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: 10408715
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10408715
• 关键词: Age; Age-Months; American; Animal Model; Anosmia; Antihypertensive Agents; Appetite Stimulants; Behavior assessment; Behavioral; Biochemical; Biochemistry; Biological Markers; Brain; Brain region; Cerebrovascular Circulation; Clinic; Clinical; Cognitive; Dependence; Detection; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Dopamine; Early Diagnosis; Early Intervention; Early identification; Economic Burden; Event; Exhibits; Exposure to; Functional Magnetic Resonance Imaging; Functional disorder; High Fat Diet; Homeostasis; Hormones; Human; Imaging technology; Immunohistochemistry; Impairment; Inflammation; Journals; Lead; Learning; Letters; Link; Magnetic Resonance Imaging; Measurable; Mediator of activation protein; Metabolic; Metabolism; Military Personnel; Modality; Morbidity - disease rate; Motor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurosciences; Neurotoxins; Non-Insulin-Dependent Diabetes Mellitus; Olfactory Pathways; Olfactory dysfunction; Onset of illness; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Prevalence; Process; Publications; Renin-Angiotensin System; Reporting; Research; Resolution; Risk; Risk Factors; Role; Signaling Molecule; Smell Perception; Symptoms; Testing; Time; Toxic effect; Transgenic Mice; Translating; Traumatic Brain Injury; Up-Regulation; Veterans; Vietnam; Work; age group; aging demographic; antagonist; arterial spin labeling; baby boomer; base; clinical diagnosis; diagnostic biomarker; disabling symptom; early detection biomarkers; functional decline; improved outcome; innovation; insight; interest; military veteran; mitochondrial dysfunction; mortality; mouse model; multimodality; neurobehavioral test; neuroimaging; neuroinflammation; novel; olfactory bulb; overexpression; pre-clinical; prevent; receptor; response; synuclein; synucleinopathy

More than one million Americans suffer from Parkinson’s disease (PD), of whom at least 80,000 are Veterans. Although PD is currently diagnosed on the basis of motor signs, these manifestations are preceded by a period that lasts several years to decades, in which neurodegeneration spreads to many brain regions. The earlier we can detect PD, the longer the window of opportunity to treat it before disabling symptoms appear. Learning how to prevent disabling symptoms will require identifying markers that not only enable accurate early diagnosis, but also enhance understanding of disease pathogenesis, paving the way for the development of early intervention with disease-modifying drugs. Sense of smell is the first casualty of PD. Although the possibility of using olfaction as a biomarker for PD has garnered increased interest in recent years, it will only be possible once we have achieved a better understanding of the mechanisms of this olfactory loss and its cause-and-effect relationship to -synuclein pathology, a hallmark of PD. Our over-arching hypothesis is that olfactory damage in PD is an early event directly linked to upstream - synuclein toxicity and based on specific neuroanatomical changes with measurable functional impact. By capitalizing on a well-established transgenic mouse model overexpressing human wild-type -synuclein in the brain, we showed in our current VAMR a causative role for -synuclein pathology in cerebral blood flow (CBF) deficit and olfactory dysfunction in PD. To develop further the potential of olfactory dysfunction as a multi-faceted biomarker, we seek in-depth understanding of the role of CBF alterations in olfactory dysfunction, including its mechanistic relationship to -synuclein pathology. Using the -synuclein transgenic mouse, we will assess how progressive accumulation of -synuclein leads to disruption of the counter-regulatory mechanism between the brain renin-angiotensin system (RAS) and dopamine, leading to abnormal local upregulation of the RAS and deficits in CBF. In addition, we will elucidate the role of progressive -synuclein accumulation in metabolic dysregulation, altered energy homeostasis, mitochondrial dysfunction, oxidative stress, and neuroinflammation, as well as the relationships of these processes to CBF deficit and olfactory dysfunction. Our approach features immunohistochemistry, biochemistry, behavioral assessments, and advanced neuroimaging modalities (arterial spin-labeling MRI, diffusion tensor imaging, and fMRI) that are readily translatable to patients. Focusing on progressive -synucleinopathy in transgenic mice at 4, 9, and 16 months of age, representing prodromal, preclinical, and clinical stages of PD, respectively, our specific objectives are: 1. To elucidate the relationship between abnormal-synuclein aggregation and CBF deficit in PD-related olfactory dysfunction; 2. To understand the mechanism of -synuclein overexpression-induced oxidative stress and neuroinflammation, leading to CBF deficit and impaired sense of smell; and 3. To explore the relationship between abnormal -synuclein aggregation and the dysregulation of energy homeostasis in PD-related olfactory dysfunction. These studies are significant, as the results will substantially enhance understanding of the mechanistic relationships among olfactory loss, CBF deficit, and -synucleinopathy in PD, thereby accelerating efforts to move much-needed early diagnosis to clinical reality. Our approaches are innovative since they exploit cutting- edge non-invasive multimodal MRI in a fashion that could be readily translated to the clinic. Owing to our investigative team’s in-depth expertise in olfaction, PD, neurodegeneration, oxidative stress, inflammation, neurobehavioral testing, and advanced imaging technologies, along with the unique advantage of an 11.7 Tesla magnet for high-resolution MRI, the proposed studies have high feasibility.

