Norepinephrine Transporter Availability Research Articles

Noradrenergic control of neurobehavior in human binge-eating disorder and obesity (NOBEAD): A smartphone-supported behavioral emotion regulation intervention study protocol integrating molecular brain imaging.

The neurobehavioral underpinnings of binge-eating disorder (BED), co-occurring with obesity (OB), are largely unknown. This research project conceptualizes BED as a disorder with dysfunctional emotion regulation (ER) linked with changes in central noradrenaline (NA) transmission and NA-modulated neuronal networks. We expect abnormalities in NA activity in both BED and OB, but most pronounced in BED. We expect these abnormalities to be modifiable through state-of-the-art ER intervention, specifically in BED. To assess the role of NA transmission, we will quantify changes in NA transporter (NAT) availability using the highly NAT-specific [11 C]methylreboxetin (MRB) and positron emission tomography-magnetic resonance imaging (PET-MRI) that allows measuring molecular and neuronal changes before and after an ER intervention. Individual 12-session smartphone-supported acceptance-based behavioral therapy will be conducted to improve ER. Thirty individuals with OB and BED (OB + BED), 30 individuals with OB without BED (OB - BED), and 20 individuals with normal weight will undergo assessments of NAT availability and neuronal network activity under rest and stimulated conditions, clinical interviews, self-report questionnaires on eating behavior, ER, mental and physical health, and quality of life, and neuropsychological tests on executive function. Afterwards, in an experimental randomized-controlled design, individuals with OB + BED and OB - BED will be allocated to smartphone-supported ER intervention versus a waitlist and re-assessed after 10 weeks. By obtaining biological and behavioral markers, the proposed study will disentangle the involvement of NAT and the central NA system in the modulation of emotion-supporting neuronal networks that influence eating behavior. Neurobehavioral mechanisms of change during an ER intervention will be determined. German Clinical Trials Register (DRKS): DRKS00029367. This study investigates the central noradrenaline system by using hybrid brain imaging in conjunction with emotion regulation as a putative core biological mechanism in individuals with obesity with or without binge-eating disorder that is targeted by emotion regulation intervention. The results will provide a molecular signature beyond functional imaging biomarkers as a predictive biomarker toward precision medicine for tailoring treatments for individuals with binge-eating disorders and obesity.

Relationships of in vivo brain norepinephrine transporter and age, BMI, and gender.

Previous research reported an age-related decline in brain norepinephrine transporter (NET) using (S, S)-[11C]O-methylreboxetine ([11C]MRB) as a radiotracer. Studies with the same tracer have been mixed in regard to differences related to body mass index (BMI). Here, we investigated potential age-, BMI-, and gender-related differences in brain NET availability using [11C]MRB, the most selective available radiotracer. Forty-three healthy participants (20 females, 23 males; age range 18-49 years), including 12 individuals with normal/lean weight, 15 with overweight, and 16 with obesity were scanned with [11C]MRB using a positron emission tomography (PET) high-resolution research tomograph (HRRT). We evaluated binding potential (BPND ) in brain regions with high NET availability using multilinear reference tissue model 2 (MRTM2) with the occipital cortex as a reference region. Brain regions were delineated with a defined anatomic template applied to subjects' structural MR scans. We found a negative association between age and NET availability in the locus coeruleus, raphe nucleus, and hypothalamus, with a 17%, 19%, and 14% decrease per decade, respectively, in each region. No gender or BMI relationships with NET availability were observed. Our findings suggest an age-related decline, but no BMI- or gender-related differences, in NET availability in healthy adults.

Association between Individual Norepinephrine Transporter (NET) Availability and Response to Pharmacological Therapy in Adults with Attention-Deficit/Hyperactivity Disorder (ADHD).

Background: The role of the norepinephrine transporter (NET) has received increased focus in recent studies on the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). The predictive value for pharmacological treatment and its link to other health or social limitations has been little-studied. This follow-up research on adult patients with ADHD aimed to explore whether the therapy response and health and social impairments depend on baseline individual NET availability. Methods: Data were collected from 10 patients on personal, family and professional situations, mental and physical health and treatments received after baseline via online and telephone surveys and were compared to baseline data to evaluate treatment-related changes. Results: The majority of our ADHD patients did not show therapy responses but showed improvements due to pharmacological treatment. There was no evidence of relationships between pre-treatment NET availability and therapy response or health/social limitations. Conclusions: Pharmacological monotherapy was insufficient to promote symptom remission, especially for participants with extreme insufficiency in NET availability, but improved outcomes in academic and social functioning. Psychotherapy should be considered as an add-on to the standard treatment approach due to its positive outcome in reducing social limitations. The prognostic value of individual NET availability in predicting the response to therapy needs further studies with large sample sizes.

In vivo imaging of LC‐NE Integrity: Mechanism for racial/ethnic disparity in preclinical AD

AbstractBackgroundDespite studies suggesting that blacks may be at greater risk of developing AD, there have been few studies investigating health disparities, and blacks have been underrepresented in many prominent AD biomarker studies and clinical trials. The current ATN biomarker classification system may not fully account for health disparities and can’t explain the increased prevalence among blacks for both AD and AD vascular risks of diabetes and hypertension when compared to whites. Research on cognitive aging has traditionally focused on how decline in various cortical and hippocampal (Hip) regions influences cognition. However, tau pathology emerges decades before amyloid pathology, appearing first in the brainstem (BS); particularly in the locus coeruleus (LC), the source of brain’s norepinephrine (NE). Our decade‐long studies in humans using a norepinephrine transporter (NET)‐selective radiotracer ([11C]MRB) have demonstrated a special vulnerability of LC to aging and stress.MethodCo‐registration of PET (dynamic [11C]MRB), MRI and the FreeSurfer (FS) atlas images of each individual was used to generate regional time‐activity curves using Firevoxel. Binding potential (BPND) values were determined using MRTM2 with occipital as the reference region. Annual percent change (APC) of BPND was calculated based on linear regression (APC = 100 × (em – 1), m: slope) and effects of age, gender and ethnicity on tracer binding were evaluated.ResultFor all HC (N=31), with both genders and all races included, age‐sensitive decline of NET availability was observed; e.g., 0.3‐0.5%/yr for Hip, BS and olfactory. However, our data reveals that the decline rate of NET is much faster among blacks starting in the mid‐30s, particularly in black males; e.g., 2‐3%/yr vs. 0.14‐0.23%/yr in thalamus and brainstem for black males vs. white males (p<0.00001).ConclusionIn addition to our previously determined age effect on MRB‐NET binding, this report further reveals the role of ethnicity effects on NET availability. Our study showed that a faster decline of LC‐NE function occurs in blacks, possibly caused by cumulative stress to socioeconomic disadvantage and racial discrimination, and may be responsible for the different disease expression among blacks. Thus, NET availability imaging represents a novel biomarker approach to racial‐dependent strategies for diagnosis and assessment of therapeutic interventions.

CSF and PET biomarkers for noradrenergic dysfunction in neurodegenerative disease: A systematic review and meta‐analysis

AbstractBackgroundAlterations to the noradrenergic system may occur in the early stages of Alzheimer’s disease (AD) and Parkinson’s disease (PD) and could contribute to clinical symptoms. The aim of this study was to conduct a meta‐analysis of noradrenergic differences in AD and PD assessed using cerebrospinal fluid (CSF) and positron emission tomography (PET) measuresMethodCSF noradrenaline (NA) and its metabolite 3‐Methoxy‐4‐hydroxyphenylglycol (MHPG) as well as NA transporter availability (PET MeNER) levels in controls, AD and PD patients were pooled across studies. Differences between controls and patients were calculated with Hedge’s g and combined using a random‐effects model meta‐analysis. A random‐effect meta‐regression was conducted using the volume of the CSF samples, the sample sizes, the years post diagnosis, the severity of the diseases as covariates using laboratory analysis technique as a between‐study factor.ResultTwenty‐seven studies met the inclusion criteria. Seven studies with extreme effect sizes influencing between‐study heterogeneity were identified as outliers and subsequently removed from further analyses. In PD patients, significant reductions in CSF NA (n= 132, g= ‐0.26, p=0.01) and MHPG (n=257, g = ‐0.27, p<0.01), in addition to reduced PET MeNER binding in the hypothalamus (n=29, g = ‐0.87, p<0.05), were observed compared with control subjects (n=166 for NA, n=227 for MHPG respectively). In AD patients, no significant difference in CSF NA levels (n=194, g= ‐0.06, p= 0.78) and only a trend for increased MHPG levels (n=208, g= 0.24, p= 0.07) were observed compared with controls (n=196 for NA, n=218 for MHPG respectively), see Figure 1. The number of articles addressing PET MeNER in AD was not sufficient to conduct a meta‐analysis. The hypothesized explanatory variables, namely the volume of CSF samples, the sample size, the years post diagnosis and the severity of the disease, were not significant (p>0.05) in any of the investigated groups.ConclusionOur results indicate that noradrenergic dysfunction in neurodegenerative diseases can be detected using CSF or PET measures and may be more pronounced in PD compared to AD. Further studies using longitudinal CSF and PET measures are required to elucidate the relationship between noradrenergic dysfunction and the progression of neurodegenerative diseases.

