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Published in: BMC Neurology 1/2023

Open Access 01-12-2023 | Magnetic Resonance Imaging | Research article

Time course of neuroinflammation after human stroke – a pilot study using co-registered PET and MRI

Authors: Lucio D’Anna, Graham Searle, Kirsten Harvey, Paul M. Matthews, Roland Veltkamp

Published in: BMC Neurology | Issue 1/2023

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Abstract

Background

Microglial activation contributes to both inflammatory damage and repair in experimental ischemic stroke. However, because of the logistical challenges, there have been few clinical imaging studies directly describing inflammatory activation and its resolution after stroke. The purpose of our pilot study was to describe the spatio-temporal profile of brain inflammation after stroke using 18kD translocator protein (TSPO) positron emission tomography (PET) with magnetic resonance (MR) co-registration in the subacute and chronic stage after stroke.

Methods

Three patients underwent magnetic resonance imaging (MRI) and PET scans with TSPO ligand [11C]PBR28 15 ± 3 and 90 ± 7 days after an ischaemic stroke. Regions of interest (ROI) were defined on MRI images and applied to the dynamic PET data to derive regional time-activity curves. Regional uptake was quantified as standardised uptake values (SUV) over 60 to 90 min post-injection. ROI analysis was applied to identify binding in the infarct, and in frontal, temporal, parietal, and occipital lobes and cerebellum excluding the infarcted area.

Results

The mean age of participants was 56 ± 20.4 years and mean infarct volume was 17.9 ± 18.1 ml. [11C]PBR28 showed increased tracer signal in the infarcted area compared to non-infarcted areas of the brain in the subacute phase of stroke (Patient 1 SUV 1.81; Patient 2 SUV 1.15; Patient 3 SUV 1.64). [11C]PBR28 uptake returned to the level of non-infarcted areas at 90 days Patient 1 SUV 0.99; Patient 3 SUV 0.80). No additional upregulation was detected elsewhere at either time point.

