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.

Project Narrative It is predicted that 16% of the world’s population will be older than 65 years by 2050. The proposed research project will develop new methods to assess the brain metabolism across the healthy lifespan. These techniques will contribute to our understanding of healthy aging and its link to cognitive performance, may identify biomarkers for healthy aging, and may lead to earlier identification of subject-specific abnormalities associated with a higher risk of age-related disease.