Towards a comprehensive neurometabolic profile in patients with mild cognitive impairment.

为轻度认知障碍患者提供全面的神经代谢特征。

• 批准号: 9901421
• 负责人: Georg Oeltzschner
• 金额: $ 8.57万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901421
• 关键词: 3-Dimensional; Acceleration; Affect; Age; Alzheimer' s Disease; Amyloid beta-Protein; Anaerobic Bacteria; Anterior; Antioxidants; Area; Aspartate; Award; Basic Science; Brain; Brain region; Chemicals; Clinical; Clinical Research; Cognition Disorders; Cognitive; Complement; Data; Dementia; Deposition; Detection; Deterioration; Development; Disease; Disease Progression; Early Intervention; Early identification; Economics; Elderly; Functional disorder; Glutamates; Glutathione; Goals; Grant; Imaging Techniques; Impaired cognition; Individual; Intervention; Life Expectancy; Link; Longevity; Magnetic Resonance; Magnetic Resonance Spectroscopy; Maps; Measurement; Measures; Medial; Memory; Mental disorders; Mentors; Metabolic; Metabolic Marker; Metabolism; Methodology; Methods; Mitochondria; N-acetylaspartate; N-acetylaspartylglutamate; Neurobiology; Neurofibrillary Tangles; Neuromodulator; Neuronal Injury; Neurons; Neurotransmitters; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Phase; Physiologic pulse; Positron-Emission Tomography; Prevalence; Prevention; Prevention approach; Preventive treatment; Process; Proteins; Quality of life; Reproducibility; Research; Research Project Grants; Resolution; Resource Development; Risk; Role; Route; Signal Transduction; Spectrum Analysis; System; Techniques; Temporal Lobe; Testing; Therapeutic Intervention; Time; Training; United States; Universities; abeta deposition; aging population; amyloid formation; ascorbate; career development; cohort; disorder risk; executive function; gamma-Aminobutyric Acid; imaging modality; improved; in vivo; interest; metabolic abnormality assessment; metabolic profile; mild cognitive impairment; mitochondrial dysfunction; molecular imaging; multimodality; nervous system disorder; neurochemistry; neuropsychiatric disorder; neurotransmission; normal aging; novel; pre-clinical; prevent; profiles in patients; programs; reconstruction; social; spectroscopic imaging; targeted treatment; tau Proteins; tool; training opportunity

Project Summary As global life expectancy continues to grow, the prevalence of Alzheimer’s disease (AD) is expected to double every 20 years until 2040. The cognitive decline associated with AD has devastating impact on the quality of life and lifespan of affected individuals, and the enormous societal and economic consequences – currently around $100B per year in the United States alone – are one of the major challenges of the 21st century. The preventive treatment necessary to mitigate the impact of AD requires early identification of subjects at risk and reliable predictors of disease progression. Developing such early-intervention strategies requires a thorough understanding of the neurobiological basis of AD and its preclinical stages, such as mild cognitive impairment (MCI). Basic and clinical research has established key pathophysiological processes in MCI/AD development, including deposition of amyloid-b and tau proteins, mitochondrial dysfunction, oxidative stress, and disturbed neurotransmission. Few studies have elucidated the interactions between these processes, and their interactions and relationships ultimately leading to cognitive decline remain poorly understood. Recent advances in edited magnetic resonance spectroscopy (MRS) techniques have opened a new avenue to study the roles of multiple low-concentration brain metabolites in vivo with greatly reduced examination times. It is now possible to simultaneously determine levels of neurotransmitters and neuromodulators (GABA, glutamate, N-acetylaspartylglutamate, aspartate), redox compounds (glutathione, ascorbate), and indicators of mitochondrial dysfunction (lactate) and neuronal integrity (N-acetylaspartate). The initial goal of this proposal is to extend the spatial coverage of these multi-metabolite methods, which are currently restricted to single-voxel measurements, by advancing them into multi-voxel and spectroscopic imaging (MRSI) techniques. In an unprecedented multimodal approach, these methods will be applied in patients with amnestic multi-domain mild cognitive impairment (aMCI-MD, a MCI subtype with particularly high conversion rates to AD), who have previously undergone positron emission tomography (PET) imaging of amyloid-b and tau deposition. Combining the extensive neurometabolic profile with protein mapping will allow to test hypotheses of interactions between amyloid-b and tau deposition, levels of neurotransmitters, antioxidants, and metabolic markers in multiple affected brain regions, and indicators of memory and executive functioning. This Pathway to Independence award will be supported by excellent career development resources at Johns Hopkins University, and training from a mentoring team of globally recognized experts in the fields of MRSI, MRS, molecular imaging and clinical MCI/AD research. It will generate novel tools to study metabolic processes in neurological and neuropsychiatric disorders, and leverage their potential to advance the understanding of MCI/AD neurobiology, potentially indicating new routes toward prediction and prevention.

项目概要 随着全球预期寿命持续增长，阿尔茨海默病 (AD) 的患病率预计将翻倍 每 20 年一次，直到 2040 年。与 AD 相关的认知能力下降会对认知质量产生毁灭性影响 受影响个人的生命和寿命，以及巨大的社会和经济后果——目前 仅在美国每年就花费约 100B 美元——这是 21 世纪的主要挑战之一。 减轻 AD 影响所需的预防性治疗需要及早识别处于危险中的受试者，并 制定这种早期干预策略需要彻底的疾病进展预测。 了解 AD 的神经生物学基础及其临床前阶段，例如轻度认知障碍 (MCI)。基础和临床研究已经确定了 MCI/AD 发展的关键病理生理过程， 包括淀粉样蛋白 B 和 tau 蛋白的沉积、线粒体功能障碍、氧化应激和紊乱 很少有研究阐明这些过程及其之间的相互作用。 导致认知能力下降的相互作用和最终关系仍然知之甚少。 编辑磁共振波谱 (MRS) 技术的最新进展开辟了一条新途径 研究体内多种低浓度脑代谢物的作用，并大大减少检查 现在可以同时测定神经递质和神经调节剂（GABA、 谷氨酸、N-乙酰天冬氨酰谷氨酸、天冬氨酸）、氧化还原化合物（谷胱甘肽、抗坏血酸）和指标 该提案的最初目标是线粒体功能障碍（乳酸）和神经元完整性（N-乙酰天冬氨酸）。 扩展这些多代谢物方法的空间覆盖范围，这些方法目前仅限于单体素 通过将其推进到多体素和光谱成像（MRSI）技术中来进行测量。 前所未有的多模式方法，这些方法将应用于遗忘症多域患者 轻度认知障碍（aMCI-MD，一种 MCI 亚型，AD 转化率特别高） 之前接受过淀粉样蛋白-b 和 tau 沉积的正电子发射断层扫描 (PET) 成像。 将广泛的神经代谢特征与蛋白质图谱相结合将可以检验以下假设： B 型淀粉样蛋白和 tau 蛋白沉积、神经递质水平、抗氧化剂和代谢之间的相互作用 多个受影响大脑区域的标记，以及记忆和执行功能的指标。 该独立之路奖将得到约翰斯优秀的职业发展资源的支持 霍普金斯大学，并接受 MRSI 领域全球知名专家组成的指导团队的培训， MRS、分子成像和临床 MCI/AD 研究将产生研究代谢的新工具。 神经系统和神经精神疾病的过程，并利用其潜力来推进 对 MCI/AD 神经生物学的了解，可能表明预测和预防的新途径。