Alzheimer's disease (AD), the leading cause of dementia in older individuals, is a devastating disease for which treatment in later stages has yielded disappointing outcomes. In order to be able to develop effective treatments in earlier stages of the disease, there is a need for sensitive biomarkers that can detect early neurodegeneration independent of (and complementary to) amyloid pathology. Physiological biomarkers can play an important role in this process. The parent award, R01NS109029, focuses on the development of a novel MR imaging technique for the measurement of oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) in human neonates as a biomarker of hypoxic ischemic injuries due to birth asphyxia. Since cerebral oxygen consumption represents a key marker for tissue viability and brain function, it can also be an important biomarker in neurodegeneration. Previous studies using Positron Emission Tomography (PET) techniques have demonstrated reduced brain metabolism in AD. However, the PET methods to measure brain metabolism requires the injection of radioactive tracers and thus is not suitable for large-scale screening in clinical trials. Therefore, a cost-effective MRI technique to measure regional brain metabolism without exogenous tracers is desired to facilitate the utilization of brain metabolism as an early biomarker of AD. In this supplement, we propose and request funds to obtain quantitative maps of OEF and CMRO2 in Alzheimer's disease (AD) by studying 20 mild cognitive impairment (MCI) patients and 20 normal elderly subjects using the accelerated T2-Relaxation-Under-Phase-Contrast (aTRU-PC) MRI technique developed in the parent award.
We aim to test the hypothesis that the brain's oxygen consumption, which can be measured with our novel techniques on a standard MRI in less than 5 minutes, can provide a practical and cost-effective biomarker of cognitive decline in elderly individuals. Specifically, we will compare the OEF and CMRO2 values between the two groups, and also evaluate their association with cognitive performance (overall cognition and cognitive domains), disease severity (Clinical-Dementia-Rating, CDR), vascular risk factors (hypertension, hypercholesterolemia, diabetes, smoking and obesity) and other imaging and blood biomarkers (white-matter hyperintensities, HbA1C, homocysteine, LDL, and HDL). As an exploratory analysis, AD pathological markers of beta-amyloid will be measured from plasma and their associations with OEF and CMRO2 will also be assessed. While the limited sample size will not allow conclusive results with respect to MCI and AD, this pilot study will allow us to get a first preliminary data set to judge the feasibility of a larger study for which we will request funding through the R01 mechanism.
Brain's oxygen consumption can be an important biomarker of neural degeneration and brain tissue viability in Alzheimer's disease. The present project aims to test the hypothesis that the brain's oxygen consumption, which can be measured with our novel techniques on a standard MRI in less than 5 minutes, can provide a practical and cost-effective biomarker of cognitive decline in elderly individuals.
