| 1. |
- Cervenka, Simon, et al.
(författare)
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PET Studies of D2-Receptor Binding in Striatal and Extrastriatal Brain Regions : Biochemical Support In Vivo for Separate Dopaminergic Systems in Humans
- 2010
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Ingår i: Synapse. - : Wiley. - 0887-4476 .- 1098-2396. ; 64:6, s. 478-485
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Tidskriftsartikel (refereegranskat)abstract
- Most molecular imaging studies of the dopamine (DA) system performed to date have focused on the striatum, a region receiving dense dopaminergic innervation. In clinical research on the DA D2-receptor, striatal binding has often been regarded as an index of global DA function, based on the underlying assumption of common regulatory mechanisms for receptor expression across brain regions. Recent data has challenged this view, suggesting differences in genetic regulation between striatal and extrastriatal brain regions. The relationship between binding levels in brain regions has, however, not been directly examined in the same sample. In this study, we searched for interregional correlations between DA D2-receptor availability as determined with Positron Emission Tomography in 16 control subjects. The radioligands [C-11]raclopride and [C-11]FLB 457 were used for measurements of D2-receptor binding in striatal and extrastriatal regions, respectively. No correlation was observed between D2-receptor availability in striatum and any of the extrastriatal regions, as assessed using both region of interest- and voxel-based analyses. Instead, the pattern of correlations was consistent with the model of separate dopaminergic systems as has been originally observed in rodents. These preliminary results encourage approaches searching for individual patterns of receptor binding across the whole brain volume in clinical studies on the dopamine system.
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| 2. |
- Chiotis, Konstantinos, et al.
(författare)
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Dual tracer tau PET imaging reveals different molecular targets for C-11-THK5351 and C-11-PBB3 in the Alzheimer brain
- 2018
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 45:9, s. 1605-1617
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Tidskriftsartikel (refereegranskat)abstract
- Several tau PET tracers have been developed, but it remains unclear whether they bind to the same molecular target on the heterogeneous tau pathology. In this study we evaluated the binding of two chemically different tau-specific PET tracers (C-11-THK5351 and C-11-PBB3) in a head-to-head, in vivo, multimodal design. Nine patients with a diagnosis of mild cognitive impairment or probable Alzheimer's disease and cerebrospinal fluid biomarker evidence supportive of the presence of Alzheimer's disease brain pathology were recruited after thorough clinical assessment. All patients underwent imaging with the tau-specific PET tracers C-11-THK5351 and C-11-PBB3 on the same day, as well as imaging with the amyloid-beta-specific tracer C-11-AZD2184, a T1-MRI sequence, and neuropsychological assessment. The load and regional distribution of binding differed between C-11-THK5351 and C-11-PBB3 with no statistically significant regional correlations observed between the tracers. The binding pattern of C-11-PBB3, but not that of C-11-THK5351, in the temporal lobe resembled that of C-11-AZD2184, with strong correlations detected between C-11-PBB3 and C-11-AZD2184 in the temporal and occipital lobes. Global cognition correlated more closely with C-11-THK5351 than with C-11-PBB3 binding. Similarly, cerebrospinal fluid tau measures and entorhinal cortex thickness were more closely correlated with C-11-THK5351 than with C-11-PBB3 binding. This research suggests different molecular targets for these tracers; while C-11-PBB3 appeared to preferentially bind to tau deposits with a close spatial relationship to amyloid-beta, the binding pattern of C-11-THK5351 fitted the expected distribution of tau pathology in Alzheimer's disease better and was more closely related to downstream disease markers.
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| 3. |
- Huttunen, Henri J., et al.
