title: The norepinephrine transporter in attention-deficit/hyperactivity disorder investigated with positron emission tomography.
abstract: OBJECTIVE
  Attention-deficit/hyperactivity disorder (ADHD) research has long focused on the dopaminergic system's contribution to pathogenesis, although the results have been inconclusive. However, a case has been made for the involvement of the noradrenergic system, which modulates cognitive processes, such as arousal, working memory, and response inhibition, all of which are typically affected in ADHD. Furthermore, the norepinephrine transporter (NET) is an important target for frequently prescribed medication in ADHD. Therefore, the NET is suggested to play a critical role in ADHD.
  
  
  OBJECTIVE
  To explore the differences in NET nondisplaceable binding potential (NET BPND) using positron emission tomography and the highly selective radioligand (S,S)-[18F]FMeNER-D2 [(S,S)-2-(α-(2-[18F]fluoro[2H2]methoxyphenoxy)benzyl)morpholine] between adults with ADHD and healthy volunteers serving as controls.
  
  
  METHODS
  Twenty-two medication-free patients with ADHD (mean [SD] age, 30.7 [10.4] years; 15 [68%] men) without psychiatric comorbidities and 22 age- and sex-matched healthy controls (30.9 [10.6] years; 15 [68%] men) underwent positron emission tomography once. A linear mixed model was used to compare NET BPND between groups.
  
  
  METHODS
  The NET BPND in selected regions of interest relevant for ADHD, including the hippocampus, putamen, pallidum, thalamus, midbrain with pons (comprising a region of interest that includes the locus coeruleus), and cerebellum. In addition, the NET BPND was evaluated in thalamic subnuclei (13 atlas-based regions of interest).
  
  
  RESULTS
  We found no significant differences in NET availability or regional distribution between patients with ADHD and healthy controls in all investigated brain regions (F1,41<0.01; P=.96). Furthermore, we identified no significant association between ADHD symptom severity and regional NET availability. Neither sex nor smoking status influenced NET availability. We determined a significant negative correlation between age and NET availability in the thalamus (R2=0.29; P<.01 corrected) and midbrain with pons, including the locus coeruleus (R2=0.18; P<.01 corrected), which corroborates prior findings of a decrease in NET availability with aging in the human brain.
  
