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; 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.

项目摘要 生物能功能障碍可能是第二普通神经发生的早期，关键的成分 神经退行性痴呆症，痴呆症具有路易体（DLB）。但是，很难阐明特定 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 能量储备的失败在该疾病的神经病发生中体内。阐明不同的机械途径 DLB发病机理涉及的代谢功能障碍，并确定这些临时序列和模式 事件对于开发目标疗法至关重要。利用我们的联合专业知识和我们的进步 神经影像学方法，我们有能力组合一个新的PET放射线，该PET可以量化大脑线粒体 复合物I，均具有氟脱氧葡萄糖（FDG）-PET，以评估糖酵解能量代谢和超高的田间强度 7T 31p-MR用于评估ATP和其他高能磷酸盐生物能代谢物。利用此多模式 神经影像学，以及广泛的临床表征，我们将确定线粒体呼吸道和糖酵解 通过评估对照，风险，前驱和临床，对整个临床光谱的ATP失调的贡献 已建立的DLB。我们将解决以下目的：1）表征特定的线粒体呼吸链功能障碍 在大脑中，随着DLB发病机制从处于危险中发展到已建立的疾病。 2）剖析特定的生物能途径 导致DLB中的ATP失调； 3）分析脑线粒体与生物能量之间的关系 生物能学的认知功能和外围测量的功能障碍和变化； 4）探索差异 在DLB和阿尔茨海默氏病之间的生物能途径功能障碍中。