(författare)
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Intraputamenal Cerebral Dopamine Neurotrophic Factor in Parkinson's Disease: A Randomized, Double-Blind, Multicenter Phase 1 Trial
- 2023
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Ingår i: Movement Disorders. - : John Wiley & Sons. - 0885-3185 .- 1531-8257. ; 38:7, s. 1209-1222
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that protects dopamine neurons and improves motor function in animal models of Parkinson's disease (PD). Objective: The primary objectives of this study were to assess the safety and tolerability of both CDNF and the drug delivery system (DDS) in patients with PD of moderate severity. Methods: We assessed the safety and tolerability of monthly intraputamenal CDNF infusions in patients with PD using an investigational DDS, a bone-anchored transcutaneous port connected to four catheters. This phase 1 trial was divided into a placebo-controlled, double-blind, 6-month main study followed by an active-treatment 6-month extension. Eligible patients, aged 35 to 75 years, had moderate idiopathic PD for 5 to 15 years and Hoehn and Yahr score ≤ 3 (off state). Seventeen patients were randomized to placebo (n = 6), 0.4 mg CDNF (n = 6), or 1.2 mg CDNF (n = 5). The primary endpoints were safety and tolerability of CDNF and DDS and catheter implantation accuracy. Secondary endpoints were measures of PD symptoms, including Unified Parkinson's Disease Rating Scale, and DDS patency and port stability. Exploratory endpoints included motor symptom assessment (PKG, Global Kinetics Pty Ltd, Melbourne, Australia) and positron emission tomography using dopamine transporter radioligand [18F]FE-PE2I. Results: Drug-related adverse events were mild to moderate with no difference between placebo and treatment groups. No severe adverse events were associated with the drug, and device delivery accuracy met specification. The severe adverse events recorded were associated with the infusion procedure and did not reoccur after procedural modification. There were no significant changes between placebo and CDNF treatment groups in secondary endpoints between baseline and the end of the main and extension studies. Conclusions: Intraputamenally administered CDNF was safe and well tolerated, and possible signs of biological response to the drug were observed in individual patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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| 4. |
- Kanegawa, Naoki, et al.
(författare)
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In vivo evidence of a functional association between immune cells in blood and brain in healthy human subjects
- 2016
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Ingår i: Brain, behavior, and immunity. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0889-1591 .- 1090-2139. ; 54, s. 149-157
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Tidskriftsartikel (refereegranskat)abstract
- Microglia, the resident macrophages in the central nervous system, are thought to be maintained by a local self-renewal mechanism. Although preclinical and in vitro studies have suggested that the brain may contain immune cells also from peripheral origin, the functional association between immune cells in the periphery and brain at physiological conditions is poorly understood. We examined 32 healthy individuals using positron emission tomography (PET) and [C-11]PBR28, a radioligand for the 18-kDa translocator protein (TSPO) which is expressed both in brain microglia and blood immune cells. In 26 individuals, two measurements were performed with varying time intervals. In a subgroup of 19 individuals, of which 12 had repeat examinations, leukocyte numbers in blood was measured on each day of PET measurements. All individuals were genotyped for TSPO polymorphism and categorized as high, mixed, and low affinity binders. We assessed TSPO binding expressed as total distribution volume of [C-11]PBR28 in brain and in blood cells. TSPO binding in brain was strongly and positively correlated to binding in blood cells both at baseline and when analyzing change between two PET examinations. Furthermore, there was a significant correlation between change of leukocyte numbers and change in TSPO binding in brain, and a trend level correlation to change in TSPO binding in blood cells. These in vivo findings indicate an association between immunological cells in blood and brain via intact BBB, suggesting a functional interaction between these two compartments, such as interchange of peripherally derived cells or a common regulatory mechanism. Measurement of radioligand binding in blood cells may be a way to control for peripheral immune function in PET studies using TSPO as a marker of brain immune activation. (C) 2016 Elsevier Inc. All rights reserved.
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| 5. |
- Kerstens, Vera S, et al.
(författare)
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Reliability of dopamine transporter PET measurements with [18F]FE-PE2I in patients with Parkinson's disease.
