| 1. |
- Aarnio, Mikko, et al.
(författare)
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Evaluation of PET tracers [11C]D-deprenyl, [11C]L-dideuteriumdeprenyl and [18F]FDG for Visualization of Acute Inflammation in a Rat Model of Pain - Preliminary Findings.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Purpose: Positron emission tomography with the radioligand [11C]D-deprenyl has shown an increased signal at the location of pain in patients with ankle sprains, rheumatoid arthritis and chronic whiplash injury, but the mechanism of this tracer uptake and its exact binding site in inflammation or tissue injury is still unclear. The aim of this study was to further evaluate [11C]D-deprenyl´s usefulness as a marker of acute inflammation.Methods: An animal PET/CT study was performed three days after the induction of a rat model of inflammatory or surgical pain. Fourteen adult male Sprague-Dawley rats and three tracers [11C]D-deprenyl, [11C]L-dideuterumdeprenyl and [18F]fluorodeoxyglucose were used. Results: No [11C]D-deprenyl accumulation was seen in a rat model of musculoskeletal pain. In the rat model of inflammatory pain all three ligands were shown to visualize the inflamed ankle joint with much lower uptake in the control ankle joint. The uptake was largest with [11C]D-deprenyl and [11C]L- dideuteriumdeprenyl, where approximately 1 % of the injected dose could be found in the affected ankle joint during the first minutes, whereas the uptake of [18F]FDG was approximately 0.5 % of the injected dose. However, the ratio of uptake of the injected ankle joint versus the control ankle joint was much higher for [18F]FDG (around 10 fold increase) than for the two deprenyl enantiomers (2 – 3 fold increase). The uptake pattern of [11C]D-deprenyl and [11C]L-dideuteriumdeprenyl did not show signs of specific binding or irreversible trapping.Conclusions: Contrary to our expectations, of the three tracers only [18F]FDG may be used as markers of peripheral inflammation in a rat model of inflammatory pain. However, as a high site-specificity is required, [11C]D-deprenyl and [11C]L-dideyteriumdeprenyl deserve further exploration regarding sensitivity, specificity and uptake mechanisms in human pain syndromes.
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| 2. |
- Aarnio, Mikko, et al.
(författare)
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Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [(11)C]-D-deprenyl PET/CT.
- 2017
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Ingår i: Scandinavian Journal of Pain. - : Walter de Gruyter. - 1877-8860 .- 1877-8879. ; 17:1, s. 418-424
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Positron emission tomography (PET) with the radioligand [(11)C]-D-deprenyl has shown increased signal at location of pain in patients with rheumatoid arthritis and chronic whiplash injury. The binding site of [(11)C]-D-deprenyl in peripheral tissues is suggested to be mitochondrial monoamine oxidase in cells engaged in post-traumatic inflammation and tissue repair processes. The association between [(11)C]-D-deprenyl uptake and the transition from acute to chronic pain remain unknown. Further imaging studies of musculoskeletal pain at the molecular level would benefit from establishing a clinical model in a common and well-defined injury in otherwise healthy and drug-naïve subjects. The aim of this study was to investigate if [(11)C]-D-deprenyl uptake would be acutely elevated in unilateral ankle sprain and if tracer uptake would be reduced as a function of healing, and correlated with pain localizations and pain experience.METHODS: Eight otherwise healthy patients with unilateral ankle sprain were recruited at the emergency department. All underwent [(11)C]-D-deprenyl PET/CT in the acute phase, at one month and 6-14 months after injury.RESULTS: Acute [(11)C]-D-deprenyl uptake at the injury site was a factor of 10.7 (range 2.9-37.3) higher than the intact ankle. During healing, [(11)C]-D-deprenyl uptake decreased, but did not normalize until after 11 months. Patients experiencing persistent pain had prolonged [(11)C]-D-deprenyl uptake in painful locations.CONCLUSIONS AND IMPLICATIONS: The data provide further support that [(11)C]-D-deprenyl PET can visualize, quantify and follow processes in peripheral tissue that may relate to soft tissue injuries, inflammation and associated nociceptive signaling. Such an objective correlate would represent a progress in pain research, as well as in clinical pain diagnostics and management.
