Marius Hienert

Effects of Selective Serotonin Reuptake Inhibitors on Interregional Relation of Serotonin Transporter Availability in Major Depression

Selective serotonin reuptake inhibitors (SSRIs) modulate serotonergic neurotransmission by blocking reuptake of serotonin from the extracellular space. Up to now, it remains unclear how SSRIs achieve their antidepressant effect. However, task-based and resting state functional magnetic resonance imaging studies, have demonstrated connectivity changes between brain regions. Here, we use positron emission tomography (PET) to quantify SSRI’s main target, the serotonin transporter (SERT), and assess treatment-induced molecular changes in the interregional relation of SERT binding potential (BPND). Nineteen out-patients with major depressive disorder (MDD) and 19 healthy controls (HC) were included in this study. Patients underwent three PET measurements with the radioligand [11C]DASB: (1) at baseline, (2) after a first SSRI dose; and (3) following at least 3 weeks of daily intake. Controls were measured once with PET. Correlation analyses were restricted to brain regions repeatedly implicated in MDD pathophysiology. After 3 weeks of daily SSRI administration a significant increase in SERT BPND correlations of anterior cingulate cortex and insula with the amygdala, midbrain, hippocampus, pallidum and putamen (p < 0.05; false discovery rate, FDR corrected) was revealed. No significant differences were found when comparing MDD patients and HC at baseline. These findings are in line with the clinical observation that treatment response to SSRIs is often achieved only after a latency of several weeks. The elevated associations in interregional SERT associations may be more closely connected to clinical outcomes than regional SERT occupancy measures and could reflect a change in the regional interaction of serotonergic neurotransmission during antidepressant treatment.

Effects of norepinephrine transporter gene variants on NET binding in ADHD and healthy controls investigated by PET

Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disorder with a strong genetic component. The norepinephrine transporter (NET) is a key target for ADHD treatment and the NET gene has been of high interest as a possible modulator of ADHD pathophysiology. Therefore, we conducted an imaging genetics study to examine possible effects of single nucleotide polymorphisms (SNPs) within the NET gene on NET nondisplaceable binding potential (BPND) in patients with ADHD and healthy controls (HCs). Twenty adult patients with ADHD and 20 HCs underwent (S,S)‐[18F]FMeNER‐D2 positron emission tomography (PET) and were genotyped on a MassARRAY MALDI‐TOF platform using the Sequenom iPLEX assay. Linear mixed models analyses revealed a genotype‐dependent difference in NET BPND between groups in the thalamus and cerebellum. In the thalamus, a functional promoter SNP (−3081 A/T) and a 5′‐untranslated region (5′UTR) SNP (−182 T/C), showed higher binding in ADHD patients compared to HCs depending on the major allele. Furthermore, we detected an effect of genotype in HCs, with major allele carriers having lower binding. In contrast, for two 3′UTR SNPs (*269 T/C, *417 A/T), ADHD subjects had lower binding in the cerebellum compared to HCs depending on the major allele. Additionally, symptoms of hyperactivity and impulsivity correlated with NET BPND in the cerebellum depending on genotype. Symptoms correlated positively with cerebellar NET BPND for the major allele, while symptoms correlated negatively to NET BPND in minor allele carriers. Our findings support the role of genetic influence of the NE system on NET binding to be pertubated in ADHD. Hum Brain Mapp 37:884–895, 2016.

Quantification of Task-Specific Glucose Metabolism with Constant Infusion of 18F-FDG

The investigation of cerebral metabolic rate of glucose (CMRGlu) at baseline and during specific tasks previously required separate scans with the drawback of high intrasubject variability. We aimed to validate a novel approach to assessing baseline glucose metabolism and task-specific changes in a single measurement with a constant infusion of 18F-FDG. Methods: Fifteen healthy subjects underwent two PET measurements with arterial blood sampling. As a reference, baseline CMRGlu was quantified from a 60-min scan after 18F-FDG bolus application using the Patlak plot (eyes closed). For the other scan, a constant radioligand infusion was applied for 95 min, during which the subjects opened their eyes at 10–20 min and 60–70 min and tapped their right thumb to their fingers at 35–45 min and 85–95 min. The constant-infusion scan was quantified in two steps. First, the general linear model was used to fit regional time–activity curves with regressors for baseline metabolism, task-specific changes for the eyes-open and finger-tapping conditions, and movement parameters. Second, the Patlak plot was used for quantification of CMRGlu. Multiplication of the baseline regressor by β-values from the general linear model yielded regionally specific time–activity curves for baseline metabolism. Further, task-specific changes in metabolism are directly proportional to changes in the slope of the time–activity curve and hence to changes in CMRGlu. Results: Baseline CMRGlu from the constant-infusion scan matched that from the bolus application (test–retest variability, 1.1% ± 24.7%), which was not the case for a previously suggested approach (variability, −39.9% ± 25.2%, P < 0.001). Task-specific CMRGlu increased in the primary visual and motor cortices for eyes open and finger tapping, respectively (P < 0.05, familywise error–corrected), with absolute changes of up to 2.1 μmol/100 g/min and 6.3% relative to baseline. For eyes open, a decreased CMRGlu was observed in default-mode regions (P < 0.05, familywise error–corrected). CMRGlu quantified with venous blood samples (n = 6) showed excellent agreement with results obtained from arterial samples (r > 0.99). Conclusion: Baseline glucose metabolism and task-specific changes can be quantified in a single measurement with constant infusion of 18F-FDG and venous blood sampling. The high sensitivity and regional specificity of the approach offer novel possibilities for functional and multimodal brain imaging.

