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100万美国人患有帕金森病，其中至少有8万人患有帕金森病