Alzheimer?s disease (AD) is a devastating disease that affects more than five million people in the U.S. alone. Early neurodegeneration biomarkers can play an important role in clinical trials of AD, especially biomarkers that are non-invasive, inexpensive, and radiation-free. Our laboratory has recently developed and validated a technique, T2-Relaxation-Under-Spin-Tagging (TRUST), to measure the brain?s oxygen extraction fraction (OEF) and metabolism with MRI. The technique does not require any exogenous tracer, can be completed within 5 minutes on a standard 3T, has high test-retest reproducibility, and has been successfully evaluated in a multi-site setting. Mounting evidence suggests that OEF is a potential marker of neurodegeneration in AD. First, we have shown that patients with amnestic Mild Cognitive Impairment (MCI), a mild form of AD, have significantly diminished OEF. Second, cognitively normal elderly individuals with genetic risk to developed AD, e.g. APOE4 carriers, have reduced OEF. Finally, brain oxygen extraction and metabolism have also been found to be associated with cognitive dysfunction and tauopathy measured from the CSF. To validate the oxygen metabolism biomarker using gold-standard measures of neurodegeneration, human studies often require a long follow-up period and a relatively high cost. Therefore, it is logical to first conduct an exploratory/developmental (R21) study to demonstrate the plausibility of such hypothesis in animal models. Toward this goal, we propose a longitudinal study in AD mouse model using a novel oxygenation MRI technique, and validate its association with neurodegeneration as measured by histology. This study has two specific aims.
Aim 1 is to determine cross-sectional and longitudinal characteristics of brain oxygenation and metabolism in AD mouse model relative to control mice. We will measure OEF and cerebral metabolic rate of oxygen (CMRO2) in a novel AD model that our co-investigator, Dr. Wong, recently developed. We hypothesize that cross-sectionally OEF will be lower in the AD mice compared to control mice, and the difference will be more pronounced at an advanced age. Longitudinally, OEF in the AD mice will show progressive decrease starting 6 months of age.
Aim 2 is to validate the imaging biomarkers with histological measurement of neurodegeneration. The animals undergoing imaging will be sacrificed at three time points (a sub-sample at each time point) and histology will be performed to measure neuron count and tau burden. Imaging markers will be compared to these histological measures to determine the degree to which they can predict current and future neurodegeneration. Impact: Upon the completion of this study, we will have established a concrete relationship between imaging measures of brain oxygen metabolism and hallmarks of AD pathology such as tauopathy and amyloidosis, which will provide a strong foundation for human validation studies in a larger-scale project.
Diagnosis and treatment selection of Alzheimer?s disease (AD) require non-invasive biomarkers to inform neurobiology of the brain. This project will test the utility of an oxygen metabolism imaging technique in a mouse model of AD and will compare its results with gold-standard, but invasive, measures.
| Wei, Zhiliang; Chen, Lin; Lin, Zixuan et al. (2018) Optimization of phase-contrast MRI for the estimation of global cerebral blood flow of mice at 11.7T. Magn Reson Med : |
