title: GABA deficiency in NF1: A multimodal [11C]-flumazenil and spectroscopy study.
abstract: OBJECTIVE
  To provide a comprehensive investigation of the γ-aminobutyric acid (GABA) system in patients with neurofibromatosis type 1 (NF1) that allows understanding the nature of the GABA imbalance in humans at pre- and postsynaptic levels.
  
  
  METHODS
  In this cross-sectional study, we employed multimodal imaging and spectroscopy measures to investigate GABA type A (GABAA) receptor binding, using [(11)C]-flumazenil PET, and GABA concentration, using magnetic resonance spectroscopy (MRS). Fourteen adult patients with NF1 and 13 matched controls were included in the study. MRS was performed in the occipital cortex and in a frontal region centered in the functionally localized frontal eye fields. PET and MRS acquisitions were performed in the same day.
  
  
  RESULTS
  Patients with NF1 have reduced concentration of GABA+ in the occipital cortex (p = 0.004) and frontal eye fields (p = 0.026). PET results showed decreased binding of GABAA receptors in patients in the parieto-occipital cortex, midbrain, and thalamus, which are not explained by decreased gray matter levels.
  
  
  CONCLUSIONS
  Abnormalities in the GABA system in NF1 involve both GABA concentration and GABAA receptor density suggestive of neurodevelopmental synaptopathy with both pre- and postsynaptic involvement.
authors.affiliation: From the Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine (I.R.V., M.P., I.B., J.R., M.C.-B.), Laboratory of Biostatistics and Medical Informatics, Faculty of Medicine (M.P., M.C.-B.), and Institute of Nuclear Sciences Applied to Health (A.J.A., N.F., M.C.-B.), University of Coimbra, Portugal; and Division of Brain Sciences (I.R.V.), Department of Medicine, Hammersmith Hospital Campus, Imperial College London, UK. i.violante@imperial.ac.uk.
authors.forename: Inês R
authors.initials: IR
authors.lastname: Violante
authors.affiliation: From the Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine (I.R.V., M.P., I.B., J.R., M.C.-B.), Laboratory of Biostatistics and Medical Informatics, Faculty of Medicine (M.P., M.C.-B.), and Institute of Nuclear Sciences Applied to Health (A.J.A., N.F., M.C.-B.), University of Coimbra, Portugal; and Division of Brain Sciences (I.R.V.), Department of Medicine, Hammersmith Hospital Campus, Imperial College London, UK.
authors.forename: Miguel
authors.initials: M
authors.lastname: Patricio
authors.affiliation: From the Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine (I.R.V., M.P., I.B., J.R., M.C.-B.), Laboratory of Biostatistics and Medical Informatics, Faculty of Medicine (M.P., M.C.-B.), and Institute of Nuclear Sciences Applied to Health (A.J.A., N.F., M.C.-B.), University of Coimbra, Portugal; and Division of Brain Sciences (I.R.V.), Department of Medicine, Hammersmith Hospital Campus, Imperial College London, UK.
authors.forename: Inês
authors.initials: I
authors.lastname: Bernardino
authors.affiliation: From the Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine (I.R.V., M.P., I.B., J.R., M.C.-B.), Laboratory of Biostatistics and Medical Informatics, Faculty of Medicine (M.P., M.C.-B.), and Institute of Nuclear Sciences Applied to Health (A.J.A., N.F., M.C.-B.), University of Coimbra, Portugal; and Division of Brain Sciences (I.R.V.), Department of Medicine, Hammersmith Hospital Campus, Imperial College London, UK.
authors.forename: José
authors.initials: J
authors.lastname: Rebola
authors.affiliation: From the Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine (I.R.V., M.P., I.B., J.R., M.C.-B.), Laboratory of Biostatistics and Medical Informatics, Faculty of Medicine (M.P., M.C.-B.), and Institute of Nuclear Sciences Applied to Health (A.J.A., N.F., M.C.-B.), University of Coimbra, Portugal; and Division of Brain Sciences (I.R.V.), Department of Medicine, Hammersmith Hospital Campus, Imperial College London, UK.
authors.forename: Antero J
authors.initials: AJ
authors.lastname: Abrunhosa
authors.affiliation: From the Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine (I.R.V., M.P., I.B., J.R., M.C.-B.), Laboratory of Biostatistics and Medical Informatics, Faculty of Medicine (M.P., M.C.-B.), and Institute of Nuclear Sciences Applied to Health (A.J.A., N.F., M.C.-B.), University of Coimbra, Portugal; and Division of Brain Sciences (I.R.V.), Department of Medicine, Hammersmith Hospital Campus, Imperial College London, UK.
authors.forename: Nuno
authors.initials: N
authors.lastname: Ferreira
authors.affiliation: From the Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine (I.R.V., M.P., I.B., J.R., M.C.-B.), Laboratory of Biostatistics and Medical Informatics, Faculty of Medicine (M.P., M.C.-B.), and Institute of Nuclear Sciences Applied to Health (A.J.A., N.F., M.C.-B.), University of Coimbra, Portugal; and Division of Brain Sciences (I.R.V.), Department of Medicine, Hammersmith Hospital Campus, Imperial College London, UK.
authors.forename: Miguel
authors.initials: M
authors.lastname: Castelo-Branco
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D005260:Female; D005442:Flumazenil / Q000493:pharmacokinetics*; D018757:GABA Modulators / Q000493:pharmacokinetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D009456:Neurofibromatosis 1 / Q000000981:diagnostic imaging* / Q000378:metabolism*; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D011963:Receptors, GABA-A / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000172:deficiency*
chemical_list: D018757:GABA Modulators; D011963:Receptors, GABA-A; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid