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: 10360721
• 负责人: Georg Oeltzschner
• 金额: $ 24.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360721
• 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.

项目摘要 随着全球预期寿命的持续增长，阿尔茨海默病(AD)的患病率预计将翻一番 每20年一次，直到2040年。与阿尔茨海默病相关的认知功能减退对生活质量有毁灭性的影响 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，每年约有1000亿美元-是21世纪的主要挑战之一。这个 减轻AD影响所需的预防性治疗需要及早识别有风险的受试者，并 疾病进展的可靠预测指标。制定这样的早期干预战略需要彻底的 了解阿尔茨海默病的神经生物学基础及其临床前阶段，如轻度认知障碍 (MCI)。基础和临床研究已经确立了MCI/AD发展中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。 神经传递。很少有研究阐明这些过程之间的相互作用，以及它们的 相互作用和关系最终导致认知能力下降，人们对此仍知之甚少。 编辑磁共振波谱(MRS)技术的最新进展开辟了一条新的途径 研究多种低浓度脑代谢产物在体内的作用，大大减少检查 泰晤士报。现在可以同时测定神经递质和神经调节剂(GABA， 谷氨酸、N-乙酰天冬氨酸、天冬氨酸)、氧化还原化合物(谷胱甘肽、抗坏血酸)以及 线粒体功能障碍(乳酸)和神经元完整性(N-乙酰天冬氨酸)。这项提议的最初目标是 为了扩大这些多代谢物方法的空间覆盖范围，目前这些方法仅限于单体素 通过将它们推进到多体素和光谱成像(MRSI)技术中，测量。在一个 前所未有的多模式方法，这些方法将应用于遗忘症患者的多领域 轻度认知障碍(aMCI-MD，一种向AD转化率特别高的MCI亚型)， 之前接受过正电子发射断层扫描(PET)的淀粉样蛋白b和tau沉积的成像。 将广泛的神经代谢图谱与蛋白质图谱相结合，将允许测试以下假设 淀粉样蛋白b和tau沉积、神经递质、抗氧化剂和代谢水平之间的相互作用 多个受影响大脑区域的标志物，以及记忆和执行功能的指标。 这一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，以及由全球公认的MRSI领域专家组成的指导团队的培训， MRS、分子成像与临床MCI/AD研究。它将产生研究新陈代谢的新工具 神经和神经精神障碍的过程，并利用它们的潜力来推动 对MCI/AD神经生物学的了解，可能为预测和预防提供新的途径。