Analysis of Olfactory Dysfunction for Early Diagnosis of Parkinson's Disease

嗅觉障碍对帕金森病早期诊断的分析

• 批准号: 9137152
• 负责人: ROBERT A CLARK
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9137152
• 关键词: Address; Age; Age-Years; American; Animal Model; Axon; Behavioral; Biochemical; Biological Markers; Brain; Breeding; Cellular Morphology; Code; Cognitive; Confocal Microscopy; Consensus; Demographic Aging; Dendrites; Deposition; Deterioration; Diagnosis; Diagnostic; Discrimination; Disease; Disease Outcome; Disease Progression; Early Diagnosis; Economic Burden; Electron Microscopy; Enrollment; Epidemiologic Studies; Etiology; Event; Exposure to; Face; Family; Functional Magnetic Resonance Imaging; Functional disorder; Funding Opportunities; Genetic; Genetic Models; Histology; Human; Idiopathic Parkinson Disease; Imaging technology; Injury; Internal Ribosome Entry Site; Interneurons; Knowledge; LacZ Genes; Lead; Link; Magnetic Resonance Imaging; Manganese; Maps; Measurable; Methods; Military Personnel; Modality; Modeling; Monitor; Morbidity - disease rate; Motor; Mouse Protein; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotoxins; Odorant Receptors; Odors; Olfactory Pathways; Oxidative Stress; Parkinson Disease; Pathologic; Pathway interactions; Patients; Pattern; Phase; Play; Population; Prevalence; Proteins; Research; Resolution; Risk; Risk Factors; Role; Sensory; Signal Transduction; Smell Perception; Societies; Sorting - Cell Movement; Staging; Structure; Synapses; System; Therapeutic; Time; Toxic effect; Transgenic Mice; Veterans; alpha synuclein; awake; base; cognitive task; cost; disease diagnosis; disorder risk; dopaminergic neuron; in vivo; innovation; insight; interest; mitral cell; mortality; neural circuit; neurobehavioral test; neuroimaging; novel therapeutics; olfactory bulb; olfactory bulb glomeruli; olfactory sensory neurons; population based; pre-clinical; prospective; public health relevance; research study; synuclein; synucleinopathy; tau Proteins; tool

 DESCRIPTION (provided by applicant): Of the challenges that face Parkinson's disease (PD) research, few are more pressing than early detection of preclinical disease. Currently no method exists to diagnose PD before the irreversible deterioration of the brain. The lack of useful biomarkers is also a roadblock for studies of disease-modifying therapies, leading to the strong consensus that a major initiative to develop PD biomarkers is essential. Sense of smell is among the first casualties of PD, with olfactory loss occurring in up to 90% of patients. Furthermore, an association between impaired olfaction and subsequent PD diagnosis has been found in prospective population-based studies, suggesting that olfactory dysfunction is a very early sign of idiopathic PD. Although interest in using olfaction as a biomarker for PD has increased substantially in recent years, the mechanism of olfactory loss and its cause-and-effect relationship to -synucleinopathy, a major pathological hallmark of PD, remain unclear. This knowledge gap has created a major roadblock to diagnostic and therapeutic progress. Thus, it is critical that we understand the olfactory system neuroanatomical changes that lead to loss of smell in both the preclinical and symptomatic phases of PD, since an understanding of this pathway in well-defined animal models would significantly impact our knowledge of the mechanisms for loss of dopaminergic neurons, and at the same time provide a means for rapid and objective assessment of disease risk. Our over-arching hypothesis is that olfactory damage in PD is an early event based on specific neuroanatomical changes with measurable functional impact, and is directly linked to upstream -synuclein toxicity. We will assess the olfactory system by capitalizing on a well-established murine genetic model of PD, namely α-synuclein aggregate deposition in mThy1-hSNCA transgenic mice, and emphasizing experiments during the prodromal stage. This model is highly relevant to the etiology of olfactory dysfunction in human PD owing to its construct and face validity with PD in humans. Moreover, we will achieve high-level definition of olfactory system injury by exploiting: i) tagged odorant receptor-expressing transgenic mice (M72- or P2-IRES- tau-LacZ) for precise tracking of olfactory sensory neurons (OSNs) and their stereotypic olfactory sensory map, ii) thy1-yellow fluorescent protein (YFP) transgenic mice for analyzing mitral cells, their neural circuitry and archicortical projections, and iii) advanced non-invasive functional neuroimaging (fMRI, MEMRI, and GT-tMRI). By combining these incisive modalities with behavioral, biochemical, and histological assessments, we will elucidate the neuroanatomical substrate for early olfactory loss in PD, while also addressing the role of synucleinopathy in PD-associated olfactory dysfunction. Three aims are proposed: Aim 1 - To understand the role of post-synaptic -synuclein toxicity in structural and functional changes in the olfactory sensory neurons and their stereotypic olfactory sensory map leading to impaired sense of smell in PD. Aim 2 - To elucidate how abnormal -synuclein aggregates induce structural changes in the olfactory bulb mitral cells, their neural circuitry and modulatory interneurons, leading to impaired sense of smell in PD. Aim 3 - To elucidate how abnormal -synuclein aggregates alter archicortical projections and targets of mitral cells leading to impaire odor identification and discrimination in PD. These studies are significant, as the results will enhance understanding of the mechanisms of olfactory loss in PD and its relationship to pathologic -synuclein. Our results will in turn provide clues to new therapies, as well as biomarkers useful for early detection, prognostication, and monitoring of either disease progression or outcomes of disease-modifying therapies. Our approaches are innovative, since they exploit incisive genetic and cutting-edge analytic tools, and the study is highly feasible due to the team's expertise in olfaction, PD, neurodegeneration, oxidative stress, neurobehavioral testing, and advanced imaging technologies.

 描述（由申请人提供）： 在面对帕金森氏病的挑战中，在不可逆的大脑恶化之前，很少有对临床前疾病的早期检测。 PD生物标志物的主要倡议。在最近的耳朵损失以及与synucleinopathy的因果关系和效应的关系中，PD的主要病理标志是诊断和治疗程序的主要障碍。 PD d的临床前和症状Pass在多巴胺能神经元的丧失机制上显着影响，同时，通过可测量的功能影响系统的变化，为快速和客观评估疾病提供了一种手段。 PD d的鼠类遗传模型在前驱阶段强调了实验。 ：i）d表达气味受体的转基因小鼠（M72-OR P2-IRES-TAU-LACZ），用于精确跟踪嗅觉感觉神经元（OSN）及其定型嗅觉感觉图）细胞，神经回路和考古投影以及iii）晚期非侵入性功能性神经成像（fMRI，MEMRI和GT-TMRI），通过将这些敏锐的方式与行为，生化和组织学评估相结合。 PD的早期嗅觉损失，同时还解决了突触核酸的作用在PD相关的嗅觉功能障碍中。 嗅觉神经元和tere型嗅觉图导致PD中的嗅觉受损。对PD的嗅觉损失及其关系的理解具有创新性，因为它们利用了遗传芳族和杂物 - 边缘分析工具，并且我的研究高度可行 授予团队在嗅觉，PD，神经变性，氧化应激，神经黑维测试和高级成像技术方面的专业知识。