IMAGING THE GLUTAMATERGIC SYSTEM WITH GLUCEST MRI: CYTOARCHITECTURE, AGING, AND INTERVENTION

Glutamate (Glu) is the primary excitatory neurotransmitter in the mammalian brain and a key metabolic intermediate in neurons and astrocytes. Shifts in glutamatergic biology can both reflect and drive changes in circuit excitability, synaptic structure, glial function, and cellular metabolism, providing a mechanistic bridge from cellular perturbations to systems-level phenotypes including aging and major depressive disorder. Ultra-high field 7T glutamate-weighted chemical exchange saturation transfer (GluCEST) imaging is emerging as a promising biomarker for in vivo glutamatergic function. This work addresses critical gaps in the literature and explores glutamatergic underpinnings of aging, depression, and neuromodulatory intervention using GluCEST.The thesis comprises four interconnected studies. First, we use multimodal analysis to reveal that cortical GluCEST correlates with normative glutamatergic receptor density maps derived from positron emission tomography and with glutamate-related gene expression levels derived from the Allen Human Brain Atlas. This study helps establish GluCEST as a measure biologically grounded in receptor systems and transcriptional environments. Second, an investigation of healthy aging shows lateralized hippocampal changes wherein older adults exhibit lower right hippocampal GluCEST, positioning GluCEST as a potential marker of early neurometabolic alterations. Third, a meta-analysis of twelve proton magnetic resonance spectroscopy studies reveals that repetitive transcranial magnetic stimulation (rTMS), a neuromodulatory treatment for depression, significantly increases glutamatergic metabolites in clinical responders, with evidence of dose-dependent effects. This study summarizes contemporary literature and motivates the final chapter. Fourth, preliminary GluCEST data from an rTMS study in major depressive disorder demonstrate widespread cortical increases in disease-relevant regions following intervention. These findings suggest rTMS may improve symptoms partly through glutamatergic upregulation, supporting the use of high-resolution neurometabolic mapping to characterize neuromodulation mechanisms. Ultimately, this work establishes GluCEST as a powerful translational tool for investigating glutamatergic function across health, aging, and disease – highlighting new avenues for understanding brain metabolism, plasticity, and neuropsychiatric interventions.

Author dc:creator

• Pecsok, Margaret, Kasey

Advisor dc:contributor.advisor

• Roalf, David, R

• Neuroscience and Neurobiology

Language dc:language.iso

en

Repository record dc:identifier.uri

https://repository.upenn.edu/handle/20.500.14332/62717

OAI identifier oai:identifier

oai:repository.upenn.edu:20.500.14332/62717