- 2020
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Ingår i: EJNMMI Research. - : Springer Nature. - 2191-219X. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Reliable quantification of dopamine transporter (DAT), a biomarker for Parkinson's disease (PD), is essential for diagnostic purposes as well as for evaluation of potential disease-modifying treatment. Due to degeneration of dopaminergic neurons and thus lower expected radioligand binding to DAT, higher measurement variability in PD patients might be expected than earlier reproducibility results in healthy controls. Therefore, we aimed to examine the test-retest properties of [18F]FE-PE2I-PET in PD patients.METHODS: Nine patients with PD (Hoehn and Yahr stage < 3) were included (men/women 6/3; mean age 65.2 ± 6.8 years). Each patient underwent two [18F]FE-PE2I-PET measurements within 7-28 days. The outcome measure was non-displaceable binding potential generated using wavelet-aided parametric imaging with cerebellum as reference region. We assessed test-retest performance using estimates of reliability and repeatability. Regions for primary analysis were caudate, putamen, ventral striatum, and substantia nigra. Exploratory analysis was performed for functional subdivisions of the striatum. We also compared the more vs. less affected side.RESULTS: [18F]FE-PE2I showed absolute variability estimates of 5.3-7.6% in striatal regions and 11% in substantia nigra and ICCs of 0.74-0.97 (median 0.91). The absolute variability for functional striatal subdivisions was 6.0-9.6% and ICCs of 0.76-0.91 (median 0.91). The less affected substantia nigra exhibited greater consistency than the more affected side. According to power calculations based on the current sample size, DAT changes of 5-11% in the striatum and 28% in the substantia nigra can be detected with a power of 0.8 (p < 0.0125).CONCLUSION: DAT-PET measurements with [18F]FE-PE2I in PD patients showed good repeatability and reliability. The slightly lower reliability in the substantia nigra in patients may be explained by lower DAT density and smaller anatomical size. Power calculations suggest that [18F]FE-PE2I PET is a suitable marker for longitudinal DAT decline in PD.TRIAL REGISTRATION: EudraCT 2017-003327-29.
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| 6. |
- Lizana, Helena, et al.
(författare)
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Whole-Body Biodistribution and Dosimetry of the Dopamine Transporter Radioligand 18F-FE-PE2I in Human Subjects
- 2018
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 59:8, s. 1275-1280
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Tidskriftsartikel (refereegranskat)abstract
- F-18-(E)-N-(3-iodoprop-2-enyl)-2 beta-carbofluoroethoxy-3 beta-(4'-methylphenyl) nortropane (F-18-FE-PE2I) was recently developed and has shown adequate affinity and high selectivity for the dopamine transporter (DAT). Previous studies have shown promising results for F-18-FE-PE2I as a suitable radioligand for DAT imaging. In this study, we investigated the whole-body biodistribution and dosimetry of F-18-FE-PE2I in healthy volunteers to support its utility as a suitable PET imaging agent for the DAT. Methods: Five healthy volunteers were given a mean activity of 2.5 MBq/kg, and 3 PET scans, head to thigh, were performed immediately after injection followed by 4 whole-body PET/CT scans between 0.5 and 6 h after injection. Blood samples were drawn in connection with the whole-body scans, and all urine was collected until 6 h after injection. Volumes of interest were delineated around 17 organs on all images, and the areas under the time-activity curves were calculated to obtain the total number of decays in the organs. The absorbed doses to organs and the effective dose were calculated using the software IDAC. Results: The highest activity concentration was observed in the liver (0.9%-1.2% injected activity/100 g) up to 30 min after injection. At later time points, the highest concentration was seen in the gallbladder (1.1%-0.1% injected activity/100 g). The activity excreted with urine ranged between 23% and 34%, with a mean of 28%. The urinary bladder received the highest absorbed dose (119 mu Gy/MBq), followed by the liver (46 mu Gy/MBq). The effective dose was 23 mu Sv/MBq (range, 19-28 mu Sv/MBq), resulting in an effective dose of 4.6 mSv for an administered activity of 200 MBq. Conclusion: The effective dose is within the same order of magnitude as other commonly used PET imaging agents as well as DAT agents. The reasonable effective dose, together with the previously reported favorable characteristics for DAT imaging and quantification, indicates that F-18-FE-PE2I is a suitable radioligand for DAT imaging.