Conclusions

The neuroinflammatory reaction after ischaemic stroke is limited in time and circumscribed in space suggesting that post-ischaemic inflammation is tightly controlled but regulatory mechanisms.
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Literature
2.
go back to reference Liesz A, Zhou W, Mracskó É, et al. Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke. Brain. 2011;134:704–20.CrossRefPubMed Liesz A, Zhou W, Mracskó É, et al. Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke. Brain. 2011;134:704–20.CrossRefPubMed
3.
go back to reference Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999;22:391–7.CrossRefPubMed Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999;22:391–7.CrossRefPubMed
8.
go back to reference Alam MdM, Lee J, Lee S-Y. Recent progress in the development of TSPO PET ligands for Neuroinflammation Imaging in Neurological Diseases. Nucl Med Mol Imaging. 2017;51:283–96.CrossRefPubMedPubMedCentral Alam MdM, Lee J, Lee S-Y. Recent progress in the development of TSPO PET ligands for Neuroinflammation Imaging in Neurological Diseases. Nucl Med Mol Imaging. 2017;51:283–96.CrossRefPubMedPubMedCentral
9.
go back to reference Chen W-H, Yeh H-L, Tsao C-W, et al. Plasma translocator protein levels and outcomes of acute ischemic stroke: a pilot study. Dis Markers. 2018;2018:1–7.CrossRef Chen W-H, Yeh H-L, Tsao C-W, et al. Plasma translocator protein levels and outcomes of acute ischemic stroke: a pilot study. Dis Markers. 2018;2018:1–7.CrossRef
10.
go back to reference Schweitzer PJ, Fallon BA, Mann JJ, et al. PET tracers for the peripheral benzodiazepine receptor and uses thereof. Drug Discov Today. 2010;15:933–42.CrossRefPubMed Schweitzer PJ, Fallon BA, Mann JJ, et al. PET tracers for the peripheral benzodiazepine receptor and uses thereof. Drug Discov Today. 2010;15:933–42.CrossRefPubMed
11.
go back to reference Trapani A, Palazzo C, de Candia M, et al. Targeting of the translocator protein 18 kDa (TSPO): a valuable approach for nuclear and optical imaging of activated microglia. Bioconjug Chem. 2013;24:1415–28.CrossRefPubMed Trapani A, Palazzo C, de Candia M, et al. Targeting of the translocator protein 18 kDa (TSPO): a valuable approach for nuclear and optical imaging of activated microglia. Bioconjug Chem. 2013;24:1415–28.CrossRefPubMed
12.
go back to reference Luus C, Hanani R, Reynolds A, et al. The development of PET radioligands for imaging the translocator protein (18 kDa): What have we learned?. J Labelled Comp Radiopharm. 2010;53(7):501–10. Luus C, Hanani R, Reynolds A, et al. The development of PET radioligands for imaging the translocator protein (18 kDa): What have we learned?. J Labelled Comp Radiopharm. 2010;53(7):501–10.
13.
go back to reference Camsonne R, Crouzel C, Comar D, et al. Synthesis of N-(11C) methyl, N-(methyl-1 propyl), (chloro-2 phenyl)-1 isoquinoleine carboxamide-3 (PK 11195): a new ligand for peripheral benzodiazepine receptors. J Labelled Comp Radiopharm. 1984;21:985–91.CrossRef Camsonne R, Crouzel C, Comar D, et al. Synthesis of N-(11C) methyl, N-(methyl-1 propyl), (chloro-2 phenyl)-1 isoquinoleine carboxamide-3 (PK 11195): a new ligand for peripheral benzodiazepine receptors. J Labelled Comp Radiopharm. 1984;21:985–91.CrossRef
14.
go back to reference Gerhard A, Neumaier B, Elitok E, et al. In vivo imaging of activated microglia using [11 C]PK11195 and positron emission tomography in patients after ischemic stroke. NeuroReport. 2000;11:2957–60.CrossRefPubMed Gerhard A, Neumaier B, Elitok E, et al. In vivo imaging of activated microglia using [11 C]PK11195 and positron emission tomography in patients after ischemic stroke. NeuroReport. 2000;11:2957–60.CrossRefPubMed
15.
go back to reference Gerhard A, Schwarz J, Myers R, et al. Evolution of microglial activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study. Neuroimage. 2005;24:591–5.CrossRefPubMed Gerhard A, Schwarz J, Myers R, et al. Evolution of microglial activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study. Neuroimage. 2005;24:591–5.CrossRefPubMed
16.
go back to reference Pappata S, Levasseur M, Gunn RN, et al. Thalamic microglial activation in ischemic stroke detected in vivo by PET and [11C]PK11195. Neurology. 2000;55:1052–4.CrossRefPubMed Pappata S, Levasseur M, Gunn RN, et al. Thalamic microglial activation in ischemic stroke detected in vivo by PET and [11C]PK11195. Neurology. 2000;55:1052–4.CrossRefPubMed
17.
go back to reference Price CJS, Wang D, Menon DK, et al. Intrinsic Activated Microglia Map to the Peri-infarct Zone in the Subacute Phase of Ischemic Stroke. Stroke. 2006;37:1749–53.CrossRefPubMed Price CJS, Wang D, Menon DK, et al. Intrinsic Activated Microglia Map to the Peri-infarct Zone in the Subacute Phase of Ischemic Stroke. Stroke. 2006;37:1749–53.CrossRefPubMed
18.
go back to reference Radlinska BA, Ghinani SA, Lyon P, et al. Multimodal microglia imaging of fiber tracts in acute subcortical stroke. Ann Neurol. 2009;66:825–32.CrossRefPubMed Radlinska BA, Ghinani SA, Lyon P, et al. Multimodal microglia imaging of fiber tracts in acute subcortical stroke. Ann Neurol. 2009;66:825–32.CrossRefPubMed
19.
go back to reference Zinnhardt B, Wiesmann M, Honold L, et al. In vivo imaging biomarkers of neuroinflammation in the development and assessment of stroke therapies - towards clinical translation. Theranostics. 2018;8:2603–20.CrossRefPubMedPubMedCentral Zinnhardt B, Wiesmann M, Honold L, et al. In vivo imaging biomarkers of neuroinflammation in the development and assessment of stroke therapies - towards clinical translation. Theranostics. 2018;8:2603–20.CrossRefPubMedPubMedCentral
20.
21.
go back to reference Grabner G, Janke AL, Budge MM, et al. Symmetric Atlasing and Model Based Segmentation: An Application to the Hippocampus in Older Adults. 2006. p. 58–66. Grabner G, Janke AL, Budge MM, et al. Symmetric Atlasing and Model Based Segmentation: An Application to the Hippocampus in Older Adults. 2006. p. 58–66.
