Can Exogenous Ketone Supplementation Compensate for Glucose Hypometabolism and Improve Cognitive Processing Speed in Veterans With Prediabetes?

Metabolic dysfunction and impaired brain energy metabolism are increasingly recognized as early contributors to cognitive decline and dementia risk. Type 2 diabetes is a well-established risk factor for cognitive impairment; however, less is known about whether cerebral metabolic alterations are already present during the prediabetes stage, prior to clinically apparent cognitive symptoms. Prediabetes is characterized by impaired glucose regulation and early insulin resistance, both of which may reduce the efficiency of glucose transport and utilization in the brain. Because glucose is the brain's primary fuel under usual dietary conditions, even subtle reductions in cerebral glucose uptake may create a relative energy deficit that affects neural efficiency and cognitive performance.

Reductions in cerebral glucose metabolism have been observed years before the onset of dementia symptoms. These changes are particularly evident in frontal and temporoparietal regions that support higher-order cognitive functions, including processing speed. Cognitive processing speed is one of the earliest cognitive domains to decline in both metabolic disease and neurodegenerative conditions and is closely linked to functional independence in older adults. Identifying early metabolic and neural alterations in individuals with prediabetes may therefore provide insight into mechanisms linking metabolic dysfunction to later dementia risk.

This study uses hybrid fluorodeoxyglucose positron emission tomography combined with magnetic resonance imaging (18F-FDG PET/MRI) to quantify regional brain glucose uptake while participants perform a cognitive processing speed task during the imaging session. Fluorodeoxyglucose (FDG) is a radiolabeled glucose analog that allows measurement of tissue glucose uptake as an index of metabolic activity. Simultaneous magnetic resonance imaging (MRI), including functional MRI (fMRI), provides complementary measures of neural activation and network engagement during task performance. This multimodal approach allows assessment of neural efficiency, defined as cognitive task performance relative to regional glucose uptake and blood oxygen level-dependent (BOLD) signal changes.

The first objective of the study is to determine whether older adults with prediabetes exhibit reduced regional brain glucose uptake and slower cognitive processing speed compared to metabolically normal older adults. Metabolic status will be characterized using standardized clinical testing to define glycemic phenotype. The primary neural outcome is regional FDG uptake during task performance, and the primary cognitive outcome is processing speed performance acquired during the scan.

The second objective is to determine whether acute elevation of circulating ketone bodies through ingestion of an exogenous ketone monoester (DeltaG, Oxford, England) modifies cognitive performance and cerebral glucose uptake. Ketone bodies, including beta-hydroxybutyrate, serve as an alternative fuel for the brain and can be utilized even when glucose metabolism is impaired. Acute ketone supplementation increases circulating ketone concentrations without requiring prolonged dietary modification. This study evaluates whether providing an alternative metabolic substrate acutely influences neural efficiency and cognitive processing speed in individuals at risk for metabolic-related cognitive decline.