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Title: The Interrogation of Traumatic Brain Injury with MR Spectroscopy and Molecular Imaging
Author: Lama, Sanju
Advisor: Sutherland, Garnette
Tomanek, Boguslaw
Keywords: Neuroscience
Abstract: Metabolic perturbations in early acute severe traumatic brain injury (TBI) using magnetic resonance (MR) spectroscopy, and the prospects of molecular imaging of repetitive mild TBI, form the driving principles of this thesis work. Brain metabolism is thought to be maintained by neuronal-glial metabolic coupling, whereby glia take up glutamate from the synaptic cleft for conversion into glutamine, triggering glial glycolysis and lactate production. This lactate is shuttled into neurons and further metabolized. Using a weight drop model of severe TBI and MR spectroscopy with infusion of 13C labeled glucose, lactate and acetate, this portion of the thesis investigated the hypothesis that neuronal-glial metabolism is uncoupled following severe TBI. High resolution MR spectroscopy revealed significant labeling of lactate irrespective of the infused substrate and decreased labelling of other metabolites. Histopathology, while showing features of severe brain injury, also stained positive for tau. A microtubule associated protein, tau has been shown to accumulate in brains following TBI, particularly those related to sports and combat. It was further hypothesized that tau could be visualized through the administration of a unique anti-tau single domain antibody (sdAb)-nanoparticle complex. Through llama immunization, tau specific sdAbs were isolated, panned and characterized for bioconjugation to MR sensitive NaDyF4-NaGdF4 nanoparticles, towards non-invasive imaging of tau in vivo. At a ratio of ~4 sdAbs per nanoparticle, the complex was able to cross the neuronal membrane and bind to intracellular tau in live hippocampal neuronal cultures. Preliminary in vivo studies, establishing the model for repetitive mild TBI showed considerable tau staining within the entorhinal cortex, dentate gyrus and hippocampal CA3 sector sparing CA1. While there were some T1 changes in MR imaging, clinical translation will require further tests for sdAb – nanoparticle affinity to both tau and hyperphosphorylated tau, optimal dosage and safety, toxicology and clearance profile. It may be concluded that the early increase in brain lactate or lactate storm marks severe TBI; and tau abnormality and associated disrupted axonal transport, may be the hallmark of repetitive mild TBI, making it a potential MR visible biomarker for TBI. These concepts may guide future diagnostic and therapeutic directions.
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