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: 10254880
• 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/10254880
• 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; Spin Labels; Structure; Symptoms; Testing; Time; Toxic effect; Transgenic Mice; Translating; Traumatic Brain Injury; Up-Regulation; Veterans; Vietnam; Work; age group; aging demographic; 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 100 万美国人患有帕金森病 (PD)，其中至少 80,000 人患有帕金森病 (PD) 虽然目前帕金森病是根据运动体征来诊断的，但这些表现是先于退伍军人的。 在持续数年至数十年的时期内，神经退行性病变蔓延至许多大脑区域。 我们越早发现帕金森病，在出现致残症状之前治疗帕金森病的机会就越长。 了解如何预防致残症状将需要识别标记物，这些标记物不仅能够实现准确的早期诊断 诊断，同时也增强对疾病发病机制的认识，为疾病的发展铺平道路 尽管有可能，嗅觉是帕金森病的第一个受害者。 近年来，使用嗅觉作为帕金森病的生物标志物引起了越来越多的兴趣，这是有可能的 一旦我们更好地了解了这种嗅觉丧失的机制及其因果关系 与 α-突触核蛋白病理学的关系，这是 PD 的一个标志。 我们的首要假设是 PD 中的嗅觉损伤是与上游 - 直接相关的早期事件 突触核蛋白毒性和基于特定神经解剖学变化的可测量的功能影响。 利用成熟的转基因小鼠模型，该模型在体内过表达人类野生型 α-突触核蛋白 我们在当前的 VAMR 中证明了 α-突触核蛋白病理学在脑血流 (CBF) 中的致病作用 PD 中的缺陷和嗅觉功能障碍 进一步开发嗅觉功能障碍作为多方面功能障碍的潜力。 生物标志物，我们寻求深入了解 CBF 改变在嗅觉功能障碍中的作用，包括其 使用 α-突触核蛋白转基因小鼠，我们将评估与 α-突触核蛋白病理学的机制关系。 α-突触核蛋白的逐渐积累会导致 α-突触核蛋白之间的反调节机制被破坏。 脑肾素-血管紧张素系统 (RAS) 和多巴胺，导致 RAS 局部异常上调， 此外，我们将阐明渐进性 α-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 缺陷和嗅觉功能障碍的关系。 免疫组织化学、生物化学、行为评估和先进的神经影像学模式（动脉 自旋标记 MRI、扩散张量成像和功能磁共振成像 (fMRI)，这些技术很容易转化为患者使用。 重点关注 4、9 和 16 个月龄转基因小鼠的进行性 α-突触核蛋白病，代表 分别针对 PD 的前驱期、临床前期和临床期，我们的具体目标是： 1. 阐明PD相关的α-synuclein异常聚集与CBF缺乏之间的关系 嗅觉功能障碍； 2. 了解α-synuclein过表达诱导氧化应激和氧化应激的机制 神经炎症，导致 CBF 缺陷和嗅觉受损；以及 3. 探讨α-synuclein异常聚集与能量失调的关系 PD 相关嗅觉功能障碍中的稳态。 这些研究意义重大，因为结果将大大增强对机制的理解 PD 中嗅觉丧失、CBF 缺陷和 α-突触核蛋白病之间的关系，从而加速努力 将急需的早期诊断转化为临床现实。我们的方法是创新的，因为它们利用了切割技术。 由于我们的技术，边缘无创多模态 MRI 可以很容易地转化为临床。 研究团队在嗅觉、PD、神经退行性变、氧化应激、炎症、 神经行为测试、先进的成像技术以及 11.7 特斯拉的独特优势 磁体用于高分辨率MRI，所提出的研究具有很高的可行性。