title: Tubers are neither static nor discrete: Evidence from serial diffusion tensor imaging.
abstract: OBJECTIVE
  To assess the extent and evolution of tissue abnormality of tubers, perituber tissue, and normal-appearing white matter (NAWM) in patients with tuberous sclerosis complex using serial diffusion tensor imaging.
  
  
  METHODS
  We applied automatic segmentation based on a combined global-local intensity mixture model of 3T structural and 35 direction diffusion tensor MRIs (diffusion tensor imaging) to define 3 regions: tuber tissue, an equal volume perituber rim, and the remaining NAWM. For each patient, scan, lobe, and tissue type, we analyzed the averages of mean diffusivity (MD) and fractional anisotropy (FA) in a generalized additive mixed model.
  
  
  RESULTS
  Twenty-five patients (mean age 5.9 years; range 0.5-24.5 years) underwent 2 to 6 scans each, totaling 70 scans. Average time between scans was 1.2 years (range 0.4-2.9). Patient scans were compared with those of 73 healthy controls. FA values were lowest, and MD values were highest in tubers, next in perituber tissue, then in NAWM. Longitudinal analysis showed a positive (FA) and negative (MD) correlation with age in tubers, perituber tissue, and NAWM. All 3 tissue types followed a biexponential developmental trajectory, similar to the white matter of controls. An additional qualitative analysis showed a gradual transition of diffusion values across the tissue type boundaries.
  
  
  CONCLUSIONS
  Similar to NAWM, tuber and perituber tissues in tuberous sclerosis complex undergo microstructural evolution with age. The extent of diffusion abnormality decreases with distance to the tuber, in line with known extension of histologic, immunohistochemical, and molecular abnormalities beyond tuber pathology.
authors.affiliation: From the Division of Epilepsy and Clinical Neurophysiology, Department of Neurology (J.M.P., M.S.), Computational Radiology Laboratory, Department of Radiology (J.M.P., A.K.P., X.K.T.-F., M.T., B.S., S.P.P., J.M.S., S.K.W., A.S.), and Department of Pathology (H.G.L.), Boston Children's Hospital and Harvard Medical School, MA; ICTEAM Institute (M.T.), Université catholique de Louvain, Louvain-la-Neuve, Belgium; and Brain Center Rudolf Magnus (F.E.J., K.P.J.B.), Department of Pediatric Neurology, University Medical Center Utrecht, the Netherlands.
authors.forename: Jurriaan M
authors.initials: JM
authors.lastname: Peters
authors.affiliation: From the Division of Epilepsy and Clinical Neurophysiology, Department of Neurology (J.M.P., M.S.), Computational Radiology Laboratory, Department of Radiology (J.M.P., A.K.P., X.K.T.-F., M.T., B.S., S.P.P., J.M.S., S.K.W., A.S.), and Department of Pathology (H.G.L.), Boston Children's Hospital and Harvard Medical School, MA; ICTEAM Institute (M.T.), Université catholique de Louvain, Louvain-la-Neuve, Belgium; and Brain Center Rudolf Magnus (F.E.J., K.P.J.B.), Department of Pediatric Neurology, University Medical Center Utrecht, the Netherlands.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Prohl
authors.affiliation: From the Division of Epilepsy and Clinical Neurophysiology, Department of Neurology (J.M.P., M.S.), Computational Radiology Laboratory, Department of Radiology (J.M.P., A.K.P., X.K.T.-F., M.T., B.S., S.P.P., J.M.S., S.K.W., A.S.), and Department of Pathology (H.G.L.), Boston Children's Hospital and Harvard Medical School, MA; ICTEAM Institute (M.T.), Université catholique de Louvain, Louvain-la-Neuve, Belgium; and Brain Center Rudolf Magnus (F.E.J., K.P.J.B.), Department of Pediatric Neurology, University Medical Center Utrecht, the Netherlands.
