The spreading hypothesis of neurodegeneration assumes an expansion of neural pathologies along existing neural pathways. Multimodal neuroimaging studies have demonstrated distinct topographic patterns of cerebral pathologies in neurodegeneration. For Parkinson's disease the hypothesis so far rests largely on histopathological evidence of α-synuclein spreading in a characteristic pattern and progressive nigrostriatal dopamine depletion. Functional consequences of nigrostriatal dysfunction on cortical activity remain to be elucidated. Our goal was to investigate multimodal imaging correlates of degenerative processes in Parkinson's disease by assessing dopamine depletion and its potential effect on striatocortical connectivity networks and cortical metabolism in relation to parkinsonian symptoms. We combined 18F-DOPA-PET, 18F-fluorodeoxyglucose (FDG)-PET and resting state functional MRI to multimodally characterize network alterations in Parkinson's disease. Forty-two patients with mild-to-moderate stage Parkinson's disease and 14 age-matched healthy control subjects underwent a multimodal imaging protocol and comprehensive clinical examination. A voxel-wise group comparison of 18F-DOPA uptake identified the exact location and extent of putaminal dopamine depletion in patients. Resulting clusters were defined as seeds for a seed-to-voxel functional connectivity analysis. 18F-FDG metabolism was compared between groups at a whole-brain level and uptake values were extracted from regions with reduced putaminal connectivity. To unravel associations between dopaminergic activity, striatocortical connectivity, glucose metabolism and symptom severity, correlations between normalized uptake values, seed-to-cluster β-values and clinical parameters were tested while controlling for age and dopaminergic medication. Aside from cortical hypometabolism, 18F-FDG-PET data for the first time revealed a hypometabolic midbrain cluster in patients with Parkinson's disease that comprised caudal parts of the bilateral substantia nigra pars compacta. Putaminal dopamine synthesis capacity was significantly reduced in the bilateral posterior putamen and correlated with ipsilateral nigral 18F-FDG uptake. Resting state functional MRI data indicated significantly reduced functional connectivity between the dopamine depleted putaminal seed and cortical areas primarily belonging to the sensorimotor network in patients with Parkinson's disease. In the inferior parietal cortex, hypoconnectivity in patients was significantly correlated with lower metabolism (left P = 0.021, right P = 0.018). Of note, unilateral network alterations quantified with different modalities corresponded with contralateral motor impairments. In conclusion, our results support the hypothesis that degeneration of nigrostriatal fibres functionally impairs distinct striatocortical connections, disturbing the efficient interplay between motor processing areas and impairing motor control in patients with Parkinson's disease. The present study is the first to reveal trimodal evidence for network-dependent degeneration in Parkinson's disease by outlining the impact of functional nigrostriatal pathway impairment on striatocortical functional connectivity networks and cortical metabolism.

中文翻译：

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帕金森氏病的网络变性：黑质纹状体皮质功能障碍的多峰成像。

关于神经退行性疾病的扩散假说假设沿着现有的神经途径扩展了神经病理学。多模式神经影像学研究已经证明了神经退行性变中脑病理学的独特地形图。对于帕金森氏病，到目前为止，该假设主要取决于组织病理学证据，即α-突触核蛋白以特征性方式扩散和进行性黑纹状体多巴胺消耗。纹状体黑质纹状体功能障碍的功能后果尚待阐明。我们的目标是通过评估多巴胺的消耗及其对纹状皮质连接网络和与帕金森病症状相关的皮质代谢的潜在影响，研究帕金森氏病退化过程的多峰成像相关性。我们结合了18F-DOPA-PET，18F-氟脱氧葡萄糖（FDG）-PET和静息状态功能MRI可多模式表征帕金森氏病的网络变化。对42例轻度至中度帕金森氏病患者和14名年龄匹配的健康对照受试者进行了多模式成像方案和全面的临床检查。对18F-DOPA摄取进行体素分组比较，确定了患者中肠类多巴胺消耗的确切位置和程度。将得到的簇定义为种子到体素功能连接性分析的种子。在全脑水平上比较了两组之间的18F-FDG代谢，并从肠连接性降低的区域提取了摄取值。为了揭示多巴胺能活性，纹状体皮质连通性，葡萄糖代谢和症状严重程度之间的关联，在控制年龄和多巴胺能药物的同时，测试了标准化摄取值，种子到簇的β值与临床参数之间的相关性。除了皮层代谢不足，18F-FDG-PET数据首次显示帕金森氏病患者的中代谢代谢异常，其中包括双侧黑质致密部的尾部。双侧后部壳状核中的am胺多巴胺合成能力显着降低，并与同侧黑色素18F-FDG摄取相关。静息状态的功能性MRI数据表明，帕金森氏病患者中，多巴胺贫化的am虫种子与主要属于感觉运动网络的皮质区域之间的功能连通性显着降低。在顶下皮质中 患者的低连通性与较低的代谢密切相关（左P = 0.021，右P = 0.018）。值得注意的是，用不同方式量化的单侧网络改变与对侧运动障碍相对应。总而言之，我们的结果支持以下假设：黑质纹状体纤维的功能损害了独特的纹状体皮层连接，扰乱了运动加工区域之间的有效相互作用，并损害了帕金森氏病患者的运动控制。本研究是第一个通过概述功能性黑纹状体途径损伤对纹状体皮层功能连接网络和皮层代谢的影响，揭示帕金森氏病网络依赖性变性的三峰证据。021，右P = 0.018）。值得注意的是，用不同方式量化的单侧网络改变与对侧运动障碍相对应。总而言之，我们的结果支持以下假设：黑质纹状体纤维的功能损害了独特的纹状体皮层连接，扰乱了运动加工区域之间的有效相互作用，并损害了帕金森氏病患者的运动控制。本研究是第一个通过概述功能性黑纹状体途径损害对纹状体皮层功能连接网络和皮层代谢的影响，揭示帕金森氏病网络依赖性变性的三峰证据。021，右P = 0.018）。值得注意的是，用不同方式量化的单侧网络改变与对侧运动障碍相对应。总而言之，我们的结果支持以下假设：黑质纹状体纤维的功能损害了独特的纹状体皮层连接，扰乱了运动加工区域之间的有效相互作用，并损害了帕金森氏病患者的运动控制。本研究是第一个通过概述功能性黑纹状体途径损害对纹状体皮层功能连接网络和皮层代谢的影响，揭示帕金森氏病网络依赖性变性的三峰证据。总而言之，我们的结果支持以下假设：黑质纹状体纤维的功能损害了独特的纹状体皮层连接，扰乱了运动加工区域之间的有效相互作用，并损害了帕金森氏病患者的运动控制。本研究是第一个通过概述功能性黑纹状体途径损害对纹状体皮层功能连接网络和皮层代谢的影响，揭示帕金森氏病网络依赖性变性的三峰证据。总而言之，我们的结果支持以下假设：黑质纹状体纤维的功能损害了独特的纹状体皮层连接，扰乱了运动加工区域之间的有效相互作用，并损害了帕金森氏病患者的运动控制。本研究是第一个通过概述功能性黑纹状体途径损害对纹状体皮层功能连接网络和皮层代谢的影响，揭示帕金森氏病网络依赖性变性的三峰证据。