Microglia Activation in Recent-Onset Schizophrenia: A Quantitative (R)-[11C]PK11195 Positron Emission Tomography Study

Berckel, Bart N. van; Bossong, Matthijs G.; Boellaard, Ronald; Kloet, Reina W.; Schuitemaker, Alie; Caspers, Esther; Luurtsema, Gert; Windhorst, Albert D.; Cahn, Wiepke; Lammertsma, Adriaan A.; Kahn, René S.

doi:10.1016/j.biopsych.2008.04.025

Cited by 520 publications

(360 citation statements)

References 18 publications

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“…Activated M1 microglia produce prostaglandins, chemokines, cytokines, complement proteins, proteinases, reactive oxygen species, and reactive nitrogen species, the sustained production of which can have a deleterious effect on susceptible cell populations by enhancing oxidative stress and activating cell death pathways through stimulation of kinases and caspase cascades [43]. Postmortem evidence is growing: brain microglial activation has been suggested in postmortem and positron emission tomography studies using (R)-[11C]PK11195, a ligand that recognizes the translocator protein [44][45][46][47]. Other postmortem studies have found increased numbers and structural degenerative impairments of human leukocyte antigen-antigen D related+ microglia in schizophrenia [48][49][50].…”

Section: Discussionmentioning

confidence: 99%

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

et al. 2016

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Alterations in the innate inflammatory response may underlie the pathophysiology of psychiatric diseases. Current antipsychotics modulate pro-/anti-inflammatory pathways, but their specific actions on these pathways remain only partly explored. This study was conducted to elucidate the regulatory role of paliperidone (1 mg/kg i.p.) on acute (6 h) and chronic (6 h/day for 21 consecutive days) restraint stressinduced alterations in 2 emerging endogenous anti-inflammatory/antioxidant mechanisms: nuclear factor erythroid-related factor 2 (NRF2)/antioxidant enzymes pathway, and the cytokine milieu regulating M1/M2 polarization in microglia, analyzed at the mRNA and protein levels in prefrontal cortex samples. In acute stress conditions, paliperidone enhanced NRF2 levels, possibly related to phosphoinositide 3-kinase upregulation and reduced kelch-Like ECH-associated protein 1 expression. In chronic conditions, paliperidone tended to normalize NRF2 levels through a phosphoinositide 3-kinase related-mechanism, with no effects on kelch-Like ECH-associated protein 1. Antioxidant response element-dependent antioxidant enzymes were upregulated by paliperidone in acute stress, while in chronic stress, paliperidone tended to prevent stress-induced downregulation of the endogenous antioxidant machinery. However, paliperidone increased transforming growth factor-β and interleukin-10 in favor of an M2 microglia profile in acute stress conditions, which was also corroborated by paliperidone-induced increased levels of the M2 cellular markers arginase I and folate receptor 2. This latter effect was also produced in chronic conditions. Immunofluorescence studies suggested an increase in the number of microglial cells expressing arginase I and folate receptor 2 in the stressed animals pretreated with paliperidone. In conclusion, the enhancement of endogenous antioxidant/anti-inflammatory pathways by current and new antipsychotics could represent an interesting therapeutic strategy for the future.

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Section: Discussionmentioning

confidence: 99%

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

et al. 2016

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“…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. Early reports using the first-generation TSPO radioligand (R)-[ 11 C]PK11195 showed higher binding in small patient groups (n = 7 and n = 10) (10,11), albeit with outcome measures that show low accuracy and reliability (i.e., binding potential estimated from rate constants) (12)(13)(14). More recent studies in larger samples using the same radioligand, but without blood sampling for full quantification, did not replicate these findings (15)(16)(17).…”

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confidence: 97%

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

106

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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“…In vivo positron emission tomography (PET) imaging studies have also identified microgliosis in schizophrenia. A study of people with recent-onset schizophrenia and another study of individuals who were recovering from a psychotic episode both found increases in a marker indicative of microgliosis (binding of [ 11 C]PK11195 to the mitochondrial 18kDa translocator protein (TSPO)) in grey matter (Doorduin et al, 2009;Van Berckel et al, 2008); whereas another study of chronic patients with schizophrenia failed to find a change using another microglial marker (Takano et al, 2010) (binding of [ 11 C] DAA1106, an agonist with greater affinity for TSPO than PK11195). The latter study did find a positive correlation between microglial marker binding and positive symptoms, and thus the three in vivo PET studies are consistent with increased microgliosis being especially prominent in those with recent psychotic exacerbation.…”

Section: Introductionmentioning

confidence: 99%

Increased expression of astrocyte markers in schizophrenia: Association with neuroinflammation

Catts

Wong

Fillman

et al. 2014

Aust N Z J Psychiatry

122

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Objective: While schizophrenia may have a progressive component, the evidence for neurodegenerative processes as indicated by reactive astrocytes is inconclusive. We recently identified a subgroup of individuals with schizophrenia with increased expression of inflammatory markers in prefrontal cortex, and hypothesized that this subgroup would also have reactive astrocytes. Method:We measured glial fibrillary acidic protein (GFAP) mRNA by quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) and protein levels by immunoblotting in grey matter homogenate from 37 individuals with schizophrenia and 37 unaffected controls. We examined the morphology of GFAP-positive astrocytes in immunostained sections of middle frontal gyrus. We tested if GFAP expression or astrocyte morphology were altered in people with schizophrenia with increased expression of inflammatory markers. We used RNA-Seq data on a subset of patients and controls (n=20/group) to ascertain whether mRNA transcripts associated with astrogliosis were elevated in the individuals with active neuroinflammation.Results: GFAP (mRNA and protein) levels and astrocyte morphology were not significantly different between people with schizophrenia and controls overall. However, individuals with schizophrenia with neuroinflammation had increased expression of GFAP mRNA (t(33)=2.978, p=0.005), hypertrophic astrocyte morphology (χ 2 (2)=6.281, p=0.043), and statistically significant elevated expression of three mRNA transcripts previously associated with astrogliosis. Conclusions:We found clear evidence of astrogliosis in a subset of people with schizophrenia. We suggest that the lack of astrogliosis reported in previous studies may be due to cohort differences in aetiopathology, illness stage, treatment exposure, or a failure to examine subsets of people with schizophrenia.

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Microglia Activation in Recent-Onset Schizophrenia: A Quantitative (R)-[11C]PK11195 Positron Emission Tomography Study

Cited by 520 publications

References 18 publications

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

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

Increased expression of astrocyte markers in schizophrenia: Association with neuroinflammation

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