Central Noradrenergic Neurotransmission and Weight Loss 6 Months After Gastric Bypass Surgery in Patients with Severe Obesity

PurposeRoux-en-Y gastric bypass (RYGB) surgery is currently the most efficient treatment to achieve long-term weight loss in individuals with severe obesity. This is largely attributed to marked reductions in food intake mediated in part by changes in gut-brain communication. Here, we investigated for the first time whether weight loss after RYGB is associated with alterations in central noradrenaline (NA) neurotransmission.Materials and MethodsWe longitudinally studied 10 individuals with severe obesity (8 females; age 43.9 ± 13.1 years; body mass index (BMI) 46.5 ± 4.8 kg/m2) using (S,S)-[11C]O-methylreboxetine and positron emission tomography to estimate NA transporter (NAT) availability before and 6 months after surgery. NAT distribution volume ratios (DVR) were calculated by volume-of-interest analysis and the two-parameter multilinear reference tissue model (reference region: occipital cortex).ResultsThe participants responded to RYGB surgery with a reduction in BMI of 12.0 ± 3.5 kg/m2 (p < 0.001) from baseline. This was paralleled by a significant reduction in DVR in the dorsolateral prefrontal cortex (pre-surgery 1.12 ± 0.04 vs. post-surgery 1.07 ± 0.04; p = 0.019) and a general tendency towards reduced DVR throughout the brain. Furthermore, we found a strong positive correlation between pre-surgery DVR in hypothalamus and the change in BMI (r = 0.78; p = 0.01).ConclusionReductions in BMI after RYGB surgery are associated with NAT availability in brain regions responsible for decision-making and homeostasis. However, these results need further validation in larger cohorts, to assess whether brain NAT availability could prognosticate the outcome of RYGB on BMI.Graphical abstract

Changes of central noradrenaline transporter availability in immunotherapy-na\xefve multiple sclerosis patients

The neurotransmitter noradrenaline (NA) mediates arousal, attention and mood, and exerts anti-inflammatory and neuroprotective effects. Alterations of monoamine signalling were reported in multiple sclerosis (MS) and psychiatric illness and may account for the high prevalence of comorbid depression and fatigue in MS patients. We assessed central noradrenaline transporter (NAT) availability using positron emission tomography (PET) and the NAT selective radiotracer S,S-[11C]O-methylreboxetine in immunotherapy-naïve patients with relapsing–remitting MS (RRMS; n = 11) compared to healthy controls (HC; n = 12), and its association to lesion load, time since manifestation, the expanded disability status scale (EDSS), the fatigue scale Würzburger Erschöpfungsinventar bei MS (WEIMuS) and Beck Depression Inventory (BDI). We found NAT availability to be increased in the thalamus, amygdala, putamen and pons/midbrain of MS patients. No relation to clinical or psychometric variables was found. These first data indicate higher NAT availability in subcortical brain regions of immunotherapy-naïve RRMS patients. If these changes of noradrenergic neurotransmission predispose to psychiatric symptoms or associate with disease activity needs to be investigated in longitudinal studies or a larger sample which allows subgroup analyses.

