Date of Award

January 2014

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Dennis D. Spencer

Second Advisor

Tore Eid

Subject Area(s)

Neurosciences, Medicine

Abstract

High levels of extracellular brain glutamate have been identified as a possible trigger of seizures in humans with localization-related epilepsies (LREs); however, the cause of the glutamate excess is not known. Here we explore the novel hypothesis that alterations in the branched-chain amino acids (BCAAs) valine, leucine and isoleucine in the brain are implicated in the glutamate excess observed in epilepsy. In a first effort to test this hypothesis, we explored the relationships among BCAAs, glutamate, and seizures in humans with LREs. Intracerebral microdialysis combined with tandem mass spectrometry was used to monitor extracellular levels of glutamate, glutamine, and BCAAs in epileptogenic and non-epileptogenic brain areas in 31 patients with medically refractory LREs. Intracranial electroencephalogram (EEG) recordings from depth electrodes attached to 79 microdialysis catheters were used to identify epileptogenic and non-epileptogenic areas. Basal samples were collected 1 day after electrode implantation and at least 6 hours away from a seizure. Microdialysis samples from selected patients were analyzed every hour starting 6 hours before a seizure and ending 6 hours after a seizure. Basal levels of valine, leucine and isoleucine were significantly correlated with glutamate (P < 0.0001). All amino acids levels except glutamine were significantly higher in epileptogenic vs. non-epileptogenic areas (P < 0.05). A ratio of 2:2:1 of valine:leucine:isoleucine was uniformly present across brain regions and time points. Finally, glutamate, glutamine, valine, leucine and isoleucine increased in concentration hours before a seizure in epileptogenic brain areas, but not in non-epileptogenic areas. These data suggest a novel role for BCAAs in the regulation of extracellular glutamate, and possibly also in the initiation of seizures in human LREs. However, further studies are required to establish whether a causal relationship exists among BCAAs, glutamate, and seizures. If such a cause-effect relationship exists, then BCAAs or their associated metabolic pathways can be considered as potential diagnostic or therapeutic targets for medically refractory LREs.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

Download

Share

COinS