Bridging Preclinical and Clinical Approaches to Hyperpolarized Metabolic Imaging: Translational Research of Alzheimer’s Disease

Idiopathic neurodegenerative diseases, particularly Alzheimer’s disease (AD), present significant challenges for patients, healthcare systems, and researchers due to their complex and poorly understood pathogenesis. Globally, AD affects an increasing number of people, and no prevention nor cure is known. Metabolic dysfunction is increasingly regarded as a key contributor to the disease due to findings from ¹⁸F-FDG-PET imaging and postmortem analyses, but it is difficult to study pre-mortem neurometabolism in detail in humans. Hyperpolarized metabolic imaging using dissolution-dynamic nuclear polarization (d-DNP) is a promising tool for studying these metabolic alterations in real time, offering insights into fast metabolic processes with ¹³C-stable isotope labeled tracers. However, the tool is still relatively new, and is not routinely used in the clinic. Only few sites around the world are capable of clinical studies with hyperpolarized metabolic tracers, but more are able to carry out preclinical studies.

This thesis explores key advancements in hyperpolarized metabolic imaging that aim to enhance the translation of this technology from preclinical to clinical studies with a focus on AD. Three aspects are presented:

First, the development of hyperpolarized contrast agents optimized for production in high-field d-DNP polarisers and for use in both large animal and human research as well as in preclinical rodent reseacrch, is introduced. Next is presented a hybrid imaging setup that adapts clinical magnetic resonance scanners for use with rodent models and enables a more seamless transition of findings from animal studies to human applications. Finally is presented an investigation into hyperpolarized [1-¹³C]pyruvate as a metabolic biomarkers in the 5xFAD mouse model of AD.

By bridging preclinical studies with clinical imaging systems and focusing on metabolic alterations in AD, this thesis contributes to the development of more translatable imaging methodologies that could facilitate earlier diagnosis and better understanding of neurodegenerative diseases, ultimately advancing the progress towards disease-modifying treatment.