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| 3. |
- Aarnio, Mikko
(författare)
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Visualization of Peripheral Pain Generating Processes and Inflammation in Musculoskeletal Tissue using [11C]-D-deprenyl PET
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- An objective visualization and quantification of pain-generating processes in the periphery would alter pain diagnosis and represent an important paradigm shift in pain research. Positron emission tomography (PET) radioligand [11C]-D-deprenyl has shown an elevated uptake in painful inflammatory arthritis and whiplash-associated disorder. However, D-Deprenyl’s molecular binding target and uptake mechanism in inflammation and musculoskeletal injuries are still unknown. The present thesis aimed to gain insight into the mechanisms of D-deprenyl binding and uptake and to verify whether pain-associated sites and inflammation in acute musculoskeletal injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET-computed tomography (PET/CT).To identify the D-deprenyl binding target, a high-throughput analysis and competitive radioligand binding studies were performed. D-deprenyl inhibited monoamine oxidase A (MAO-A) activity by 55%, MAO-B activity by 99% and angiotensin-converting enzyme (ACE) by 70%, which identified these enzymes as higher-affinity targets. Furthermore, radioligand receptor binding assays pointed favorably towards the concept of MAO-B as the primary target. To investigate the biochemical characteristics of the binding site, we used radioligand binding assays to assess differences in the binding profile in inflamed human synovial membranes exhibiting varying levels of inflammation. D-deprenyl bound to a single, saturable population of membrane-bound protein in synovial membrane homogenates and the level of inflammation correlated with an increase in D-deprenyl binding affinity.To verify whether D-deprenyl can visualize pain-generating processes, patients with musculoskeletal injuries were investigated and followed-up with [11C]-D-deprenyl PET/CT. In the study of eight patients with ankle sprain, the molecular aspects of inflammation and tissue injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET/CT. The pain coexisted with increased [11C]-D-deprenyl uptake. In the study of 16 whiplash patients, an altered [11C]-D-deprenyl uptake in the cervical bone structures and facet joints was associated with subjective pain levels and self-rated disability.To further evaluate D-Deprenyl’s usefulness as a marker of inflammation, three PET tracers were compared in an animal PET/CT study. Preliminary findings showed that [11C]-D-deprenyl had an almost identical uptake pattern when compared with [11C]-L-deprenyl. The two deprenyl enantiomers showed no signs of specific binding or trapping and therefore may not be useful to study further in models of inflammatory pain, surgical pain, or both.This thesis demonstrates that D-deprenyl visualizes painful inflammation in musculoskeletal injuries and that the probable underlying mechanism of [11C]-D-deprenyl uptake is binding to MAO.
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| 4. |
- Aarnio, Mikko, et al.
(författare)
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Whiplash injuries associated with experienced pain and disability can be visualized with [11C]-D-deprenyl PET/CT
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The understanding of etiological mechanisms of whiplash associated disorder is still inadequate. Objective visualization and quantification of peripheral musculoskeletal injury and possible painful inflammation in whiplash associated disorder would facilitate diagnosis, strengthen patients’ subjective pain reports and aid clinical decisions eventually leading to better treatments. In the current study, we further evaluated the potential to use [11C]D-deprenyl PET/CT to visualize inflammation after whiplash injury. Sixteen patients with whiplash injury grade II were recruited at the emergency department and underwent [11C]D-deprenyl PET/CT in the acute phase and at 6 months after injury. Subjective pain levels, self rated neck disability and active cervical range of motion were recorded at each imaging session. Results showed that the molecular aspects of inflammation and possible tissue injuries after acute whiplash injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET/CT. An altered [11C]D-deprenyl uptake in the cervical bone structures and facet joints was associated with subjective pain levels and self rated disability during both imaging occasions. These findings may contribute to a better understanding of affected peripheral structures in whiplash injury and strengthens the idea that PET/CT detectable organic lesions in peripheral tissue may be relevant for the development of persistent pain and disability in whiplash injury.Perspective: This article presents a novel way of objectively visualizing possible structural damage and inflammation that cause pain and disability in whiplash injury. This PET method can bring an advance in pain research and eventually would facilitate the clinical management of patients in pain.
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| 5. |
- Aarnio, Mikko, et al.
(författare)
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Whiplash injuries associated with experienced pain and disability can be visualized with [11C]-D-deprenyl positron emission tomography and computed tomography
- 2022
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Ingår i: Pain. - : Lippincott Williams & Wilkins. - 0304-3959 .- 1872-6623. ; 163:3, s. 489-495
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge of etiological mechanisms underlying whiplash-associated disorders is incomplete. Localisation and quantification of peripheral musculoskeletal injury and inflammation in whiplash-associated disorders would facilitate diagnosis, strengthen patients' subjective pain reports, and aid clinical decisions, all of which could lead to improved treatment. In this longitudinal observational study, we evaluated combined [11C]-D-deprenyl positron emission tomography and computed tomography after acute whiplash injury and at 6-month follow-up. Sixteen adult patients (mean age 33 years) with whiplash injury grade II were recruited at the emergency department. [11C]-D-deprenyl positron emission tomography and computed tomography, subjective pain levels, self-rated neck disability, and active cervical range of motion were recorded within 7 days after injury and again at 6-month follow-up. Imaging results showed possible tissue injuries after acute whiplash with an altered [11C]-D-deprenyl uptake in the cervical bone structures and facet joints, associated with subjective pain locale and levels, as well as self-rated disability. At follow-up, some patients had recovered and some showed persistent symptoms and reductions in [11C]-D-deprenyl uptake correlated to reductions in pain levels. These findings help identify affected peripheral structures in whiplash injury and strengthen the idea that positron emission tomography and computed tomography detectable organic lesions in peripheral tissue are relevant for the development of persistent pain and disability in whiplash injury.
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| 6. |
- Lesniak, Anna, et al.
(författare)
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Characterization of the binding site for d-deprenyl in human inflamed synovial membrane.
