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.

项目摘要 随着全球预期寿命的持续增长，阿尔茨海默氏病（AD）的患病率预计将两倍 每20年直到2040年。与广告相关的认知下降对 受影响个人的生活和寿命以及巨大的社会和经济后果 - 目前 仅在美国，每年约100亿美元 - 是21世纪的主要挑战之一。这 减轻AD影响所需的预防治疗需要尽早确定有风险的受试者 可靠的疾病进展预测指标。制定这样的早期干预策略需要彻底 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）。基础研究和临床研究已经在MCI/AD开发中建立了关键的病理生理过程， 包括淀粉样蛋白B和Tau蛋白的沉积，线粒体功能障碍，氧化应激和受干扰 神经传递。很少有研究阐明了这些过程及其之间的相互作用 互动和关系最终导致认知下降仍然知之甚少。 编辑的磁共振光谱（MRS）技术的最新进展开放了新的途径 研究体内多种低浓度脑代谢物的作用，检查大大降低 时代。现在可以轻松确定神经递质和神经调节剂的水平（GABA， 谷氨酸，N-乙酰甲基谷氨酸，天冬氨酸），氧化还原化合物（谷胱甘肽，抗坏血酸）和指标 线粒体功能障碍（乳酸）和神经元完整性（N-乙酰天冬氨酸）。该提议的最初目标是 为了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腔 通过将它们推进多素和光谱成像（MRSI）技术来测量。在 前所未有的多模式方法，这些方法将应用于羊膜多域患者 轻度认知障碍（AMCI-MD，MCI亚型，其转换率特别高） 以前处理了淀粉样蛋白B和TAU沉积的正电子发射断层扫描（PET）成像。 将广泛的神经代谢谱与蛋白质映射相结合将允许检验 淀粉样蛋白B和Tau沉积，神经递质的水平，抗氧化剂和代谢之间的相互作用 多个受影响的大脑区域的标记，以及记忆和执行功能的指标。 这项获得独立奖的途径将得到约翰斯出色的职业发展资源的支持 霍普金斯大学，以及由MRSI领域全球认可专家的心理团队的培训， MRS，分子成像和临床MCI/AD研究。它将生成新的工具来研究代谢 神经和神经精神疾病的过程，并利用其潜力 了解MCI/AD神经生物学，有可能表明预测和预防的新途径。