Neuroimaging Assessments of Brain Integrity in Aging Mice

The long-term goal of my research career is to use state-of-the-art, non-invasive brain imaging methods (magnetic resonance imaging and spectroscopy (MRI/MRS) and positron emission tomography (PET)) to assess brain metabolic, hemodynamic and neuronal (structural and functional) integrity and its associations with cognitive function in animal models of healthy aging and of age-related neurodegenerative disorders. The goals of my training program are: 1) to “reversely translate” the neuroimaging methods for assessing hemodynamics and metabolism from humans to rodent models; 2) to receive training in the biology of aging using rodent models, with an emphasis on metabolic physiology; 3) to apply these newly found skills to the investigation of the mechanisms of action of aging and potential protective effects of caloric restriction (CR); and, 4) to have hands-on training in behavioral testing for rodents and identify the association between imaging and behavioral results. The research objective of this proposal is to use high-field MRI/MRS and PET to investigate the brain integrity of aging mice and identify possible protective effects of CR. In the brain, mitochondrial oxidative phosphorylation of glucose is the predominant source of energy (ATP production), supporting energy demands (maintaining neuronal integrity and basal firing rates). A widely accepted cause of the functional losses that accompany aging, both in the brain and in other organs, is decreased brain metabolism. In support of this viewpoint, a host of neuroimaging studies show that cerebral metabolic rates of oxygen (CMRO2), glucose (CMRGlc) and cerebral blood flow (CBF) decline with age and decline still more rapidly and profoundly in neurodegenerative disorders, such as Alzheimer’s Disease (AD). It is generally believed, therefore, that preserving bioenergetics (i.e., glucose oxidative capacity) is critical for optimizing lifespan and healthspan. Interventions have been introduced to preserve metabolism in aging process. CR perhaps is the most well-studied one for various model organisms of extended longevity, including Saccharomyces cerevisiae, Caenorhabditis elegans, rodents and monkeys. In the neuronal system, CR has shown to attenuate age-related metabolic dysfunction and neuromuscular synaptic loss and to enhance cognitive function. The rationale of the study, therefore, is to characterize the effect of CR on in vivo brain metabolic, hemodynamic, and neuronal (structural and functional) integrity in aging using non-invasive, multimodal neuroimaging methods, and the association of the neuroimaging indices with the cognitive testing. The central hypothesis of this proposal is that cerebral metabolic function will decline in normal aging and consequently reduce brain structural, functional and cognitive integrity; mice with CR intervention will demonstrate: preserved CMRO2, CBF, CMRGlc, total ATP concentration; and, thus preserved brain structure, functional connectivity, and cognition during aging. The hypothesis will be tested by pursuing three specific aims: 1) Determine effects of normal aging on brain metabolic and hemodynamic integrity and possible protective effects of CR; 2) Determine effects of normal aging on neuronal (structural and functional) integrity and possible protective effects of CR; and, 3) Determine effects of normal aging on cognitive integrity and possible protective effects of CR. The approach is innovative, because it investigates the CR protective effect on in vivo brain metabolism in aging process with non-invasive neuroimaging methods; it uses complementary, multiparametric, non-invasive imaging methods (MRI, MRS and PET) to explore the physiological effects of mitochondrial alterations, for the first time; it uses quantitative imaging techniques (developed by the PI for humans) at ultra-high field (11.7T) and in rodents, the first time this has been done; and, it will be the first study to investigate the correlation between cognitive effects (memory and spatial information processing) and brain imaging results in the CR mouse model. The proposed research is significant because 1) physiological effects of metabolic alterations in aging and age-related neuronal disorders, disease progression and treatment efficacy can be monitored non-invasively and nondestructively; 2) the interplay between brain metabolic, structural and cognitive functions in aging can be identified; and, 3) these multi-metric imaging methods can be translated seamlessly from rodents to non-human primates and to humans. Collectively, the training provide by the Career Development Award will place me at the cutting edge of aging research, of animal neuroimaging, and of their combination: translational neuroimaging of aging. Translational neuroimaging is an emerging field with extraordinary promise. My ambition is to become pioneer in this emerging discipline.