Neuroticism Associates with Cerebral in Vivo Serotonin Transporter Binding Differently in Males and Females

Background: Neuroticism is a major risk factor for affective disorders. This personality trait has been hypothesized to associate with synaptic availability of the serotonin transporter, which critically controls serotonergic tone in the brain. However, earlier studies linking neuroticism and serotonin transporter have failed to produce converging findings. Because sex affects both the serotonergic system and the risk that neuroticism poses to the individual, sex may modify the association between neuroticism and serotonin transporter, but this question has not been investigated by previous studies. Methods: Here, we combined data from 4 different positron emission tomography imaging centers to address whether neuroticism is related to serotonin transporter binding in vivo. The data set included serotonin transporter binding potential values from the thalamus and striatum and personality scores from 91 healthy males and 56 healthy females. We specifically tested if the association between neuroticism and serotonin transporter is different in females and males. Results: We found that neuroticism and thalamic serotonin transporter binding potentials were associated in both males and females, but with opposite directionality. Higher neuroticism associated with higher serotonin transporter binding potential in males (standardized beta 0.292, P = .008), whereas in females, higher neuroticism associated with lower serotonin transporter binding potential (standardized beta -0.288, P = .014). Conclusions: The finding is in agreement with recent studies showing that the serotonergic system is involved in affective disorders differently in males and females and suggests that contribution of thalamic serotonin transporter to the risk of affective disorders depends on sex.Peer reviewe

Associations between tricuspid annular plane systolic excursion to reflect right ventricular function and acute kidney injury in critically ill patients : a SICS-I sub-study

Acute kidney injury (AKI) occurs in up to 50% of all critically ill patients and hemodynamic abnormalities are assumed to contribute, but their nature and share is still unclear. We explored the associations between hemodynamic variables, including cardiac index and right ventricular function, and the occurrence of AKI in critically ill patients. In this prospective cohort study, we included all patients acutely admitted to an intensive care unit (ICU). Within 24 h after ICU admission clinical and hemodynamic variables were registered including ultrasonographic measurements of cardiac index and right ventricular function, assessed using tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic excursion (RV S'). Maximum AKI stage was assessed according to the KDIGO criteria during the first 72 h after admission. Multivariable logistic regression modeling was used including both known predictors and univariable significant predictors of AKI. Secondary outcomes were days alive outside ICU and 90-day mortality. A total of 622 patients were included, of which 338 patients (54%) had at least AKI stage 1 within 72 h after ICU admission. In the final multivariate model higher age (OR 1.01, 95% CI 1.00-1.03, for each year), higher weight (OR 1.03 CI 1.02-1.04, for each kg), higher APACHE IV score (OR 1.02, CI 1.01-1.03, per point), lower mean arterial pressure (OR 1.02, CI 1.01-1.03, for each mmHg decrease) and lower TAPSE (OR 1.05, CI 1.02-1.09 per millimeter decrease) were all independent predictors for AKI in the final multivariate logistic regression model. Sepsis, cardiac index, RV S' and use of vasopressors were not significantly associated with AKI in our data. AKI patients had fewer days alive outside of ICU, and their mortality rate was significantly higher than those without AKI. In our cohort of acutely admitted ICU patients, the incidence of AKI was 54%. Hemodynamic variables were significantly different between patients with and without AKI. A worse right ventricle function was associated with AKI in the final model, whereas cardiac index was not.Peer reviewe

The Rotterdam Study: objectives and design update

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in the Netherlands. The study targets cardiovascular, neurological, ophthalmological and endocrine diseases. As of 2008 about 15,000 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in some 600 research articles and reports (see http://www.epib.nl/rotterdamstudy). This article gives the reasons for the study and its design. It also presents a summary of the major findings and an update of the objectives and methods

Common genetic determinants of intraocular pressure and primary open-angle Glaucoma

10.1371/journal.pgen.1002611PLoS Genetics85

The Rotterdam Study: 2010 objectives and design update

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in close to a 1,000 research articles and reports (see www.epib.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods

The Rotterdam Study: 2012 objectives and design update

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods

Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract

Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10−16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 1

Dopamine type-1 receptor binding in major depressive disorder assessed using positron emission tomography and [11c]nnc-112

The dopamine type-1 receptor has been implicated in major depressive disorder (MDD) by clinical and preclinical evidence from neuroimaging, post mortem, and behavioral studies. To date, however, selective in vivo assessment of D-1 receptors has been limited to the striatum in MDD samples manifesting anger attacks. We employed the PET radioligand, [C-11] NNC-112, to selectively assess D-1 receptor binding in extrastriatal and striatal regions in a more generalized sample of MDD subjects. The [C-11] NNC-112 nondisplaceable binding potential (BPND) was assessed using PET in 18 unmedicated, currently depressed subjects with MDD and 19 healthy controls, and compared between groups using MRI-based region-of-interest analysis. The mean v receptor BPND was reduced (14%) in the left middle caudate of the MDD group relative to control group (p<0.05). Among the MDD subjects D-1 receptor BPND in this region correlated negatively with illness duration (r = -0.53; p = 0.02), and the left-to-right BPND ratio correlated inversely with anhedonia ratings (r = -0.65, p = 0.0040). The D-1 receptor BPND was strongly lateralized in striatal regions (p<0.002 for main effects of hemisphere in accumbens area, putamen, and caudate). In post hoc analyses, a group-by-hemisphere-by-gender interaction was detected in the dorsal putamen, which was accounted for by a loss of the normal asymmetry in depressed women (F = 7.33, p = 0.01). These data extended a previous finding of decreased striatal D-1 receptor binding in an MDD sample manifesting anger attacks to a sample selected more generally according to MDD criteria. Our data also more specifically localized this abnormality in MDD to the left middle caudate, which is the target of afferent neural projections from the orbitofrontal and anterior cingulate cortices where neuropathological changes have been reported in MDD. Finally, D-1 receptor binding was asymmetrical across hemispheres in healthy humans, compatible with evidence that dopaminergic function in the striatum is lateralized during reward processing, voluntary movement, and self-stimulation behavior

Gender-specific abnormalities in the serotonin transporter system in panic disorder

The central serotonergic system has been implicated in the pathophysiology of panic disorder (PD) by evidence of abnormally elevated serotonin-turnover, reduced pre- and post-synaptic 5-HT(1A-)receptor sensitivity and binding and clinical improvement during administration of agents that enhance serotonergic transmission. Polymorphisms in genes that putatively influence serotonergic neurotransmission increase the vulnerability for developing PD specifically in males. We tested the hypotheses that serotonin transporter (5-HTT) binding is elevated in PD subjects vs. healthy controls in regions where in vivo evidence exists for both elevated 5-HTT and 5-HT1A receptor levels in PD and investigated whether the extent of this difference depends upon gender. Volunteers were out-patients with current PD (n=24) and healthy controls (n=24). The non-displaceable component of 5-HTT binding-potential (BPND) was measured using positron emission tomography and the 5-HTT selective radioligand, [C-11]DASB. PD severity was assessed using the PD Severity Scale. The 5-HTT-BPND was increased in males with PD relative to male controls in the anterior cingulate cortex (F=8.96, p(FDR)=0.01) and midbrain (F=5.09, p(FDR)=0.03). In contrast, BPND did not differ between females with PD and female controls in any region examined. The finding that 5-HTT-binding is elevated in males but not in females with PD converges with other evidence suggesting that dysfunction within the central serotonergic system exists in PD, and also indicates that such abnormalities are influenced by gender. These findings conceivably may reflect a sexual dimorphism that underlies the greater efficacy of serotonin reuptake inhibitor treatment in females vs. males with PD