authors.forename: Xavier K
authors.initials: XK
authors.lastname: Tomas-Fernandez
authors.affiliation: From the Division of Epilepsy and Clinical Neurophysiology, Department of Neurology (J.M.P., M.S.), Computational Radiology Laboratory, Department of Radiology (J.M.P., A.K.P., X.K.T.-F., M.T., B.S., S.P.P., J.M.S., S.K.W., A.S.), and Department of Pathology (H.G.L.), Boston Children's Hospital and Harvard Medical School, MA; ICTEAM Institute (M.T.), Université catholique de Louvain, Louvain-la-Neuve, Belgium; and Brain Center Rudolf Magnus (F.E.J., K.P.J.B.), Department of Pediatric Neurology, University Medical Center Utrecht, the Netherlands.
authors.forename: Maxime
authors.initials: M
authors.lastname: Taquet
authors.affiliation: From the Division of Epilepsy and Clinical Neurophysiology, Department of Neurology (J.M.P., M.S.), Computational Radiology Laboratory, Department of Radiology (J.M.P., A.K.P., X.K.T.-F., M.T., B.S., S.P.P., J.M.S., S.K.W., A.S.), and Department of Pathology (H.G.L.), Boston Children's Hospital and Harvard Medical School, MA; ICTEAM Institute (M.T.), Université catholique de Louvain, Louvain-la-Neuve, Belgium; and Brain Center Rudolf Magnus (F.E.J., K.P.J.B.), Department of Pediatric Neurology, University Medical Center Utrecht, the Netherlands.
authors.forename: Benoit
authors.initials: B
authors.lastname: Scherrer
authors.affiliation: From the Division of Epilepsy and Clinical Neurophysiology, Department of Neurology (J.M.P., M.S.), Computational Radiology Laboratory, Department of Radiology (J.M.P., A.K.P., X.K.T.-F., M.T., B.S., S.P.P., J.M.S., S.K.W., A.S.), and Department of Pathology (H.G.L.), Boston Children's Hospital and Harvard Medical School, MA; ICTEAM Institute (M.T.), Université catholique de Louvain, Louvain-la-Neuve, Belgium; and Brain Center Rudolf Magnus (F.E.J., K.P.J.B.), Department of Pediatric Neurology, University Medical Center Utrecht, the Netherlands.
authors.forename: Sanjay P
authors.initials: SP
authors.lastname: Prabhu
authors.affiliation: From the Division of Epilepsy and Clinical Neurophysiology, Department of Neurology (J.M.P., M.S.), Computational Radiology Laboratory, Department of Radiology (J.M.P., A.K.P., X.K.T.-F., M.T., B.S., S.P.P., J.M.S., S.K.W., A.S.), and Department of Pathology (H.G.L.), Boston Children's Hospital and Harvard Medical School, MA; ICTEAM Institute (M.T.), Université catholique de Louvain, Louvain-la-Neuve, Belgium; and Brain Center Rudolf Magnus (F.E.J., K.P.J.B.), Department of Pediatric Neurology, University Medical Center Utrecht, the Netherlands.
authors.forename: Hart G
authors.initials: HG
authors.lastname: Lidov
authors.affiliation: From the Division of Epilepsy and Clinical Neurophysiology, Department of Neurology (J.M.P., M.S.), Computational Radiology Laboratory, Department of Radiology (J.M.P., A.K.P., X.K.T.-F., M.T., B.S., S.P.P., J.M.S., S.K.W., A.S.), and Department of Pathology (H.G.L.), Boston Children's Hospital and Harvard Medical School, MA; ICTEAM Institute (M.T.), Université catholique de Louvain, Louvain-la-Neuve, Belgium; and Brain Center Rudolf Magnus (F.E.J., K.P.J.B.), Department of Pediatric Neurology, University Medical Center Utrecht, the Netherlands.