Notice of Retractions: “Association of Posttraumatic Stress Disorder With Reduced In Vivo Norepinephrine Transporter Availability in the Locus Coeruleus” and “Association of In Vivo κ-Opioid Receptor Availability and the Transdiagnostic Dimensional Expression of Trauma-Related Psychopathology” by Alexander Neumeister

Notice of Retractions: “Association of Posttraumatic Stress Disorder With Reduced In Vivo Norepinephrine Transporter Availability in the Locus Coeruleus” and “Association of In Vivo κ-Opioid Receptor Availability and the Transdiagnostic Dimensional Expression of Trauma-Related Psychopathology” by Alexander Neumeister

Adult attention-deficit/hyperactivity disorder is associated with reduced norepinephrine transporter availability in right attention networks: a (S,S)-O-[11C]methylreboxetine positron emission tomography study

The norepinephrine transporter (NET) has been suggested to play a critical role in attention-deficit/hyperactivity disorder (ADHD). In this prospective controlled study we tested the a-priori-hypothesis that central NET availability is altered in adult ADHD patients compared to healthy controls. Study participants underwent single positron emission tomography-magnetic resonance imaging (PET-MRI). MRI sequences included high resolution T1-MPRAGE data for regions of interest (ROI) delineation and voxel-based morphometry (VBM) and T2-weighted fluid-attenuated inversion-recovery for detection and exclusion of pathological abnormalities. NET availability was assessed by NET-selective (S,S)-O-[11C]methylreboxetine; regional distribution volume ratios (DVR) were calculated based on individual PET-MRI data co-registration and a multi-linear reference tissue model with two constraints (MRTM2; reference region: occipital cortex). VBM analysis revealed no difference in local distribution of gray matter between the 20 ADHD patients (9 females, age 31.8 ± 7.9 years, 488 ± 8 MBq injected activity) and the 20 age-matched and sex-matched control participants (9 females, age 32.3 ± 7.9 years, 472 ± 72 MBq). In mixed-model repeated-measures analysis with NET availability as dependent and ROI as repeated measure we found a significant main effect group in fronto-parietal-thalamic-cerebellar regions (regions on the right: F1,25 = 12.30, p = .002; regions on the left: F1,41 = 6.80, p = .013) indicating a reduced NET availability in ADHD patients. None of the other investigated brain regions yielded significant differences in NET availability between groups after applying a Benjamini-Hochberg correction at a significance level of 0.05. Overall our findings demonstrate the pathophysiological involvement of NET availability in adult ADHD.

Norepinephrine transporter availability in brown fat is reduced in obesity: a human PET study with [11C] MRB.

The energy-dissipating properties of brown adipose tissue (BAT) have been proposed as therapeutic targets for obesity and diabetes. Little is known about basal BAT activity. Capitalizing on the dense sympathetic innervation of BAT, we have previously shown that BAT can be detected in humans under resting room temperature (RT) conditions by using (S,S)-11C-O-methylreboxetine (MRB), a selective ligand for the norepinephrine transporter (NET). In this study, we determine whether MRB labeling of human BAT is altered by obesity. Fifteen healthy, nondiabetic Caucasian women (nine lean, age 25.6 ± 1.7, BMI 21.8 ± 1.3 kg/m2; six obese age 30.8 ± 8.8 BMI 37.9 ± 6.6 kg/m2) underwent PET-CT imaging of the neck/supraclavicular region using 11C-MRB under RT conditions. The distribution volume ratio (DVR) for 11C-MRB was estimated via multilinear reference tissue model 2 (MRTM2) referenced to the occipital cortex. Two women (one lean and one with obesity) had no detectable BAT. Of the women with detectable BAT, women with obesity had lower 11C-MRB DVR (0.80 ± 0.12 BAT DVR) compared to lean (1.15 ± 0.19 BAT DVR) (p = 0.004). Our findings are consistent with reports that NET is decreased in obesity and suggest that the sympathetic innervation of BAT is altered in obesity.