Association of Protein Distribution and Gene Expression Revealed by PET and Post-Mortem Quantification in the Serotonergic System of the Human Brain.

Abstract Regional differences in posttranscriptional mechanisms may influence in vivo protein densities. The association of positron emission tomography (PET) imaging data from 112 healthy controls and gene expression values from the Allen Human Brain Atlas, based on post‐mortem brains, was investigated for key serotonergic proteins. PET binding values and gene expression intensities were correlated for the main inhibitory (5‐HT1A) and excitatory (5‐HT2A) serotonin receptor, the serotonin transporter (SERT) as well as monoamine oxidase‐A (MAO‐A), using Spearmans correlation coefficients (rs) in a voxel‐wise and region‐wise analysis. Correlations indicated a strong linear relationship between gene and protein expression for both the 5‐HT1A (voxel‐wise rs = 0.71; region‐wise rs = 0.93) and the 5‐HT2A receptor (rs = 0.66; 0.75), but only a weak association for MAO‐A (rs = 0.26; 0.66) and no clear correlation for SERT (rs = 0.17; 0.29). Additionally, region‐wise correlations were performed using mRNA expression from the HBT, yielding comparable results (5‐HT1Ars = 0.82; 5‐HT2Ars = 0.88; MAO‐A rs = 0.50; SERT rs = −0.01). The SERT and MAO‐A appear to be regulated in a region‐specific manner across the whole brain. In contrast, the serotonin‐1A and ‐2A receptors are presumably targeted by common posttranscriptional processes similar in all brain areas suggesting the applicability of mRNA expression as surrogate parameter for density of these proteins.

Simple and rapid quantification of serotonin transporter binding using [ 11 C]DASB bolus plus constant infusion

Introduction: In‐vivo quantification of serotonin transporters (SERT) in human brain has been a mainstay of molecular imaging in the field of neuropsychiatric disorders and helped to explore the underpinnings of several medical conditions, therapeutic and environmental influences. The emergence of PET/MR hybrid systems and the heterogeneity of SERT binding call for the development of efficient methods making the investigation of larger or vulnerable populations with limited scanner time and simultaneous changes in molecular and functional measures possible. We propose [11C]DASB bolus plus constant infusion for these applications and validate it against standard analyses of dynamic PET data. Methods: [11C]DASB bolus/infusion optimization was performed on data acquired after [11C]DASB bolus in 8 healthy subjects. Subsequently, 16 subjects underwent one scan using [11C]DASB bolus plus constant infusion with Kbol 160–179 min and one scan after [11C]DASB bolus for inter‐method reliability analysis. Arterial blood sampling and metabolite analysis were performed for all scans. Distribution volumes (VT) were obtained using Logan plots for bolus scans and ratios between tissue and plasma parent activity for bolus plus infusion scans for different time spans of the scan (VT‐70 for 60–70 min after start of tracer infusion, VT‐90 for 75–90 min, VT‐120 for 100–120 min) in 9 subjects. Omitting blood data, binding potentials (BPND) obtained using multilinear reference tissue modeling (MRTM2) and cerebellar gray matter as reference region were compared in 11 subjects. Results: A Kbol of 160 min was observed to be optimal for rapid equilibration in thalamus and striatum. VT‐70 showed good intraclass correlation coefficients (ICCs) of 0.61–0.70 for thalamus, striatal regions and olfactory cortex with bias ≤5.1% compared to bolus scans. ICCs increased to 0.72–0.78 for VT‐90 and 0.77–0.93 for VT‐120 in these regions. BPND‐90 had negligible bias ≤2.5%, low variability ≤7.9% and ICCs of 0.74–0.87; BPND‐120 had ICCs of 0.73–0.90. Low‐binding cortical regions and cerebellar gray matter showed a positive bias of ˜8% and ICCs 0.57–0.68 at VT‐90. Cortical BPND suffered from high variability and bias, best results were obtained for olfactory cortex and anterior cingulate cortex with ICC=0.74–0.75 for BPND‐90. High‐density regions amygdala and midbrain had a negative bias of −5.5% and −22.5% at VT‐90 with ICC 0.70 and 0.63, respectively. Conclusions: We have optimized the equilibrium method with [11C]DASB bolus plus constant infusion and demonstrated good inter‐method reliability with accepted standard methods and for SERT quantification using both VT and BPND in a range of different brain regions. With as little as 10–15 min of scanning valid estimates of SERT VT and BPND in thalamus, amygdala, striatal and high‐binding cortical regions could be obtained. Blood sampling seems vital for valid quantification of SERT in low‐binding cortical regions. These methods allow the investigation of up to three subjects with a single radiosynthesis. HighlightsSERT binding potentials in 15 min of scan time using [11C]DASB bolus + infusion.Reliability was compared to gold‐standard tracer bolus and arterial blood sampling.High reliability of BP in thalamus and striatal regions with ICCs 0.73–0.90.A protocol for SERT quantification in up to 3 patients with one radiosynthesis.