authors.forename: Jolene M
authors.initials: JM
authors.lastname: Singh
authors.affiliation: From the Division of Epilepsy and Clinical Neurophysiology, Department of Neurology (J.M.P., M.S.), Computational Radiology Laboratory, Department of Radiology (J.M.P., A.K.P., X.K.T.-F., M.T., B.S., S.P.P., J.M.S., S.K.W., A.S.), and Department of Pathology (H.G.L.), Boston Children's Hospital and Harvard Medical School, MA; ICTEAM Institute (M.T.), Université catholique de Louvain, Louvain-la-Neuve, Belgium; and Brain Center Rudolf Magnus (F.E.J., K.P.J.B.), Department of Pediatric Neurology, University Medical Center Utrecht, the Netherlands.
authors.forename: Floor E
authors.initials: FE
authors.lastname: Jansen
authors.affiliation: From the Division of Epilepsy and Clinical Neurophysiology, Department of Neurology (J.M.P., M.S.), Computational Radiology Laboratory, Department of Radiology (J.M.P., A.K.P., X.K.T.-F., M.T., B.S., S.P.P., J.M.S., S.K.W., A.S.), and Department of Pathology (H.G.L.), Boston Children's Hospital and Harvard Medical School, MA; ICTEAM Institute (M.T.), Université catholique de Louvain, Louvain-la-Neuve, Belgium; and Brain Center Rudolf Magnus (F.E.J., K.P.J.B.), Department of Pediatric Neurology, University Medical Center Utrecht, the Netherlands.
authors.forename: Kees P J
authors.initials: KP
authors.lastname: Braun
authors.affiliation: From the Division of Epilepsy and Clinical Neurophysiology, Department of Neurology (J.M.P., M.S.), Computational Radiology Laboratory, Department of Radiology (J.M.P., A.K.P., X.K.T.-F., M.T., B.S., S.P.P., J.M.S., S.K.W., A.S.), and Department of Pathology (H.G.L.), Boston Children's Hospital and Harvard Medical School, MA; ICTEAM Institute (M.T.), Université catholique de Louvain, Louvain-la-Neuve, Belgium; and Brain Center Rudolf Magnus (F.E.J., K.P.J.B.), Department of Pediatric Neurology, University Medical Center Utrecht, the Netherlands.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Sahin
authors.affiliation: From the Division of Epilepsy and Clinical Neurophysiology, Department of Neurology (J.M.P., M.S.), Computational Radiology Laboratory, Department of Radiology (J.M.P., A.K.P., X.K.T.-F., M.T., B.S., S.P.P., J.M.S., S.K.W., A.S.), and Department of Pathology (H.G.L.), Boston Children's Hospital and Harvard Medical School, MA; ICTEAM Institute (M.T.), Université catholique de Louvain, Louvain-la-Neuve, Belgium; and Brain Center Rudolf Magnus (F.E.J., K.P.J.B.), Department of Pediatric Neurology, University Medical Center Utrecht, the Netherlands. simon.warfield@childrens.harvard.edu.
authors.forename: Simon K
authors.initials: SK
authors.lastname: Warfield
authors.affiliation: From the Division of Epilepsy and Clinical Neurophysiology, Department of Neurology (J.M.P., M.S.), Computational Radiology Laboratory, Department of Radiology (J.M.P., A.K.P., X.K.T.-F., M.T., B.S., S.P.P., J.M.S., S.K.W., A.S.), and Department of Pathology (H.G.L.), Boston Children's Hospital and Harvard Medical School, MA; ICTEAM Institute (M.T.), Université catholique de Louvain, Louvain-la-Neuve, Belgium; and Brain Center Rudolf Magnus (F.E.J., K.P.J.B.), Department of Pediatric Neurology, University Medical Center Utrecht, the Netherlands.
authors.forename: Aymeric
authors.initials: A
authors.lastname: Stamm
mesh_terms: D000293:Adolescent; D016880:Anisotropy; D001921:Brain / Q000473:pathology*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D038524:Diffusion Magnetic Resonance Imaging; D056324:Diffusion Tensor Imaging; D018450:Disease Progression; D005260:Female; D006801:Humans; D007223:Infant; D008137:Longitudinal Studies; D008297:Male; D012189:Retrospective Studies; D014402:Tuberous Sclerosis / Q000473:pathology*; D066127:White Matter / Q000473:pathology*; D055815:Young Adult