title: White matter alterations in patients with MRI-negative temporal lobe epilepsy and their asymptomatic siblings.
abstract: OBJECTIVE
  The identification of "endophenotypes"-measurable variations along the pathways between genes and distal disease state-may help deconstruct focal epilepsies into more sensitive phenomena and improve future efforts to map the genetic underpinnings of the disorder. In this study, we set out to determine if diffusion tensor imaging (DTI)-inferred white matter (WM) alterations represent a suitable structural endophenotype for focal epilepsy.
  
  
  METHODS
  We recruited 25 patients with sporadic mesial temporal lobe epilepsy (MTLE) with normal magnetic resonance imaging (MRI) findings, 25 of their gender-matched, asymptomatic siblings, and 60 control subjects. Whole-brain, voxelwise statistics were conducted to identify regions of microstructural degeneration in patients with MTLE and/or their asymptomatic siblings. WM tracts exhibiting evidence of microstructural disruption were then reconstructed using deterministic tractography. Diffusion metrics including fractional anisotropy (FA) and mean diffusivity (MD) were compared across groups using a series of one-way multivariate analyses of covariance (MANCOVAs).
  
  
  RESULTS
  Voxelwise statistics revealed significant FA reductions in the corpus callosum (CC), bilateral superior longitudinal fasciculi (SLF), bilateral inferior longitudinal fasciculi (ILF), and left corticospinal tract (CST) in MTLE patients only. MD increases were observed in MTLE patients and their asymptomatic siblings in the left SLF and left CST. Deterministic tractography supported the voxelwise results, revealing significant FA alterations in the left SLF and CST in patients only and significant MD alterations in MTLE patients and their unaffected siblings. The diffusion scalars of MTLE patients and their asymptomatic siblings were highly correlated in the SLF and CST ipsilateral to patients' sides of seizure onset.
  
  
  CONCLUSIONS
  These findings confirm the presence of microstructural WM alterations in patients with MRI-negative MTLE and provide preliminary support for a diffusion-based endophenotype in the disorder. Further studies of narrow-sense heritability in larger cohorts of first-degree relatives of MTLE patients are required to confirm these results.
authors.affiliation: Molecular and Cellular Therapeutics Department, Royal College of Surgeons in Ireland, Dublin, Ireland.|Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, California, U.S.A.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Whelan
authors.affiliation: Molecular and Cellular Therapeutics Department, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Saud
authors.initials: S
authors.lastname: Alhusaini
authors.affiliation: Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Erik
authors.initials: E
authors.lastname: O'Hanlon
authors.affiliation: Molecular and Cellular Therapeutics Department, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Maria
authors.initials: M
authors.lastname: Cheung
authors.affiliation: Neurology Department, St. James's Hospital, Dublin, Ireland.
authors.forename: Parames M
authors.initials: PM
authors.lastname: Iyer
authors.affiliation: Centre for Advanced Medical Imaging (CAMI), St. James's Hospital, Dublin, Ireland.
authors.forename: James F
authors.initials: JF
authors.lastname: Meaney
authors.affiliation: Centre for Advanced Medical Imaging (CAMI), St. James's Hospital, Dublin, Ireland.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Fagan
authors.affiliation: Centre for Advanced Medical Imaging (CAMI), St. James's Hospital, Dublin, Ireland.
authors.forename: Gerard
authors.initials: G
authors.lastname: Boyle
authors.affiliation: Molecular and Cellular Therapeutics Department, Royal College of Surgeons in Ireland, Dublin, Ireland.|Division of Neurology, Beaumont Hospital, Dublin, Ireland.
authors.forename: Norman
authors.initials: N
authors.lastname: Delanty
authors.affiliation: Neurology Department, St. James's Hospital, Dublin, Ireland.
authors.forename: Colin P
authors.initials: CP
authors.lastname: Doherty
authors.affiliation: Molecular and Cellular Therapeutics Department, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Gianpiero L
authors.initials: GL
authors.lastname: Cavalleri
mesh_terms: D000328:Adult; D016880:Anisotropy; D016022:Case-Control Studies; D003337:Corpus Callosum / Q000473:pathology*; D056324:Diffusion Tensor Imaging; D004833:Epilepsy, Temporal Lobe / Q000175:diagnosis*; D005260:Female; D007839:Functional Laterality / Q000502:physiology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011712:Pyramidal Tracts / Q000473:pathology*; D035781:Siblings; D020530:Subthalamus / Q000473:pathology; D066127:White Matter / Q000473:pathology*
keywords: Along-tract segmentation; Diffusion tensor imaging; Endophenotype; Temporal lobe epilepsy; White matter