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
基本信息
- 批准号:10738869
- 负责人:
- 金额:$ 143.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAdenosine TriphosphateAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAnimal ModelAutopsyBehavioralBioenergeticsBiologicalBlood PlateletsBrainBrain imagingBrain regionCell modelClinicalComplexDataDefectDementiaDementia with Lewy BodiesDevelopmentDiseaseEnergy MetabolismEvaluationEventFailureFunctional disorderGlycolysisHumanImageImaging TechniquesImpaired cognitionLinkMagnetic Resonance SpectroscopyMeasurementMeasuresMetabolic PathwayMetabolic dysfunctionMetabolismMethodologyMitochondriaMotorNeurocognitiveNeuropathogenesisNoiseOutcomeParticipantPathogenesisPathologicPathway interactionsPatientsPatternPeripheralPersonsPhosphocreatinePhosphorusPositron-Emission TomographyProcessPublishingRegulationReportingResolutionRespirationRespiration DisordersRespiratory ChainRiskRoleSignal TransductionSkinSleep DisordersSmell PerceptionSystemTestingTimealpha synucleinamyloid pathologybrain cellcognitive functioncognitive performancecohortfluorodeoxyglucose positron emission tomographyimaging modalityin vivoinorganic phosphatelongitudinal designmitochondrial dysfunctionmultimodal neuroimagingneurocognitive testneurodegenerative dementianeuroimagingneuroprotectionradioligandrespiratorysynucleinopathytargeted treatmenttherapeutic target
项目摘要
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常见的神经发病机制的早期关键组成部分,
神经退行性痴呆,路易体痴呆(DLB)。然而,很难阐明具体的
生物能功能障碍的模式和机制,如线粒体呼吸功能障碍、糖酵解失败,或
在这种疾病的神经发病机制中体内能量储备的失败。阐明不同的机制途径
代谢功能障碍参与DLB发病机制,并确定这些时间顺序和模式,
事件,将是开发靶向治疗的关键。利用我们的综合专业知识和我们在以下方面的进步
神经影像学方法,我们有能力结合联合收割机一种新的PET放射性配体,
复合物I,使用氟脱氧葡萄糖(FDG)-PET评估糖酵解能量代谢,并使用超高场强
7 T 31 P-MRS用于评估ATP和其他高能磷酸盐生物能代谢物。利用这种多模式
神经影像学,沿着广泛的临床特征,我们将确定线粒体呼吸和糖酵解
通过评价控制、风险、前驱和临床表现,
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
随着DLB发病机制从危险发展到确定的疾病,
3)分析脑线粒体与生物能量代谢的关系
功能障碍和认知功能的变化以及生物能量学的外周测量;以及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。
项目成果
期刊论文数量(0)
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{{ truncateString('HOWARD J AIZENSTEIN', 18)}}的其他基金
Imaging Advancements in Small Vessel and CSF Flow Pathophysiology of Pre-clinical Alzheimer's Disease
临床前阿尔茨海默氏病小血管和脑脊液流病理生理学的成像进展
- 批准号:
10343792 - 财政年份:2019
- 资助金额:
$ 143.41万 - 项目类别:
Imaging Advancements in Small Vessel and CSF Flow Pathophysiology of Pre-clinical Alzheimer's Disease
临床前阿尔茨海默氏病小血管和脑脊液流病理生理学的成像进展
- 批准号:
9912701 - 财政年份:2019
- 资助金额:
$ 143.41万 - 项目类别:
Imaging Advancements in Small Vessel and CSF Flow Pathophysiology of Pre-clinical Alzheimer's Disease
临床前阿尔茨海默氏病小血管和脑脊液流病理生理学的成像进展
- 批准号:
10549382 - 财政年份:2019
- 资助金额:
$ 143.41万 - 项目类别:
Imaging Advancements in Small Vessel and CSF Flow Pathophysiology of Pre-clinical Alzheimer's Disease
临床前阿尔茨海默氏病小血管和脑脊液流病理生理学的成像进展
- 批准号:
9765902 - 财政年份:2019
- 资助金额:
$ 143.41万 - 项目类别:
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