Brain mitochondrial PET imaging and 31P-MR spectroscopy to dissect the role of mitochondrial dysfunction in bioenergetic dysregulation in Dementia with Lewy Bodies pathogenesis

脑线粒体 PET 成像和 31P-MR 光谱剖析线粒体功能障碍在路易体痴呆发病机制中生物能失调的作用

• 批准号: 10738869
• 负责人: HOWARD J AIZENSTEIN
• 金额: $ 143.41万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738869
• 关键词: Address; Adenosine Triphosphate; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Animal Model; Autopsy; Behavioral; Bioenergetics; Biological; Blood Platelets; Brain; Brain imaging; Brain region; Cell model; Clinical; Complex; Data; Defect; Dementia; Dementia with Lewy Bodies; Development; Disease; Energy Metabolism; Evaluation; Event; Failure; Functional disorder; Glycolysis; Human; Image; Imaging Techniques; Impaired cognition; Link; Magnetic Resonance Spectroscopy; Measurement; Measures; Metabolic Pathway; Metabolic dysfunction; Metabolism; Methodology; Mitochondria; Motor; Neurocognitive; Neuropathogenesis; Noise; Outcome; Participant; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Peripheral; Persons; Phosphocreatine; Phosphorus; Positron-Emission Tomography; Process; Publishing; Regulation; Reporting; Resolution; Respiration; Respiration Disorders; Respiratory Chain; Risk; Role; Signal Transduction; Skin; Sleep Disorders; Smell Perception; System; Testing; Time; alpha synuclein; amyloid pathology; brain cell; cognitive function; cognitive performance; cohort; fluorodeoxyglucose positron emission tomography; imaging modality; in vivo; inorganic phosphate; longitudinal design; mitochondrial dysfunction; multimodal neuroimaging; neurocognitive test; neurodegenerative dementia; neuroimaging; neuroprotection; radioligand; respiratory; synucleinopathy; targeted treatment; therapeutic target

PROJECT SUMMARY Bioenergetic dysfunction is likely an early, critical component of neuropathogenesis of the second-most common neurodegenerative dementia, Dementia with Lewy Bodies (DLB). However, it has been difficult to elucidate the specific patterns and mechanisms of bioenergetic dysfunction, such as mitochondrial respiratory dysfunction, glycolytic failure, or failure of energy reserves in vivo in the neuropathogenesis of this disease. Elucidating the different mechanistic pathways of metabolic dysfunction involved in DLB pathogenesis, and determining the temporal sequence and pattern of these events, will be critical to developing targeted therapies. Capitalizing on our combined expertise and our advancements in neuroimaging methodologies, we have the capacity to combine a new PET radioligand that quantifies brain mitochondrial Complex I, with both fluorodeoxyglucose (FDG)-PET to assess glycolytic energy metabolism, and ultra-high field strength 7T 31P-MRS for assessment of ATP and other high-energy phosphate bioenergetic metabolites. Utilizing this multimodal neuroimaging, along with extensive clinical characterization, we will determine mitochondrial respiratory and glycolytic contribution to ATP dysregulation across the clinical spectrum via evaluation of control, at-risk, prodromal, and clinically established DLB. We will address the following aims: 1) characterize specific mitochondrial respiratory chain dysfunction in the brain as DLB pathogenesis progresses from at-risk to established disease; 2) dissect specific bioenergetic pathways contributing to ATP dysregulation in DLB; 3) analyze the relationship between brain mitochondrial and bioenergetic dysfunction and changes in cognitive function and peripheral measurements of bioenergetics; and 4) explore differences in bioenergetic pathway dysfunction between DLB and Alzheimer’s disease.

项目概要 生物能功能障碍可能是第二常见神经病变的早期关键组成部分 神经退行性痴呆，路易体痴呆（DLB），但目前很难阐明其具体情况。 生物能功能障碍的模式和机制，例如线粒体呼吸功能障碍、糖酵解衰竭或 体内能量储备的失败在这种疾病的神经发病机制中阐明了不同的机制途径。 DLB 发病机制中涉及的代谢功能障碍的研究，并确定这些代谢功能障碍的时间顺序和模式 事件，对于利用我们的综合专业知识和进步来开发靶向疗法至关重要。 神经影像方法，我们有能力结合一种新的 PET 放射性配体来量化脑线粒体 复合物 I，具有用于评估糖酵解能量代谢的氟脱氧葡萄糖 (FDG)-PET 和超高场强 7T 31P-MRS 利用这种多模式评估 ATP 和其他高能磷酸盐生物能代谢物。 神经影像学，广泛的临床特征，我们将确定线粒体呼吸和糖酵解 通过对控制、风险、前驱和临床的评估，对整个临床范围内的 ATP 失调做出贡献 建立DLB。我们将解决以下目标：1）表征特定的线粒体呼吸链功能障碍。 DLB 发病机制从危险状态进展为已确定的疾病时在大脑中的变化；2) 剖析特定的生物能途径； 导致 DLB 中 ATP 失调；3）分析脑线粒体和生物能之间的关系 认知功能和外周生物能量测量的功能障碍和变化；4) 探索差异 DLB 和阿尔茨海默病之间的生物能量通路功能障碍。