Neuroimaging Assessments of Brain Integrity in Aging Mice

Summary

Principal Investigator: Ai Ling Lin
Abstract: DESCRIPTION (provided by applicant): 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 fr 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 i 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, multi- parametric, 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.
Funding Period: 2012-08-15 - 2017-07-31
more information: NIH RePORT

Top Publications

  1. pmc Decreased in vitro mitochondrial function is associated with enhanced brain metabolism, blood flow, and memory in Surf1-deficient mice
    Ai Ling Lin
    1 Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA 2 Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA 3 Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
    J Cereb Blood Flow Metab 33:1605-11. 2013

Detail Information

Publications1

  1. pmc Decreased in vitro mitochondrial function is associated with enhanced brain metabolism, blood flow, and memory in Surf1-deficient mice
    Ai Ling Lin
    1 Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA 2 Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA 3 Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
    J Cereb Blood Flow Metab 33:1605-11. 2013
    ..Exploring the relationship between mitochondrial activity, oxidative stress, and brain function will enhance our understanding of cognitive aging and of age-related neurologic disorders. ..

Research Grants30

  1. HEALTHY AGING AND SENILE DEMENTIA
    John Morris; Fiscal Year: 2013
    ..Together, these projects and their supporting cores will focus on preclinical DAT in comparison with healthy brain aging and address the issue of detecting preclinical disease. ..
  2. Shock Center for Aging Research at The Jackson Laboratory
    Gary Churchill; Fiscal Year: 2013
    ..In the long term, JSC will continue to focus JAX expertise in genomics and biology on aging, leading to enhanced resources for the research community and a better understanding of the molecular mechanisms of lifespan and healthspan. ..
  3. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..
  4. Mayo Alzheimer's Disease Research Center
    Ronald C Petersen; Fiscal Year: 2013
    ..The ADRC will also continue to be a training platform for young investigators. ..
  5. A Gene therapeutic approach to stable suppression of HIV-1 replication
    MICHAEL R FARZAN; Fiscal Year: 2013
    ..These studies will establish principles and protocols directly applicable to subsequent human clinical trials. ..
  6. High-resolution Brain Imaging of Medial Temporal Lobe in Neurocognitive Aging
    CRAIG E STARK; Fiscal Year: 2013
    ....
  7. EARLY INDICATORS OF LATER WORK LEVELS, DISEASE AND DEATH
    Dora L Costa; Fiscal Year: 2013
    ..Project 4 deals with the differences across urban and rural areas in the process of aging. ..
  8. Center for Novel Therapeutics for HIV-Associated Cognitive Disorders
    Justin C McArthur; Fiscal Year: 2013
    ..5. To identify and validate surrogate biomarkers based on proteomics and lipomics. ..
  9. Arterial Aging, Brain Perfusion &Exercise: Impact on Brain Structure &Function.
    Rong Zhang; Fiscal Year: 2013
    ..Practically, the new findings are potentially important for developing new strategies to maintain cognitive vitality with age. ..
  10. The Aging Pituitary-Gonadal Axis
    George R Bousfield; Fiscal Year: 2013
    ..While currently available preparations work well in young women, they become increasingly ineffective in older women, requiring higher doses and prolonged administration yet producing fewer oocytes. ..
  11. Impact of Amyloid on the Aging Brain
    Reisa A Sperling; Fiscal Year: 2013
    ..This PPG brings together an exceptional multidisciplinary team of clinical, statistical, cognitive neuroscience, imaging, and laboratory investigators dedicated to exploring the impact of amyloid on the aging brain. ..
  12. PHYSIOLOGY OF BONE METABOLISM IN AN AGING POPULATION
    Sundeep Khosla; Fiscal Year: 2013
    ..Collectively, these studies strive to provide a comprehensive assesment of the pathogenesis and clinical impact of one of the most important disorders facing our aging population. ..
  13. Mitochondrial Proteins in Parkinson's Disease
    J Timothy Greenamyre; Fiscal Year: 2013
    ....
  14. Massachusetts Alzheimer's Disease Research Center
    Bradley T Hyman; Fiscal Year: 2013
    ..Going forward, the MADRC will continue to expand its clinical and neuropathological resources, its innovative training and scientific programs directed toward AD research. ..
  15. The Effect of Calorie Restriction on Brain Aging
    Sterling C Johnson; Fiscal Year: 2013
    ....
  16. The Canine as an Animal Model of Human Aging
    CARL WAYNE COTMAN; Fiscal Year: 2013
    ..These results will be compared to our previous findings, and will allow the parcelling out of key factors contributing to successful aging. ..
  17. Alzheimer's Disease Research Center
    Thomas J Montine; Fiscal Year: 2013
    ..Montine;Project 2: Therapeutic Effects of Intra-Nasal Insulin Detemir, Dr. Suzanne Craft;Project 3: Modulation of A peptide accumulation and neuron damage in vivo with adult bone marrow transplants, Dr. C. Dirk Keene. ..