Publications by authors named "Swen Hesse"

79 Publications

Cognitive fatigue in multiple sclerosis is associated with alterations in the functional connectivity of monoamine circuits.

Brain Commun 2021 5;3(2):fcab023. Epub 2021 Mar 5.

Department of Neuroscience, Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9RR, UK.

Fatigue is a highly prevalent and debilitating symptom in multiple sclerosis, but currently the available treatment options have limited efficacy. The development of innovative and efficacious targeted treatments for fatigue in multiple sclerosis has been marred by the limited knowledge of the underlying mechanisms. One of the hypotheses postulates that multiple sclerosis pathology might cause reduced monoaminergic release in the central nervous system with consequences on motivation, mood and attention. Here, we applied the recently developed Receptor-Enriched Analysis of Functional Connectivity by Targets method to investigate whether patients with high and low fatigue differ in the functional connectivity (FC) of the monoamine circuits in the brain. We recruited 55 patients with multiple sclerosis, which were then classified as highly fatigued or mildly fatigued based on their scores on the cognitive sub-scale of the Modified Fatigue Impact scale. We acquired resting-state functional MRI scans and derived individual maps of connectivity associated with the distribution of the dopamine, noradrenaline and serotonin transporters as measured by positron emission tomography. We found that patients with high fatigue present decreased noradrenaline transporter (NAT)-enriched connectivity in several frontal and prefrontal areas when compared to those with lower fatigue. The NAT-enriched FC predicted negatively individual cognitive fatigue scores. Our findings support the idea that alterations in the catecholaminergic functional circuits underlie fatigue in multiple sclerosis and identify the NAT as a putative therapeutic target directed to pathophysiology.
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http://dx.doi.org/10.1093/braincomms/fcab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023545PMC
March 2021

Striatal dopamine transporter availability and individual clinical course within the 1-year follow-up of deep brain stimulation of the subthalamic nucleus in patients with Parkinson's disease.

J Neurosurg 2021 Feb 19:1-7. Epub 2021 Feb 19.

2Neurosurgery, and.

Objective: Degeneration of dopaminergic neurons in the substantia nigra projecting to the striatum is responsible for the motor symptoms in Parkinson's disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established procedure to alleviate these symptoms in advanced PD. Yet the mechanism of action, especially the effects of STN-DBS on the availability of striatal dopamine transporter (DAT) as a marker of nigrostriatal nerve cell function, remains largely unknown. The aim of this study was therefore to evaluate whether 1) DAT availability changes within 1 year of STN-DBS and 2) the clinical outcome can be predicted based on preoperative DAT availability.

Methods: Twenty-seven PD patients (mean age 62.7 ± 8.9 years; mean duration of illness 13.0 ± 4.9 years; PD subtypes: akinetic-rigid, n = 11; equivalence, n = 13; and tremor-dominant, n = 3) underwent [123I]FP-CIT SPECT preoperatively and after 1 year of STN-DBS. DAT availability as determined by the specific binding ratio (SBR) was assessed by volume of interest (VOI) analysis of the caudate nucleus and the putamen ipsilateral and contralateral to the clinically more affected side.

Results: Unified Parkinson's Disease Rating Scale (UPDRS) III scores improved significantly (mean preoperative on medication 25.6 ± 12.3, preoperative off medication 42.3 ± 15.2, postoperative on medication/off stimulation 41.4 ± 13.2, and postoperative on medication/on stimulation 16.1 ± 9.4; preoperative on medication vs postoperative on medication/on stimulation, p = 0.006), while the levodopa-equivalent daily dose was reduced (mean preoperative 957 ± 440 mg vs postoperative 313 ± 189 mg, p < 0.001). The SBR did not differ significantly before and 1 year after DBS, regardless of PD subtype. Preoperative DAT availability was not related to the change in UPDRS III score, but the change in DAT availability was significantly correlated with the change in UPDRS III score (contralateral head of the caudate VOI, p = 0.014; contralateral putamen VOI, p = 0.018).

Conclusions: Overall, DAT availability did not change significantly after 1 year of STN-DBS. However, on an individual basis, the improvement in UPDRS III score was associated with an increase in DAT availability, whereas DAT availability before STN-DBS surgery did not predict the clinical outcome. Whether a subtype-specific pattern of preoperative DAT availability can become a reliable predictor of successful STN-DBS must be evaluated in larger study cohorts.
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http://dx.doi.org/10.3171/2020.8.JNS192740DOI Listing
February 2021

Evidence of fNIRS-Based Prefrontal Cortex Hypoactivity in Obesity and Binge-Eating Disorder.

Brain Sci 2020 Dec 26;11(1). Epub 2020 Dec 26.

Integrated Research and Treatment Center Adiposity Diseases, Behavioural Medicine Research Unit, Department of Psychosomatic Medicine and Psychotherapy, University of Leipzig Medical Center, Semmelweisstrasse 10, 04103 Leipzig, Germany.

Obesity (OB) and associated binge-eating disorder (BED) show increased impulsivity and emotional dysregulation. Albeit well-established in neuropsychiatric research, functional near-infrared spectroscopy (fNIRS) has rarely been used to study OB and BED. Here, we investigated fNIRS-based food-specific brain signalling, its association with impulsivity and emotional dysregulation, and the temporal variability in individuals with OB with and without BED compared to an age- and sex-stratified normal weight (NW) group. Prefrontal cortex (PFC) responses were recorded in individuals with OB ( = 15), OB + BED ( = 13), and NW ( = 12) in a passive viewing and a response inhibition task. Impulsivity and emotional dysregulation were self-reported; anthropometrics were objectively measured. The OB and NW groups were measured twice 7 days apart. Relative to the NW group, the OB and OB + BED groups showed PFC hyporesponsivity across tasks, whereas there were few significant differences between the OB and OB + BED groups. Greater levels of impulsivity were significantly associated with stronger PFC responses, while more emotional dysregulation was significantly associated with lower PFC responses. Temporal differences were found in the left orbitofrontal cortex responses, yet in opposite directions in the OB and NW groups. This study demonstrated diminished fNIRS-based PFC responses across OB phenotypes relative to a NW group. The association between impulsivity, emotional dysregulation, and PFC hypoactivity supports the assumption that BED constitutes a specific OB phenotype.
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http://dx.doi.org/10.3390/brainsci11010019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823505PMC
December 2020

Higher HbA1c levels associate with lower hippocampal serotonin transporter availability in non-diabetic adults with obesity.

Sci Rep 2020 12 7;10(1):21383. Epub 2020 Dec 7.

Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany.

