Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Biochemistry & Molecular Biophysics

First Advisor

Ravinder Reddy

Abstract

Malfunctions in the glutamatergic system of the central nervous system have been implicated in neurodegenerative diseases such as Alzheimer’s disease (AD), tauopathies, and Parkinson’s disease (PD). A non-invasive measurement of glutamate would enhance our understanding of neurodegenerative processes and potentially facilitate early diagnosis. The current method for measuring glutamate in vivo is proton magnetic resonance spectroscopy (1HMRS) although it has poor spatial resolution and weak sensitivity to glutamate changes. The primary objective of this thesis was to measure pathology induced changes in glutamate levels in mouse models of neurodegeneration using a novel magnetic resonance imaging technique, glutamate chemical exchange saturation transfer (GluCEST) imaging.

Several studies were performed in three mouse models of neurodegeneration: the APP-PS1 transgenic model of amyloid-beta pathology of AD, the PS19 transgenic model of tau pathology, and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model of PD. Glutamate levels derived from GluCEST imaging were correlated with results from 1HMRS and immunohistochemistry (IHC). The primary IHC antibodies that were investigated include markers of phosphorylated tau protein, synapse density, neuron density, glial cell reactivity, a glutamate transporter, and an NMDA receptor.

GluCEST contrast correlated with 1HMRS-derived glutamate levels in the striatum of APP-PS1 mice (R2=0.91) and the thalamus of PS19 mice (R2=0.64). However, GluCEST detected deficits in PS19 mice four months earlier than 1HMRS, highlighting the method’s enhanced sensitivity to glutamate. Demonstrating the advantage of high spatial resolution, GluCEST imaging measured sub-hippocampal dynamics in glutamate levels in the aging PS19 mouse. A gradient in glutamate levels along the mouse hippocampus was also measured in vivo using GluCEST. While hippocampal glutamate levels were significantly decreased in early stages of PS19 tauopathy, glutamate levels in the dentate gyrus (DG) and cornu ammonis (CA1) increased at 9-13 months. Decreased GluCEST was concurrent with synapse loss and occurred before structural volume loss. Elevated GluCEST was associated with glial fibrillary acidic protein (GFAP) immunostaining in late stages of the PS19 tauopathy model and in the striatum of the MPTP PD model.

Results of this work demonstrate the use of GluCEST imaging to study regional and temporal variations in glutamate in different pathologies associated with neurodegeneration.

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