Inflammation and Brain Structure in Schizophrenia and Other Neuropsychiatric Disorders

Williams, John A.; Burgess, Stephen; Suckling, John; Lalousis, Paris Alexandros; Batool, Fatima; Griffiths, Siân Lowri; Palmer, Edward; Karwath, Andreas; Barsky, Andrey; Gkoutos, Georgios V.; Wood, Stephen; Barnes, Nicholas M.; David, Anthony; Donohoe, Gary; Neill, Joanna C.; Deakin, Bill; Khandaker, Golam; Upthegrove, Rachel; Rogers, Jack C.; Mondelli, Valeria; Dazzan, Paola; Pariante, Carmine; MacCabe, James H.; Egerton, Alice; Jones, Peter; Bullmore, Edward T.; Koutsouleris, N.; Meisenzahl, Eva; Cotter, David; Harrison, Neil L.

doi:10.1001/jamapsychiatry.2022.0407

Cited by 150 publications

(77 citation statements)

References 69 publications

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“…Simultaneously, other research does not find a strict positive correlation between the severity of positive symptoms, cognitive deficits and enhanced levels of proinflammatory cytokines, such as IL-6, IL-1β and TNF-α [ 113 , 114 , 115 ]. Moreover, inflammation leads to structural brain changes via activation of microglia and/or astrocytic dysfunction, which determine the alterations in proinflammatory factors depending on the area of the brain [ 116 ]. It thus follows that the level of cytokines and the effect of the administered drugs are largely associated not only with the “previous” status of cell activation but also with many other factors, such as the experimental procedure, the age of animals and/or patients, the course of illness and the pharmacotherapy and its duration, which undoubtedly complicates the ability to obtain unambiguous results [ 117 ].…”

Section: Discussionmentioning

confidence: 99%

Quetiapine Ameliorates MIA-Induced Impairment of Sensorimotor Gating: Focus on Neuron-Microglia Communication and the Inflammatory Response in the Frontal Cortex of Adult Offspring of Wistar Rats

Chamera

Curzytek

Kamińska

et al. 2022

Cells

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The maternal immune activation produced by the systemic administration of lipopolysaccharide (LPS) in rats provides valuable insights into the basis of behavioural schizophrenia-like disturbances and biochemical changes in the brains of the offspring, such as microglial activation. Regarding therapy, antipsychotics continually constitute the cornerstone of schizophrenia treatment. To their various efficacy and side effects, as well as not fully recognised mechanisms of action, further characteristics have been suggested, including an anti-inflammatory action via the impact on neuron–microglia axes responsible for inhibition of microglial activation. Therefore, in the present study, we sought to determine whether chronic treatment with chlorpromazine, quetiapine or aripiprazole could influence schizophrenia-like behavioural disturbances at the level of sensorimotor gating in male offspring prenatally exposed to LPS. Simultaneously, we wanted to explore if the chosen antipsychotics display a positive impact on the neuroimmunological parameters in the brains of these adult animals with a special focus on the ligand-receptor axes controlling neuron–microglia communication as well as pro- and anti-inflammatory factors related to the microglial activity. The results of our research revealed the beneficial effect of quetiapine on deficits in sensorimotor gating observed in prenatally LPS-exposed offspring. In terms of axes controlling neuron–microglia communication and markers of microglial reactivity, we observed a subtle impact of quetiapine on hippocampal Cx3cl1 and Cx3cr1 levels, as well as cortical Cd68 expression. Hence, further research is required to fully define and explain the involvement of quetiapine and other antipsychotics in Cx3cl1-Cx3cr1 and/or Cd200-Cd200r axes modulation and inflammatory processes in the LPS-based model of schizophrenia-like disturbances.

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Section: Discussionmentioning

confidence: 99%

Quetiapine Ameliorates MIA-Induced Impairment of Sensorimotor Gating: Focus on Neuron-Microglia Communication and the Inflammatory Response in the Frontal Cortex of Adult Offspring of Wistar Rats

Chamera

Curzytek

Kamińska

et al. 2022

Cells

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“…Meta-analytical evidence shows elevated levels of IL-6 in the peripheral blood and cerebrospinal fluid (CSF) of individuals with FEP and diagnosis of schizophrenia [50][51][52]. A recent Mendelian randomization study found that genetically determined IL-6 was associated with changes in brain structure, with stronger associations in the middle temporal gyrus than in the whole brain, potentially involved in neurodevelopmental disorders, including schizophrenia and autism [53]. Therefore, an association between psychosis and a genetic variant that regulates IL-6 activity suggests that the IL-6/IL-6R pathway may be causally related to schizophrenia [54].…”

Section: Central and Peripheral Cytokines In Schizophreniamentioning

confidence: 99%

Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic Changes: Translational Relevance for Schizophrenia and Antipsychotic Treatment: a Systematic Review