22.
go back to reference Gulyás B, Tóth M, Schain M, et al. Evolution of microglial activation in ischaemic core and peri-infarct regions after stroke: A PET study with the TSPO molecular imaging biomarker [C]vinpocetine. J Neurol Sci. 2012;320:110–7.CrossRefPubMed Gulyás B, Tóth M, Schain M, et al. Evolution of microglial activation in ischaemic core and peri-infarct regions after stroke: A PET study with the TSPO molecular imaging biomarker [C]vinpocetine. J Neurol Sci. 2012;320:110–7.CrossRefPubMed
23.
go back to reference Imaizumi M, Kim H-J, Zoghbi SS, et al. PET imaging with [11C]PBR28 can localize and quantify upregulated peripheral benzodiazepine receptors associated with cerebral ischemia in rat. Neurosci Lett. 2007;411:200–5.CrossRefPubMed Imaizumi M, Kim H-J, Zoghbi SS, et al. PET imaging with [11C]PBR28 can localize and quantify upregulated peripheral benzodiazepine receptors associated with cerebral ischemia in rat. Neurosci Lett. 2007;411:200–5.CrossRefPubMed
25.
go back to reference Owen DR, Narayan N, Wells L, et al. Pro-inflammatory activation of primary microglia and macrophages increases 18 kDa translocator protein expression in rodents but not humans. J Cereb Blood Flow Metab. 2017;37:2679–90.CrossRefPubMedPubMedCentral Owen DR, Narayan N, Wells L, et al. Pro-inflammatory activation of primary microglia and macrophages increases 18 kDa translocator protein expression in rodents but not humans. J Cereb Blood Flow Metab. 2017;37:2679–90.CrossRefPubMedPubMedCentral
26.
go back to reference Nutma E, Stephenson JA, Gorter RP, et al. A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis. Brain. 2019;142:3440–55.CrossRefPubMedPubMedCentral Nutma E, Stephenson JA, Gorter RP, et al. A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis. Brain. 2019;142:3440–55.CrossRefPubMedPubMedCentral
27.
go back to reference Thiel A, Radlinska BA, Paquette C, et al. The temporal dynamics of poststroke neuroinflammation: a longitudinal diffusion tensor imaging-guided PET study with 11 C-PK11195 in acute subcortical stroke. J Nucl Med. 2010;51:1404–12.CrossRefPubMed Thiel A, Radlinska BA, Paquette C, et al. The temporal dynamics of poststroke neuroinflammation: a longitudinal diffusion tensor imaging-guided PET study with 11 C-PK11195 in acute subcortical stroke. J Nucl Med. 2010;51:1404–12.CrossRefPubMed
28.
29.
go back to reference Sun M, Deng B, Zhao X, et al. Isoflurane preconditioning provides neuroprotection against stroke by regulating the expression of the TLR4 signalling pathway to alleviate microglial activation. Sci Rep. 2015;5:11445.CrossRefPubMedPubMedCentral Sun M, Deng B, Zhao X, et al. Isoflurane preconditioning provides neuroprotection against stroke by regulating the expression of the TLR4 signalling pathway to alleviate microglial activation. Sci Rep. 2015;5:11445.CrossRefPubMedPubMedCentral
31.
go back to reference Parada E, Egea J, Buendia I, et al. The Microglial α7-Acetylcholine Nicotinic Receptor Is a Key Element in Promoting Neuroprotection by Inducing Heme Oxygenase-1 via Nuclear Factor Erythroid-2-Related Factor 2. Antioxid Redox Signal. 2013;19:1135–48.CrossRefPubMedPubMedCentral Parada E, Egea J, Buendia I, et al. The Microglial α7-Acetylcholine Nicotinic Receptor Is a Key Element in Promoting Neuroprotection by Inducing Heme Oxygenase-1 via Nuclear Factor Erythroid-2-Related Factor 2. Antioxid Redox Signal. 2013;19:1135–48.CrossRefPubMedPubMedCentral
32.
go back to reference Ponomarev ED, Veremeyko T, Weiner HL. MicroRNAs are universal regulators of differentiation, activation, and polarization of microglia and macrophages in normal and diseased CNS. Glia. 2013;61:91–103.CrossRefPubMed Ponomarev ED, Veremeyko T, Weiner HL. MicroRNAs are universal regulators of differentiation, activation, and polarization of microglia and macrophages in normal and diseased CNS. Glia. 2013;61:91–103.CrossRefPubMed
34.
go back to reference Liesz A, Suri-Payer E, Veltkamp C, et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med. 2009;15:192–9.CrossRefPubMed Liesz A, Suri-Payer E, Veltkamp C, et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med. 2009;15:192–9.CrossRefPubMed
35.
go back to reference Harberts E, Datta D, Chen S, et al. Translocator protein 18 kDa (TSPO) expression in multiple sclerosis patients. J Neuroimmune Pharmacol. 2013;8:51–7.CrossRefPubMed Harberts E, Datta D, Chen S, et al. Translocator protein 18 kDa (TSPO) expression in multiple sclerosis patients. J Neuroimmune Pharmacol. 2013;8:51–7.CrossRefPubMed
36.
go back to reference Albrecht DS, Forsberg A, Sandström A, et al. Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation. Brain Behav Immun. 2019;75:72–83.CrossRefPubMed Albrecht DS, Forsberg A, Sandström A, et al. Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation. Brain Behav Immun. 2019;75:72–83.CrossRefPubMed
37.
go back to reference Albrecht DS, Normandin MD, Shcherbinin S, et al. Pseudoreference Regions for Glial Imaging with 11 C-PBR28: Investigation in 2 Clinical Cohorts. J Nucl Med. 2018;59:107–14.CrossRefPubMedPubMedCentral Albrecht DS, Normandin MD, Shcherbinin S, et al. Pseudoreference Regions for Glial Imaging with 11 C-PBR28: Investigation in 2 Clinical Cohorts. J Nucl Med. 2018;59:107–14.CrossRefPubMedPubMedCentral
Metadata
Title
Time course of neuroinflammation after human stroke – a pilot study using co-registered PET and MRI
Authors
Lucio D’Anna
Graham Searle
Kirsten Harvey
Paul M. Matthews
Roland Veltkamp
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Neurology / Issue 1/2023
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/s12883-023-03178-7

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