Glutamate is both a significant metabolic intermediate as well as the major excitatory neurotransmitter in the brain and its changes are thought to play a crucial role in many central nervous system (CNS) disorders. Neurotransmission of glutamate has become an increasing target of drug development for the treatment of several neuropsychiatric disorders, which highlights the significance of developing novel noninvasive tools to investigate baseline and dynamic fluctuations in glutamate concentrations throughout the human brain. The major noninvasive approaches that are currently used to study this metabolite are positron emission tomography (PET) and proton Magnetic Resonance Spectroscopy (1H MRS). The primary limitations of PET are radiation exposure, short half-lives of radio ligands, and their limited applicability to dynamic studies. While 1H MRS is presently the gold standard for measuring human cortical glutamate concentration, its main limitations are low spatial resolution and long acquisition times, which preclude high resolution imaging of the spatial variation of brain glutamate under pathological conditions. The major objective of this proposal is to further optimize the recently developed glutamate imaging method (GluCEST) in mapping spatial variation of glutamate changes under disease conditions. Specifically, we will develop and optimize the GluCEST technique via experiments on known phantoms and evaluate the concentration and pH dependence of GluCEST under physiological conditions. This method will be optimized for in vivo measurements and exploited to investigate the potential of detecting brain glutamate modulation in diseases associated with aberrations of this metabolite. This will be accomplished by studying animal models of Parkinson's disease (PD) and glutaric acidemia type I (GA-I), which involve rapid and wide range of brain glutamate changes in a spatially dependent manner. Finally, the methodology will be optimized for measuring regional variation of glutamate in healthy human studies. As demonstrated by the promising preliminary data, the proposed method offers a highly novel, non-invasive, and nonradioactive method of measuring glutamate distribution in vivo throughout the brain. The method has the inherent capacity to outperform 1H MRS by at least two orders of magnitude with respect to sensitivity. In addition, GluCEST has the potential for providing information about pH changes associated with pathological conditions. Once optimized and validated on animal models with disease mediated rapid glutamate changes, and healthy humans, these experiments can be readily translated to the clinical setting paving the way for human studies dealing with an array of neuropsychiatric disorders.

Public Health Relevance

The objective of this proposal is to develop a novel high resolution, nonradioactive and noninvasive MR imaging method for spatial mapping of brain glutamate. Successful accomplishment of the aims in the proposed disease models will lead to a validated quantitative imaging technique to spatially map glutamate changes in numerous central nervous system disorders and ultimately contribute to improved noninvasive diagnosis and management of patients with neurological and psychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS087516-01
Application #
8686163
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Babcock, Debra J
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Zhou, Rong; Bagga, Puneet; Nath, Kavindra et al. (2018) Glutamate-Weighted Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Detects Glutaminase Inhibition in a Mouse Model of Triple-Negative Breast Cancer. Cancer Res 78:5521-5526
Hadar, Peter N; Kini, Lohith G; Coto, Carlos et al. (2018) Clinical validation of automated hippocampal segmentation in temporal lobe epilepsy. Neuroimage Clin 20:1139-1147
Crescenzi, Rachelle; DeBrosse, Catherine; Nanga, Ravi P R et al. (2017) Longitudinal imaging reveals subhippocampal dynamics in glutamate levels associated with histopathologic events in a mouse model of tauopathy and healthy mice. Hippocampus 27:285-302
Bagga, Puneet; Haris, Mohammad; D'Aquilla, Kevin et al. (2017) Non-caloric sweetener provides magnetic resonance imaging contrast for cancer detection. J Transl Med 15:119
Kogan, Feliks; Stafford, Randall B; Englund, Erin K et al. (2017) Perfusion has no effect on the in vivo CEST effect from Cr (CrCEST) in skeletal muscle. NMR Biomed 30:
Roalf, D R; Nanga, R P R; Rupert, P E et al. (2017) Glutamate imaging (GluCEST) reveals lower brain GluCEST contrast in patients on the psychosis spectrum. Mol Psychiatry 22:1298-1305
Haris, Mohammad; Bagga, Puneet; Hariharan, Hari et al. (2017) Molecular imaging biomarkers for cell-based immunotherapies. J Transl Med 15:140
Wilson, Neil E; D'Aquilla, Kevin; Debrosse, Catherine et al. (2016) Localized, gradient-reversed ultrafast z-spectroscopy in vivo at 7T. Magn Reson Med 76:1039-1046
Bagga, Puneet; Crescenzi, Rachelle; Krishnamoorthy, Guruprasad et al. (2016) Mapping the alterations in glutamate with GluCEST MRI in a mouse model of dopamine deficiency. J Neurochem 139:432-439

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