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

基本信息

批准号：
10514142
负责人：
ALLAN I LEVEY
金额：
$ 164.1万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/10514142
关键词：
Address Alzheimer&apos s Disease Amygdaloid structure Anti-Anxiety Agents Antipsychotic Agents Automobile Driving Autopsy Base of the Brain Biological Assay Biological Markers Blood Blood Vessels Brain Brain region Caregivers Cerebrospinal Fluid Cholinesterase Inhibitors Clinical Cognitive Collection DNA Data Delusions 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&apos s Dementia Pathway Analysis Pathway interactions Patients Pharmacotherapy Phenotype Plasma Progressive Disease Proteins Proteome Proteomics RNA Regional Disease Registries Research Sampling Schedule Source Specificity Synapses Techniques Temporal Lobe Therapeutic Thinking Tissues Translating Validation Visual Hallucination Whole Blood aptamer base biobank biomarker discovery biomarker panel biomarker validation candidate marker cohort effective therapy experience experimental study frontal lobe innovation multidisciplinary myelination 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

项目摘要

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.

项目摘要刘易身体痴呆（LBD），一类疾病，完成帕金森氏病（PDD）和痴呆症借着路易尸体（DLB），具有侵略性的认知和神经精神病性下降而无法治愈或有效缓解疗法。推动LBD周围的临床挑战是对病理生理的临床决定性以及迫切缺乏诊断，进步和治疗生物标志物。神经病理学的证据表明，皮质脂质膜性肌病紧密相关对于LBD的侵略性痴呆以及认知和神经精神病的有效生物标志物将必然反映出这种皮质脂质的功能障碍。那就是我们的中心假设是Corticolimbic LBD 大脑具有反映的神经元和非神经元途径的区域和疾病特异性改变作为CSF和血浆中独特的蛋白质特征。为了调查这一假设，我们将应用一个集成的跨大脑，脑脊液（CSF）和等离子体的基于网络的蛋白质组学管道，以鉴定LBD生物流体锚定在Corticolimbic病理生理学中的特征。我们在此管道的初步经验表明是反映潜水大脑功能障碍的多重生物标志物测定的强大启动子，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外，我们还将根据帕金森氏病生物标志物计划（PDBP）建立Emory LBD注册中心并利用其临床和生物循环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）为LBD构建纵向PDBP注册表，2）定义LBD的Corticolimbic网络蛋白质组， 3）执行脑双流体蛋白质组学整合以识别有希望的生物流体标记，4）纵向使用靶向蛋白质组学策略的生物流体验证。除了在AIM 1中收集的生物测量外，我们还将使用现有的大脑和生物流体样品来补充这些实验疾病研究中心生物疗法。最终，我们为确定认知和认知分子特征的努力和 LBD的神经精神病下降有望发现新型生物标志物以增强早期诊断，疾病监测和测量治疗反应。此外，这样的标记可以用作必要的门户为这种毁灭性的神经退行性疾病范围的有效药物疗法。