| Summary: | <p>Neurodegenerative and neurological diseases are metabolic diseases that invite metabolic treatments. Nutritional interventions that induce a state of ketosis, or “ketogenics,” are one class of metabolic treatment that have the potential to address the root pathologies of such diseases. Presented first in this thesis are three clinical studies that investigated the effects of a ketone ester (KE) drink in patients with Parkinson’s disease. The first study was a randomized, placebo-controlled, crossover trial in 14 participants that demonstrated a significant improvement in endurance exercise performance following a KE drink. Participants sustained a therapeutic cycling cadence of 80 rpm for 24% longer after ingesting KE as compared to performance following a placebo (carbohydrate) drink. The second study utilized <sup>31</sup>P magnetic resonance spectroscopy in 11 participants and demonstrated that exogenous KE did not alter brain energetics one hour following a drink. The third study was a randomized, placebo-controlled 28-day intervention in which 20 participants were to ingest either KE or placebo drinks four times daily for one month, while motor and non-motor symptoms were monitored. Four participants completed the protocol before the COVID-19 pandemic stopped Oxford clinical studies. Thus, the completed work is included herein as a validation of methods and feasibility study. This thesis also includes intellectual contributions in the form of recent peer-reviewed publications, most of which are literature reviews and theoretical papers, although one is a case report and another is a technological innovation: a tracking tool that has potential to open new avenues in nutrition research. Although the contents of this thesis may appear disparate, they are woven around the narrative that brain disorders are caused by disturbances in metabolism, and that the development of disease-modifying therapies, including ketogenics, will likely require addressing the core metabolic dysfunction that underlies each disease.</p>
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