Brain metabolism across the lifespan using multi-parametric MRS

使用多参数 MRS 分析整个生命周期的脑代谢

• 批准号: 10738647
• 负责人: Helge Joern Zoellner
• 金额: $ 10.61万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738647
• 关键词: 3-Dimensional; Age; Age Years; Aging; Algorithms; Alzheimer' s disease related dementia; Biochemical; Biochemistry; Biological Markers; Biological Process; Biophysical Process; Choline; Clinical; Clinical Research; Communities; Computer software; Consensus; Consumption; Coupled; Creatine; Data; Data Analyses; Development; Diagnostic; Dictionary; Disease; Early Intervention; Early identification; Environment; Evolution; Exposure to; Female; Fingerprint; Foundations; Generations; Glutamates; Goals; Grant; Individual; Knowledge; Learning; Life; Life Expectancy; Link; Lipids; Literature; Longevity; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Medicine; Mentors; Methodology; Methods; Modeling; Molecular; N-acetylaspartate; Neurobiology; Neurodegenerative Disorders; Neurons; North America; Paper; Participant; Pattern; Physiologic pulse; Population; Process; Protons; Recovery; Relaxation; Research; Research Design; Research Personnel; Research Project Grants; Research Proposals; Resolution; Resource Development; Risk; Role; Schedule; Sequence Analysis; Side; Signal Transduction; Societies; Source; Specificity; Structure; Techniques; Testing; Time; Training; Universities; Water; age related; biomarker identification; brain metabolism; candidate marker; career; career development; cognitive performance; cohort; density; design; early detection biomarkers; experimental study; healthy aging; healthy volunteer; high risk; human old age (65+); improved; in vivo; innovation; macromolecule; male; myoinositol; neurochemistry; next generation; normal aging; novel; novel marker; open source; preventive intervention; training opportunity; volunteer

Global life expectancy is rising, and 16% of the world’s population – up to 25% in North America – is predicted to be at least 65 years of age by 2050. Aging societies are exposed to increasing emergence of age-related diseases such as Alzheimer’s Disease and related dementias (AD/ADRD). Identifying individuals at risk using new markers of pathophysiological changes will become a key challenge of 21st century medicine to enable prevention and early intervention. Establishing normative ranges of these markers across the lifespan is imperative for early diagnostics and to improve our understanding of healthy aging and AD mechanisms. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive in-vivo method quantifying signals from endogenous metabolites, lipids and macromolecules (MM). MRS signal amplitudes are determined by the concentrations and MR relaxation times of these compounds, i.e. indicators of local biochemistry and cellular microstructure, respectively. Unfortunately, subject-specific metabolite relaxation and MM estimation is prohibitively time-consuming with conventional MRS methods, and researchers are forced to use averaged literature values and assumptions instead. This practice is highly problematic as changes in metabolite levels, relaxation times and the MM background reflect different biological processes that evolve independently across the lifespan, but cannot be distinguished using conventional MRS (e.g., signal decreases with age could reflect lower metabolite levels or shorter transverse relaxation times). Current MRS methods therefore have substantially diminished interpretability in healthy aging and neurodegenerative diseases such as ADRD. This research proposal will address this critical knowledge gap by developing novel MRS methods allowing simultaneous subject-specific metabolite concentration, relaxation time, and MM background estimation. By separating those three candidate biomarkers, a comprehensive profile of local neurochemistry and cellular microstructure with greater specificity than previously possible can be achieved. Application in a cohort of healthy volunteers between 20 and 80 years of age will establish age trajectories of the candidate biomarkers in normal aging. Developing these novel techniques requires substantial expertise both in MR sequence development and in data analysis. This proposal builds upon my exceptional record in developing our open-source MRS software package Osprey with new training in pulse sequence development from world-leading experts in the field. The Johns Hopkins University provides outstanding career development resources and training from world-renowned experts necessary to successfully mentor me in the field of MRS, pulse programming, and clinical research design in aging and AD/ADRD cohorts. This project will develop novel techniques to characterize important neurobiological processes and their role in healthy aging, laying the foundation to identify new early biomarkers of AD/ADRD.

全球预期寿命正在上升，预计到2050年，世界人口的16%--北美高达25%--将至少达到65岁。老龄化社会暴露于年龄相关疾病如阿尔茨海默病和相关痴呆（AD/ADRD）的日益增加的出现。使用病理生理变化的新标志物识别处于风险中的个体将成为21世纪医学的关键挑战，以实现预防和早期干预。建立这些标志物在整个生命周期中的规范范围对于早期诊断和提高我们对健康老龄化和AD机制的理解至关重要。 质子磁共振波谱（1H-MRS）是一种非侵入性体内方法，可定量内源性代谢物、脂质和大分子（MM）的信号。MRS信号幅度由这些化合物的浓度和MR弛豫时间确定，即分别是局部生物化学和细胞微观结构的指标。不幸的是，受试者特定的代谢物松弛和MM估计是令人望而却步的耗时与传统的MRS方法，研究人员被迫使用平均文献值和假设，而不是。这种做法是非常有问题的，因为代谢物水平、弛豫时间和MM背景的变化反映了在整个生命周期中独立进化的不同生物过程，但是不能使用常规MRS（例如，信号随年龄的降低可反映较低的代谢物水平或较短的横向弛豫时间）。因此，目前的MRS方法在健康老龄化和神经退行性疾病（如ADRD）中的可解释性大大降低。这项研究提案将通过开发新的MRS方法来解决这一关键的知识缺口，该方法允许同时进行受试者特定的代谢物浓度、弛豫时间和MM背景估计。通过分离这三种候选生物标志物，可以实现比以前可能的更高特异性的局部神经化学和细胞微观结构的全面概况。在20至80岁的健康志愿者队列中的应用将建立候选生物标志物在正常衰老中的年龄轨迹。 开发这些新技术需要在MR序列开发和数据分析方面的大量专业知识。该建议建立在我在开发我们的开源MRS软件包Osprey方面的出色记录之上，并接受了该领域世界领先专家的脉冲序列开发新培训。 约翰霍普金斯大学提供优秀的职业发展资源和培训，来自世界知名的专家，成功地指导我在MRS，脉冲编程和临床研究设计领域的老化和AD/ADRD队列。该项目将开发新技术来表征重要的神经生物学过程及其在健康老龄化中的作用，为识别AD/ADRD的新早期生物标志物奠定基础。