Origins of atrophy in Parkinson linked to early onset and local transcription patterns.
Origins of atrophy in Parkinson linked to early onset and local transcription patterns.
复制标题
帕金森萎缩的起源与早期发病和局部转录模式有关。
DOI：
10.1093/braincomms/fcaa065
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发表时间：
2020
影响因子：
4.8
通讯作者：
Raj,Ashish
中科院分区：
文献类型：
--
作者：
Maia,PedroD;Pandya,Sneha;Freeze,Benjamin;Torok,Justin;Gupta,Ajay;Zeighami,Yashar;Raj,Ashish
推断帕金森病患者最初萎缩的大脑区域，并了解其与临床和遗传风险因素的关系，具有巨大的临床价值。本研究的目的是利用一种新的用于阿尔茨海默病的种子推断算法，并根据这些早期萎缩模式将患者聚集在有意义的亚组中。我们不是单独测试每个患者的大脑区域作为可能的起始位点，而是解决了一个l1惩罚优化问题，可以返回更具预测性的异质，多位点种子模式。单个种子模式的聚类分析揭示了两个不同的亚群（S1和S2）。S1亚群的特点是累及脑干和腹侧核，S2亚群的特点是累及皮层和纹状体。聚类中未包括的特征的后期分析显示，在发病年龄和帕金森相关基因的局部转录模式方面，亚组之间存在显著差异。与区域小胶质细胞丰度相关的顶级基因与S1亚群密切相关，而与S2亚群不相关。我们的研究结果表明帕金森病有两种不同的病因机制。免疫相关基因、溶酶体基因、小胶质细胞丰度和萎缩起始位点之间的相互作用可以解释为什么S1患者的发病年龄平均比S2患者晚4.5岁。我们突出并比较了两个亚组中受影响最显著的大脑区域。总之，我们的发现可能会改善目前早期帕金森患者的筛查策略。
There is enormous clinical value in inferring the brain regions initially atrophied in Parkinson disease for individual patients and understanding its relationship with clinical and genetic risk factors. The aim of this study is to leverage a new seed-inference algorithm demonstrated for Alzheimer’s disease to the Parkinsonian context and to cluster patients in meaningful subgroups based on these incipient atrophy patterns. Instead of testing brain regions separately as the likely initiation site for each patient, we solve an L1-penalized optimization problem that can return a more predictive heterogeneous, multi-locus seed patterns. A cluster analysis of the individual seed patterns reveals two distinct subgroups (S1 versus S2). The S1 subgroup is characterized by the involvement of the brainstem and ventral nuclei, and S2 by cortex and striatum.Post hocanalysis in features not included in the clustering shows significant differences between subgroups regarding age of onset and local transcriptional patterns of Parkinson-related genes. Top genes associated with regional microglial abundance are strongly associated with subgroup S1 but not with S2. Our results suggest two distinct aetiological mechanisms operative in Parkinson disease. The interplay between immune-related genes, lysosomal genes, microglial abundance and atrophy initiation sites may explain why the age of onset for patients in S1 is on average 4.5 years later than for those in S2. We highlight and compare the most prominently affected brain regions for both subgroups. Altogether, our findings may improve current screening strategies for early Parkinson onsetters.