Date of Award

January 2017

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Ketan R. Bulsara

Second Advisor

Angeliki Louvi

Abstract

Metabolomics, an emerging technique to study hundreds of small-molecule metabolites simultaneously, has been seldom applied to diseases of neurosurgical significance. We utilized metabolomics to explore two distinct questions: 1. to identify global metabolic changes and metabolite predictors of long-term outcome in aneurysmal subarachnoid hemorrhage (SAH) patients, 2. to identify differential metabolites profiles of radiation necrosis vs. recurrent tumor of metastatic brain lesions post-Gamma Knife radiosurgery. The first study applied gas chromatography time-of-flight mass spectrometry (GC-TOF) to cerebrospinal fluid samples collected from 15 high-grade aSAH patients (modified Fisher grades 3 and 4). Analysis was performed at two time points; metabolite levels at each time point were correlated with Glasgow Outcome Scale (GOS) of patients at 1 year post-aSAH. Of 97 metabolites identified, 16 metabolites (primarily free amino acids) significantly changed between the two time points; these changes were magnified in modified Fisher grade 4 compared with grade 3. Six metabolites (2-hydroxyglutarate, tryptophan, glycine, proline, isoleucine, and alanine) correlated with GOS at 1 year post-aSAH. These results suggest that specific metabolite changes occur in the brain during the course of aSAH and that quantification of specific CSF metabolites may be used to predict long-term outcomes. This is the first study to implicate 2- hydroxyglutarate, a known marker of tissue hypoxia, in aSAH pathogenesis. The second study applied GC- TOF to histologically-validated specimens (7 each) of pure radiation necrosis and pure recurrent tumor obtained from patient brain biopsies. Of 141 metabolites identified, 17 were found to be statistically significantly different between comparison groups. Of these metabolites, 6 were increased in tumor, and 11 metabolites were increased in radiation necrosis. An unsupervised hierarchical clustering analysis found that tumor had elevated levels of metabolites associated with energy metabolism whereas radiation necrosis had elevated levels of metabolites that were fatty acids and antioxidants/cofactors. This is the first tissue- based metabolomics study of radiation necrosis and tumor. Radiation necrosis and recurrent tumor following Gamma Knife radiosurgery for brain metastases have unique metabolite profiles that may be targeted in the future to develop non-invasive metabolic imaging techniques.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 06/12/2019

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