Novel Protein Biomarkers of Corticolimbic Pathophysiology in Lewy body Dementia

项目摘要 路易体痴呆（Lewy body dementia，LBD），一类包括帕金森病痴呆（Parkinson's disease dementia，PDD）和痴呆（dementia，DAD）的疾病。 路易体（DLB），具有侵略性的认知和神经精神衰退，无法治愈或有效 缓解疗法驱动LBD周围的临床挑战是对LBD的理解不足。 其临床恶化的病理生理学基础和严重缺乏诊断，进行性， 治疗生物标志物。神经病理学证据表明皮质边缘突触核蛋白病与 LBD的侵袭性痴呆，认知和神经精神衰退的有效生物标志物将 必然反映了皮质边缘功能障碍。因此，我们的中心假设是皮质边缘LBD 脑功能的区域和疾病特异性的改变，在神经元和非神经元的途径反映 作为脑脊液和血浆中独特的蛋白质标记。为了研究这一假设，我们将应用一个综合的 基于网络的蛋白质组学管道跨脑、脑脊液（CSF）和血浆，以识别LBD生物流体 在皮质边缘病理生理学上的特征。我们对这条管道的初步经验表明， 是反映多种脑功能障碍的多重生物标志物测定的有力推动者，包括 神经元、神经胶质和内皮病理生理学。除了这些蛋白质组学实验，我们还将 在帕金森病生物标志物项目（PDBP）下建立埃默里LBD登记处，并利用其临床 和生物样本数据，以燃料蛋白质组学验证研究，并促进未来的LBD研究。我们的具体目标 包括：1）建立LBD的纵向PDBP注册表，2）定义LBD的皮质边缘网络蛋白质组， 3)进行脑-生物流体蛋白质组整合以鉴定有希望的生物流体标记物，和4）纵向 使用靶向蛋白质组学策略的生物流体验证。除了在目标1中收集的生物标本外，我们还将 使用埃默里戈伊苏埃塔阿尔茨海默氏症医院现有的大脑和生物流体样本补充这些实验， 疾病研究中心生物储存库。最终，我们努力识别认知和 LBD的神经精神下降有望发现新的生物标志物，以加强早期诊断，疾病 监测和测量治疗反应。此外，这些标记可以作为必要的网关， 有效的药物疗法来治疗这种毁灭性的神经退行性疾病。

Project Summary Lewy body dementia (LBD), a class of disorders comprising Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), features aggressive cognitive and neuropsychiatric decline without cure or effective mitigating therapies. Driving the clinical challenges surrounding LBD is a poor understanding of the pathophysiology underlying its clinical deterioration and a desperate lack of diagnostic, progressive, and therapeutic biomarkers. Neuropathological evidence suggests that corticolimbic synucleinopathy is closely linked to the aggressive dementia of LBD and that effective biomarkers of cognitive and neuropsychiatric decline would necessarily reflect this corticolimbic dysfunction. Thus, our central hypothesis is that the corticolimbic LBD brain features regional and disease-specific alterations in neuronal and non-neuronal pathways reflected as unique protein signatures in CSF and plasma. To investigate this hypothesis, we will apply an integrated network-based proteomic pipeline across brain, cerebrospinal fluid (CSF), and plasma to identify LBD biofluid signatures anchored in corticolimbic pathophysiology. Our preliminary experience with this pipeline suggests it is a powerful promoter of multiplexed biomarker assays reflective of diverse brain-based dysfunction, including neuronal, glial, and endothelial pathophysiology. In addition to these proteomic experiments, we will also establish an Emory LBD registry under the Parkinson’s Disease Biomarker Program (PDBP) and utilize its clinical and biospecimen data to fuel proteomic validation studies and promote future LBD research. Our specific aims include 1) building a longitudinal PDBP registry for LBD, 2) defining the corticolimbic network proteome of LBD, 3) performing brain-biofluid proteomic integration to identify promising biofluid markers, and 4) longitudinal biofluid validation using targeted proteomic strategies. In addition to biospecimens collected in Aim 1, we will supplement these experiments using existing brain and biofluid samples housed in Emory Goizueta Alzheimer’s Disease Research Center biorepositories. Ultimately, our efforts to identify molecular signatures of cognitive and neuropsychiatric decline in LBD promise to discover novel biomarkers to enhance early diagnosis, disease monitoring, and gauging therapeutic response. Furthermore, such markers can serve as a necessary gateway to effective drug therapies for this devastating spectrum of neurodegenerative diseases.