FV 10 Adult ADHD is associated with reduced noradrenaline transporter availability in prefrontal/ parietal/thalamic regions: A [11C] MRB-PET/MRI study

FV 10 Adult ADHD is associated with reduced noradrenaline transporter availability in prefrontal/ parietal/thalamic regions: A [11C] MRB-PET/MRI study

Noradrenaline transporter availability on [11C]MRB PET predicts weight loss success in highly obese adults.

Although the mechanisms by which the central noradrenaline (NA) system influences appetite and controls energy balance are quite well understood, its relationship to changes in body weight remains largely unknown. The main goal of this study was to further clarify whether the brain NA system is a stable trait or whether it can be altered by dietary intervention. We aimed to compare central NA transporter (NAT) availability in ten obese, otherwise healthy individuals with a body mass index (BMI) of 42.4 ± 3.7kg/m2 (age 34 ± 9years, four women) and ten matched non-obese, healthy controls (BMI 23.9 ± 2.5kg/m2, age 33 ± 10years, four women) who underwent PET with the NAT-selective radiotracer (S,S)-[11C]O-methylreboxetine (MRB) before and 6months after dietary intervention. MRI-based individual volume-of-interest analyses revealed an increase in binding potential (BPND) in the insula and the hippocampus of obese individuals, which correlated well with changes in BMI (-3.3 ± 5.3%; p = 0.03) following completion of the dietary intervention. Furthermore, voxel-wise regression analyses showed that lower BPND in these regions, but also in the midbrain and the prefrontal cortex, at baseline was associated with higher achieved weight loss (e.g., hippocampal area R2 = 0.80; p < 0.0001). No changes were observed in non-obese controls. These first longitudinal interventional data on NAT availability in highly obese individuals indicate that the central NA system is modifiable. Our findings suggest that NAT availability before intervention could help predict the amount and success of weight loss in obese individuals and help adjust treatment options individually by allowing prediction of the benefit of a dietary intervention.

Evaluation of the noradrenergic system in Parkinson's disease: an 11C-MeNER PET and neuromelanin MRI study.

Pathological involvement of the noradrenergic locus coeruleus occurs early in Parkinson's disease, and widespread noradrenaline reductions are found at post-mortem. Rapid eye movement sleep behaviour disorder (RBD) accompanies Parkinson's disease and its presence predicts an unfavourable disease course with a higher propensity to cognitive impairment and orthostatic hypotension. MRI can detect neuromelanin in the locus coeruleus while 11C-MeNER PET is a marker of noradrenaline transporter availability. Here, we use both imaging modalities to study the association of RBD, cognition and autonomic dysfunction in Parkinson's disease with loss of noradrenergic function. Thirty non-demented Parkinson's disease patients [16 patients with RBD and 14 without RBD, comparable across age (66.6 ± 6.7 years), sex (22 males), and disease stage (Hoehn and Yahr, 2.3 ± 0.5)], had imaging of the locus coeruleus with neuromelanin sensitive MRI and brain noradrenaline transporter availability with 11C-MeNER PET. RBD was confirmed with polysomnography; cognitive function was assessed with a neuropsychological test battery, and blood pressure changes on tilting were documented; results were compared to 12 matched control subjects. We found that Parkinson's disease patients with RBD showed decreased locus coeruleus neuromelanin signal on MRI (P < 0.001) and widespread reduced binding of 11C-MeNER (P < 0.001), which correlated with amount of REM sleep without atonia. Parkinson's disease with RBD was also associated with a higher incidence of cognitive impairment, slowed EEG activity, and orthostatic hypotension. Reduced 11C-MeNER binding correlated with EEG slowing, cognitive performance, and orthostatic hypotension. In conclusion, reduced noradrenergic function in Parkinson's disease was linked to the presence of RBD and associated with cognitive deterioration and orthostatic hypotension. Noradrenergic impairment may contribute to the high prevalence of these non-motor symptoms in Parkinson's disease, and may be of relevance when treating these conditions in Parkinson's disease.

