariates.
Nineteen clinically defined and pathology-confirmed PD (7 F/12 M, 81 ± 7 years) and 15 control (8 F/7 M, 73 ± 9 years) donors were included. With regional conventional measures, we found lower eigenvector centrality only in the parahippocampal gyrus in PD ( = -1.08, 95% CI 0.003-0.010, = 0.021), which did not associate with underlying pathology. No differences were found in regional clustering coefficient. With the more advanced measure of brain network resilience, we found that the PD brain network was less resilient to node failure of the dorsal anterior insula compared with the control brain network ( = -1.00, 95% CI 0.0012-0.0015, = 0.018). This change was not directly driven by neuropathologic processes within the dorsal anterior insula or in connected regions but was associated with higher Braak α-synuclein staging ( = -0.40, = 0.036).
Although our cohort might suffer from selection bias, our results highlight that regional network disturbances are more complex to interpret than previously believed. Regional neuropathologic processes did not drive regional topologic changes, but a global increase in α-synuclein pathology had a widespread effect on brain network reorganization in PD.
在帕金森病（PD）中，α-突触核蛋白通过连接的大脑区域传播，导致神经元丢失和大脑网络紊乱。使用扩散加权成像（DWI），可以捕获大脑网络组织的常规测量值以及大脑网络弹性的更高级测量值。我们旨在研究哪些神经病理学过程导致 PD 中的区域网络拓扑变化和大脑网络弹性。
使用荷兰脑库和阿姆斯特丹正常老化大脑采集的组合死后 MRI 和组织病理学方法，从这些组织中选择了具有可用死后原位 3D T1 加权 MRI、DWI 和脑组织的 PD 和对照脑供体。进行概率追踪，并计算区域特征向量中心性和聚类系数的常规网络拓扑测量值，以及大脑网络弹性（区域节点故障时全局效率的变化）。在 8 个皮质区域中量化 PSer129 α-突触核蛋白、磷酸化 tau、β-淀粉样蛋白、神经丝轻链免疫反应性和突触小体密度。使用基于等级的非参数检验评估组间差异和相关性，同时将年龄、性别和死后延迟作为协变量。
纳入了 19 名临床定义和病理证实的 PD（7 名女性/12 名男性，81±7 岁）和 15 名对照（8 名女性/7 名男性，73±9 岁）供体。使用区域常规测量值，我们仅在 PD 的海马旁回中发现特征向量中心性降低（=-1.08，95%CI 0.003-0.010，=0.021），但与潜在的病理学无关。区域聚类系数无差异。使用大脑网络弹性的更高级测量值，我们发现与对照大脑网络相比，PD 大脑网络对背侧前岛叶节点故障的弹性较小（=-1.00，95%CI 0.0012-0.0015，=0.018）。这种变化不是由背侧前岛叶或连接区域内的神经病理学过程直接驱动的，而是与更高的 Braak α-突触核蛋白分期相关（=-0.40，=0.036）。
尽管我们的队列可能存在选择偏倚，但我们的结果强调，区域网络紊乱比以前认为的更复杂。区域神经病理学过程并没有驱动区域拓扑变化，但全局α-突触核蛋白病理学的增加对 PD 中的大脑网络重组产生了广泛影响。
