Brain morphology is differentially impacted by peripheral cytokines in schizophrenia-spectrum disorder
Introduction
The pathophysiological mechanism behind the widely replicated structural brain changes in schizophrenia-spectrum disorder (SSD) remains unknown. These changes include ventricular enlargement (Olabi et al., 2011), and grey matter loss within prefrontal, temporal and subcortical structures (Ellison-Wright et al., 2008, Fornito et al., 2008). One of the mechanisms likely contributing to these structural brain changes found in SSD is neuroinflammation, including activation of microglia, and dysregulation of peripheral cytokines (Howes and McCutcheon, 2016, Jacomb et al., 2018, Laskaris et al., 2016, Miller and Goldsmith, 2016).
The ‘neuroinflammatory’ hypothesis states that the cytotoxic effects of persistent activation of the brain’s immune cells, namely microglia and astrocytes, in addition to dysregulation of the peripheral inflammatory system, might cause neuronal damage and synaptic dysfunction (Banati and Hickie, 2009, Howes and McCutcheon, 2016, Kirkpatrick and Miller, 2013, Laskaris et al., 2016, Monji et al., 2009), thus potentially contributing to the thickness and volume loss seen in imaging studies of schizophrenia (Borgwardt et al., 2007, Olabi et al., 2011, Pantelis et al., 2005). Some studies have shown increased microglial activation at various stages of SSD (Bloomfield et al., 2016, Doorduin et al., 2009, Selvaraj et al., 2018, van Berckel et al., 2008), while several studies (Goldsmith et al., 2016, Miller et al., 2011a, Rodrigues-Amorim et al., 2018) have concluded that there is dysregulation of peripheral inflammatory molecules across all stages of the illness.
Although the brain was once considered to be immune privileged, over the last decade, this has been reconceptualised. Evidence suggests that peripheral cytokines may influence the brain via direct binding to the vagus nerve or the endothelial cells of the blood brain barrier (BBB) (McCusker and Kelley, 2013). Indeed, recent studies revealed evidence of more chemo-attractants for and putative transmigration of macrophages in the brain of patients with a “high inflammatory” subtype of schizophrenia (Cai et al., 2018, Purves-Tyson et al., 2020). Given evidence for a bi-directional relationship between the immune and nervous systems, meta-analytic findings for altered cytokines in individuals with SSD (Goldsmith et al., 2016, Miller et al., 2011b), and elevations in cytokines within the frontal cortex (Fillman et al., 2015, 2013; Volk et al., 2015, Zhang et al., 2016), peripheral and central inflammatory processes may be related, with both potentially contributing to the brain structural changes seen in SSD.
A growing number of studies have examined the relationship between peripheral cytokines and grey matter structure in SSD. Although many, but not all, studies have identified associations between cytokines and brain structure, the nature, and interpretation, of the relationships remain unclear. For instance, in individuals with chronic schizophrenia, both pro-inflammatory (Fillman et al., 2015, Kudo et al., 2018, Miller et al., 2020) anti-inflammatory (Bossu et al., 2015), as well as endothelial cell activation (Dieset et al., 2015, Pillai et al., 2015) markers have been associated with smaller grey matter volume of frontal, temporal regions and hippocampus. In contrast, pro-inflammatory cytokines have been associated with an increase in grey matter volume in the striatum, cerebellum (Quidé et al., 2020) and anterior cingulate cortex (ACC) regions (Tsai et al., 2020) in schizophrenia and an absence of an association between the hippocampus and seven pro-inflammatory molecules has also been reported (Hoseth et al. 2016).
More consistent relationships have been found in individuals at the early stages of psychotic illness. In a combined sample of ultra-high risk of psychosis individuals and controls, a faster rate of thinning in the prefrontal cortex was associated with an elevated pro-inflammatory composite score (Cannon et al., 2015), while in first-episode psychosis (FEP) smaller whole brain grey matter was associated with increases in the pro-inflammatory cytokines, IFNγ and IL12 (Lesh et al., 2018). These studies suggest that inflammatory molecules may exert varying influences on grey matter across different stages of illness. Nevertheless, the considerable heterogeneity across studies in the cytokines and regions examined, stage of illness of the patients, statistical approaches employed and the degree to which potential confounds were considered, hinder interpretations that can be made. In particular, the limited number of cytokines and regions assessed in previous studies based on a priori hypotheses (Bossu et al., 2015, Fillman et al., 2013, Hoseth et al., 2016, Kudo et al., 2018, Lesh et al., 2018, Miller et al., 2020, Pillai et al., 2015) may have overlooked key relationships that have not featured in the existing literature.
