The norepinephrine transporter in attention-deficit/hyperactivity disorder investigated with positron emission tomography.

Abstract

IMPORTANCE:

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.

DESIGN, SETTING, AND PARTICIPANTS:

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.

MAIN OUTCOMES AND MEASURES:

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 AND RELEVANCE:

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: Thomas Vanicek, Marie Spies, Christina Rami-Mark, Markus Savli, Anna Höflich, Georg S Kranz, Andreas Hahn, Alexandra Kutzelnigg, Tatjana Traub-Weidinger, Markus Mitterhauser, Wolfgang Wadsak, Marcus Hacker, Nora D Volkow, Siegfried Kasper, Rupert Lanzenberger
• Journal: JAMA psychiatry (JAMA Psychiatry) Vol. 71 Issue 12 Pg. 1340-1349 (Dec 01 2014) ISSN: 2168-6238 [Electronic] United States
• PMID: 25338091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(alpha-(2-fluoromethoxyphenoxy)benzyl)morpholine
• Fluorine Radioisotopes
• Morpholines
• Norepinephrine Plasma Membrane Transport Proteins

Topics

• Adult
• Age Factors
• Attention Deficit Disorder with Hyperactivity (metabolism)
• Brain (metabolism)
• Case-Control Studies
• Female
• Fluorine Radioisotopes
• Functional Neuroimaging
• Humans
• Male
• Morpholines
• Norepinephrine Plasma Membrane Transport Proteins (metabolism)
• Positron-Emission Tomography
• Symptom Assessment
• Young Adult