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.

Figure 1. Mean (S,S)-[¹⁸F]FMeNER-D₂ Distribution Normalized to the Montreal Neurological Institute T1 Template in 22 Healthy Control Participants

High norepinephrine transporter nondisplaceable binding potential (NET BP_ND) was found in the thalamus and midbrain regions of interest, and the lowest was observed in the basal ganglia. The highest NET uptake occurred in bones, a phenomenon associated with tracer-specific defluorination. The color bar represents the BP at each voxel, with blue indicating the lowest and red the highest NET BP_ND (a unitless measure). The crosshair is set on the thalamus. (S,S)-[¹⁸F]FMeNER-D₂ indicates (S,S)-2-(α-(2-[¹⁸F]fluoro[²H₂]methoxyphenoxy)benzyl)morpholine.

Figure 2. Norepinephrine Transporter Nondisplaceable Binding Potential (NET BP_ND) in Selected Regions of Interest

There were no significant differences between the ADHD and control groups in NET BP_ND (a unitless measure) in patients with attention-deficit/hyperactivity disorder (ADHD) and healthy control participants. The heavy rule within the scatterplots indicates the mean; thin rules, SD.

Figure 3. Negative Correlation of Norepinephrine Transporter Nondisplaceable Binding Potential (NET BP_ND) and Age in the Thalamus and Midbrain/Pons

A significant negative correlation existed between the NET BP_ND (a unitless measure) and age in the thalamus (R² = 0.29; P < .01 corrected) (A) and midbrain/pons (R² = 0.18; P < .01 corrected) (B). Regions of interest were extracted from Hammers Maximum Probability Atlas. The significance level was set at P < .05 and the results were Bonferroni corrected for multiple comparisons. ADHD indicates attention-deficit/hyperactivity disorder; PET, positron emission tomography. Please note the different NET BP_ND ranges on the y-axis.