To our knowledge, no studies have examined the relationship between circulating levels of cytokines and grey matter structure across both early and late stages of SSD in the same study. This is important as it is currently not clear whether the relationship between brain structure and cytokine profile is different at early and late stages of illness or whether differences reported in the literature are due to cross-study variation. Here, we aimed to characterize the relationship between grey matter structure and peripheral cytokine protein levels in individuals at different stages of SSD; specifically, individuals with established, chronic schizophrenia and those experiencing their first episode of psychosis, as well as healthy controls. Using a data driven approach, we examined a wider range of cytokines and brain structures than previously examined in order to ascertain whether specific brain regions are more vulnerable to circulating levels of inflammatory molecules or whether cytokines exert an influence on brain structure in a uniform manner across the whole brain. We additionally considered the influence of a wider range of anti-inflammatory cytokines than previous studies given these associations may be equally important within the context of neuroinflammatory mechanisms. We expected that higher circulating proinflammatory molecules would be associated with smaller brain structure, and that this association would be stronger, or spatially more widespread, in individuals with FEP than those with chronic schizophrenia or healthy controls. We did not hypothesize relationships between specific cytokines and specific brain structures, given the absence of consistent relationships in the existing literature.
Section snippets
Subjects and methods
A total of 175 subjects participated in this study: 40 FEP patients (illness duration < 2 years), 51 chronic schizophrenia patients (illness duration > 7 years; majority treated with clozapine), and 84 healthy controls. All groups were matched on sex. Demographic data is shown in Table 1.
FEP and Chronic participants had a diagnosis of a psychotic disorder within the umbrella term of schizophrenia-spectrum disorders (Hilker et al., 2018) as determined by the Diagnostic and Statistical Manual of
Demographics
Demographic and clinical characteristics of participants are shown in Table 1. There was a significant main effect of diagnosis on age (F = 50.499, p < 0.0005) and BMI (F = 13.620, p < 0.0005) with post-hoc comparisons revealing that chronic schizophrenia patients were significantly older compared to FEP (p < 0.0005) and HC (p = 0.003), while healthy controls were significantly older compared to FEP (p < 0.0005). BMI was significantly increased in chronic schizophrenia compared to HC
Discussion
In a data-driven approach, we investigated the relationship between multiple cytokines and cortical and subcortical brain structures in healthy controls, FEP and chronic schizophrenia patients to interrogate the relationship of inflammatory molecules to regional grey matter in SSD. We report that while there was no evidence for systemic inflammation in our sample of SSD and no evidence for an overall impact of cytokines on brain morphology, specific cytokines were associated with brain
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Over the last 5 years, Christos Pantelis has participated on Advisory Boards for Janssen-Cilag, Astra-Zeneca, Lundbeck, and Servier. He has received honoraria for talks presented at educational meetings organised by Astra-Zeneca, Janssen-Cilag, Eli-Lilly, Pfizer, Lundbeck and Shire. His research work has received major support
Acknowledgements
We thank Roxanne Cadiz for providing training and assistance in protein analysis. We also thank Steven Tahtalian and Eleni Ganella for assisting with clinical data collection and Dr Christina Phassouliotis and Antonia Merritt for study coordination. We thank all the individuals who gave up their time and energy to make this study possible.
This study was supported by an Australian National Health and Medical Research Council (NHMRC) Project Grant (1065742) and University of Melbourne Early
Funding
This work was supported by an Australian National Health and Medical Research Council (NHMRC) Project Grant (1065742) and University of Melbourne Early Career Researcher grant (601253) to Vanessa Cropley; and a Royal Melbourne Hospital Grant in Aid (GIA-030-2016) and NARSAD Distinguished Investigator Grant to Christos Pantelis (18722).
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