Novel Protein Biomarkers of Corticolimbic Pathophysiology in Lewy body Dementia

路易体痴呆皮质边缘病理生理学的新型蛋白质生物标志物

• 批准号: 10704614
• 负责人: ALLAN I LEVEY
• 金额: $ 160.63万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704614
• 关键词: Acceleration; Address; Alzheimer' s Disease; Amygdaloid structure; Anti-Anxiety Agents; Antipsychotic Agents; Automobile Driving; Autopsy; Biological Assay; Biological Markers; Blood; Blood Vessels; Brain; Brain region; Caregivers; Cerebrospinal Fluid; Cholinesterase Inhibitors; Clinical; Cognitive; Collection; DNA; Data; Delusions; Dementia; Dementia with Lewy Bodies; Detection; Deterioration; Diagnostic; Disease; Distress; Early Diagnosis; Emotional Disturbance; Endothelium; Enrollment; Fostering; Functional disorder; Future; Health Care Costs; Immune; Immunologics; Individual; Knowledge; Lewy Body Dementia; Lewy Body Disease; Link; Longitudinal cohort; Mass Spectrum Analysis; Measures; Mediating; Medicine; Memory; Metabolism; Methods; Molecular Profiling; Monitor; Nerve Degeneration; Network-based; Neurodegenerative Disorders; Neurons; Paranoia; Parkinson Disease; Parkinson' s Dementia; Pathway Analysis; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Plasma; Progressive Disease; Proteins; Proteome; Proteomics; RNA; Registries; Research; Sampling; Schedule; Serum; Source; Specificity; Synapses; Techniques; Temporal Lobe; Therapeutic; Thinking; Tissues; Translating; Validation; Visual Hallucination; Whole Blood; aptamer; biobank; biomarker discovery; biomarker panel; biomarker validation; brain based; candidate identification; candidate marker; cohort; effective therapy; experience; experimental study; frontal lobe; innovation; multidisciplinary; myelination; neuropathology; neuropsychiatry; novel; novel marker; personalized care; personalized therapeutic; phenotypic data; programs; promoter; protein biomarkers; recruit; risk stratification; synuclein; synucleinopathy; targeted biomarker; therapeutic biomarker; treatment response; validation studies

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.

项目概要 路易体痴呆 (LBD)，一类疾病，包括帕金森病痴呆 (PDD) 和痴呆 路易体 (DLB)，具有侵袭性认知和神经精神下降，无法治愈或有效 缓解疗法。围绕 LBD 的临床挑战的推动因素是对 LBD 的了解不足 其临床恶化和极度缺乏诊断、进展和治疗的病理生理学基础 治疗性生物标志物。神经病理学证据表明皮质边缘突触核蛋白病与 与 LBD 的侵袭性痴呆有关，并且认知和神经精神下降的有效生物标志物将 必然反映了这种皮质边缘功能障碍。因此，我们的中心假设是皮质边缘 LBD 大脑特征反映了神经元和非神经元通路的区域和疾病特异性改变 作为脑脊液和血浆中独特的蛋白质特征。为了研究这个假设，我们将应用一个综合的 跨大脑、脑脊液 (CSF) 和血浆的基于网络的蛋白质组管道，用于识别 LBD 生物流体 植根于皮质边缘病理生理学的特征。我们对该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检测的强大促进剂，包括 神经元、神经胶质和内皮病理生理学。除了这些蛋白质组实验之外，我们还将 根据帕金森病生物标志物计划 (PDBP) 建立埃默里 LBD 登记处，并利用其临床 和生物样本数据，以促进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-生物体液蛋白质组学整合，以确定有前途的生物体液标记物，以及 4) 纵向 使用靶向蛋白质组策略进行生物流体验证。除了目标 1 中收集的生物样本外，我们还将 使用埃默里戈伊苏埃塔阿尔茨海默病中心现有的大脑和生物流体样本来补充这些实验 疾病研究中心生物样本库。最终，我们努力识别认知和认知的分子特征 LBD 的神经精神衰退有望发现新的生物标志物，以增强疾病的早期诊断 监测和衡量治疗反应。此外，此类标记可以作为必要的门户 针对这种毁灭性的神经退行性疾病的有效药物疗法。