Bartolomeis¹,

Barone²,

Vellucci³

et al. 2022

Mol Neurobiol

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Evidence from clinical, preclinical, and post-mortem studies supports the inflammatory/immune hypothesis of schizophrenia pathogenesis. Less evident is the link between the inflammatory background and two well-recognized functional and structural findings of schizophrenia pathophysiology: the dopamine-glutamate aberrant interaction and the alteration of dendritic spines architecture, both believed to be the “quantal” elements of cortical-subcortical dysfunctional network. In this systematic review, we tried to capture the major findings linking inflammation, aberrant glutamate-dopamine interaction, and post-synaptic changes under a direct and inverse translational perspective, a paramount picture that at present is lacking. The inflammatory effects on dopaminergic function appear to be bidirectional: the inflammation influences dopamine release, and dopamine acts as a regulator of discrete inflammatory processes involved in schizophrenia such as dysregulated interleukin and kynurenine pathways. Furthermore, the link between inflammation and glutamate is strongly supported by clinical studies aimed at exploring overactive microglia in schizophrenia patients and maternal immune activation models, indicating impaired glutamate regulation and reduced N-methyl-D-aspartate receptor (NMDAR) function. In addition, an inflammatory/immune-induced alteration of post-synaptic density scaffold proteins, crucial for downstream NMDAR signaling and synaptic efficacy, has been demonstrated. According to these findings, a significant increase in plasma inflammatory markers has been found in schizophrenia patients compared to healthy controls, associated with reduced cortical integrity and functional connectivity, relevant to the cognitive deficit of schizophrenia. Finally, the link between altered inflammatory/immune responses raises relevant questions regarding potential new therapeutic strategies specifically for those forms of schizophrenia that are resistant to canonical antipsychotics or unresponsive to clozapine.

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“…Similarly, IL-6 at 9 years, but not CRP, was prospectively associated with diurnal mood variation, concentration difficulties, fatigue and sleep disturbances at 18 years old (50), and with increased risk of hypomanic symptoms by age 22 years (51). A recent study also reported that genetically predicted IL-6, but not CRP, was significantly associated with gray matter volume (especially in the middle temporal gyrus and fusiform gyrus), and with cortical thickness (mainly in the superior frontal gyrus) (52), which are areas implicated in ADHD.…”

Section: Discussionmentioning

confidence: 99%

The role of inflammation in the prospective associations between early childhood sleep problems and ADHD at 10 years: Findings from a UK birth cohort study

Morales‐Muñoz

Upthegrove

Lawrence

et al. 2022

Preprint

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Background: Several underlying mechanisms potentially account for the link between sleep and attention deficit and hyperactivity disorder (ADHD), including inflammation. However, studies so far have been cross-sectional. We investigate (i) the association between early childhood sleep and probable ADHD diagnosis in childhood; and (ii) whether childhood circulating inflammatory markers mediate any associations. Methods and Findings: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) were available for 7658 10-years-old children. Parent-reported sleep duration, night awakening frequency, and regular sleep routines were collected at 3.5 years. The Development and Wellbeing Assessment (DAWBA) was administered to capture children with clinically relevant ADHD symptoms, or probable ADHD diagnosis. Further, blood samples were collected at 9 years, from which two inflammatory markers were obtained [i.e. interleukin-6 (IL-6) and C-reactive protein (CRP)]. Logistic regressions were applied to investigate the associations between sleep variables at 3.5 years and probable ADHD diagnosis at 10 years. Further, path analysis was applied to examine the mediating role of inflammation at 9 years (i.e. as measured by CRP and IL-6) in the associations between early sleep and ADHD at 10 years. We found that less regular sleep routines (OR=0.51, 95%CI=0.28-0.93, p=0.029), shorter nighttime sleep (OR=0.70, 95%CI=0.56-0.89, p=0.004), and higher night awakening (OR=1.27, 95I%CI=1.06-1.52, p=0.009) at 3.5 years were associated with higher odds of probable ADHD at 10 years. Further, IL-6 at 9 years mediated the association between irregular sleep routines and ADHD (bias-corrected estimate, -0.002; p=0.005); and between night awakening and ADHD (bias-corrected estimate, 0.002; p=0.003). Conclusions: Several sleep problems in early childhood constitute a risk factor for probable ADHD diagnosis at 10 years. These associations may be mediated by inflammation, as measured by IL-6. These results open a new research vista to the pathophysiology of ADHD and highlight sleep and inflammation as potential preventative targets for ADHD.

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Inflammation and Brain Structure in Schizophrenia and Other Neuropsychiatric Disorders

Cited by 150 publications

References 69 publications

Quetiapine Ameliorates MIA-Induced Impairment of Sensorimotor Gating: Focus on Neuron-Microglia Communication and the Inflammatory Response in the Frontal Cortex of Adult Offspring of Wistar Rats

Quetiapine Ameliorates MIA-Induced Impairment of Sensorimotor Gating: Focus on Neuron-Microglia Communication and the Inflammatory Response in the Frontal Cortex of Adult Offspring of Wistar Rats

Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic Changes: Translational Relevance for Schizophrenia and Antipsychotic Treatment: a Systematic Review

The role of inflammation in the prospective associations between early childhood sleep problems and ADHD at 10 years: Findings from a UK birth cohort study

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