Publications by authors named "Michael Rullmann"

37 Publications

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

CLINICAL UTILITY OF β-AMYLOID PET IMAGING IN PEOPLE LIVING WITH HIV WITH COGNITIVE SYMPTOMS.

J Acquir Immune Defic Syndr 2021 Feb 11. Epub 2021 Feb 11.

Centre for Global Health Research, Brighton and Sussex Med School, UK Department of Nuclear Medicine, Brighton and Sussex University Hospitals, UK Department of Nuclear Medicine, University of Leipzig, Germany Department of Infectious Diseases, University of Gothenburg, Sweden Department of Psychiatry and Neurochemistry, University of Gothenburg, Sweden Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Sweden Department of Neuropsychology, Brighton and Sussex University Hospitals, UK Faculty of Health, University of Plymouth, UK.

Background: Imaging with β-amyloid (Aβ) PET has the potential to aid the diagnosis of the cause of cognitive impairment affecting people living with HIV (PLWH) when neurodegenerative disorders are considered. We evaluated the clinical utility of [18F]Florbetaben (FBB) in PLWH with cognitive symptoms.

Methods: Imaging with FBB PET was performed in 20 patients with cognitive concerns about dementia. Neuropsychological testing, plasma neurofilament light protein, plasma Aβ40, Aβ42 and CSF Aβ42, tau, and HIV RNA were obtained. FBB PET images were assessed visually by three readers blinded to the clinical diagnosis, and quantitatively by obtaining a composite cortical to cerebellar cortex standardized uptake value ratio (SUVR). FBB SUVR from 10 age-matched healthy controls were compared to SUVR of PLWH.

Results: Most participants were male (90%) of white ethnicity (90%) with a median age (IQR) of 59 (43-79) years. Median CD4 count was 682 (74-1056). All patients were on cART with plasma and CSF HIV RNA< 40 copies/mL. Fourteen patients had objective cognitive impairment including two who met clinical criteria for a diagnosis of dementia. No significant differences in composite SUVRs between PLWH and controls [mean (SD): 1.18 (0.03) vs 1.16 (0.09); p=0.37] were observed. Four patients were FBB+ with the highest SUVR in the posterior cingulate, superior temporal and frontal superior lobe. Amyloid PET results contributed to a change in diagnosis and treatment for 10 patients.

Conclusion: [18F]Florbetaben PET has potential as an adjunctive tool in the diagnosis of PLWH with cognitive impairment, increasing diagnostic certainty and optimizing management.
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http://dx.doi.org/10.1097/QAI.0000000000002648DOI Listing
February 2021

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

Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy.

JAMA Neurol 2020 11;77(11):1408-1419

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

Importance: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis.

Objective: To investigate the potential of the novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed PSP.

Design, Setting, And Participants: In this cross-sectional study, participants underwent dynamic 18F-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019.

Main Outcomes And Measures: Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, 18F-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex.

Results: Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP-non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [50.0%] with Parkinson disease and multiple system atrophy, 7 were men; mean [SD] age, 61 [8] years; of 10 [50.0%] with Alzheimer disease, 5 were men; mean [SD] age, 69 [10] years). Postmortem autoradiography showed blockable 18F-PI-2620 binding in patients with PSP and no binding in healthy controls. The in vivo findings from the first large-scale observational study in PSP with 18F-PI-2620 indicated significant elevation of tracer binding in PSP target regions with strongest differences in PSP vs control groups in the globus pallidus internus (mean [SD] distribution volume ratios: PSP-RS, 1.21 [0.10]; PSP-non-RS, 1.12 [0.11]; healthy controls, 1.00 [0.08]; Parkinson disease/multiple system atrophy, 1.03 [0.05]; Alzheimer disease, 1.08 [0.06]). Sensitivity and specificity for detection of PSP-RS vs any control group were 85% and 77%, respectively, when using classification by at least 1 positive target region.

Conclusions And Relevance: This multicenter evaluation indicates a value of 18F-PI-2620 to differentiate suspected patients with PSP, potentially facilitating more reliable diagnosis of PSP.
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http://dx.doi.org/10.1001/jamaneurol.2020.2526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341407PMC
November 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 2020 Oct 3. 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
October 2020

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 2020 Sep 29. 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
September 2020

(+)-[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

Quantitative susceptibility mapping in β-Amyloid PET-stratified patients with dementia and healthy controls - A hybrid PET/MRI study.

Eur J Radiol 2020 Oct 29;131:109243. Epub 2020 Aug 29.

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

Purpose: Post-mortem and in-vivo MRI data suggest an accumulation of iron in the brain of Alzheimer's disease (AD) patients. The majority of studies in clinically diagnosed AD patients found an increase of iron-sensitive MRI signals in the putamen. As the clinical diagnosis shows only a moderate sensitivity, Aβ-PET was used to further stratify patients with the clinical diagnosis of AD. Aim of this exploratory study was to examine whether Aβ-positive (AD) and Aβ-negative (non-AD) patients differ in their regional magnetic susceptibility compared to healthy controls (HCs) and whether regional susceptibility values correlate with mini mental state examination (MMSE) scores or global Aβ-load.

Methods: We retrospectively analyzed [C]PiB PET/MRI data of 11 HCs, 16 AD and 10 non-AD patients. We used quantitative susceptibility mapping (QSM) as iron-sensitive MRI signal measured at the 3 T PET/MR scanner. Global cerebral Aβ-load was determined by composite [C]PiB SUV ratios.

Results: Compared to HCs, AD patients showed higher QSM values in putamen (0.049 ± 0.033 vs. 0.002 ± 0.031; p = 0.006), while non-AD patients showed lower QSM values in caudate nucleus (0.003 ± 0.027 vs. 0.051 ± 0.039; p = 0.006). There was a trend towards a significant correlation between putaminal QSM and MMSE values (ρ=-0.340, p = 0.053). In AD patients, global Aβ-load and putaminal QSM values were significantly correlated (ρ=-0.574, p = 0.020).

Conclusions: These data indicate that AD and non-AD patients may show different cerebral iron pathologies which might be detectable by QSM MRI, and might be linked to neurodegeneration. Overall, the data encourage further investigations in well-defined patient cohorts to clarify the value of QSM/magnetic susceptibility in the course of neurodegenerative diseases and its potential as diagnostic biomarker.
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http://dx.doi.org/10.1016/j.ejrad.2020.109243DOI Listing
October 2020

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

Reshaping the Amyloid Buildup Curve in Alzheimer Disease? Partial-Volume Effect Correction of Longitudinal Amyloid PET Data.

J Nucl Med 2020 12 1;61(12):1820-1824. Epub 2020 May 1.

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

It was hypothesized that the brain β-amyloid buildup curve plateaus at an early symptomatic stage of Alzheimer disease (AD). Atrophy-related partial-volume effects (PVEs) degrade signal in hot-spot imaging techniques such as amyloid PET. The current study, a longitudinal analysis of amyloid-sensitive PET data, investigated the effect on the shape of the β-amyloid curve in AD when PVE correction (PVEC) is applied. We analyzed baseline and 2-y follow-up data for 216 symptomatic individuals on the AD continuum (positive amyloid status) enrolled in the Alzheimer's Disease Neuroimaging Initiative (17 with AD dementia and 199 with mild cognitive impairment), including F-florbetapir PET, MRI, and Mini Mental State Examination scores. For PVEC, the modified Müller-Gärtner method was performed. Compared with non-PVE-corrected data, PVE-corrected data yielded significantly higher changes in regional and composite SUV ratio (SUVR) over time ( = 0.0002 for composite SUVRs). Longitudinal SUVR changes in relation to Mini Mental State Examination decreases showed a significantly higher slope for the regression line in the PVE-corrected than in the non-PVE-corrected PET data ( = 7.1, = 0.008). These PVEC results indicate that the β-amyloid buildup curve does not plateau at an early symptomatic disease stage. A further evaluation of the impact of PVEC on the in vivo characterization of time-dependent AD pathology, including the reliable assessment and comparison of other amyloid tracers, is warranted.
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http://dx.doi.org/10.2967/jnumed.119.238477DOI Listing
December 2020

Early-phase [F]PI-2620 tau-PET imaging as a surrogate marker of neuronal injury.

Eur J Nucl Med Mol Imaging 2020 11 21;47(12):2911-2922. Epub 2020 Apr 21.

Department of Nuclear Medicine, University Hospital of Munich LMU Munich, Marchioninstraße 15, 81377, Munich, Germany.

Purpose: Second-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several β-amyloid and first-generation tau-PET radiotracers, it has been shown that early-phase images can be used as a surrogate of neuronal injury. Therefore, we investigated the performance of early acquisitions of the novel tau-PET radiotracer [F]PI-2620 as a potential substitute for [F]fluorodeoxyglucose ([F]FDG).

Methods: Twenty-six subjects were referred with suspected tauopathies or overlapping parkinsonian syndromes (Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, multi-system atrophy, Parkinson's disease, multi-system atrophy, Parkinson's disease, frontotemporal dementia) and received a dynamic [F]PI-2620 tau-PET (0-60 min p.i.) and static [F]FDG-PET (30-50 min p.i.). Regional standardized uptake value ratios of early-phase images (single frame SUVr) and the blood flow estimate (R) of [F]PI-2620-PET were correlated with corresponding quantification of [F]FDG-PET (global mean/cerebellar normalization). Reduced tracer uptake in cortical target regions was also interpreted visually using 3-dimensional stereotactic surface projections by three more and three less experienced readers. Spearman rank correlation coefficients were calculated between early-phase [F]PI-2620 tau-PET and [F]FDG-PET images for all cortical regions and frequencies of disagreement between images were compared for both more and less experienced readers.

Results: Highest agreement with [F]FDG-PET quantification was reached for [F]PI-2620-PET acquisition from 0.5 to 2.5 min p.i. for global mean (lowest R = 0.69) and cerebellar scaling (lowest R = 0.63). Correlation coefficients (summed 0.5-2.5 min SUVr & R) displayed strong agreement in all cortical target regions for global mean (R 0.76, R = 0.77) and cerebellar normalization (R 0.68, R = 0.68). Visual interpretation revealed high regional correlations between early-phase tau-PET and [F]FDG-PET. There were no relevant differences between more and less experienced readers.

Conclusion: Early-phase imaging of [F]PI-2620 can serve as a surrogate biomarker for neuronal injury. Dynamic imaging or a dual time-point protocol for tau-PET imaging could supersede additional [F]FDG-PET imaging by indexing both the distribution of tau and the extent of neuronal injury.
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http://dx.doi.org/10.1007/s00259-020-04788-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567714PMC
November 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

Adiposity Related Brain Plasticity Induced by Bariatric Surgery.

Front Hum Neurosci 2019 27;13:290. Epub 2019 Aug 27.

IFB Adiposity Diseases, Leipzig University Medical Centre, Leipzig, Germany.

Previous magnetic resonance imaging (MRI) studies revealed structural-functional brain reorganization 12 months after gastric-bypass surgery, encompassing cortical and subcortical regions of all brain lobes as well as the cerebellum. Changes in the mean of cluster-wise gray/white matter density (GMD/WMD) were correlated with the individual loss of body mass index (BMI), rendering the BMI a potential marker of widespread surgery-induced brain plasticity. Here, we investigated voxel-by-voxel associations between surgery-induced changes in adiposity, metabolism and inflammation and markers of functional and structural neural plasticity. We re-visited the data of patients who underwent functional and structural MRI, 6 months ( = 27) and 12 months after surgery ( = 22), and computed voxel-wise regression analyses. Only the surgery-induced weight loss was significantly associated with brain plasticity, and this only for GMD changes. After 6 months, weight loss overlapped with altered GMD in the hypothalamus, the brain's homeostatic control site, the lateral orbitofrontal cortex, assumed to host reward and gustatory processes, as well as abdominal representations in somatosensory cortex. After 12 months, weight loss scaled with GMD changes in right cerebellar lobule VII, involved in language-related/cognitive processes, and, by trend, with the striatum, assumed to underpin (food) reward. These findings suggest time-dependent and weight-loss related gray matter plasticity in brain regions involved in the control of eating, sensory processing and cognitive functioning.
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http://dx.doi.org/10.3389/fnhum.2019.00290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718731PMC
August 2019

Homeostatic, reward and executive brain functions after gastric bypass surgery.

Appetite 2020 03 28;146:104419. Epub 2019 Aug 28.

Department of Neurology, BG University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Bochum, 44789, North Rhine-Westphalia, Germany; Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, 04103, Saxony, Germany; IFB Adiposity Diseases, University Hospital Leipzig, Leipzig, 04103, Saxony, Germany.

Obesity in part arises from the regular overconsumption of palatable, caloric-dense foods. This maladaptive eating behavior has been described as impulsive, compulsive and even addictive, and has its origins in molecular and cellular aberrations in the gut and brain. Mounting evidence from human and rodent studies suggests that Roux-en-Y gastric bypass (RYGB) surgery persistantly promotes lower caloric intake by modifying gut-brain communication. In this Review, we discuss how the changes in gut hormones, nutrient sensing andmicrobiota brought about by RYGB together favourably regulate homeostatic, reward and executive brain functions. We further speculate on how this lastingly establishes a negative whole-body energy balance in the face of plenty. Future studies will more completely characterize the role of modified gut-brain communication in the healthier eating behavior following RYGB, possibly facilitating the development of more effective, non-surgical weight loss treatments.
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http://dx.doi.org/10.1016/j.appet.2019.104419DOI Listing
March 2020

Roux-en-Y gastric bypass surgery progressively alters radiologic measures of hypothalamic inflammation in obese patients.

JCI Insight 2019 10 3;4(19). Epub 2019 Oct 3.

IFB AdiposityDiseases and.

There is increased interest in whether bariatric surgeries such as Roux-en-Y gastric bypass (RYGB) achieve their profound weight-lowering effects in morbidly obese individuals through the brain. Hypothalamic inflammation is a well-recognized etiologic factor in obesity pathogenesis and so represents a potential target of RYGB, but clinical evidence in support of this is limited. We therefore assessed hypothalamic T2-weighted signal intensities (T2W SI) and fractional anisotropy (FA) values, 2 validated radiologic measures of brain inflammation, in relation to BMI and fat mass, as well as circulating inflammatory (C-reactive protein; CrP) and metabolic markers in a cohort of 27 RYGB patients at baseline and 6 and 12 months after surgery. We found that RYGB progressively increased hypothalamic T2W SI values, while it progressively decreased hypothalamic FA values. Regression analyses further revealed that this could be most strongly linked to plasma CrP levels, which independently predicted hypothalamic FA values when adjusting for age, sex, fat mass, and diabetes diagnosis. These findings suggest that RYGB has a major time-dependent impact on hypothalamic inflammation status, possibly by attenuating peripheral inflammation. They also suggest that hypothalamic FA values may provide a more specific radiologic measure of hypothalamic inflammation than more commonly used T2W SI values.
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http://dx.doi.org/10.1172/jci.insight.131329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795400PMC
October 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

Fat perception in the human frontal operculum, insular and somatosensory cortex.

Sci Rep 2018 08 7;8(1):11825. Epub 2018 Aug 7.

Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Stephanstr. 1a, 04103, Leipzig, Germany.

Here, we combined magnetic resonance imaging with lesion-symptom mapping in patients with chronic brain lesions to investigate brain representations of sugar and fat perception. Patients and healthy controls rated chocolate milkshakes that only differed in sugar or fat content. As compared to controls, patients showed an impaired fat, but not sugar perception. Impairments in fat perception overlapped with the anterior insula and frontal operculum, together assumed to underpin gustatory processing. We also identified the mid-dorsal insula as well as the primary and secondary somatosensory cortex - regions previously assumed to integrate oral-sensory inputs. These findings suggest that fat perception involves a specific set of brain regions that were previously reported to underpin gustatory processing and oral-sensory integration processes.
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http://dx.doi.org/10.1038/s41598-018-30366-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081453PMC
August 2018

Quantitative Susceptibility Mapping of Amyloid-β Aggregates in Alzheimer's Disease with 7T MR.

J Alzheimers Dis 2018 ;64(2):393-404

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

Background: PET imaging is an established technique to detect cerebral amyloid-β (Aβ) plaques in vivo. Some preclinical and postmortem data report an accumulation of redox-active iron near Aβ plaques. Quantitative susceptibility mapping (QSM) at high-field MRI enables iron deposits to be depicted with high spatial resolution.

Objective: Aim of this study was to examine whether iron and Aβ plaque accumulation is related and thus, whether 7T MRI might be an additive diagnostic tool to Aβ PET imaging.

Methods: Postmortem human Alzheimer's disease (AD) and healthy control (HC) frontal gray matter (GM) was imaged with 7T MRI which resulted in T1 maps and QSM. Aβ plaque load was determined by histopathology. In vivo, 10 Aβ PET-positive AD patients (74.1±6.0a) and 10 Aβ PET-negative HCs (67.1±4.4a) underwent 7T MR examination and QSM maps were analyzed. Severity of cognitive deficits was determined by MMSE.

Results: Postmortem, the susceptibility of Aβ plaque-containing GM were higher than those of Aβ plaque-free GM (0.011±0.002 versus - 0.008±0.003 ppm, p < 0.001). In vivo, only the bilateral globus pallidus showed significantly higher susceptibility in AD patients compared to HCs (right: 0.277±0.018 versus - 0.009±0.009 ppm; left: 0.293±0.014 versus - 0.007±0.012 ppm, p < 0.0001). The pallidal QSM values were negatively correlated with those of the MMSE (r = - 0.69, p = 0.001).

Conclusion: The postmortem study revealed significant susceptibility differences between the Aβ plaque-containing and Aβ plaque-free GM, whereas in vivo only the QSM values of the globus pallidus differed significantly between AD and HC group. The pallidal QSM values correlated with the severity of cognitive deficits. These findings encourage efforts to optimize the 7T-QSM methodology.
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http://dx.doi.org/10.3233/JAD-180118DOI Listing
July 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

Gastric-bypass surgery induced widespread neural plasticity of the obese human brain.

Neuroimage 2018 05 28;172:853-863. Epub 2017 Oct 28.

IFB AdiposityDiseases, Leipzig University Medical Centre, Liebigstr. 20, 04103 Leipzig, Germany; Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Stephanstr. 1a, 04103 Leipzig, Germany; Collaborative Research Centre 1052 Obesity Mechanisms, University of Leipzig, Leipzig, Germany; Department of Neurology, BG University Hospital Bergmannsheil, Ruhr-University Bochum, Bürkle-de-la-Camp Place 1, 44789 Bochum, Germany; Collaborative Research Centre 874 Integration and Representation of Sensory Processes, Ruhr-University Bochum, 44801 Bochum, Germany. Electronic address:

Bariatric surgery has become the gold standard for the treatment of morbid obesity (body mass index (BMI) ≥ 40 kg/m), but only few studies investigated its plastic influences on the obese brain. In this longitudinal study, we combined structural and functional magnetic resonance brain imaging (MRI) in 27 patients (BMI 47.8 ± 5.5 kg/m) undergoing gastric-bypass surgery and 14 non-obese matched controls (BMI 24.7 ± 3.4 kg/m). Over the first year after surgery, patients presented widespread changes in white matter density (WMD) as well as gray matter density (GMD) in the cerebral cortex of all lobes, subcortical structures, the brainstem as well as the cerebellum, but no changes in white matter water diffusivity throughout the brain. Voxel-by-voxel regression analyses revealed that all GMD and WMD changes were well associated with elevated regional homogeneity of spontaneous neural activity (ReHo) in blood-oxygenation level-dependent signals. Spatial-temporal integration of structural and functional MRI suggests that gastric-bypass surgery induces widespread plastic changes in brain structure that concurrently homogenizes the functional profile of the cortex, subcortical regions as well as white matter structures.
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http://dx.doi.org/10.1016/j.neuroimage.2017.10.062DOI Listing
May 2018

Non-invasive Prefrontal/Frontal Brain Stimulation Is Not Effective in Modulating Food Reappraisal Abilities or Calorie Consumption in Obese Females.

Front Neurosci 2017 20;11:334. Epub 2017 Jun 20.

Department of Neurology, Max Planck Institute for Human Cognitive and Brain SciencesLeipzig, Germany.

Previous studies suggest that non-invasive transcranial direct current stimulation (tDCS) applied to the prefrontal cortex modulates food choices and calorie intake in obese humans. In the present fully randomized, placebo-controlled, within-subject and double-blinded study, we applied single sessions of anodal, cathodal, and sham tDCS to the left dorsolateral prefrontal cortex (DLPFC) and contralateral frontal operculum in 25 hungry obese women and investigated possible influences on food reappraisal abilities as well as calorie intake. We hypothesized that tDCS, (i) improves the ability to regulate the desire for visually presented foods and, (ii) reduces their consumption. We could not confirm an effect of anodal or cathodal tDCS, neither on the ability to modulate the desire for visually presented foods, nor on calorie consumption. The present findings do not support the notion of prefrontal/frontal tDCS as a promising treatment option for obesity.
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http://dx.doi.org/10.3389/fnins.2017.00334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476843PMC
June 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

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

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