Simultaneous PET/MR Imaging of Brain Glucose and Oxygen Metabolism to Assess Energy Deficits Related to Alzheimer's Disease and the Response to Intervention - PROJECT SUMMARY There are now close to six million people in the Unites States living with Alzheimer’s disease and related de- mentias (ADRD) and this number is only expected to grow as the population continues to age. The current lack of effective treatments for ADRD speaks to the need to better understand the multiple pathophysiological factors that contribute to these complex diseases. There is growing evidence that age-related metabolic dysfunction plays a role in the Alzheimer’s etiology. The link between vascular risk factors and AD is explained in part by insufficient nutrient delivery to match the high energy demands of the brain and less efficient energy production as the brain ages. The concept of a “brain energy gap” has led to treatments aimed at enhancing energy pro- duction and cognitive performance, notably, ketogenic dietary supplements. These have been shown to increase cerebral ketone metabolism in AD patients, suggesting improved aerobic metabolism. However, this hypothesis has not been tested given the complexity of imaging oxygen and glucose metabolism. Positron emission tomog- raphy (PET) is the current standard, but the procedure requires 18F-fluorodeoxglucose (FDG) to measure glucose metabolism, 3 15O-tracers to measure oxygen metabolism and blood flow, and arterial sampling for quantification. We hypothesize that cerebral oxygen and glucose metabolism can be imaged noninvasively within a single session using hybrid PET/magnetic resonance imaging (PET/MRI). Our team has developed a robust quantitative blood oxygenation level dependent contrast (qBOLD) method of imaging oxygen extraction, which can be combined with MRI-based perfusion (arterial spin labeling, ASL) to map cerebral oxygen metabolism. In tandem, we have developed a PET approach for quantifying glucose metabolism that does not require arterial catheterization. Combining these methods on a PET/MR scanner provides the ability to image oxygen and glu- cose metabolism simultaneously and non-invasively, thereby reducing scan time, radiation dose and patient discomfort. As part of the proposed research, we will validate our qBOLD/ASL method for imaging oxygen me- tabolism by comparison to 15O-PET. Conducting these studies on a PET/MR system will ensure the PET and MRI measurements are collected under the same physiological state. The MRI oximetry method will be combined with FDG PET to investigate the effects of a ketogenic supplement on oxygen and glucose metabolism in AD patients. The outcomes of this project will include validating an MRI-based method for imaging oxygen metabo- lism and demonstrating how it can be combined with FDG PET to evaluate a treatment that targets the brain energy gap associated with AD. Replacing 15O-PET by MRI oximetry would greatly enhance the feasibility of imaging substrate (i.e. glucose) and total energy metabolism (i.e. oxygen) considering how few PET sites with 15O capabilities remain, while FDG is the most used tracer. The longer-term goals are to provide non-invasive, neuro-imaging tools for studying individuals with ADRD and evaluate effectiveness of emerging drugs.
