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

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AD相关的认知能力下降对患者的生活质量有着毁灭性的影响。 受影响的个人的生命和寿命，以及巨大的社会和经济后果-目前 仅在美国，每年就有大约1000亿美元--是21世纪世纪的主要挑战之一。的 减轻AD影响所需的预防性治疗需要早期识别风险受试者， 疾病进展的可靠预测因子。制定这种早期干预战略需要一个全面的 了解AD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建立了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、氧化应激和干扰 神经传递很少有研究阐明了这些过程之间的相互作用， 最终导致认知能力下降的相互作用和关系仍然知之甚少。 编辑磁共振波谱（MRS）技术的最新进展开辟了一条新的途径 研究多种低浓度脑代谢物在体内的作用， 次现在可以同时测定神经递质和神经调质（GABA， 谷氨酸盐、N-乙酰基谷氨酸盐、天冬氨酸盐）、氧化还原化合物（谷胱甘肽、抗坏血酸盐）和 线粒体功能障碍（乳酸）和神经元完整性（N-乙酰天冬氨酸）。该提案的初步目标是 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，可以实现测量。中 前所未有的多模态方法，这些方法将应用于健忘症患者的多个领域 轻度认知障碍（aMCI-MD，一种向AD转化率特别高的MCI亚型）， 先前经历淀粉样蛋白-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图谱相结合，将允许测试以下假设： 淀粉样蛋白B和tau蛋白沉积之间的相互作用，神经递质，抗氧化剂和代谢水平 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。 这个独立之路奖将得到约翰斯优秀职业发展资源的支持 霍普金斯大学，以及来自MRSI领域全球公认专家的指导团队的培训， MRS、分子影像学与MCI/AD临床研究。它将产生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，以促进 了解MCI/AD神经生物学，可能为预测和预防提供新的途径。

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.