- 2018
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Ingår i: Life Sciences. - : Elsevier BV. - 0024-3205 .- 1879-0631. ; 194, s. 26-33
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Tidskriftsartikel (refereegranskat)abstract
- Aims: D-Deprenyl when used as a positron emission tomography tracer visualizes peripheral inflammation. The major aim of the current study was to identify and investigate the properties of the binding target for D-deprenyl in synovial membrane explants from arthritic patients.Main methods: Thirty patients diagnosed with arthritis or osteoarthritis were enrolled into the study. Homologous and competitive radioligand binding assays utilizing [H-3]D-deprenyl were performed to investigate the biochemical characteristics of the binding site and assess differences in the binding profile in synovial membranes exhibiting varying levels of inflammation.Key findings: The [H-3]D-deprenyl binding assay confirmed the existence of a single, saturable population of membrane-bound protein binding sites in synovial membrane homogenates. The macroscopically determined level of inflammation correlated with an increase in [H-3]D-deprenyl binding affinity, without significant alterations in binding site density. Selective monoamine oxidase B inhibitor, selegiline competed for the same site as [H-3]D-deprenyl, but failed to differentiate the samples with regard to their inflammation grade. A monoamine oxidase A inhibitor, pirlindole mesylate showed only weak displacement of [H-3]D-deprenyl binding. No significant alterations in monoamine oxidase B expression was detected, thus it was not confirmed whether it could serve as a marker for ongoing inflammation.Significance: Our study was the first to show the biochemical characteristics of the [H-3]D-deprenyl binding site in inflamed human synovium. We confirmed that d-deprenyl could differentiate between patients with varying severity of synovitis in the knee joint by binding to a protein target distinct from monoamine oxidase B.
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| 7. |
- Lesniak, Anna, et al.
(författare)
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High-throughput screening and radioligand binding studies reveal monoamine oxidase-B as the primary binding target for D-deprenyl
- 2016
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Ingår i: Life Sciences. - : Elsevier BV. - 0024-3205 .- 1879-0631. ; 152, s. 231-237
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Tidskriftsartikel (refereegranskat)abstract
- Aims: D-deprenyl is a useful positron emission tomography tracer for visualization of inflammatory processes. Studies with [C-11]-D-deprenyl showed robust uptake in peripheral painful sites of patients with rheumatoid arthritis or chronic whiplash injury. The mechanism of preferential D-deprenyl uptake is not yet known, but the existence of a specific binding site was proposed. Thus, in the present study, we sought to identify the binding site for D-deprenyl and verify the hypothesis about the possibility of monoamine oxidase enzymes as major targets for this molecule. Main methods: A high-throughput analysis of D-deprenyl activity towards 165 G-protein coupled receptors and 84 enzyme targets was performed. Additionally, binding studies were used to verify the competition of [H-3]D-deprenyl with ligands specific for targets identified in the high-throughput screen. Key findings: Our high-throughput investigation identified monoamine oxidase-B, monoamine oxidase-A and angiotensin converting enzyme as potential targets for D-deprenyl. Further competitive [3H] D-deprenyl binding studies with specific inhibitors identified monoamine oxidase-B as the major binding site. No evident high-affinity hits were identified among G-protein coupled receptors. Significance: Our study was the first to utilize a high-throughput screening approach to identify putative D-deprenyl targets. It verified 249 candidate proteins and confirmed the role of monoamine oxidase - B in D-deprenyl binding. Our results add knowledge about the possible mechanism of D-deprenyl binding, which might aid in explaining the increased uptake of this compound in peripheral inflammation. Monoamine oxidase-B will be further investigated in future studies utilizing human inflamed synovium.
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| 8. |
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| 9. |
- Peterson, Magnus, et al.
(författare)
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PET-Scan Shows Peripherally Increased Neurokinin 1 Receptor Availability in Chronic Tennis Elbow : Visualizing Neurogenic Inflammation?
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:10
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Tidskriftsartikel (refereegranskat)abstract
- In response to pain, neurokinin 1 (NK1) receptor availability is altered in the central nervous system. The NK1 receptor and its primary agonist, substance P, also play a crucial role in peripheral tissue in response to pain, as part of neurogenic inflammation. However, little is known about alterations in NK1 receptor availability in peripheral tissue in chronic pain conditions and very few studies have been performed on human beings. Ten subjects with chronic tennis elbow were therefore examined by positron emission tomography (PET) with the NK1 specific radioligand [11C]GR205171 before and after treatment with graded exercise. The radioligand signal intensity was higher in the affected arm as compared with the unaffected arm, measured as differences between the arms in volume of voxels and signal intensity of this volume above a reference threshold set as 2.5 SD above mean signal intensity of the unaffected arm before treatment. In the eight subjects examined after treatment, pain ratings decreased in all subjects but signal intensity decreased in five and increased in three. In conclusion, NK1 receptors may be activated, or up-regulated in the peripheral, painful tissue of a chronic pain condition. This up-regulation does, however, have moderate correlation to pain ratings. The increased NK1 receptor availability is interpreted as part of ongoing neurogenic inflammation and may have correlation to the pathogenesis of chronic tennis elbow.
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