Reduced task durations in functional PET imaging with [18F]FDG approaching that of functional MRI

Introduction: The brains energy budget can be non‐invasively assessed with different imaging modalities such as functional MRI (fMRI) and PET (fPET), which are sensitive to oxygen and glucose demands, respectively. The introduction of hybrid PET/MRI systems further enables the simultaneous acquisition of these parameters. Although a recently developed method offers the quantification of task‐specific changes in glucose metabolism (CMRGlu) in a single measurement, direct comparison of the two imaging modalities is still difficult because of the different temporal resolutions. Thus, we optimized the protocol and systematically assessed shortened task durations of fPET to approach that of fMRI. Methods: Twenty healthy subjects (9 male) underwent one measurement on a hybrid PET/MRI scanner. During the scan, tasks were completed in four blocks for fMRI (4×30s blocks) and fPET: participants tapped the fingers of their right hand repeatedly to the thumb while watching videos of landscapes. For fPET, subjects were randomly assigned to groups of n=5 with varying task durations of 10, 5, 2 and 1min, where task durations were kept constant within a measurement. The radiolabeled glucose analogue [18F]FDG was administered as 20% bolus plus constant infusion. The bolus increases the signal‐to‐noise ratio and leaves sufficient activity to detect task‐related effects but poses additional challenges due to a discontinuity in the tracer uptake. First, three approaches to remove task effects from the baseline term were evaluated: (1) multimodal, based on the individual fMRI analysis, (2) atlas‐based by removing presumably activated regions and (3) model‐based by fitting the baseline with exponential functions. Second, we investigated the need to capture the arterial input function peak with automatic blood sampling for the quantification of CMRGlu. We finally compared the task‐specific activation obtained from fPET and fMRI qualitatively and statistically. Results: CMRGlu quantified only with manual arterial samples showed a strong correlation to that obtained with automatic sampling (r=0.9996). The multimodal baseline definition was superior to the other tested approaches in terms of residuals (p<0.001). Significant task‐specific changes in CMRGlu were found in the primary visual and motor cortices (tM1=18.7 and tV1=18.3). Significant changes of fMRI activation were found in the same areas (tM1=16.0 and tV1=17.6) but additionally in the supplementary motor area, ipsilateral motor cortex and secondary visual cortex. Post‐hoc t‐tests showed strongest effects for task durations of 5 and 2min (all p<0.05 FWE corrected), whereas 1min exhibited pronounced unspecific activation. Percent signal change (PSC) was higher for CMRGlu (˜18%–27%) compared to fMRI (˜2%). No significant association between PSC of task‐specific CMRGlu and fMRI was found (r=0.26). Conclusion: Using a bolus plus constant infusion protocol, the necessary task duration for reliable quantification of task‐specific CMRGlu could be reduced to 5 and 2min, therefore, approaching that of fMRI. Important for valid quantification is a correct baseline definition, which was ideal when task‐relevant voxels were determined with fMRI. The absence of a correlation and the different activation pattern between fPET and fMRI suggest that glucose metabolism and oxygen demand capture complementary aspects of energy demands. HIGHLIGHTSQuantification of task‐specific CMRGlu with 20% bolus plus constant infusion.Functional PET task durations down to 1min were evaluated.Active primary regions overlap between BOLD and CMRGlu.No significant correlation between BOLD and CMRGlu.

