Neurology and Neurosurgery Department, Montreal Neurological Institute, McGill University, 3801 University Street, Room NW312, Montreal, H3A 2B4, Canada.
McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada.
Sci Rep. 2022 Mar 31;12(1):5483. doi: 10.1038/s41598-022-09506-0.
Due to the marked interpersonal neuropathologic and clinical heterogeneity of Parkinson's disease (PD), current interventions are not personalized and fail to benefit all patients. Furthermore, we continue to lack well-established methods and clinical tests to tailor interventions at the individual level in PD. Here, we identify the genetic determinants of individual-tailored treatment needs derived from longitudinal multimodal neuroimaging data in 294 PD patients (PPMI data). Advanced multivariate statistical analysis revealed that both genomic and blood transcriptomic data significantly explain (P < 0.01, FWE-corrected) the interindividual variability in therapeutic needs associated with dopaminergic, functional, and structural brain reorganization. We confirmed a high overlap between the identified highly predictive molecular pathways and determinants of levodopa clinical responsiveness, including well-known (Wnt signaling, angiogenesis, dopaminergic activity) and recently discovered (immune markers, gonadotropin-releasing hormone receptor) pathways/components. In addition, the observed strong correspondence between the identified genomic and baseline-transcriptomic determinants of treatment needs/response supports the genome's active role at the time of patient evaluation (i.e., beyond individual genetic predispositions at birth). This study paves the way for effectively combining genomic, transcriptomic and neuroimaging data for implementing successful individually tailored interventions in PD and extending our pathogenetic understanding of this multifactorial and heterogeneous disorder.
由于帕金森病（PD）的人际神经病理学和临床明显异质性，目前的干预措施不是个性化的，无法使所有患者受益。此外，我们仍然缺乏既定的方法和临床测试来针对 PD 患者进行个体化干预。在这里，我们确定了源自 294 名 PD 患者（PPMI 数据）的纵向多模态神经影像学数据的个体定制治疗需求的遗传决定因素。先进的多元统计分析表明，基因组和血液转录组数据都显著解释（P<0.01，FWE 校正）与多巴胺能、功能和结构大脑重组相关的治疗需求的个体间变异性。我们证实，确定的高度预测分子途径与左旋多巴临床反应性的决定因素之间存在高度重叠，包括众所周知的（Wnt 信号传导、血管生成、多巴胺能活性）和最近发现的（免疫标志物、促性腺激素释放激素受体）途径/成分。此外，观察到治疗需求/反应的鉴定基因组和基线转录组决定因素之间的强对应关系支持基因组在患者评估时的积极作用（即，超出出生时的个体遗传倾向）。这项研究为有效结合基因组、转录组和神经影像学数据以在 PD 中实施成功的个体化干预以及扩展我们对这种多因素和异质性疾病的发病机制理解铺平了道路。