The current study aimed to investigate whether the in vivo availability of central serotonin reuptake transporters (5-HTT) is associated with plasma levels of glycosylated hemoglobin (HbA1c) in non-diabetic humans with obesity. 5-HTT availability was measured by using positron emission tomography (PET) imaging with the 5-HTT selective radiotracer [C]DASB in 23 non-diabetic individuals with obesity and 14 healthy, non-obesity controls. Parametric images of binding potential BP were generated from the PET data and analyzed together with HbA1c levels by using volume of interest analysis for brain areas relevant to appetite control. Voxel-based morphometry (VBM) of individual magnetic resonance imaging data was further performed to correlate grey matter density (GMD) maps with HbA1c. We found significant negative correlations between HbA1c levels and BP in right and left hippocampus in obesity (r = - 0.717, p < 0.001, and r = - 0.557, p = 0.006, respectively). VBM analyses revealed that higher HbA1c levels were associated with GMD in the right para-hippocampal area. Our results indicate that chronically high blood glucose levels may evoke changes in hippocampal 5-HTT levels that are in part tied to local microstructure.
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http://dx.doi.org/10.1038/s41598-020-78227-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721891PMC
December 2020

JuSpace: A tool for spatial correlation analyses of magnetic resonance imaging data with nuclear imaging derived neurotransmitter maps.

Hum Brain Mapp 2021 Feb 20;42(3):555-566. Epub 2020 Oct 20.

Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), Research Centre Jülich, Jülich, Germany.

Recent studies have shown that drug-induced spatial alteration patterns in resting state functional activity as measured using magnetic resonance imaging (rsfMRI) are associated with the distribution of specific receptor systems targeted by respective compounds. Based on this approach, we introduce a toolbox (JuSpace) allowing for cross-modal correlation of MRI-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, and GABAergic (gamma-aminobutric acid) neurotransmission. We apply JuSpace to two datasets covering Parkinson's disease patients (PD) and risperidone-induced changes in rsfMRI and cerebral blood flow (CBF). Consistently with the predominant neurodegeneration of dopaminergic and serotonergic system in PD, we find significant spatial associations between rsfMRI activity alterations in PD and dopaminergic (D2) and serotonergic systems (5-HT1b). Risperidone induced CBF alterations were correlated with its main targets in serotonergic and dopaminergic systems. JuSpace provides a biologically meaningful framework for linking neuroimaging to underlying neurotransmitter information.
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http://dx.doi.org/10.1002/hbm.25244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814756PMC
February 2021

Effects of Hyperthyroidism on Adipose Tissue Activity and Distribution in Adults.

Thyroid 2021 03 18;31(3):519-527. Epub 2020 Nov 18.

Medical Department III-Endocrinology, Nephrology, Rheumatology; Leipzig, Germany.

Positron emission tomography (PET) has provided evidence that adult humans retain metabolically active brown adipose tissue (BAT) depots. Thyroid hormones (TH) stimulate BAT thermogenesis by central and peripheral mechanisms. However, the effect of hyperthyroidism on BAT activity and BAT volume in humans is yet not fully understood. The aim of this study was to investigate the effect of TH on (i) the metabolic activity of brown and white adipose tissue (WAT) depots, (ii) on abdominal visceral and subcutaneous adipose tissue area, and (iii) on serum levels of metabolically active cytokines. Nineteen patients with overt hyperthyroidism were investigated through repeated 2-[F]fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (2-[F]FDG PET/CT) in the hyperthyroid and in the euthyroid state. The 2-[F]FDG uptake was calculated as standard uptake ratio with blood pool as reference. Fat areas were quantified by means of CT segmentation. Serum levels of fetuin A and B, fibroblast growth factor 21, adipocyte fatty acid-binding protein (AFABP), retinol-binding protein 4, pro-enkephalin, pro-neurotensin, and neuregulin 4 were determined in the hyperthyroid and in the euthyroid state for each subject. 2-[F]FDG uptake was increased in the hyperthyroid state in BAT in comparison with the euthyroid phase ( = 0.001). There was no correlation between serum free triiodothyronine (fT3) and free thyroxine (fT4) levels and 2-[F]FDG uptake in BAT or WAT. In the hyperthyroid state, fT3 levels were positively associated with skeletal muscle standardized uptake value ratios. Areas of visceral adipose tissue and skeletal muscle were significantly decreased in hyperthyroidism. AFABP levels correlated positively with fT3 ( = 0.031, β = 0.28) and fT4 ( = 0.037, β = 0.27) in the hyperthyroid state. Our results suggest that the contribution of increased TH levels to the glucose uptake of BAT and WAT is low compared with that of the skeletal muscle. Hyperthyroid subjects have reduced areas of visceral adipose tissue and increased AFABP levels.
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http://dx.doi.org/10.1089/thy.2019.0806DOI Listing
March 2021

Increased pulmonary serotonin transporter in patients with chronic obstructive pulmonary disease who developed pulmonary hypertension.

Eur J Nucl Med Mol Imaging 2021 Apr 3;48(4):1081-1092. Epub 2020 Oct 3.

Department of Respiratory Medicine, University Hospital Leipzig, Liebigstrasse 20, 04103, Leipzig, Germany.

Purpose: Pulmonary hypertension (PH) is characterized by a progressive remodelling of the pulmonary vasculature resulting in right heart failure and eventually death. The serotonin transporter (SERT) may be involved in the pathogenesis of PH in patients with chronic-obstructive pulmonary disease (COPD). This study investigated for the first time the SERT in vivo availability in the lungs of patients with COPD and PH (COPD+PH).

Methods: SERT availability was assessed using SERT-selective [C]DASB and positron emission tomography/computed tomography (PET/CT) with dynamic acquisition over 30 min in 4 groups of 5 participants each: COPD, COPD+PH, pulmonary arterial hypertension, and a healthy control (HC). Time activity curves were generated based on a volume of interest within the middle lobe. Tissue-to-blood concentration ratios after 25 to 30 min (TTBR) served as receptor parameter for group comparison and were corrected for lung tissue attenuation. Participants underwent comprehensive pulmonary workup. Statistical analysis included group comparisons and correlation analysis.

Results: [C]DASB uptake peak values did not differ among the cohorts after adjusting for lung tissue attenuation, suggesting equal radiotracer delivery. Both the COPD and COPD+PH cohort showed significantly lower TTBR values after correction for lung attenuation than HC. Attenuation corrected TTBR values were significantly higher in the COPD+PH cohort than those in the COPD cohort and higher in non-smokers than in smokers. They positively correlated with invasively measured severity of PH and inversely with airflow limitation and emphysema. Considering all COPD patients ± PH, they positively correlated with right heart strain (NT-proBNP).

Conclusion: By applying [C]DASB and PET/CT, semiquantitative measures of SERT availability are demonstrated in the lung vasculature of patients with COPD and/or PH. COPD patients who developed PH show increased pulmonary [C]DASB uptake compared to COPD patients without PH indicating an implication of pulmonary SERT in the development of PH in COPD patients.
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http://dx.doi.org/10.1007/s00259-020-05056-7DOI Listing
April 2021

Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [F] fluspidine and [F] fallypride PET study.

Eur J Nucl Med Mol Imaging 2021 Apr 29;48(4):1103-1115. Epub 2020 Sep 29.

Department of Nuclear Medicine, University of Leipzig Medical Center, Leipzig, Germany.

Purpose: Pridopidine is an investigational drug for Huntington disease (HD). Pridopidine was originally thought to act as a dopamine stabilizer. However, pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [F] fluspidine and [F] fallypride PET, the purpose of this study was to assess in vivo target engagement/receptor occupancy of pridopidine to the S1R and dopamine D2/D3 receptor (D2/D3R) at clinical relevant doses in healthy volunteers (HVs) and as proof-of-concept in a small number of patients with HD.

Methods: Using [F] fluspidine PET (300 MBq, 0-90 min), 11 male HVs (pridopidine 0.5 to 90 mg; six dose groups) and three male patients with HD (pridopidine 90 mg) were investigated twice, without and 2 h after single dose of pridopidine. Using [F] fallypride PET (200 MBq, 0-210 min), four male HVs were studied without and 2 h following pridopidine administration (90 mg). Receptor occupancy was analyzed by the Lassen plot.

Results: S1R occupancy as function of pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg pridopidine. In contrast, at 90 mg pridopidine, the D2/D3R occupancy was only minimal (~ 3%).

Conclusions: Our PET findings indicate that at clinically relevant single dose of 90 mg, pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of pridopidine to the S1R. Our findings provide significant clarification about pridopidine's mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41.
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http://dx.doi.org/10.1007/s00259-020-05030-3DOI Listing
April 2021

(+)-[F]Flubatine as a novel α4β2 nicotinic acetylcholine receptor PET ligand-results of the first-in-human brain imaging application in patients with β-amyloid PET-confirmed Alzheimer's disease and healthy controls.

Eur J Nucl Med Mol Imaging 2021 Mar 16;48(3):731-746. Epub 2020 Sep 16.

Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany.

Purposes: We present the first in-human brain PET imaging data of the new α4β2 nicotinic acetylcholine receptor (nAChR)-targeting radioligand (+)-[F]Flubatine. Aims were to develop a kinetic modeling-based approach to quantify (+)-[F]Flubatine and compare the data of healthy controls (HCs) and patients with Alzheimer's disease (AD); to investigate the partial volume effect (PVE) on regional (+)-[F]Flubatine binding; and whether (+)-[F]Flubatine binding and cognitive test data respective β-amyloid radiotracer accumulation were correlated.

Methods: We examined 11 HCs and 9 mild AD patients. All subjects underwent neuropsychological testing and [C]PiB PET/MRI examination. (+)-[F]Flubatine PET data were evaluated using full kinetic modeling and regional as well as voxel-based analyses.

Results: With 270-min p.i., the unchanged parent compound amounted to 97 ± 2%. Adequate fits of the time-activity curves were obtained with the 1 tissue compartment model (1TCM). (+)-[F]Flubatine distribution volume (binding) was significantly reduced in bilateral mesial temporal cortex in AD patients compared with HCs (right 10.6 ± 1.1 vs 11.6 ± 1.4, p = 0.049; left 11.0 ± 1.1 vs 12.2 ± 1.8, p = 0.046; one-sided t tests each). PVE correction increased not only (+)-[F]Flubatine binding of approximately 15% but also standard deviation of 0.4-70%. Cognitive test data and (+)-[F]Flubatine binding were significantly correlated in the left anterior cingulate, right posterior cingulate, and right parietal cortex (r > 0.5, p < 0.05 each). In AD patients, (+)-[F]Flubatine binding and [C]PiB standardized uptake value ratios were negatively correlated in several regions; whereas in HCs, a positive correlation between cortical (+)-[F]Flubatine binding and [C]PiB accumulation in the white matter was found. No adverse event related to (+)-[F]Flubatine occurred.

Conclusion: (+)-[F]Flubatine is a safe and stable PET ligand. Full kinetic modeling can be realized by 1TCM without metabolite correction. (+)-[F]Flubatine binding affinity was high enough to detect group differences. Of interest, correlation between white matter β-amyloid PET uptake and (+)-[F]Flubatine binding indicated an association between white matter integrity and availability of α4β2 nAChRs. Overall, (+)-[F]Flubatine showed favorable characteristics and has therefore the potential to serve as α4β2 nAChR-targeting PET ligand in further clinical trials.
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http://dx.doi.org/10.1007/s00259-020-05029-wDOI Listing
March 2021

Changes of central noradrenaline transporter availability in immunotherapy-naïve multiple sclerosis patients.

Sci Rep 2020 09 4;10(1):14651. Epub 2020 Sep 4.

Department of Neurology, University of Leipzig, Leipzig, Germany.

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-[C]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.
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http://dx.doi.org/10.1038/s41598-020-70732-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474089PMC
September 2020

Unravelling the effects of methylphenidate on the dopaminergic and noradrenergic functional circuits.

Neuropsychopharmacology 2020 08 30;45(9):1482-1489. Epub 2020 May 30.

Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, Brighton, UK.

Functional magnetic resonance imaging (fMRI) can be combined with drugs to investigate the system-level functional responses in the brain to such challenges. However, most psychoactive agents act on multiple neurotransmitters, limiting the ability of fMRI to identify functional effects related to actions on discrete pharmacological targets. We recently introduced a multimodal approach, REACT (Receptor-Enriched Analysis of functional Connectivity by Targets), which offers the opportunity to disentangle effects of drugs on different neurotransmitters and clarify the biological mechanisms driving clinical efficacy and side effects of a compound. Here, we focus on methylphenidate (MPH), which binds to the dopamine transporter (DAT) and the norepinephrine transporter (NET), to unravel its effects on dopaminergic and noradrenergic functional circuits in the healthy brain at rest. We then explored the relationship between these target-enriched resting state functional connectivity (FC) maps and inter-individual variability in behavioural responses to a reinforcement-learning task encompassing a novelty manipulation to disentangle the molecular systems underlying specific cognitive/behavioural effects. Our main analysis showed a significant MPH-induced FC increase in sensorimotor areas in the functional circuit associated with DAT. In our exploratory analysis, we found that MPH-induced regional variations in the DAT and NET-enriched FC maps were significantly correlated with some of the inter-individual differences on key behavioural responses associated with the reinforcement-learning task. Our findings show that main MPH-related FC changes at rest can be understood through the distribution of DAT in the brain. Furthermore, they suggest that when compounds have mixed pharmacological profiles, REACT may be able to capture regional functional effects that are underpinned by the same cognitive mechanism but are related to engagement of distinct molecular targets.
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http://dx.doi.org/10.1038/s41386-020-0724-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360745PMC
August 2020

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

Transl Psychiatry 2019 11 15;9(1):301. Epub 2019 Nov 15.

Department of Psychiatry and Psychotherapy, University of Leipzig Medical Center, 04103, Leipzig, Germany.

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-[C]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: F = 12.30, p = .002; regions on the left: F = 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.
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http://dx.doi.org/10.1038/s41398-019-0619-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858438PMC
November 2019

Current radiotracers to image neurodegenerative diseases.

EJNMMI Radiopharm Chem 2019 Jul 26;4(1):17. Epub 2019 Jul 26.

Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany.

The term of neurodegenerative diseases covers a heterogeneous group of disorders that are distinguished by progressive degeneration of the structure and function of the nervous system such as dementias, movement disorders, motor neuron disorders, as well as some prion disorders. In recent years, a paradigm shift started for the diagnosis of neurodegenerative diseases, for which successively clinical testing is supplemented by biomarker information. In research scenarios, it was even proposed recently to substitute the current syndromic by a biological definition of Alzheimer's diseases. PET examinations with various radiotracers play an important role in providing non-invasive biomarkers and co-morbidity information in neurodegeneration. Information on co-morbidity, e.g. Aβ plaques and Lewy-bodies or Aβ plaques in patients with aphasia or the absence of Aβ plaques in clinical AD patients are of interest to expand our knowledge about the pathogenesis of different phenotypically defined neurodegenerative diseases. Moreover, this information is also important in therapeutic trials targeting histopathological abnormalities.The aim of this review is to present an overview of the currently available radiotracers for imaging neurodegenerative diseases in research and in routine clinical settings. In this context, we also provide a short summary of the most frequent neurodegenerative diseases from a nuclear medicine point of view, their clinical and pathophysiological as well as nuclear imaging characteristics, and the resulting need for new radiotracers.
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http://dx.doi.org/10.1186/s41181-019-0070-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660543PMC
July 2019

and Human Metabolism of ()-[F]Fluspidine - A Radioligand for Imaging σ Receptors With Positron Emission Tomography (PET).

Front Pharmacol 2019 13;10:534. Epub 2019 Jun 13.

Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany.

()-[F]fluspidine (()-[F]) has recently been explored for positron emission tomography (PET) imaging of sigma-1 receptors in humans. In the current report, we have used plasma samples of healthy volunteers to investigate the radiometabolites of ()-[F] and elucidate their structures with LC-MS/MS. For the latter purpose additional studies were conducted by incubation of ()-[F] and ()- with human liver microsomes (HLM). metabolites were characterized by interpretation of MS/MS fragmentation patterns from collision-induced dissociation or by use of reference compounds. Thereby, structures of corresponding radio-HPLC-detected radiometabolites, both and (human), could be identified. By incubation with HLM, mainly debenzylation and hydroxylation occurred, beside further mono- and di-oxygenations. The product hydroxylated at the fluoroethyl side chain was glucuronidated. Plasma samples (10, 20, 30 min p.i., = 5-6), obtained from human subjects receiving 250-300 MBq ()-[F] showed 97.2, 95.4, and 91.0% of unchanged radioligand, respectively. In urine samples (90 min p.i.) the fraction of unchanged radioligand was only 2.6% and three major radiometabolites were detected. The one with the highest percentage, also found in plasma, matched the glucuronide formed . Only a small amount of debenzylated metabolite was detected. In conclusion, our metabolic study, in particular the high fractions of unchanged radioligand in plasma, confirms the suitability of ()-[F] as PET radioligand for sigma-1 receptor imaging.
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http://dx.doi.org/10.3389/fphar.2019.00534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585474PMC
June 2019

Early after Administration [11C]PiB PET Images Correlate with Cognitive Dysfunction Measured by the CERAD Test Battery.

J Alzheimers Dis 2019 ;68(1):65-76

Department of Nuclear Medicine, University of Leipzig, University of Leipzig, Leipzig, Germany.

Background: Amyloid-β (Aβ) and [18F]FDG PET are established as amyloid pathology and neuronal injury biomarkers. Early after administration Aβ PET images have the potential to replace [18F]FDG PET images allowing dual biomarker delivery by the administration of a single tracer. For [18F]FDG PET data, a correlation with cognitive performance is known.

Objective: The aim of this study was to investigate whether early after administration [11C]PiB PET data also correlate with cognitive performance.

Methods: The early after administration [11C]PiB PET data of 31 patients with cognitive impairment were evaluated. CERAD subtests were summarized to five cognitive domains. The resulting z scores were correlated with the PET data on a voxel- and VOI-based approach. Additional subgroup analyses (MCI versus dementia, Aβ-positive versus Aβ-negative subjects) were performed.

Results: Significant correlations between cognitive performance and early after administration [11C]PiB PET data were found between left temporo-parietal SUVR and language domain, bilateral occipital as well as left temporal SUVR and executive function, left pre- and postcentral SUVRs, and visuospatial abilities. For the episodic and immediate memory domains, the analysis at the high significance level did not show any correlated cluster, however, the exploratory analysis did.

Conclusion: Our study revealed correlations between deficits in different cognitive domains and regional early after administration [11C]PiB PET data similar to those known from [18F]FDG PET studies. Thus, our data support the assumption that early [11C]PiB PET data have a potential as neuronal injury biomarker. Head-to-head double-tracer studies of larger cohorts are needed to confirm this assumption.
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http://dx.doi.org/10.3233/JAD-180217DOI Listing
June 2020

Dual Time-Point [18F]Florbetaben PET Delivers Dual Biomarker Information in Mild Cognitive Impairment and Alzheimer's Disease.

J Alzheimers Dis 2018 ;66(3):1105-1116

Department of Nuclear Medicine, Leipzig University Hospital, Leipzig, Germany.

Background: Current research diagnostic criteria for Alzheimer's disease (AD) and mild cognitive impairment (MCI) due to AD include biomarkers to supplement clinical testing. Recently, we demonstrated that dual time-point [18F]FBB PET is able to deliver both blood flow and amyloid-β (Aβ) load surrogates.

Objective: The aim of this study was to investigate whether these surrogates can be utilized as AD biomarkers.

Methods: 112 subjects (41 with MCI, 50 with probable/possible AD, 21 with other dementias) underwent dual time-point [18F]FBB PET. Data were visually and relative quantitatively (Herholz scores for the early and composite SUVRs for the late PET data) analyzed.

Results: In the early images AD-typical patterns were present in 42% /27% /33% of probable/possible AD/MCI/other dementia cases. In late [18F]FBB PET, 42% /29% /38% of probable/possible AD/ MCI/other dementia cases were Aβ-positive. 17% of the MCIs were categorized as "MCI due to AD-high likelihood", 44% of the probable ADs as "probable AD with high evidence of AD pathophysiological process" and 28% of the possible ADs as "possible AD with evidence of AD pathophysiological process". 27% of all subjects showed a positive diagnostic and progression biomarker. Herholz scores were lower (0.85±0.05 versus 0.88±0.04, p = 0.015) for probable/possible AD versus MCI. Composite late phase SUVRs were significantly higher (1.65±0.23 versus 1.15±0.17, p < 0.005) in Aβ-positive versus Aβ-negative patients. Herholz and MMSE scores were positively correlated (R = 0.30 p = 0.006).

Conclusion: Dual time-point [18F]FBB PET provides dual biomarker information which enables to categorize MCI and AD dementia patients according to established diagnostic criteria. Thus, dual time-point [18F]FBB PET has great potential to supplement diagnostic dementia workups.
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http://dx.doi.org/10.3233/JAD-180522DOI Listing
November 2019

Central noradrenaline transporter availability is linked with HPA axis responsiveness and copeptin in human obesity and non-obese controls.

Stress 2019 01 29;22(1):93-102. Epub 2018 Oct 29.

a Integrated Research and Treatment Center (IFB) Adiposity Diseases , Leipzig University Medical Center , Leipzig , Germany.

The central noradrenaline (NA) stress-response network co-mediates hypothalamic-pituitary-adrenal (HPA) axis activation and arginine-vasopressin (AVP) release. Dysregulation of these systems contributes to stress-related diseases such as human obesity, but their interrelation remains unclear. The study was aimed to test for the first time in vivo whether central noradrenergic activity quantitatively indexed by the availability of the presynaptic NA transporter (NAT) is associated with HPA axis responsiveness as measured with the combined dexamethasone suppression/corticotropin releasing hormone stimulation (dex/CRH) test and copeptin as a surrogate marker of the serum AVP tone in highly obese, otherwise, healthy individuals compared to age- and sex-matched non-obese, healthy controls. In order to assess central NAT availability, positron emission tomography (PET) was applied using the NAT-selective radiotracer S,S-[C]O-methylreboxetine (MRB) and correlated with curve indicators derived from the dex/CRH test (maximum, MAX, and area under the curve, AUC, for cortisol and adrenocorticotropic hormone, ACTH) as well as with copeptin. In non-obese controls, positive correlations were found between the NAT distribution volume ratios (DVR) of the orbitofrontal cortex (OFC) and the amygdala with the HPA response (OFC: ACTH r = 0.87, p = .001; cortisol r = 0.86, p = .002; amygdala: ACTH r = 0.86, p = .002; cortisol r = 0.79, p = .006), while in obesity, the hypothalamic DVR correlated inversely with the HPA axis response (cortisol, r = -0.66, p = .04) and with copeptin (r = -0.71, p = .02). This association of central NAT availability with HPA axis responsiveness and copeptin suggests a mechanistic interaction between noradrenergic transmission with HPA axis activity and the serum AVP system that differs between non-obese individuals with prefrontal-limbic involvement and obesity with a hypothalamic-centered relationship. Whether the latter finding contributes to obesogenic behavior needs to be further explored.
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http://dx.doi.org/10.1080/10253890.2018.1511698DOI Listing
January 2019

Cognitive correlates of α4β2 nicotinic acetylcholine receptors in mild Alzheimer's dementia.

Brain 2018 06;141(6):1840-1854

Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Leipzig, Germany.

In early Alzheimer's dementia, there is a need for PET biomarkers of disease progression with close associations to cognitive dysfunction that may aid to predict further cognitive decline and neurodegeneration. Amyloid biomarkers are not suitable for that purpose. The α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) are widely abundant in the human brain. As neuromodulators they play an important role in cognitive functions such as attention, learning and memory. Post-mortem studies reported lower expression of α4β2-nAChRs in more advanced Alzheimer's dementia. However, there is ongoing controversy whether α4β2-nAChRs are reduced in early Alzheimer's dementia. Therefore, using the recently developed α4β2-nAChR-specific radioligand (-)-18F-flubatine and PET, we aimed to quantify the α4β2-nAChR availability and its relationship to specific cognitive dysfunction in mild Alzheimer's dementia. Fourteen non-smoking patients with mild Alzheimer's dementia, drug-naïve for cholinesterase therapy, were compared with 15 non-smoking healthy controls matched for age, sex and education by applying (-)-18F-flubatine PET together with a neuropsychological test battery. The one-tissue compartment model and Logan plot method with arterial input function were used for kinetic analysis to obtain the total distribution volume (VT) as the primary, and the specific binding part of the distribution volume (VS) as the secondary quantitative outcome measure of α4β2-nAChR availability. VS was determined by using a pseudo-reference region. Correlations between VT within relevant brain regions and Z-scores of five cognitive functions (episodic memory, executive function/working memory, attention, language, visuospatial function) were calculated. VT (and VS) were applied for between-group comparisons. Volume of interest and statistical parametric mapping analyses were carried out. Analyses revealed that in patients with mild Alzheimer's dementia compared to healthy controls, there was significantly lower VT, especially within the hippocampus, fronto-temporal cortices, and basal forebrain, which was similar to comparisons of VS. VT decline in Alzheimer's dementia was associated with distinct domains of impaired cognitive functioning, especially episodic memory and executive function/working memory. Using (-)-18F-flubatine PET in patients with mild Alzheimer's dementia, we show for the first time a cholinergic α4β2-nAChR deficiency mainly present within the basal forebrain-cortical and septohippocampal cholinergic projections and a relationship between lower α4β2-nAChR availability and impairment of distinct cognitive domains, notably episodic memory and executive function/working memory. This shows the potential of (-)-18F-flubatine as PET biomarker of cholinergic α4β2-nAChR dysfunction and specific cognitive decline. Thus, if validated by longitudinal PET studies, (-)-18F-flubatine might become a PET biomarker of progression of neurodegeneration in Alzheimer's dementia.
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http://dx.doi.org/10.1093/brain/awy099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972585PMC
June 2018

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

Eur J Nucl Med Mol Imaging 2018 07 7;45(9):1618-1625. Epub 2018 Apr 7.

Integrated Research and Treatment Center (IFB) AdiposityDiseases, University Medical Center, Leipzig, Germany.

Purpose: 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.

Methods: We aimed to compare central NA transporter (NAT) availability in ten obese, otherwise healthy individuals with a body mass index (BMI) of 42.4 ± 3.7 kg/m (age 34 ± 9 years, four women) and ten matched non-obese, healthy controls (BMI 23.9 ± 2.5 kg/m, age 33 ± 10 years, four women) who underwent PET with the NAT-selective radiotracer (S,S)-[C]O-methylreboxetine (MRB) before and 6 months after dietary intervention.

Results: MRI-based individual volume-of-interest analyses revealed an increase in binding potential (BP) 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 BP 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 R = 0.80; p < 0.0001). No changes were observed in non-obese controls.

Conclusion: 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.
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http://dx.doi.org/10.1007/s00259-018-4002-7DOI Listing
July 2018

News and views on in-vivo imaging of neurotransmission using PET and MRI.

Q J Nucl Med Mol Imaging 2017 Dec 27;61(4):414-428. Epub 2017 Jul 27.

Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany.

Molecular neuroimaging with PET is an integrated tool in psychiatry research and drug-development for as long as this modality has been available, in particular for studying neurotransmission and endogenous neurotransmitter release. Pharmacologic, behavioral and other types of challenges are currently applied to induce changes in neurochemical levels that can be inferred through their effects on changes in receptor binding and related outcome measures. Based on the availability of tracers that are sensitive for measuring neurotransmitter release these experiments have focused on the brain's dopamine system, while recent developments have extended those studies to other targets such as the serotonin or choline system. With the introduction of hybrid, truly simultaneous PET/MRI systems, in-vivo imaging of the dynamics of neuroreceptor signal transmission in the brain using PET and functional MRI (fMRI) has become possible. fMRI has the ability to provide information about the effects of receptor function that are complementary to the PET measurement. Dynamic acquisition of both PET and fMRI signals enables not only an in-vivo real-time assessment of neurotransmitter or drug binding to receptors but also dynamic receptor adaptations and receptor-specific neurotransmission. While fMRI temporal resolution is comparatively fast in relation to PET, the timescale of observable biological processes is highly dependent on the kinetics of radiotracers and study design. Overall, the combination of the specificity of PET radiotracers to neuroreceptors, fMRI signal as a functional readout and integrated study design promises to expand our understanding of the location, propagation and connections of brain activity in health and disease.
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http://dx.doi.org/10.23736/S1824-4785.17.03019-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916779PMC
December 2017

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

Psychiatry Res Neuroimaging 2017 Sep 23;267:9-14. Epub 2017 Jun 23.

Integrated Treatment and Research Centre (IFB) AdiposityDiseases, Leipzig University Medical Centre, Liebigstraße 20, 04103 Leipzig, Germany; Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.

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-[C]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/m to 47.8kg/m. 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.
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http://dx.doi.org/10.1016/j.pscychresns.2017.06.013DOI Listing
September 2017

Feasibility of in vivo F-florbetaben PET/MR imaging of human carotid amyloid-β.

Eur J Nucl Med Mol Imaging 2017 Jul 21;44(7):1119-1128. Epub 2017 Mar 21.

Department of Nuclear Medicine, Leipzig University Medical Centre, Leipzig, Germany.

Purpose: Amyloid-beta (Aβ) peptides are involved in the inflammatory pathology of atherosclerosis. F-Florbetaben is a PET tracer for clinical imaging of cerebral Aβ plaques in Alzheimer's disease (AD). We sought to determine whether specific uptake of F-florbetaben in the carotid arteries can be identified using a fully integrated hybrid PET/MRI system and whether this uptake is associated with clinical cardiovascular disease (CVD) risk factors.

Methods: Carotid F-florbetaben uptake was quantified as the mean of the maximum target-to-background ratio (TBR) in 40 cognitively impaired subjects (age 68.2 ± 9.5 years) undergoing F-florbetaben PET/MRI to diagnose AD. Associations between carotid F-florbetaben uptake and several CVD risk factors were assessed by univariate analysis followed by a multivariate linear regression analysis. Furthermore, carotid F-florbetaben uptake was compared between patients with and without a positive cerebral Aβ PET scan.

Results: F-Florbetaben uptake was clearly visualized in the carotid arteries. Values of TBR corrected for the blood pool activity of the tracer showed specific F-florbetaben uptake in the carotid wall. Male gender was associated with carotid F-florbetaben uptake in the univariate analysis, and was found to be an independent predictor of F-florbetaben uptake in the multivariate regression analysis (standardized regression coefficient β = 0.407, p = 0.009). Carotid F-florbetaben TBR in patients with a positive cerebral Aβ scan did not differ from that in patients without cerebral Aβ deposits.

Conclusion: Specific F-florbetaben uptake in human carotid arteries was detected. Male gender was identified as an independent clinical risk factor. Therefore, F-florbetaben PET/MRI might provide new insights into the pathophysiological process in atherosclerosis.
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http://dx.doi.org/10.1007/s00259-017-3651-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434137PMC
July 2017

Test-retest measurements of dopamine D-type receptors using simultaneous PET/MRI imaging.

Eur J Nucl Med Mol Imaging 2017 Jun 14;44(6):1025-1032. Epub 2017 Feb 14.

Department of Nuclear Medicine, University of Leipzig, Liebigstrasse 18, D-04103, Leipzig, Germany.

Purpose: The role of dopamine D-type receptor (DR)-expressing neurons in the regulation of motivated behavior and reward prediction has not yet been fully established. As a prerequisite for future research assessing D-mediated neuronal network regulation using simultaneous PET/MRI and DR-selective [C]SCH23390, this study investigated the stability of central DR measurements between two independent PET/MRI sessions under baseline conditions.

Methods: Thirteen healthy volunteers (7 female, age 33 ± 13 yrs) underwent 90-min emission scans, each after 90-s bolus injection of 486 ± 16 MBq [C]SCH23390, on two separate days within 2-4 weeks using a PET/MRI system. Parametric images of DR distribution volume ratio (DVR) and binding potential (BP) were generated by a multi-linear reference tissue model with two parameters and the cerebellar cortex as receptor-free reference region. Volume-of-interest (VOI) analysis was performed with manual VOIs drawn on consecutive transverse MRI slices for brain regions with high and low DR density.

Results: The DVR varied from 2.5 ± 0.3 to 2.9 ± 0.5 in regions with high DR density (e.g. the head of the caudate) and from 1.2 ± 0.1 to 1.6 ± 0.2 in regions with low DR density (e.g. the prefrontal cortex). The absolute variability of the DVR ranged from 2.4% ± 1.3% to 5.1% ± 5.3%, while Bland-Altman analyses revealed very low differences in mean DVR (e.g. 0.013 ± 0.17 for the nucleus accumbens). Intraclass correlation (one-way, random) indicated very high agreement (0.93 in average) for both DVR and BP values. Accordingly, the absolute variability of BP ranged from 7.0% ± 4.7% to 12.5% ± 10.6%; however, there were regions with very low DR content, such as the occipital cortex, with higher mean variability.

Conclusion: The test-retest reliability of DR measurements in this study was very high. This was the case not only for DR-rich brain areas, but also for regions with low DR density. These results will provide a solid base for future joint PET/MRI data analyses in stimulation-dependent mapping of DR-containing neurons and their effects on projections in neuronal circuits that determine behavior.
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http://dx.doi.org/10.1007/s00259-017-3645-0DOI Listing
June 2017

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

Psychoneuroendocrinology 2017 04 16;78:39-47. Epub 2017 Jan 16.

Department of Neurology, University of Leipzig, Leipzig, Germany; Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig, Germany. Electronic address:

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/m) were compared to twenty-two NOC (f/m 12/10; age 35.3±8.5years; BMI 23.1±2.4kg/m), 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.
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http://dx.doi.org/10.1016/j.psyneuen.2017.01.004DOI Listing
April 2017

Suppressed Fat Appetite after Roux-en-Y Gastric Bypass Surgery Associates with Reduced Brain μ-opioid Receptor Availability in Diet-Induced Obese Male Rats.

Front Neurosci 2016 13;10:620. Epub 2017 Jan 13.

Department of Medicine, Integrated Research and Treatment Centre for Adiposity Diseases, University of Leipzig Leipzig, Germany.

Brain μ-opioid receptors (MORs) stimulate high-fat (HF) feeding and have been implicated in the distinct long term outcomes on body weight of bariatric surgery and dieting. Whether alterations in fat appetite specifically following these disparate weight loss interventions relate to changes in brain MOR signaling is unknown. To address this issue, diet-induced obese male rats underwent either Roux-en-Y gastric bypass (RYGB) or sham surgeries. Postoperatively, animals were placed on a two-choice diet consisting of low-fat (LF) and HF food and sham-operated rats were further split into fed (Sham-LF/HF) and body weight-matched (Sham-BWM) to RYGB groups. An additional set of sham-operated rats always only on a LF diet (Sham-LF) served as lean controls, making four experimental groups in total. Corresponding to a stage of weight loss maintenance for RYGB rats, two-bottle fat preference tests in conjunction with small-animal positron emission tomography (PET) imaging studies with the selective MOR radioligand [C]carfentanil were performed. Brains were subsequently collected and MOR protein levels in the hypothalamus, striatum, prefrontal cortex and orbitofrontal cortex were analyzed by Western Blot. We found that only the RYGB group presented with intervention-specific changes: having markedly suppressed intake and preference for high concentration fat emulsions, a widespread reduction in [C]carfentanil binding potential (reflecting MOR availability) in various brain regions, and a downregulation of striatal and prefrontal MOR protein levels compared to the remaining groups. These findings suggest that the suppressed fat appetite caused by RYGB surgery is due to reduced brain MOR signaling, which may contribute to sustained weight loss unlike the case for dieting.
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http://dx.doi.org/10.3389/fnins.2016.00620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233681PMC
January 2017

[I]FP-CIT ENC-DAT normal database: the impact of the reconstruction and quantification methods.

EJNMMI Phys 2017 Dec 28;4(1). Epub 2017 Jan 28.

Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.

Background: [I]FP-CIT is a well-established radiotracer for the diagnosis of dopaminergic degenerative disorders. The European Normal Control Database of DaTSCAN (ENC-DAT) of healthy controls has provided age and gender-specific reference values for the [I]FP-CIT specific binding ratio (SBR) under optimised protocols for image acquisition and processing. Simpler reconstruction methods, however, are in use in many hospitals, often without implementation of attenuation and scatter corrections. This study investigates the impact on the reference values of simpler approaches using two quantifications methods, BRASS and Southampton, and explores the performance of the striatal phantom calibration in their harmonisation.

Results: BRASS and Southampton databases comprising 123 ENC-DAT subjects, from gamma cameras with parallel collimators, were reconstructed using filtered back projection (FBP) and iterative reconstruction OSEM without corrections (IRNC) and compared against the recommended OSEM with corrections for attenuation and scatter and septal penetration (ACSC), before and after applying phantom calibration. Differences between databases were quantified using the percentage difference of their SBR in the dopamine transporter-rich striatum, with their significance determined by the paired t test with Bonferroni correction. Attenuation and scatter losses, measured from the percentage difference between IRNC and ACSC databases, were of the order of 47% for both BRASS and Southampton quantifications. Phantom corrections were able to recover most of these losses, but the SBRs remained significantly lower than the "true" values (p < 0.001). Calibration provided, in fact, "first order" camera-dependent corrections, but could not include "second order" subject-dependent effects, such as septal penetration from extra-cranial activity. As for the ACSC databases, phantom calibration was instrumental in compensating for partial volume losses in BRASS (~67%, p < 0.001), while for the Southampton method, inherently free from them, it brought no significant changes and solely corrected for residual inter-camera variability (-0.2%, p = 0.44).

Conclusions: The ENC-DAT reference values are significantly dependent on the reconstruction and quantification methods and phantom calibration, while reducing the major part of their differences, is unable to fully harmonize them. Clinical use of any normal database, therefore, requires consistency with the processing methodology. Caution must be exercised when comparing data from different centres, recognising that the SBR may represent an "index" rather than a "true" value.
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http://dx.doi.org/10.1186/s40658-017-0175-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5272851PMC
December 2017

The impact of reconstruction and scanner characterisation on the diagnostic capability of a normal database for [I]FP-CIT SPECT imaging.

EJNMMI Res 2017 Dec 24;7(1):10. Epub 2017 Jan 24.

Department of Nuclear Medicine, Municipal Hospital of Karlsruhe Inc., Karlsruhe, Germany.

Background: The use of a normal database for [I]FP-CIT SPECT imaging has been found to be helpful for cases which are difficult to interpret by visual assessment alone, and to improve reproducibility in scan interpretation. The aim of this study was to assess whether the use of different tomographic reconstructions affects the performance of a normal [I]FP-CIT SPECT database and also whether systems benefit from a system characterisation before a database is used. Seventy-seven [I]FP-CIT SPECT studies from two sites and with 3-year clinical follow-up were assessed quantitatively for scan normality using the ENC-DAT normal database obtained in well-documented healthy subjects. Patient and normal data were reconstructed with iterative reconstruction with correction for attenuation, scatter and septal penetration (ACSC), the same reconstruction without corrections (IRNC), and filtered back-projection (FBP) with data quantified using small volume-of-interest (VOI) (BRASS) and large VOI (Southampton) analysis methods. Test performance was assessed with and without system characterisation, using receiver operating characteristics (ROC) analysis for age-independent data and using sensitivity/specificity analysis with age-matched normal values. The clinical diagnosis at follow-up was used as the standard of truth.

Results: There were no significant differences in the age-independent quantitative assessment of scan normality across reconstructions, system characterisation and quantitative methods (ROC AUC 0.866-0.924). With BRASS quantification, there were no significant differences between the values of sensitivity (67.4-83.7%) or specificity (79.4-91.2%) across all reconstruction and calibration strategies. However, the Southampton method showed significant differences in sensitivity between ACSC (90.7%) vs IRNC (76.7%) and FBP (67.4%) reconstructions with calibration. Sensitivity using ACSC reconstruction with this method was also significantly better with calibration than without calibration (65.1%). Specificity using the Southampton method was unchanged across reconstruction and calibration choices (82.4-88.2%).

Conclusions: The ability of a normal [I]FP-CIT SPECT database to assess clinical scan normality is equivalent across all reconstruction, system characterisation, and quantification strategies using BRASS quantification. However, when using the Southampton quantification method, performance is sensitive to the reconstruction and calibration strategy used.
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http://dx.doi.org/10.1186/s13550-016-0253-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5265228PMC
December 2017

Dissociation Between Brown Adipose Tissue F-FDG Uptake and Thermogenesis in Uncoupling Protein 1-Deficient Mice.

J Nucl Med 2017 07 12;58(7):1100-1103. Epub 2017 Jan 12.

Integrated Research and Treatment Centre for Adiposity Diseases, Department of Medicine, University of Leipzig, Leipzig, Germany

F-FDG PET imaging is routinely used to investigate brown adipose tissue (BAT) thermogenesis, which requires mitochondrial uncoupling protein 1 (UCP1). It remains uncertain, however, whether BAT F-FDG uptake is a reliable surrogate measure of UCP1-mediated heat production. UCP1 knockout (KO) and wild-type (WT) mice housed at thermoneutrality were treated with the selective β3 adrenergic receptor agonist CL 316, 243 and underwent metabolic cage, infrared thermal imaging and F-FDG PET/MRI experiments. Primary brown adipocytes were additionally examined for their bioenergetics by extracellular flux analysis as well as their uptake of 2-deoxy-H-glucose. In response to CL 316, 243 treatments, oxygen consumption, and BAT thermogenesis were diminished in UCP1 KO mice, but BAT F-FDG uptake was fully retained. Isolated UCP1 KO brown adipocytes exhibited defective induction of uncoupled respiration whereas their glycolytic flux and 2-deoxy-H-glucose uptake rates were largely unaffected. Adrenergic stimulation can increase BAT F-FDG uptake independently of UCP1 thermogenic function.
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http://dx.doi.org/10.2967/jnumed.116.186460DOI Listing
July 2017

Central noradrenaline transporter availability in highly obese, non-depressed individuals.

Eur J Nucl Med Mol Imaging 2017 Jun 9;44(6):1056-1064. Epub 2017 Jan 9.

Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany.

Purpose: The brain noradrenaline (NA) system plays an important role in the central nervous control of energy balance and is thus implicated in the pathogenesis of obesity. The specific processes modulated by this neurotransmitter which lead to obesity and overeating are still a matter of debate.

Methods: We tested the hypothesis that in vivo NA transporter (NAT) availability is changed in obesity by using positron emission tomography (PET) and S,S-[C]O-methylreboxetine (MRB) in twenty subjects comprising ten highly obese (body mass index BMI > 35 kg/m), metabolically healthy, non-depressed individuals and ten non-obese (BMI < 30 kg/m) healthy controls.

Results: Overall, we found no significant differences in binding potential (BP) values between obese and non-obese individuals in the investigated brain regions, including the NAT-rich thalamus (0.40 ± 0.14 vs. 0.41 ± 0.18; p = 0.84) though additional discriminant analysis correctly identified individual group affiliation based on regional BP in all but one (control) case. Furthermore, inter-regional correlation analyses indicated different BP patterns between both groups but this did not survive testing for multiple comparions.

Conclusions: Our data do not find an overall involvement of NAT changes in human obesity. However, preliminary secondary findings of distinct regional and associative patterns warrant further investigation.
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http://dx.doi.org/10.1007/s00259-016-3590-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538358PMC
June 2017

Gastric Bypass Surgery Recruits a Gut PPAR-α-Striatal D1R Pathway to Reduce Fat Appetite in Obese Rats.

Cell Metab 2017 02 5;25(2):335-344. Epub 2017 Jan 5.

Integrated Research and Treatment Centre for Adiposity Diseases, Department of Medicine, Universität Leipzig, Liebigstraße 21, 04103 Leipzig, Germany. Electronic address:

Bariatric surgery remains the single most effective long-term treatment modality for morbid obesity, achieved mainly by lowering caloric intake through as yet ill-defined mechanisms. Here we show in rats that Roux-en-Y gastric bypass (RYGB)-like rerouting of ingested fat mobilizes lower small intestine production of the fat-satiety molecule oleoylethanolamide (OEA). This was associated with vagus nerve-driven increases in dorsal striatal dopamine release. We also demonstrate that RYGB upregulates striatal dopamine 1 receptor (D1R) expression specifically under high-fat diet feeding conditions. Mechanistically, interfering with local OEA, vagal, and dorsal striatal D1R signaling negated the beneficial effects of RYGB on fat intake and preferences. These findings delineate a molecular/systems pathway through which bariatric surgery improves feeding behavior and may aid in the development of novel weight loss strategies that similarly modify brain reward circuits compromised in obesity.
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http://dx.doi.org/10.1016/j.cmet.2016.12.006DOI Listing
February 2017