超过一百万的美国人患有帕金森氏病（PD），其中至少80,000是 退伍军人。尽管目前是根据电动标志诊断的，但这些表现已在 到了持续数年的时期，神经退行性变成了许多大脑区域。 早些时候，我们可以检测到PD，在出现禁用症状之前，将其治疗的机会窗口越长。 学习如何防止残疾症状将需要识别标记，而不仅仅是能够早期准确 诊断，但也增强了对疾病发病机理的理解，为发展铺平了道路 早期干预疾病改良药物。嗅觉是PD的第一个休闲感。虽然有可能 近年来，将嗅觉用作PD的生物标志物已增加了兴趣，只有可能 一旦我们对这种嗅觉损失的机制有了更好的了解及其因果关系的理解 与PD的标志的synuclein病理学的关系。 我们的规范假设是，PD中的嗅觉损害是与上游--的早期事件。 突触核蛋白毒性和基于特定的神经解剖学变化，具有可测量的功能影响。经过 利用良好的转基因小鼠模型过表达人类野生型 - 核蛋白 大脑，我们在当前的VAMR中表明了核蛋白病理学在脑血流（CBF）中的病因作用。 PD中的赤字和嗅觉功能障碍。进一步发展嗅觉功能障碍的潜力 生物标志物，我们寻求对CBF改变在嗅觉功能障碍中的作用的深入了解，包括其 机械关系与核蛋白病理学。使用-突触核蛋白转基因小鼠，我们将评估如何 突出核蛋白的逐步积累导致破坏了反调节机制 脑肾素 - 血管紧张素系统（RAS）和多巴胺，导致RA和RAS异常上调 CBF中的缺陷。此外，我们将阐明进行性突触核蛋白积累在代谢中的作用 失调，能量稳态改变，线粒体功能障碍，氧化应激和神经炎症， 以及这些过程与CBF赤字和嗅觉功能障碍的关系。我们的方法功能 免疫组织化学，生物化学，行为评估和高级神经影像学（动脉 自旋标记的MRI，扩散张量成像和fMRI）容易翻译成患者。 专注于4、9和16个月大的转基因小鼠的进行性核核疾病，代表 PD的前驱，临床前和临床阶段，我们的具体目标是： 1。阐明异常的关系核素聚集与PD相关的CBF防御之间的关系 嗅觉功能障碍； 2。了解-突触核蛋白过表达诱导的氧化应激和 神经炎症，导致CBF赤字和嗅觉受损；和 3。探索异常突出核蛋白聚集与能量失调之间的关系 与PD相关的嗅觉功能障碍中的稳态。 这些研究很重要，因为结果将大大增强对机械的理解。 PD中的嗅觉损失，CBF赤字和核核疾病之间的关系，从而加速了努力 将急需的早期诊断转移到临床现实中。我们的方法是创新的，因为它们利用了替代品 - 边缘非侵入性多模式MRI，可以很容易地转化为诊所。由于我们的 调查团队在嗅觉，PD，神经变性，氧化应激，炎症， 神经行为测试和高级成像技术，以及11.7 Tesla的独特优势 用于高分辨率MRI的磁铁，拟议的研究具有很高的可行性。