NET in Attention Deficit Hyperactivity Disorder (PET)

Title: The Norepinephrine Transporter in Attention Deficit Hyperactivity Disorder investigated with PET Background: Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric condition that affects 2.5 to 4 % of the adult population with enormous economic and social burden for the society. The norepinephrine (NET) transporter is suspected to play a pivotal role in the pathophysiology of ADHD. Compounds blocking the NET act as an effective treatment of ADHD. Further, a single nucleotide polymorphism of the human NET gene that potentially affects its expression is associated with ADHD. Several lines of evidence suggest an increase of NET density in patients with ADHD. Objective: The aim of this study is to investigate NET binding in adult untreated patients with ADHD compared to matched healthy controls using PET and the recently developed radioligand (S,S)-[ 18F]FMeNER-D2 . Hypotheses: 1. NET binding in adult patients with ADHD is significantly increased compared to healthy controls. 2. There will be an association between total ADHD symptom scores (CAARS-Inv:SV 18-item) and NET binding potential. Methods: This study is designed as a cross-sectional mono-center study with duration of 36 months. Twenty patients (10 females, 10 males, aged 18-50 years) with ADHD and twenty age and sex matched healthy controls will be enrolled in the study. Each subject will be measured once using a GE Advance PET scanner. The radioligand (S,S)-[ 18F]FMeNER-D2 will be used for NET quantification. Main outcome measure is the NET binding potential in brain areas of interest, among patients with ADHD and healthy controls. To demonstrate significant differences of NET binding potentials in patients with ADHD compared to controls, analyses of covariance (ANCOVA) will be performed with regional NET binding potentials as dependent variables and group as the independent variable (ADHD versus HC). Relevance and implications: This study will be the first PET investigation of alterations in NET binding in patients with ADHD. The results will give important insights into the pathophysiology of ADHD. Furthermore, these findings will pave the way towards a better clinical understanding in ADHD treatment acting through the NET. Molecular imaging of the human brain in vivo is a particularly promising approach to reveal important mechanisms in the pathogenesis and pharmacotherapy of psychiatric disorders, therefore methods developed in this project will be applied to other psychiatric diseases.

Attention Deficit Hyperactivity Disorder (ADHD) is characterized as a neurodevelopmental disorder that begins in childhood and persists into adulthood in 30-60% of cases. The disorder is associated with detrimental socio-economic costs on a personal and societal level. Currently available options for the treatment of ADHD, such as methylphenidate and atomoxetine, modulate the dopaminergic and norepinephrine neurotransmitter systems. In particular, ADHD medication targets the norepinephrine transporter (NET), which is responsible for reuptake of norepinephrine in the synaptic cleft, hereby regulating noradrenergic neurotransmission. Considering that modulation of the NET results in ADHD symptom improvement, it has long been hypothesized that changes in the distribution of NET in the brain may underlie ADHD pathology. However, highly sensitive and specific in-vivo imaging of the NET was only recently made possible. However, recent research in the neurosciences and nuclear medicine fields has led to the development of the positron emission tomography (PET) tracer (S,S)-[18F]FMeNER-D2. The Department of Biomedical Imaging und Image-guided Therapy from the Division of Nuclear Medicine at the Medical University of Vienna was also involved in this development, in particular in establishment and testing of effective radiosynthesis procedures (Rami-Mark et al. Nucl Med Biol. 2013). Utilizing the opportunity of highly sensitive and specific (S,S)-[18F]FMeNER-D2 PET imaging, we were able to investigate distribution of the NET in the brain in 22 medication-naive ADHD patients (7 W/15 M) and 22 healthy controls. Contrary to our hypothesis, we were able to demonstrate that NET levels did not differ between ADHD patients and controls in regions high in NET, such as the thalamus, hippocampus, putamen, and locus coeruleus. Therefore, our results suggest that changes to NET in these regions are not necessarily associated with ADHD and reveal intriguing insight into the norepinephrine system in ADHD. In summary, comprehensive information on the noradrenergic system in ADHD is essential for understanding the symptomatology and pathophysiology of ADHD.