TR&D3: Downfield Spectroscopy at Ultrahigh Fields Project PIs: Walter Witschey, Ph.D. and Ravinder Reddy, Ph.D. Abstract This technology research and development component focuses on the development of downfield 1H magnetic resonance spectroscopic (DFS) technologies to measure several important metabolites (NAD+, Glutamine, PCr, Carnosine and ATP) that are not accessible from the conventional upfield spectroscopy (UFS), and serve as biomarkers for different diseases. Specifically, it develops novel technologies including (i) Spectral selective excitation pulses and spatially localized pulse sequences with optimal excitation profiles and capable of ultra- short echo acquisition without water suppression (ii) Strategies to detect and assign the DFS metabolites and measure cross-relaxation (iii) Optimal metabolic cycling schemes capable of providing simultaneous UFS and DFS with short echo acquisition and (iv) a post-processing pipeline integrating receive coil selection, eddy current correction and spectral curve fitting and metabolite quantitation. These technological developments are driven by collaborations and service projects from within PENN and from other institutions distributed across the US and abroad. Successful completion of the goals will lead to technologies that contribute to our improved understanding of aging, neurodegeneration, mitochondrial disease in skeletal muscle and heart and, thereby improving diagnosis of these disorders and guiding the development of targeted therapies and enabling longitudinal evaluation of the efficacy of these therapies. Furthermore, wide dissemination of these technologies, potential commercialization, and training of the next generation of biomedical scientists, will have sustained national impact.