Anke Bresch

Serotonin transporter gene promoter methylation status correlates with in vivo prefrontal 5-HTT availability and reward function in human obesity

A polymorphism in the promoter region of the human serotonin transporter (5-HTT)-coding SLC6A4 gene (5-HTTLPR) has been implicated in moderating susceptibility to stress-related psychopathology and to possess regulatory functions on human in vivo 5-HTT availability. However, data on a direct relation between 5-HTTLPR and in vivo 5-HTT availability have been inconsistent. Additional factors such as epigenetic modifications of 5-HTTLPR might contribute to this association. This is of particular interest in the context of obesity, as an association with 5-HTTLPR hypermethylation has previously been reported. Here, we tested the hypothesis that methylation rates of 14 cytosine–phosphate–guanine (CpG) 5-HTTLPR loci, in vivo central 5-HTT availability as measured with [11C]DASB positron emission tomography (PET) and body mass index (BMI) are related in a group of 30 obese (age: 36±10 years, BMI>35 kg/m2) and 14 normal-weight controls (age 36±7 years, BMI<25 kg/m2). No significant association between 5-HTTLPR methylation and BMI overall was found. However, site-specific elevations in 5-HTTLPR methylation rates were significantly associated with lower 5-HTT availability in regions of the prefrontal cortex (PFC) specifically within the obese group when analyzed in isolation. This association was independent of functional 5-HTTLPR allelic variation. In addition, negative correlative data showed that CpG10-associated 5-HTT availability determines levels of reward sensitivity in obesity. Together, our findings suggest that epigenetic mechanisms rather than 5-HTTLPR alone influence in vivo 5-HTT availability, predominantly in regions having a critical role in reward processing, and this might have an impact on the progression of the obese phenotype.

Sex differences in serotonin–hypothalamic connections underpin a diminished sense of emotional well-being with increasing body weight

Background/Objectives:The neurobiological mechanisms linking obesity to emotional distress related to weight remain largely unknown.Participants/Methods:Here we combined positron emission tomography, using the serotonin transporter (5-HTT) radiotracer [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, with functional connectivity magnetic resonance imaging, the Beck Depression Inventory (BDI-II) and the Impact of Weight on Quality of Life–Lite questionnaire (IWQOL-Lite) to investigate the role of central serotonin in the severity of depression (BDI-II), as well as in the loss of emotional well-being with body weight (IWQOL-Lite).Results:In a group of lean to morbidly obese individuals (n=28), we found sex differences in the 5-HTT availability-related connectivity of the hypothalamus. Males (n=11) presented a strengthened connectivity to the lateral orbitofrontal cortex, whereas in females (n=17) we found strengethened projections to the ventral striatum. Both regions are known as reward regions involved in mediating the emotional response to food. Their resting-state activity correlated positively to the body mass index (BMI) and IWQOL-Lite scores, suggesting that each region in both sexes also underpins a diminished sense of emotional well-being with body weight. Contrarily to males, we found that in females also the BDI-II positively correlated with the BMI and by trend with the activity in ventral striatum, suggesting that in females an increased body weight may convey to other mood dimensions than those weight-related ones included in the IWQOL-Lite.Conclusions:This study suggests sex differences in serotonin–hypothalamic connections to brain regions of the reward circuitry underpinning a diminished sense of emotional well-being with an increasing body weight.

Primary Intradural Extramedullary Spinal Melanoma in the Lower Thoracic Spine

Background Context. Up to date, only four cases of primary intradural extramedullary spinal cord melanoma (PIEM) have been reported. No previous reports have described a case of PIEM located in the lower thoracic spine with long-term follow-up. Purpose. Demonstrating an unusual, extremely rare case of melanoma manifestation. Study Design. Case report. Methods. We report a case of a 57-year-old female suffering from increasing lower extremity pain, left-sided paresis, and paraesthesia due to spinal cord compression caused by PIEM in the lower thoracic spine. Results. Extensive investigation excluded other possible primary melanoma sites and metastases. For spinal cord decompression, the tumor at level T12 was resected, yet incompletely. Adjuvant radiotherapy was administered two weeks after surgery. The patient was recurrence-free at 104 weeks after radiotherapy but presents with unchanged neurological symptoms. Conclusion. Primary intradural extramedullary melanoma (PIEM) is extremely rare and its clinical course is unpredictable.

