title: Longitudinal imaging reveals subhippocampal dynamics in glutamate levels associated with histopathologic events in a mouse model of tauopathy and healthy mice.
abstract: Tauopathies are neurodegenerative disorders characterized by abnormal intracellular aggregates of tau protein, and include Alzheimer's disease, corticobasal degeneration, frontotemporal dementia, and traumatic brain injury. Glutamate metabolism is altered in neurodegenerative disorders manifesting in higher or lower concentrations of glutamate, its transporters or receptors. Previously, glutamate chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) demonstrated that glutamate levels are reduced in regions of synapse loss in the hippocampus of a mouse model of late-stage tauopathy. We performed a longitudinal GluCEST imaging experiment paired with a cross-sectional study of histologic markers of tauopathy to determine whether (1) early GluCEST changes are associated with synapse loss before volume loss occurs in the hippocampus, and whether (2) subhippocampal dynamics in GluCEST are associated with histopathologic events related to glutamate alterations in tauopathy. Live imaging of the hippocampus in three serial slices was performed without exogenous contrast agents, and subregions were segmented based on a k-means cluster model. Subregions of the hippocampus were analyzed (cornu ammonis CA1, CA3, dentate gyrus DG, and ventricle) in order to associate local MRI-observable changes in glutamate with histological measures of glial cell proliferation (GFAP), synapse density (synaptophysin, VGlut1) and glutamate receptor (NMDA-NR1) levels. Early differences in GluCEST between healthy and tauopathy mice were measured in the CA1 and DG subregions (30% reduction, P ≤ 0.001). Synapse density was also significantly reduced in every subregion of the hippocampus in tauopathy mice by 6 months. Volume was not significantly reduced in any subregion until 13 months. Further, a gradient in glutamate levels was observed in vivo along hippocampal axes that became polarized as tauopathy progressed. Dynamics in hippocampal glutamate levels throughout lifetime were most closely correlated with combined changes in synaptophysin and GFAP, indicating that GluCEST imaging may be a surrogate marker of glutamate concentration in glial cells and at the synaptic level. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Biochemistry and Molecular Biophysics (BMB), University of Pennsylvania, Philadelphia, Pennsylvania.|Center for Magnetic Resonance and Optical Imaging (CMROI), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Rachelle
authors.initials: R
authors.lastname: Crescenzi
authors.affiliation: Department of Biochemistry and Molecular Biophysics (BMB), University of Pennsylvania, Philadelphia, Pennsylvania.|Center for Magnetic Resonance and Optical Imaging (CMROI), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Catherine
authors.initials: C
authors.lastname: DeBrosse
authors.affiliation: Center for Magnetic Resonance and Optical Imaging (CMROI), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ravi P R
authors.initials: RP
authors.lastname: Nanga
authors.affiliation: Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Byrne
authors.affiliation: Center for Magnetic Resonance and Optical Imaging (CMROI), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Guruprasad
authors.initials: G
authors.lastname: Krishnamoorthy
authors.affiliation: Center for Magnetic Resonance and Optical Imaging (CMROI), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kevin
authors.initials: K
authors.lastname: D'Aquilla
authors.affiliation: Center for Magnetic Resonance and Optical Imaging (CMROI), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Hari
authors.initials: H
authors.lastname: Nath
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Knashawn H
authors.initials: KH
authors.lastname: Morales
authors.affiliation: Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Iba
authors.affiliation: Center for Magnetic Resonance and Optical Imaging (CMROI), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Hari
authors.initials: H
authors.lastname: Hariharan
authors.affiliation: Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Center for Functional Neuroimaging (CfN), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: John A
authors.initials: JA
authors.lastname: Detre
authors.affiliation: Center for Magnetic Resonance and Optical Imaging (CMROI), University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ravinder
authors.initials: R
authors.lastname: Reddy
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008137:Longitudinal Studies; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D016708:Synaptophysin / Q000378:metabolism; D024801:Tauopathies / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; C121673:Gprin1 protein, mouse; C054369:MAPT protein, human; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C493465:Slc17a7 protein, mouse; D016708:Synaptophysin; C569015:Syp protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; C528900:glial fibrillary astrocytic protein, mouse; D016875:tau Proteins; D018698:Glutamic Acid
keywords: CEST; glia; glutamate; synapse; tauopathy