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| 7. |
- Paul-Visse, Gesine, et al.
(författare)
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Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients
- 2015
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 125:3, s. 1339-1346
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson's disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 mu g rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD.
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| 8. |
- Plaven-Sigray, Pontus, et al.
(författare)
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Accuracy and reliability of [C-11]PBR28 specific binding estimated without the use of a reference region
- 2019
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Ingår i: NeuroImage. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1053-8119 .- 1095-9572. ; 188, s. 102-110
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Tidskriftsartikel (refereegranskat)abstract
- [C-11]PBR28 is a positron emission tomography radioligand used to examine the expression of the 18 kDa translocator protein (TSPO). TSPO is located in glial cells and can function as a marker for immune activation. Since TSPO is expressed throughout the brain, no true reference region exists. For this reason, an arterial input function is required for accurate quantification of [C-11]PBR28 binding and the most common outcome measure is the total distribution volume (V-T). Notably, V-T reflects both specific binding and non-displaceable binding. Therefore, estimates of specific binding, such as binding potential (e.g. BPND) and specific distribution volume (V-S) should theoretically be more sensitive to underlying differences in TSPO expression. It is unknown, however, if unbiased and accurate estimates of these outcome measures are obtainable for [C-11]PBR28. The Simultaneous Estimation (SIME) method uses time-activity-curves from multiple brain regions with the aim to obtain a brain-wide estimate of the non-displaceable distribution volume (V-ND), which can subsequently be used to improve the estimation of BPND and V-S. In this study we evaluated the accuracy of SIME-derived V-ND, and the reliability of resulting estimates of specific binding for [C-11]PBR28, using a combination of simulation experiments and in vivo studies in healthy humans. The simulation experiments, based on data from 54 unique [C-11]PBR28 examinations, showed that V-ND values estimated using SIME were both precise and accurate. Data from a pharmacological competition challenge (n = 5) showed that SIME provided V-ND values that were on average 19% lower than those obtained using the Lassen plot, but similar to values obtained using the Likelihood-Estimation of Occupancy technique. Test-retest data (n = 11) showed that SIME-derived V-S values exhibited good reliability and precision, while larger variability was observed in SIME-derived BPND values. The results support the use of SIME for quantifying specific binding of [C-11]PBR28, and suggest that V-S can be used in complement to the conventional outcome measure V-T. Additional studies in patient cohorts are warranted.
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| 9. |
- Schain, Martin, et al.
(författare)
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Arterial input function derived from pairwise correlations between PET-image voxels
- 2013
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : Nature Publishing Group. - 0271-678X .- 1559-7016. ; 33:7, s. 1058-1065
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Tidskriftsartikel (refereegranskat)abstract
- A metabolite corrected arterial input function is a prerequisite for quantification of positron emission tomography (PET) data by compartmental analysis. This quantitative approach is also necessary for radioligands without suitable reference regions in brain. The measurement is laborious and requires cannulation of a peripheral artery, a procedure that can be associated with patient discomfort and potential adverse events. A non invasive procedure for obtaining the arterial input function is thus preferable. In this study, we present a novel method to obtain image-derived input functions (IDIFs). The method is based on calculation of the Pearson correlation coefficient between the time-activity curves of voxel pairs in the PET image to localize voxels displaying blood-like behavior. The method was evaluated using data obtained in human studies with the radioligands [11C]flumazenil and [11C]AZ10419369, and its performance was compared with three previously published methods. The distribution volumes (VT) obtained using IDIFs were compared with those obtained using traditional arterial measurements. Overall, the agreement in VT was good (~3% difference) for input functions obtained using the pairwise correlation approach. This approach performed similarly or even better than the other methods, and could be considered in applied clinical studies. Applications to other radioligands are needed for further verification.
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| 10. |
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