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.

Effortful control as a dimension of temperament is negatively associated with prefrontal serotonin transporter availability in obese and non‐obese individuals

There is evidence that temperamental factors are associated with obesity; however, the biological mechanism of such association remains elusive. We aimed to investigate a possible association between serotonin transmission and regulative temperament in obese and non‐obese individuals by using positron emission tomography (PET) imaging of serotonin transporters (SERT) and the Adult Temperament Questionnaire. Twenty‐nine obese individuals with body mass index (BMI) ≥ 35 kg/m2 and 13 non‐obese controls (BMI < 30 kg/m2) underwent PET with [11C]‐labeled DASB (highly selective for SERT) and self‐completed the Effortful Control (EC) scale of the Adult Temperament Questionnaire‐Short Form (ATQ). With the help of this questionnaire, we aimed to assess the capacity of self‐regulation. Overall, for obese and non‐obese individuals together, VOI‐based (volume of interest) analysis showed significant negative correlations between SERT BPND and ATQ‐EC AC (Activation Control) subscale in several brain regions (all r ≤ −0.47). Obese and non‐obese individuals separated showed equally strong positive, but non‐significant correlations. The analysis did not reveal any significant correlations of SERT availability and ATQ‐EC IC (Inhibitory Control) or ATQ‐EC AtC (Attentional Control) subscale within and between the two groups. The results indicate that regulative temperament – particularly the capacity to mitigate negatively toned impulses and to resist inappropriate avoidance behavior – might be associated with the prefrontal serotonergic system.

Post-dexamethasone serum copeptin corresponds to HPA axis responsiveness in human obesity

CONTEXT Increased activities of the arginine-vasopressin (AVP) system and the hypothalamic-pituitary-adrenal (HPA) axis were shown to be associated with human obesity, but relationships between these systems in obesity remain unclear. OBJECTIVES To assess HPA axis responsiveness and its relation to serum concentrations of the AVP-surrogate copeptin in subjects with obesity (OB) in comparison to non-obesity controls (NOC). METHODS In a cross-sectional monocentric study, thirty-nine OB (f/m 25/14; age 36.5±10.0years; body mass index, BMI, 41.5±4.7kg/m2) were compared to twenty-two NOC (f/m 12/10; age 35.3±8.5years; BMI 23.1±2.4kg/m2), matched for age and sex. All individuals underwent the combined dexamethasone/CRH test. MAIN OUTCOME MEASURES Plasma ACTH and cortisol curve indicators derived from the dex/CRH test (post-CRH concentrations 30min after 100μg CRH; maximum concentration, MAX; area-under-the-curve, AUC; ACTH/cortisol ratios). Copeptin was assessed in 1500h samples of the dex/CRH test (after 1.5mg of oral dexamethasone, prior to CRH administration). RESULTS Copeptin serum concentrations were higher in OB (median [IQR]: OB 4.62 [2.60-5.88] vs. NOC 3.04 [2.52-4.29] pmol/l, P=0.04). Correspondingly, OB showed higher post-CRH cortisol concentrations (OB: 51.5 [25.9-159.3] vs. NOC: 28.6 [20.0-41.6] nmol/l, P=0.01) and a lower post-CRH ACTH/cortisol ratio (OB: 0.028 [0.016-0.053] vs. NOC: 0.048 [0.034-0.070] pmol/nmol, P<0.01). Serum copeptin was significantly associated with HPA responsiveness in OB (post-CRH ACTH: R=0.42, P<0.01), driven by OB men (post-CRH ACTH: R=0.76, P<0.01, post-CRH cortisol: R=0.64, P=0.02). All associations withstand adjustments for BMI and age. CONCLUSIONS The association between increased copeptin with ACTH and cortisol release suggests a potential mechanistic interaction of the AVP system with HPA activation in human obesity. The relation of copeptin and HPA responsiveness should be further validated in situations with pronounced HPA activation, such as depression or multiple sclerosis.