  
  CONCLUSIONS
  Our results do not indicate involvement of changes in brain NET availability or distribution in the pathogenesis of ADHD. However, the noradrenergic transmitter system may be affected on a different level, such as in cortical regions, which cannot be reliably quantified with this positron emission tomography ligand. Alternatively, different key proteins of noradrenergic neurotransmission might be affected.
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (Vanicek, Spies, Savli, Höflich, Kranz, Hahn, Kutzelnigg, Kasper, Lanzenberger); Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria (Rami-Mark, Traub-Weidinger, Mitterhauser, Wadsak, Hacker); National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (Volkow).
authors.forename: Thomas
authors.initials: T
authors.lastname: Vanicek
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (Vanicek, Spies, Savli, Höflich, Kranz, Hahn, Kutzelnigg, Kasper, Lanzenberger); Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria (Rami-Mark, Traub-Weidinger, Mitterhauser, Wadsak, Hacker); National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (Volkow).
authors.forename: Marie
authors.initials: M
authors.lastname: Spies
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (Vanicek, Spies, Savli, Höflich, Kranz, Hahn, Kutzelnigg, Kasper, Lanzenberger); Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria (Rami-Mark, Traub-Weidinger, Mitterhauser, Wadsak, Hacker); National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (Volkow).
authors.forename: Christina
authors.initials: C
authors.lastname: Rami-Mark
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (Vanicek, Spies, Savli, Höflich, Kranz, Hahn, Kutzelnigg, Kasper, Lanzenberger); Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria (Rami-Mark, Traub-Weidinger, Mitterhauser, Wadsak, Hacker); National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (Volkow).
authors.forename: Markus
authors.initials: M
authors.lastname: Savli
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (Vanicek, Spies, Savli, Höflich, Kranz, Hahn, Kutzelnigg, Kasper, Lanzenberger); Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria (Rami-Mark, Traub-Weidinger, Mitterhauser, Wadsak, Hacker); National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (Volkow).
authors.forename: Anna
authors.initials: A
authors.lastname: Höflich
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (Vanicek, Spies, Savli, Höflich, Kranz, Hahn, Kutzelnigg, Kasper, Lanzenberger); Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria (Rami-Mark, Traub-Weidinger, Mitterhauser, Wadsak, Hacker); National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (Volkow).
authors.forename: Georg S
authors.initials: GS
authors.lastname: Kranz
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (Vanicek, Spies, Savli, Höflich, Kranz, Hahn, Kutzelnigg, Kasper, Lanzenberger); Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria (Rami-Mark, Traub-Weidinger, Mitterhauser, Wadsak, Hacker); National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (Volkow).
authors.forename: Andreas
authors.initials: A
authors.lastname: Hahn
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (Vanicek, Spies, Savli, Höflich, Kranz, Hahn, Kutzelnigg, Kasper, Lanzenberger); Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria (Rami-Mark, Traub-Weidinger, Mitterhauser, Wadsak, Hacker); National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (Volkow).
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kutzelnigg
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (Vanicek, Spies, Savli, Höflich, Kranz, Hahn, Kutzelnigg, Kasper, Lanzenberger); Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria (Rami-Mark, Traub-Weidinger, Mitterhauser, Wadsak, Hacker); National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (Volkow).
authors.forename: Tatjana
authors.initials: T
authors.lastname: Traub-Weidinger
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (Vanicek, Spies, Savli, Höflich, Kranz, Hahn, Kutzelnigg, Kasper, Lanzenberger); Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria (Rami-Mark, Traub-Weidinger, Mitterhauser, Wadsak, Hacker); National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (Volkow).
authors.forename: Markus
authors.initials: M
authors.lastname: Mitterhauser
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (Vanicek, Spies, Savli, Höflich, Kranz, Hahn, Kutzelnigg, Kasper, Lanzenberger); Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria (Rami-Mark, Traub-Weidinger, Mitterhauser, Wadsak, Hacker); National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (Volkow).
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wadsak
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (Vanicek, Spies, Savli, Höflich, Kranz, Hahn, Kutzelnigg, Kasper, Lanzenberger); Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria (Rami-Mark, Traub-Weidinger, Mitterhauser, Wadsak, Hacker); National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (Volkow).
authors.forename: Marcus
authors.initials: M
authors.lastname: Hacker
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (Vanicek, Spies, Savli, Höflich, Kranz, Hahn, Kutzelnigg, Kasper, Lanzenberger); Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria (Rami-Mark, Traub-Weidinger, Mitterhauser, Wadsak, Hacker); National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (Volkow).
authors.forename: Nora D
authors.initials: ND
authors.lastname: Volkow
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (Vanicek, Spies, Savli, Höflich, Kranz, Hahn, Kutzelnigg, Kasper, Lanzenberger); Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria (Rami-Mark, Traub-Weidinger, Mitterhauser, Wadsak, Hacker); National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (Volkow).
authors.forename: Siegfried
authors.initials: S
authors.lastname: Kasper
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (Vanicek, Spies, Savli, Höflich, Kranz, Hahn, Kutzelnigg, Kasper, Lanzenberger); Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria (Rami-Mark, Traub-Weidinger, Mitterhauser, Wadsak, Hacker); National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (Volkow).
authors.forename: Rupert
authors.initials: R
authors.lastname: Lanzenberger
mesh_terms: D000328:Adult; D000367:Age Factors; D001289:Attention Deficit Disorder with Hyperactivity / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005462:Fluorine Radioisotopes; D059907:Functional Neuroimaging; D006801:Humans; D008297:Male; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography; D063189:Symptom Assessment; D055815:Young Adult
chemical_list: C506462:2-(alpha-(2-fluoromethoxyphenoxy)benzyl)morpholine; D005462:Fluorine Radioisotopes; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins