Showing papers by "Swen Hesse published in 2021"

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

Abstract: 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.

Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [18F] fluspidine and [18F] fallypride PET study.

Abstract: 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 [18F] fluspidine and [18F] 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. Using [18F] 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 [18F] 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. 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%). 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.

(+)-[ 18 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

Abstract: We present the first in-human brain PET imaging data of the new α4β2 nicotinic acetylcholine receptor (nAChR)–targeting radioligand (+)-[18F]Flubatine. Aims were to develop a kinetic modeling-based approach to quantify (+)-[18F]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 (+)-[18F]Flubatine binding; and whether (+)-[18F]Flubatine binding and cognitive test data respective β-amyloid radiotracer accumulation were correlated. We examined 11 HCs and 9 mild AD patients. All subjects underwent neuropsychological testing and [11C]PiB PET/MRI examination. (+)-[18F]Flubatine PET data were evaluated using full kinetic modeling and regional as well as voxel-based analyses. 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). (+)-[18F]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 (+)-[18F]Flubatine binding of approximately 15% but also standard deviation of 0.4–70%. Cognitive test data and (+)-[18F]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, (+)-[18F]Flubatine binding and [11C]PiB standardized uptake value ratios were negatively correlated in several regions; whereas in HCs, a positive correlation between cortical (+)-[18F]Flubatine binding and [11C]PiB accumulation in the white matter was found. No adverse event related to (+)-[18F]Flubatine occurred. (+)-[18F]Flubatine is a safe and stable PET ligand. Full kinetic modeling can be realized by 1TCM without metabolite correction. (+)-[18F]Flubatine binding affinity was high enough to detect group differences. Of interest, correlation between white matter β-amyloid PET uptake and (+)-[18F]Flubatine binding indicated an association between white matter integrity and availability of α4β2 nAChRs. Overall, (+)-[18F]Flubatine showed favorable characteristics and has therefore the potential to serve as α4β2 nAChR–targeting PET ligand in further clinical trials.

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

Abstract: 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.

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

Abstract: Background: Positron emission tomography (PET) has provided evidence that adult humans retain metabolically active brown adipose tissue (BAT) depots. Thyroid hormones (TH) stimulate BAT thermogenes...

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.

Abstract: 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.

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

Abstract: 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). SERT availability was assessed using SERT-selective [11C]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 (TTBR25–30) 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. [11C]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 TTBR25–30 values after correction for lung attenuation than HC. Attenuation corrected TTBR25–30 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). By applying [11C]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 [11C]DASB uptake compared to COPD patients without PH indicating an implication of pulmonary SERT in the development of PH in COPD patients.

Central Noradrenergic Neurotransmission and Weight Loss 6 Months After Gastric Bypass Surgery in Patients with Severe Obesity.

Abstract: Roux-en-Y gastric bypass (RYGB) surgery is currently the most efficient treatment to achieve long-term weight loss in individuals with severe obesity. This is largely attributed to marked reductions in food intake mediated in part by changes in gut-brain communication. Here, we investigated for the first time whether weight loss after RYGB is associated with alterations in central noradrenaline (NA) neurotransmission. We longitudinally studied 10 individuals with severe obesity (8 females; age 43.9 ± 13.1 years; body mass index (BMI) 46.5 ± 4.8 kg/m2) using (S,S)-[11C]O-methylreboxetine and positron emission tomography to estimate NA transporter (NAT) availability before and 6 months after surgery. NAT distribution volume ratios (DVR) were calculated by volume-of-interest analysis and the two-parameter multilinear reference tissue model (reference region: occipital cortex). The participants responded to RYGB surgery with a reduction in BMI of 12.0 ± 3.5 kg/m2 (p < 0.001) from baseline. This was paralleled by a significant reduction in DVR in the dorsolateral prefrontal cortex (pre-surgery 1.12 ± 0.04 vs. post-surgery 1.07 ± 0.04; p = 0.019) and a general tendency towards reduced DVR throughout the brain. Furthermore, we found a strong positive correlation between pre-surgery DVR in hypothalamus and the change in BMI (r = 0.78; p = 0.01). Reductions in BMI after RYGB surgery are associated with NAT availability in brain regions responsible for decision-making and homeostasis. However, these results need further validation in larger cohorts, to assess whether brain NAT availability could prognosticate the outcome of RYGB on BMI.