Project summary/Abstract Alzheimer's disease (AD) is the most common type of dementia, affecting ~5.7 million people in the U.S. alone. Early and accurate diagnosis of AD are critically important in its management. MRI has been playing an important role in the diagnosis of AD. However, currently the primary MRI-based biomarker has been structural MRI measures, specifically atrophy in medial temporal lobe (MTL), which is a crucial region for memory formation. Unfortunately, structural atrophy represents a late stage of MTL impairment and is generally considered irreversible. Therefore, it is highly desirable to develop a biomarker based on the function, rather than structure, of MTL, which may provide an early-diagnosis tool in AD. Cerebral oxygen extraction fraction (OEF) is an important index of the brain's energy metabolism. Because neural activity is tightly coupled to the brain's energy consumption, measurement of OEF in the medial temporal lobe (MTL-OEF) is thought to provide an assessment of brain function in this critical region and may serve as a novel biomarker in AD. In fact, previous studies have demonstrated that OEF, even only measured at a global level, is sensitive to AD. Since MTL is an early site of pathological involvement in AD, localized MTL-OEF is expected to have superior sensitivity and specificity compared to previous global OEF measurements. However, quantitative measurement of MTL-OEF remains a challenge in the MRI field, due to technical issues such as macroscopic susceptibility artifacts and partial volume effects. Therefore, the goals of the present exploratory/developmental (R21) study are to develop a novel non-invasive MRI technique to measure MTL-OEF and then apply it to the study of mild cognitive impairment (MCI), which is an early form of AD. This study has two specific aims. Aim 1 is the technical development. We will develop a novel MRI pulse sequence and related scan procedures to specifically measure the blood oxygenation in veins draining the MTL tissue (i.e., the basal veins of Rosenthal), so that MTL-OEF can calculated as the arterio-venous difference in oxygenation. This Aim will also compare this new technique to a 15O-PET-validated TRUST MRI technique and will determine benchmarks of the technique such as the accuracy of OEF quantification, test-retest reproducibility and the sensitivity to known alterations in OEF via physiological challenges. Aim 2 is to evaluate the initial clinical utility of MTL-OEF as a functional biomarker in MCI patients. This study focuses on MCI rather than full-blown AD because it is an early form of the disease and most treatment trials are aimed at this stage. MTL-OEF will be compared between MCI patients and cognitively normal elderly controls. Associations of MTL-OEF with blood plasma AD biomarkers (including beta-amyloid and phosphorylated tau) and cognitive function (especially episodic memory) will be examined. MTL-OEF will be compared with MTL volume (measured by M...