3D MRI Method for CMRO2 Mapping of the Brain in Dementia

About This Grant

PROJECT SUMMARY The prevalence of Alzheimer’s disease (AD) and related dementias (ADRD) in the United States is on the order of seven million and likely to grow over the next two decades. The molecular hallmarks of ADRD are misfolded proteins (b-amyloid and tau), and although anti-amyloid antibody drugs have recently been approved for AD treatment, they have limited effectiveness, are often associated with significant side effects, and amyloid depo- sition correlates only moderately with cognitive status. This situation has spurred the search for additional mech- anisms underlying the disease. Glucose is the main substrate for ATP synthesis in the brain. A well-known feature of ADRD is disruption of the brain’s energy metabolism, which has been linked to defective processing of, or reduced access to, glucose resulting in brain hypometabolism. It is also known that ketones (b-hydroxy- butyrate and acetoacetate) formed in the liver from medium-chain length fatty acids can act as an alternate fuel for oxidative phosphorylation. Non-invasive assessment of the cerebral metabolic rate of oxygen (CMRO2) glob- ally and regionally would allow the age and neurodegeneration related brain energy gap to be quantified and validate ketogenic intervention by quantitative brain imaging. Currently, positron emission tomography (PET)- based brain oximetry relying on oxygen-15 tracers is considered the “gold-standard” imaging method for mapping cerebral energy O2 metabolism. But 15O PET is complex, costly, and not widely available. Over the past decade magnetic resonance imaging (MRI) methods have emerged for measuring CMRO2 noninvasively. Both PET and MRI derive CMRO2 from measures of venous and arterial O2 saturation to estimate oxygen extraction fraction (OEF) and, along with cerebral blood flow (CBF), CMRO2. The proposed research builds on recent developments in the applicants’ lab for 3D CMRO2 mapping via a new constrained qBOLD technique based on an extension of the Yablonskiy model for signal decay due to partially deoxygenated hemoglobin in the capillary network, in combination with quantitative susceptibility mapping. We propose to first enhance the method in terms of image acquisition efficiency and to examine its sensitivity to detect regional variations in OEF, CBF, and CMRO2 both at baseline and in response to physiologic stimuli in test subjects. Subsequently, we will investigate the growing energy gap with age and, more so, in ADRD, and evaluate the hypothesis in a small group of AD patients that ingestion of a ketone ester drink in the form of triacyl triglycerides of C-8 saturated fatty acids induces a transient increase in O2 metabolism and, possibly, acute improvement of cognition. This new MRI-based imaging tech- nology for brain oximetry can readily be integrated into standard brain imaging protocols to provide means for evaluation of the metabolic consequences of ADRD at baseline and in response to intervention.