The association between in vivo central noradrenaline transporter availability and trait impulsivity

The brain noradrenaline (NA) system, particularly NA transporters (NAT), are thought to play an important role in modulating impulsive behavior. Impaired impulsivity is implicated in a variety of neuropsychiatric conditions; however, an in vivo link between central NAT availability and human impulsivity has not been shown. Using positron emission tomography (PET) and S,S-[11C]O-methylreboxetine (MRB), we tested whether NAT availability is associated with this basic behavioral trait based on the Barratt Impulsiveness Scale (BIS-11) in twenty healthy individuals (12 females, 33.8±9.3, 21–52 years of age) with a body mass index (BMI) ranging from 21.7kg/m2 to 47.8kg/m2. Applying both voxel-wise and volume-of-interest (VOI) based analyses, we found that distribution volume ratios (DVR) used as PET outcome measures negatively correlated with BIS-11 total scores in the orbitofrontal cortex (OFC) and in the hippocampus as well as in parts of the cerebellar cortex. These associations however did not remain after correction for multiple testing. Thus, although it appears that low NAT availability is associated with greater scores of impaired behavioral control, this needs to be confirmed in a larger series of individuals with highly impulsive behavior.

Hunger and disinhibition but not cognitive restraint are associated with central norepinephrine transporter availability

The relationship between food-intake related behaviours measured by the Three-Factor Eating Questionnaire (TFEQ) and in vivo norepinephrine transporter (NET) availability has not been explored yet. We investigated ten obese individuals (body mass index (BMI) 42.4 ± 3.7 kg/m2) and ten normal-weight healthy controls (HC, BMI 23.9 ± 2.5 kg/m2) with (S,S)-[11C]-O-methylreboxetine ([11C]MRB) positron emission tomography (PET). All participants completed the TFEQ, which measures cognitive restraint, disinhibition and hunger. Image analysis required magnetic resonance imaging data sets onto which volumes-of-interests were drawn. Tissue time activity curves (TACs) were obtained from the dynamic PET data followed by kinetic modeling of these regional brain TACs applying the multilinear reference tissue model (2 parameters) with the occipital cortex as reference region.Obese individuals scored significantly higher on the hunger subscale of the TFEQ. Correlative data analysis showed that a higher degree of hunger correlated negatively with the NET availability of the insular cortex in both obese individuals and HC; however, this finding was more pronounced in obesity. Further, for obese individuals, a negative correlation between disinhibition and NET BPND of the locus coeruleus was detected.In conclusion, these initial data provide in vivo imaging support for the involvement of the central NE system in maladaptive eating behaviors such as susceptibility to hunger.

Norepinephrine Transporter in Major Depressive Disorder: A PET Study.

The norepinephrine transporter has been suggested to play a crucial role in major depressive disorder. However, norepinephrine transporter availability in major depressive disorder and its role with clinical symptoms are not known. The authors tested norepinephrine transporter availability in patients with major depressive disorder with the aim to identify any associations between test results and clinical symptoms. The present research was a cross-sectional study in which 19 patients with major depressive disorder and 19 age- and sex-matched healthy comparison subjects underwent positron emission tomography scanning to evaluate the norepinephrine transporter availability measured by the radioligand (S,S)-[18F]FMeNER-D2. Norepinephrine transporter availability in the thalamus and its subregions was quantified in terms of nondisplaceable binding potential (BPND). The authors also analyzed the association between norepinephrine transporter availability and clinical symptoms. Compared with healthy subjects, patients with major depressive disorder showed 29.0% higher BPND values in the thalamus and, in particular, 28.2% higher values in the thalamic subregion anatomically connected to the prefrontal cortex. Elevated norepinephrine transporter availability in the thalamus in patients was positively correlated with attention, as measured by the Trail Making Test, part A. These findings revealed altered norepinephrine transmission in patients with major depressive disorder, suggesting that this alteration could be related to attention in this patient population.

Emotional eating and in vivo norepinephrine transporter availability in obesity: A [11 C]MRB PET pilot study.

