Abstract / Summary
Abstract Background Dysregulated brain metabolism is increasingly recognized to play a significant role in the development and progression of neurodegenerative diseases (NDDs). Conventional imaging methods, such as positron emission tomography (PET), are limited to assessing tracer uptake and offer no insight into its downstream metabolic fate. Additionally, PET provides no insight into dynamic metabolic fluxes and turnover, which reflect biochemical processes. In contrast, magnetic resonance spectroscopy and spectroscopic imaging MRS(I) allow non-invasive, spatially resolved in vivo investigation of specific metabolites, without the use of radioactive tracers. Main body 1 H-MRS(I) is one of the most widely utilized techniques due to its accessibility, while heteronuclear approaches, including 2 H-, 13 C-, 15 N-, and 17 O-MRS(I), broaden MRS(I)’s utility by expanding the scope of accessible metabolites. Technical and methodological advances in nuclear spin hyperpolarization-enhanced MRI further improve signal-to-noise ratio, enabling in vivo detection of low-abundance metabolites. Furthermore, revival of 2 H-MRS(I) has opened new avenues for dynamic metabolic investigation without hyperpolarization. In this review, we provide a conceptual framework for transitioning from a static to a dynamic MRS(I) approach and discuss key considerations for tracer selection, nuclear spin hyperpolarization methods, acquisition hardware, reconstruction, preprocessing, and metabolic modeling. We outline major methodological and translational challenges, including low signal-to-noise ratio, field strength, and vendor hardware variability, as well as a lack of standardization across acquisition, reconstruction, preprocessing, and modeling strategies. Conclusion Dynamic MRS(I) provides a promising foundation for in vivo brain metabolism investigation in NDDs, offering mechanistic insights into metabolic fluxes, reprogramming, and bottlenecks. Although dynamic MRS(I) is limited to a few research institutions, ongoing technical and methodological advances are improving its feasibility, biochemical specificity, and broader implementation. Standardized and harmonized acquisition, reconstruction, and preprocessing protocols are necessary to enable broad clinical implementation of these approaches. Nevertheless, the shift from static to dynamic MRS(I) has great potential to advance biomarker and diagnostic tool development, patient stratification, and longitudinal disease monitoring in NDDs, provided that current challenges and limitations are sufficiently addressed.