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).
JAMA Psychiatry. 2014 Dec 1;71(12):1340-1349. doi: 10.1001/jamapsychiatry.2014.1226.
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.
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.
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).
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.
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.
注意力缺陷/多动障碍（ADHD）的研究长期以来一直关注多巴胺能系统对发病机制的贡献，尽管结果尚无定论。然而，去甲肾上腺素能系统的参与已经得到证实，该系统调节认知过程，如觉醒、工作记忆和反应抑制，所有这些在 ADHD 中通常都受到影响。此外，去甲肾上腺素转运蛋白（NET）是 ADHD 中经常开处方的药物的重要靶点。因此，NET 被认为在 ADHD 中发挥着关键作用。
使用正电子发射断层扫描和高度选择性放射性配体（S，S）-[18F]FMeNER-D2（（S，S）-2-（α-（2-[18F]氟[2H2]甲氧基苯氧基）苄基）吗啡啉），探索 ADHD 患者与健康对照组之间 NET 不可置换结合潜能（NET BPND）的差异。
设计、地点和参与者：22 名未服用药物的 ADHD 患者（平均[标准差]年龄 30.7[10.4]岁；15[68%]男性）无精神共病，22 名年龄和性别匹配的健康对照组（30.9[10.6]岁；15[68%]男性）接受一次正电子发射断层扫描。使用线性混合模型比较组间 NET BPND。
包括海马体、壳核、苍白球、丘脑、中脑与脑桥（包括蓝斑核的感兴趣区）和小脑在内的与 ADHD 相关的选定感兴趣区的 NET BPND。此外，还评估了丘脑核团（13 个基于图谱的感兴趣区）中的 NET BPND。
我们没有发现 ADHD 患者和健康对照组在所有研究的脑区中 NET 可用性或区域分布存在显著差异（F1,41<0.01；P=.96）。此外，我们没有发现 ADHD 症状严重程度与区域 NET 可用性之间存在显著关联。性别和吸烟状况均不影响 NET 可用性。我们发现，在丘脑（R2=0.29；P<.01 校正）和中脑与脑桥，包括蓝斑核（R2=0.18；P<.01 校正）中，年龄与 NET 可用性之间存在显著负相关，这与先前在人类大脑中发现的随着年龄增长 NET 可用性下降的发现相符。
我们的研究结果表明，ADHD 发病机制中不涉及脑 NET 可用性或分布的变化。然而，去甲肾上腺素能递质系统可能在不同的水平受到影响，例如在皮质区域，这是无法用这种正电子发射断层扫描配体可靠地量化的。或者，去甲肾上腺素能神经传递的不同关键蛋白可能受到影响。