Brain monoamine oxidase A in seasonal affective disorder and treatment with bright light therapy

Increased cerebral monoamine oxidase A (MAO-A) levels have been shown in non-seasonal depression using positron emission tomography (PET). Seasonal affective disorder (SAD) is a sub-form of major depressive disorder and is typically treated with bright light therapy (BLT). The serotonergic system is affected by season and light. Hence, this study aims to assess the relevance of brain MAO-A levels to the pathophysiology and treatment of SAD. Changes to cerebral MAO-A distribution (1) in SAD in comparison to healthy controls (HC), (2) after treatment with BLT and (3) between the seasons, were investigated in 24 patients with SAD and 27 HC using [11C]harmine PET. PET scans were performed in fall/winter before and after 3 weeks of placebo-controlled BLT, as well as in spring/summer. Cerebral MAO-A distribution volume (VT, an index of MAO-A density) did not differ between patients and HC at any of the three time-points. However, MAO-A VT decreased from fall/winter to spring/summer in the HC group (F1, 187.84 = 4.79, p < 0.050), while SAD showed no change. In addition, BLT, but not placebo, resulted in a significant reduction in MAO-A VT (F1, 208.92 = 25.96, p < 0.001). This is the first study to demonstrate an influence of BLT on human cerebral MAO-A levels in vivo. Furthermore, we show that SAD may lack seasonal dynamics in brain MAO-A levels. The lack of a cross-sectional difference between patients and HC, in contrast to studies in non-seasonal depression, may be due to the milder symptoms typically shown by patients with SAD.

Assessment of Ketamine Binding of the Serotonin Transporter in Humans with Positron Emission Tomography

Abstract Background Comprehensive description of ketamine’s molecular binding profile becomes increasingly pressing as use in real-life patient cohorts widens. Animal studies attribute a significant role in the substance’s antidepressant effects to the serotonergic system. The serotonin transporter is a highly relevant target in this context, because it is central to depressive pathophysiology and treatment. This is, to our knowledge, the first study investigating ketamine’s serotonin transporter binding in vivo in humans. Methods Twelve healthy subjects were assessed twice using [11C]DASB positron emission tomography. A total of 0.50 mg/kg bodyweight ketamine was administered once i.v. prior to the second positron emission tomography scan. Ketamine plasma levels were determined during positron emission tomography. Serotonin transporter nondisplaceable binding potential was computed using a reference region model, and occupancy was calculated for 4 serotonin transporter-rich regions (caudate, putamen, thalamus, midbrain) and a whole-brain region of interest. Results After administration of the routine antidepressant dose, ketamine showed <10% occupancy of the serotonin transporter, which is within the test-retest variability of [11C]DASB. A positive correlation between ketamine plasma levels and occupancy was shown. Conclusions Measurable occupancy of the serotonin transporter was not detectable after administration of an antidepressant dose of ketamine. This might suggest that ketamine binding of the serotonin transporter is unlikely to be a primary antidepressant mechanism at routine antidepressant doses, as substances that facilitate antidepressant effects via serotonin transporter binding (e.g., selective serotonin reuptake inhibitors) show 70% to 80% occupancy. Administration of high-dose ketamine is widening. Based on the positive relationship we find between ketamine plasma levels and occupancy, there is a need for investigation of ketamine’s serotonin transporter binding at higher doses.

Quality of medical therapy in heart failure patients undergoing elective revascularisation: A protective effect of disease modifying therapy at discharge.

The STICH(-ES) trial showed that coronary artery bypass grafting was superior to medical therapy alone in treating ischemic heart failure. However, dosages of disease modifying drugs were not reported. We included 128 (84% male, mean age 66 ± 11 years) consecutive patients with ischemic heart failure and an ejection fraction ≤35% undergoing isolated elective coronary artery bypass grafting. We defined optimal medical therapy (OMT) as prescription of ≥50% dosages of guideline recommended medications (i.e. beta-blocker (BB) and renin angiotensin system (RAS) antagonist) plus prescription of a mineralocorticoid receptor antagonist (MRA). The mean logistic EuroSCORE was 12.3 ± 13.8%. The five year survival was 74%. At discharge, 111 patients (87%) were on a BB and 106 (83%) were on a RAS antagonist. Forty-nine patients (38%) received an MRA. Only 8 patients (6%) received OMT. A Cox regression analysis revealed EuroSCORE (p < 0.001) and the use of MRA (p = 0.003) and BB (p = 0.037) at discharge as significant predictors of 5 year survival. Prescription rates of heart failure medication are comparable to those reported in the STICH trial, but rates of OMT are very low at admission and discharge. Prescription of BB and MRA was associated with improved survival, highlighting the need for disease management programs and rigorous discharge management.