Emotional eating (EE) has been linked to norepinephrine dysfunction. Therefore, we aimed to investigate the relationship between EE and norepinephrine transporter (NET) availability. Ten severely obese individuals (body mass index (BMI) 42.4 ± 3.7 kg/m2 ) and ten non-obese, healthy controls (BMI 23.9 ± 2.5 kg/m2 ) matched for age and sex were studied using (S,S)-[11 C]-O-methylreboxetine ([11 C]MRB) positron emission tomography (PET). Kinetic modeling of regional tissue time activity curves was performed using multilinear reference tissue model 2 (MRTM2, with the occipital cortex as a reference region) to estimate binding potential based on individual PET-MR coregistration. To test for associations of EE and NET availability, participants completed the EE subscale of the Dutch Eating Behavior Questionnaire before scanning. Obese individuals and non-obese, healthy controls did not significantly differ regarding EE scores and regional NET availability. For obese individuals only, correlative data analyses pointed to a sinoidal distribution pattern as a higher degree of EE related to lower NET availability in the locus coeruleus and to higher NET availability in the left thalamus. These results indicate that central in vivo NET availability is altered in EE of individuals with obesity. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2017; 50:152-156).

The central nervous norepinephrine network links a diminished sense of emotional well-being to an increased body weight.

The neurobiological mechanisms linking obesity to emotional distress remain largely undiscovered. In this pilot study, we combined positron emission tomography, using the norepinephrine transporter (NET) tracer [(11)C]-O-methylreboxetine, with functional connectivity magnetic resonance imaging, the Beck depression inventory (BDI), and the impact of weight on quality of life-Lite questionnaire (IWQOL-Lite), to investigate the role of norepinephrine in the severity of depression (BDI), as well as in the loss of emotional well-being with body weight (IWQOL-Lite). In a small group of lean-to-morbidly obese individuals (n=20), we show that an increased body mass index (BMI) is related to a lowered NET availability within the hypothalamus, known as the brain's homeostatic control site. The hypothalamus displayed a strengthened connectivity in relation to the individual hypothalamic NET availability to the anterior insula/frontal operculum, as well as the medial orbitofrontal cortex, assumed to host the primary and secondary gustatory cortex, respectively (n=19). The resting-state activity in these two regions was correlated positively to the BMI and IWQOL-Lite scores, but not to the BDI, suggesting that the higher the resting-state activity in these regions, and hence the higher the BMI, the stronger the negative impact of the body weight on the individual's emotional well-being was. This pilot study suggests that the loss in emotional well-being with weight is embedded within the central norepinephrine network.

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

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. 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.

Association of Posttraumatic Stress Disorder With Reduced In Vivo Norepinephrine Transporter Availability in the Locus Coeruleus

Animal data suggest that chronic stress is associated with a reduction in norepinephrine transporter (NET) availability in the locus coeruleus. However, it is unclear whether such models are relevant to posttraumatic stress disorder (PTSD), which has been linked to noradrenergic dysfunction in humans. To use positron emission tomography and the radioligand [11C]methylreboxetine to examine in vivo NET availability in the locus coeruleus in the following 3 groups of individuals: healthy adults (HC group), adults exposed to trauma who did not develop PTSD (TC group), and adults exposed to trauma who developed PTSD (PTSD group) and to evaluate the relationship between NET availability in the locus coeruleus and a contemporary phenotypic model of PTSD symptoms. Cross-sectional positron emission tomography study under resting conditions at academic and Veterans Affairs medical centers among 56 individuals in the following 3 study groups: HC (n = 18), TC (n = 16), and PTSD (n = 22). The [11C]methylreboxetine-binding potential of NET availability in the locus coeruleus and the severity of PTSD symptoms assessed using the Clinician-Administered PTSD Scale. The PTSD group had significantly lower NET availability than the HC group (41% lower, Cohen d = 1.07). NET availability did not differ significantly between the TC and HC groups (31% difference, Cohen d = 0.79) or between the TC and PTSD groups (15% difference, Cohen d = 0.28). In the PTSD group, NET availability in the locus coeruleus was independently positively associated with the severity of anxious arousal (ie, hypervigilance) symptoms (r = 0.52) but not with any of the other PTSD symptom clusters. These results suggest that PTSD is associated with significantly reduced NET availability in the locus coeruleus and that greater NET availability in this brain region is associated with increased severity of anxious arousal symptoms in individuals with PTSD.