PET imaging of TSPO in a rat model of local neuroinflammation induced by intracerebral injection of lipopolysaccharide

Ory, Dieter; Planas, Anna M.; Dresselaers, Tom; Gsell, Willy; Postnov, Andrey; Celen, Sofie; Casteels, Cindy; Debyser, Z.; Laere, Koen Van; Verbruggen, Alfons; Bormans, Guy

doi:10.1016/j.nucmedbio.2015.06.010

Cited by 50 publications

(53 citation statements)

References 18 publications

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“…In a rat model of neuroinflammation induced by intracerebral injection of lipopolysaccharides, the area of microglial activation corresponded TSPO in vitro binding whereas the area of astroglial activation was considerably smaller than, albeit still located within, the area of TSPO binding (18). In the same animal model, double immunostaining revealed prominent TSPO expression by reactive microglia and low levels of TSPO expression by reactive astrocytes (33). Activated microglia and astroglia were both found to express TSPO in a rat model of stroke; however, the PET-derived time profile of in vivo TSPO expression corresponded to microglial and not astroglial activation (34).…”

Section: Discussionmentioning

confidence: 85%

Serial Quantitative TSPO-Targeted PET Reveals Peak Microglial Activation up to 2 Weeks After an Epileptogenic Brain Insult

et al. 2016

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Experimental and clinical evidence suggests that neuroinflammation, triggered by epileptogenic insults, contributes to seizure development. We used translocator protein-targeted molecular imaging to obtain further insights into the role of microglial activation during epileptogenesis. Methods: As epileptogenic insult, a status epilepticus (SE) was induced in rats by lithium pilocarpine. Rats were subjected to 11 C-PK11195 PET scans before SE; at 4 h after SE; at 1, 2, 5, 7, 14, and 22 d after SE; and at 14-16 wk after SE. For data evaluation, brain regions were outlined by coregistration with a standard rat brain atlas, and percentage injected dose/cm 3 and binding potential (simplified reference tissue model with cerebellar gray matter as a reference region) were calculated. For autoradiography and immunohistochemical evaluation, additional rats were decapitated without prior SE or 2, 5, or 14 d after SE. Results: After SE, increases in 11 C-PK11195 uptake and binding potential were evident in epileptogenesis-associated brain regions, such as the hippocampus, thalamus, or piriform cortex, but not in the cerebellum beginning at 2-5 d and persisting at least 3 wk after SE. Maximal regional signal was observed at 1-2 wk after SE. Autoradiography confirmed the spatiotemporal profile. Immunohistochemical evaluation revealed microglial and astroglial activation as well as neuronal cell loss in epileptogenesis-associated brain regions at all investigated time points. The time course of microglial activation was consistent with that demonstrated by tracer techniques. Conclusion: Translocator protein-targeted PET is a reliable tool for identifying brain inflammation during epileptogenesis. Neuroinflammation mainly affects brain regions commonly associated with seizure generation and spread. Definition of the time profile of neuroinflammation may facilitate the development of inflammation-targeted, antiepileptogenic therapy.

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Section: Discussionmentioning

confidence: 85%

Serial Quantitative TSPO-Targeted PET Reveals Peak Microglial Activation up to 2 Weeks After an Epileptogenic Brain Insult

et al. 2016

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“…44,45 Animal studies have shown that the TSPO signal in brain is mainly derived from microglia, 20,46 with a significant contribution from astrocytes during certain conditions. 19,47 Apart from these resident immune cell populations, peripherally derived myeloid cells in the form of infiltrating or perivascular macrophages may also contribute to the signal.…”

Section: Discussionmentioning

confidence: 99%

“…Arterial blood was sampled using an automated system for the first 5 minutes. Manual samples were drawn at 2, 4,6,8,10,15,20,25,30,45, and 60 minutes. All patients were genotyped for the genetic polymorphism of rs6971, which affects binding of TSPO radioligands, including [ 11 C]PBR28, both in vitro and in vivo.…”

Section: Pet Imagingmentioning

confidence: 99%

“…This protein can be viewed as a marker for CNS immune activation, because changes in TSPO levels have been shown to reflect changes in glial cell activity. 19,20 TSPO expression is typically elevated in several acute and chronic CNS disorders involving the immune system [21][22][23][24][25] as well as in animal models of acute inflammation 26 or stroke. 19 With regard to periphery-to-brain interactions, lipopolysaccharide (LPS)-induced acute systemic inflammation is followed by a rapid and transient activation of the brain immune system, as demonstrated using the TSPO radioligand [ 11 C]PBR28 in nonhuman primates 27 and humans.…”

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confidence: 99%

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The immune response of the human brain to abdominal surgery

