PROJECT SUMMARY Quantitative assessment of brain oxygen metabolism, usually expressed in terms of cerebral metabolic rate of oxygen (CMRO2), can provide important information on many neurological disorders as well as normal cerebral physiology. MRI permits noninvasive, nonradiative measurement of the two key parameters – cerebral blood flow and oxygen extraction fraction (OEF) – that determine the rate of oxygen consumption, thus CMRO2. Currently, robust regional quantification of CMRO2 in the brain is not possible, primarily as techniques for OEF mapping are still at an early stage of development. MRI-based OEF mapping methods are commonly based on signal modulations resulting from the paramag- netism of blood deoxyhemoglobin (dHb). Current techniques either calibrate the effect of dHb’s magnetic suscepti- bility in a separate procedure, or derive the parameter by estimating the RF-reversible transverse relaxation rate constant R2¢ (class of methods termed ‘quantitative BOLD (qBOLD)’). Alternatively, a model accounting for several sources in voxel susceptibility has been invoked based on quantitative susceptibility mapping (QSM). Among these approaches, qBOLD is unique in that it requires no intervention, and thus is essentially calibration-free. One major challenge in qBOLD is to separate dHb’s contribution to R2¢ from other sources, typically non- heme iron stored, for instance, in the form of ferritin in the basal ganglia. While a recent approach combining qBOLD and QSM (termed ‘qBOLD+QSM’) mitigates the issue, the method is still prone to errors because acquired signals are entangled by the effects from the RF-irreversible transverse relaxation rate constant R2, as well as macroscopic magnetic field variations, in addition to those arising from R2¢. In addition, current techniques for direct R2¢ mapping are impractically slow for 3D encoding. Furthermore, extracting OEF from the estimate of heme-originated R2¢ is challenging because of limited sensitivity in the qBOLD model. The proponents’ recent work has addressed the issue by deriving prior information for the unknown qBOLD parameters. Aim 1 of this project seeks to develop a rapid R2¢-sensitive 3D pulse sequence, and implement a data processing pipeline that addresses the above-mentioned confounders via prior information guided qBOLD. The newly developed 3D MRI oximetry protocol will be validated at 3T field strength in a group of healthy test subjects at various physiologic states in comparison to qBOLD+QSM and in terms of reproducibility (Aim 2). Finally, the protocol’s feasibility towards clinical translation will be examined. To this end, Aim 3 evaluates patients with unilateral carotid steno-occlusive disease to address the hypothesis that parenchymal hypoxia is manifested ipsilaterally by greater OEF and lower CMRO2, and these parameters’ association with cerebrovascular reactivity. Successful completion of the proposed project will yield a robust, reliable, and clinically practical 3D MRI oximetry protocol as a means to study brain physiology in health and disease, with the long-term goal of the method’s translation to the clinic to help guide treatment of patients with neurometabolic disorders.

PROJECT NARRATIVE Many common neurological disorders, including arterial stenosis induced ischemic stroke, result in regional disturb- ance of brain oxygen metabolism. Thus, reliable measurements of oxygen utilization regionally in the brain should provide new insight into cerebral physiology in health and disease. This project proposes to develop and validate a MRI-based method for robust 3D mapping of oxygen metabolism across the entire brain, with the long-term goal of the method’s translation to the clinic for evaluating patients with neurometabolic disorders and providing guidance to clinical management. 1