Neuroinflammation as measured by positron emission tomography in patients with recent onset and established schizophrenia: implications for immune pathogenesis

Conen, Silke; Gregory, Catherine J.; Hinz, Rainer; Smallman, Richard; Corsi-Zuelli, Fabiana; Deakin, Bill; Talbot, Peter S.

doi:10.1038/s41380-020-0829-y

Cited by 41 publications

(45 citation statements)

References 38 publications

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“…More directly, a number of positron emission tomography (PET) studies in patients at various stages of schizophrenia now report no increase in radioligand binding to the translocator protein (TSPO), which is a biomarker for activated microglia 11 . Our recent study found that reductions in TSPO binding in schizophrenia, which we hypothesised, are an indication that microglia are in a non-inflamed phagocytic mode driven by astrogliosis 12 . These findings together with large scale transcriptomic evidence in postmortem brain, discussed below, suggest that microglial inflammation may not be central to pathogenesis in schizophrenia, hence the lack of efficacy of minocycline.…”

Section: Introductionmentioning

confidence: 75%

A randomised clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis

et al. 2020

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NMDA autoantibody encephalitis presenting as schizophrenia suggests the possible role of adaptive cell-mediated immunity in idiopathic schizophrenia. However, to our knowledge there have been no trials of the immune-suppressant methotrexate in schizophrenia. We tested if low-dose methotrexate as used in the treatment of systemic autoimmune disorders would be tolerable and effective in people with schizophrenia in a feasibility study. Ninety-two participants within 5 years of schizophrenia diagnosis were recruited from inpatient and outpatient facilities in Karachi, Pakistan. They were randomised to receive once weekly 10-mg oral methotrexate (n = 45) or matching placebo (n = 47) both with daily 5-mg folic acid, in addition to treatment as usual for 12 weeks. There were eight dropouts per group. Side effects were non-significantly more common in those on methotrexate and were not severe. One person developed leukopenia. Positive symptom scores improved more in those receiving methotrexate than placebo (β = −2.5; [95% CI −4.7 to −0.4]), whereas negative symptoms were unaffected by treatment (β = −0.39; [95% CI −2.01 to 1.23]). There were no immune biomarkers but methotrexate did not affect group mean leucocyte counts or C-reactive protein. We conclude that further studies are feasible but should be focussed on subgroups identified by advances in neuroimmune profiling. Methotrexate is thought to work in autoimmune disorders by resetting systemic regulatory T-cell control of immune signalling; we show that a similar action in the CNS would account for otherwise puzzling features of the immuno-pathogenesis of schizophrenia.

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Section: Introductionmentioning

confidence: 75%

A randomised clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis

et al. 2020

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“…A meta-analysis by Marques et al [48] of TSPO PET studies and microglial activation exposed a moderate effect on gray matter relative to other brain tissue in schizophrenia when using binding potential as an outcome measure but no difference when using volume of distribution as an outcome measure. The TSPO PET study by Conen et al [49] found no microglial activation in patients with recent onset and established schizophrenia compared with healthy control subjects in the ACC, PFC, parietal cortex, and brainstem, but significant changes in the thalamus and putamen.…”

Section: The Role Of Microglial Cells In Schizophreniamentioning

confidence: 97%

The role of microglia in neuropsychiatric disorders and suicide

Brisch

Wojtylak

Saniotis

et al. 2021

Eur Arch Psychiatry Clin Neurosci

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This narrative review examines the possible role of microglial cells, first, in neuroinflammation and, second, in schizophrenia, depression, and suicide. Recent research on the interactions between microglia, astrocytes and neurons and their involvement in pathophysiological processes of neuropsychiatric disorders is presented. This review focuses on results from postmortem, positron emission tomography (PET) imaging studies, and animal models of schizophrenia and depression. Third, the effects of antipsychotic and antidepressant drug therapy, and of electroconvulsive therapy on microglial cells are explored and the upcoming development of therapeutic drugs targeting microglia is described. Finally, there is a discussion on the role of microglia in the evolutionary progression of human lineage. This view may contribute to a new understanding of neuropsychiatric disorders.

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“…(2018) found that minocycline, a potent inhibitor of microglial inflammation, was ineffective in recent-onset patients. The findings were followed by meta-analyses of in vivo Positron Emission Tomography (PET) imaging, providing compelling evidence that the translocator protein TSPO (a putative biomarker for inflamed microglia) is not increased but reduced in psychosis ( Plavén-Sigray et al, 2018 , 2020 ), as we had observed in several brain regions of antipsychotic-free patients ( Conen et al., 2020 ). We proposed that microglia are driven into a non-inflamed synaptic pruning state by overactivity of TGF-β mediated astroglial restraint ( Conen et al., 2020 ).…”

Section: Tregs: Role In the Neuroimmune Network And Therapeutic Implicationsmentioning

confidence: 94%

T regulatory cells as a potential therapeutic target in psychosis? Current challenges and future perspectives

Corsi-Zuelli

Deakin

Lima

et al. 2021

Brain, Behavior, & Immunity - Health

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Many studies have reported that patients with psychosis, even before drug treatment, have mildly raised levels of blood cytokines relative to healthy controls. In contrast, there is a remarkable scarcity of studies investigating the cellular basis of immune function and cytokine changes in psychosis. The few flow-cytometry studies have been limited to counting the proportion of the major classes of monocyte and lymphocytes without distinguishing their pro- and anti-inflammatory subsets. Moreover, most of the investigations are cross-sectional and conducted with patients on long-term medication. These features make it difficult to eliminate confounding of illness-related changes by lifestyle factors, disease duration, and long exposure to antipsychotics. This article focuses on regulatory T cells (Tregs), cornerstone immune cells that regulate innate and adaptive immune forces and neuroimmune interactions between astrocytes and microglia. Tregs are also implicated in cardio-metabolic disorders that are common comorbidities of psychosis. We have recently proposed that Tregs are hypofunctional (‘h-Tregs’) in psychosis driven by our clinical findings and other independent research. Our h-Treg-glial imbalance hypothesis offers a new account for the co-occurrence of systemic immune dysregulation and mechanisms of psychosis development. This article extends our recent review, the h-Treg hypothesis, to cover new discoveries on Treg-based therapies from pre-clinical findings and their clinical implications. We provide a detailed characterisation of Treg studies in psychosis, identifying important methodological limitations and perspectives for scientific innovation. The outcomes presented in this article reaffirms our proposed h-Treg state in psychosis and reveals emerging preclinical research suggesting the potential benefit of Treg-enhancing therapies. There is a clear need for longitudinal studies conducted with drug-naïve or minimally treated patients using more sophisticated techniques of flow-cytometry, CyTOF expression markers, and in vitro co-culture assays to formally test the suppressive capacity of Tregs. Investment in Treg research offers major potential benefits in targeting emerging immunomodulatory treatment modalities on person-specific immune dysregulations.

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Neuroinflammation as measured by positron emission tomography in patients with recent onset and established schizophrenia: implications for immune pathogenesis

Cited by 41 publications

References 38 publications

A randomised clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis

A randomised clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis

The role of microglia in neuropsychiatric disorders and suicide

T regulatory cells as a potential therapeutic target in psychosis? Current challenges and future perspectives

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