The Application of Quantitative Magnetic Resonance Imaging (QMRI) to Identify Neuroanatomical Endophenotypes in Epilepsy

To date, efforts to identify genetic risk factors for common forms of epilepsy have been largely limited by the heterogeneity of epilepsy phenotypes and susceptibility genes. In an effort to characterize homogenous phenotypes for epilepsy, this thesis aimed to apply the latest techniques in quantitative magnetic resonance imaging (QMRI) to identify relevant neuroanatomical quantitative traits (QTs) that may represent endophenotypes for epilepsy. Two epilepsy syndromes were considered: mesial temporal lobe epilepsy (MTLE) and juvenile myoclonic epilepsy (JME). One hundred and nine patients with 'sporadic' MTLE [78 patients with hippocampal sclerosis (MTLE+HS) and 31 patients with normal MRI (MRI-negative TLE)] and 24 JME patients were recruited. In addition, 83 unaffected full siblings of MTLE patients and 86 healthy controls were considered. All participants underwent Tl-weighted brain magnetic resonance imaging (MRI). Images were processed using an automated surface-based morphometry analysis tool (FreeSurfer) to: 1) generate volumetric segmentations of brain subcortical structures and 2) construct cerebral cortex surfaces. Within each epilepsy syndrome, patients were compared to the healthy controls to identify syndrome-related subcortical volumetric QTs and cerebral cortex geometric traits, including volume, surface area, thickness and geometric distortion. Further, the heritability of subcortical volumetric QTs was estimated in MTLE patients and their unaffected siblings. In MTLE+HS patients, several QTs were identified, including volume deficits in particular subcortical structures and contractions in ipsilateral temporal lobe cortical surface area. The majority of these QTs appeared to correlate with the duration of epilepsy. In contrast, MRI-negative TLE patients displayed no change in the volume of subcortical structures. However, a number of cerebral cortex morphological traits were identified. In JME patients, bilateral thalamic volume loss was noted as was an increase in fronto-temporal cortical thickness. These cortical thickness traits were independent from cortical area surface abnormalities, which appeared widespread throughout the cerebral cortex. None of subcortical volumetric traits identified in MTLE+HS patients were present in the unaffected siblings of patients and the heritability estimates of the impacted structures were reduced. These findings highlight a number of neuroanatomical QTs specific to each epilepsy syndrome. Such QTs likely reflect significant underlying mechanisms and may represent suitable endophenotypes. The results, however, signify the importance of disease-related factors in contributing to these QTs, which may influence their endophenotypic potential.