Forsberg

Červenka

Fagerlund

et al. 2017

Annals of Neurology

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Objective: Surgery launches a systemic inflammatory reaction that reaches the brain and associates with immune activation and cognitive decline. Although preclinical studies have in part described this systemic-to-brain signaling pathway, we lack information on how these changes appear in humans. This study examines the short-and longterm impact of abdominal surgery on the human brain immune system by positron emission tomography (PET) in relation to blood immune reactivity, plasma inflammatory biomarkers, and cognitive function. Methods: Eight males undergoing prostatectomy under general anesthesia were included. Prior to surgery (baseline), at postoperative days 3 to 4, and after 3 months, patients were examined using [ 11 C]PBR28 brain PET imaging to assess brain immune cell activation. Concurrently, systemic inflammatory biomarkers, ex vivo blood tests on immunoreactivity to lipopolysaccharide (LPS) stimulation, and cognitive function were assessed. Results: Patients showed a global downregulation of gray matter [ 11 C]PBR28 binding of 26 6 26% (mean 6 standard deviation) at 3 to 4 days postoperatively compared to baseline (p 5 0.023), recovering or even increasing after 3 months. LPS-induced release of the proinflammatory marker tumor necrosis factor-a in blood displayed a reduction (41 6 39%) on the 3rd to 4th postoperative day, corresponding to changes in [ 11 C]PBR28 distribution volume. Change in Stroop Color-Word Test performance between postoperative days 3 to 4 and 3 months correlated to change in [ 11 C]PBR28 binding (p 5 0.027). Interpretation: This study translates preclinical data on changes in the brain immune system after surgery to humans, and suggests an interplay between the human brain and the inflammatory response of the peripheral innate immune system. These findings may be related to postsurgical impairments of cognitive function. ANN NEUROL 2017;81:572-582 A growing body of evidence suggests that surgical trauma launches a systemic inflammatory response that ultimately reaches and activates the intrinsic immune system of the brain. [1][2][3][4] Triggered by surgery-induced damage-associated molecular patterns (DAMPs), an array of proinflammatory mediators and activated blood-borne immune cells orchestrate a rapid spread of this systemic response to the central nervous system (CNS), with inflammatory markers detectable in human cerebrospinal fluid (CSF) within 12 hours. [4][5][6][7] In surgical rodent models, this periphery-to-brain pathway seems critically dependent on NF-jB and proinflammatory cytokine signaling (eg, tumor necrosis factor-a [TNF-a]) associated with a shortlasting disruption of blood-brain barrier integrity, 2,3,8 migration of peripheral macrophages into the CNS, and subsequent hippocampal neuronal dysfunction and cognitive impairment. 8 In addition to an acute and transient response, often referred to as a syndrome of sickness behavior including fatigue, anorexia, and fever, surgery-induced immune activation may be associated with prolonged impairments in learning,...

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“…Using positron emission tomography (PET), the localization and activation state of central nervous system immune response modulators can be assessed with radioligands targeting the 18-kDa translocator protein (TSPO), which is expressed in glial cells (7)(8)(9). During the last decade, a handful of TSPO PET studies have been performed in patients with early-stage psychosis or manifest schizophrenia, showing inconclusive results.…”

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confidence: 99%

Positron Emission Tomography Studies of the Glial Cell Marker Translocator Protein in Patients With Psychosis: A Meta-analysis Using Individual Participant Data

Plavén-Sigray

Matheson

Collste

et al. 2018

Biological Psychiatry

110

102

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BACKGROUND: Accumulating evidence suggests that the immune system may be an important target for new treatment approaches in schizophrenia. Positron emission tomography and radioligands binding to the translocator protein (TSPO), which is expressed in glial cells in the brain including immune cells, represents a potential method for patient stratification and treatment monitoring. This study examined whether patients with first-episode psychosis and schizophrenia had altered TSPO levels compared with healthy control subjects. METHODS: PubMed was searched for studies comparing patients with psychosis with healthy control subjects using second-generation TSPO radioligands. The outcome measure was total distribution volume (V T ), an index of TSPO levels, in frontal cortex, temporal cortex, and hippocampus. Bayes factors (BFs) were applied to examine the relative support for higher, lower, or no difference in patients' TSPO levels compared with healthy control subjects. RESULTS: Five studies, with 75 participants with first-episode psychosis or schizophrenia and 77 healthy control subjects, were included. BFs showed strong support for lower V T in patients relative to no difference (all BFs .

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PET imaging of TSPO in a rat model of local neuroinflammation induced by intracerebral injection of lipopolysaccharide

Cited by 50 publications

References 18 publications

Serial Quantitative TSPO-Targeted PET Reveals Peak Microglial Activation up to 2 Weeks After an Epileptogenic Brain Insult

Serial Quantitative TSPO-Targeted PET Reveals Peak Microglial Activation up to 2 Weeks After an Epileptogenic Brain Insult

The immune response of the human brain to abdominal surgery

Positron Emission Tomography Studies of the Glial Cell Marker Translocator Protein in Patients With Psychosis: A Meta-analysis Using Individual Participant Data

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