Infections, Inflammation, and Psychiatric Illness: Review of Postmortem Evidence

Webster, Maree J.

doi:10.1007/7854_2022_362

Cited by 9 publications

(5 citation statements)

References 90 publications

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“…Genetic, postmortem and epidemiological studies support the role of immune-mediated activity in the pathophysiology of SMI (Andreassen et al, 2023; Benros et al, 2014; Webster, 2023). Dysregulated levels of peripheral inflammatory and immune-related markers and mediators are apparent at all stages of illness (Goldsmith et al, 2016; Halstead et al, 2023; Perry et al, 2021; Upthegrove et al, 2014).…”

Section: Introductionmentioning

confidence: 90%

“…Increasing our mechanistic understanding of inflammatoryimmune involvement may enable the development of novel treatment strategies for cognitive impairment across brain disorders including SMI. Genetic, postmortem and epidemiological studies support the role of immune-mediated activity in the pathophysiology of SMI (Andreassen et al, 2023;Benros et al, 2014;Webster, 2023). Dysregulated levels of peripheral inflammatory and immune-related markers and mediators are apparent at all stages of illness Halstead et al, 2023;Perry et al, 2021;Upthegrove et al, 2014).…”

Section: Introductionmentioning

confidence: 98%

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Cognitive and inflammatory heterogeneity in severe mental illness: Translating findings from blood to brain

Sæther,

Szabo,

Akkouh

et al. 2023

Preprint

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Recent findings link cognitive impairment and inflammatory-immune dysregulation in schizophrenia (SZ) and bipolar (BD) spectrum disorders. However, heterogeneity and translation between the periphery and central (blood-to-brain) mechanisms remains a challenge. Starting with a large SZ, BD and healthy control cohort (n=1235), we aimed to i) identify candidate peripheral markers (n=25) associated with cognitive domains (n=9) and elucidate heterogenous immune-cognitive patterns, ii) evaluate the regulation of candidate markers using human induced pluripotent stem cell (iPSC)-derived astrocytes and neural progenitor cells (n=10), and iii) evaluate candidate marker messenger RNA expression in leukocytes using microarray in available data from a subsample of the main cohort (n=776), and in available RNA-sequencing deconvolution analysis of postmortem brain samples (n=474) from the CommonMind Consortium (CMC). We identified transdiagnostic subgroups based on covariance between cognitive domains (measures of speed and verbal learning) and peripheral markers reflecting inflammatory response (CRP, sTNFR1, YKL-40), innate immune activation (MIF) and extracellular matrix remodelling (YKL-40, CatS). Of the candidate markers there was considerable variance in secretion of YKL-40 in iPSC-derived astrocytes and neural progenitor cells in SZ compared to HC. Further, we provide evidence of dysregulated RNA expression of genes encoding YKL-40 and related signalling pathways in a high inflammatory subgroup consisting predominantly of SZ in the postmortem brain samples. Our findings suggest a relationship between peripheral inflammatory-immune activity and cognitive impairment, and highlight YKL-40 as a potential marker of cognitive functioning in a subgroup of individuals with severe mental illness.

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Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 98%

Cognitive and inflammatory heterogeneity in severe mental illness: Translating findings from blood to brain

Sæther,

Szabo,

Akkouh

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…Current pharmacotherapies targeting symptom relief in SMI have limited effects on cognition, which may have a different underlying pathophysiology (Howes et al, 2024; McCutcheon et al, 2023). Evidence suggests immune- and inflammatory-related abnormalities, which are well documented across the psychosis spectrum (Andreassen et al, 2023; Benros et al, 2014; Goldsmith et al, 2016; Steen et al, 2023; Webster, 2023), are associated with cognitive impairment (Jovasevic et al, 2024; Morozova et al, 2022; Rosenblat et al, 2015; Wang et al, 2022). Dysregulated systemic levels of inflammatory markers have been observed in first-episode and chronic stages of SMI (Halstead et al, 2023; Perry et al, 2021), including in medication naïve patients (Dunleavy et al, 2022; Fernandes et al, 2016; van den Ameele et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Longitudinal course of inflammatory-cognitive subgroups across first treatment severe mental illness and healthy controls

Sæther,

Ueland,

Haatveit

et al. 2024

Preprint

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Background While inflammation is associated with cognitive impairment in severe mental illnesses (SMI), there is substantial heterogeneity and evidence of transdiagnostic subgroups across schizophrenia (SZ) and bipolar (BD) spectrum disorders. There is however, limited knowledge about the longitudinal course of this relationship. Methods Systemic inflammation (C-Reactive Protein, CRP) and cognition (nine cognitive domains) was measured from baseline to 1 year follow-up in first treatment SZ and BD (n=221), and healthy controls (HC, n=220). Linear mixed models were used to evaluate longitudinal changes separately in CRP and cognitive domains specific to diagnostic status (SZ, BD, HC). Hierarchical clustering was applied on the entire sample to investigate the longitudinal course of transdiagnostic inflammatory-cognitive subgroups. Results There were no case-control differences or change in CRP from baseline to follow-up. We confirm previous observations of case-control differences in cognition at both time-points and domain specific stability/improvement over time regardless of diagnostic status. We identified transdiagnostic inflammatory-cognitive subgroups at baseline with differing demographics and clinical severity. Despite improvement in cognition, symptoms and functioning, the higher inflammation-lower cognition subgroup (75% SZ; 48% BD; 38% HC) had sustained inflammation and lower cognition, more symptoms, and lower functioning (SMI only) at follow-up. This was in comparison to a lower inflammation-higher cognition subgroup (25% SZ, 52% BD, 62% HC), where SMI participants showed cognitive functioning at HC level with a positive clinical course. Conclusions Our findings support heterogenous and transdiagnostic inflammatory-cognitive subgroups that are stable over time, and may benefit from targeted interventions.

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“…Schizophrenia is a neurodevelopmental disorder with an etiology and pathophysiology increasingly linked to interacting environmental and genetic immune sources [1][2][3][4]. Pathogen exposures, autoimmune comorbidities, gut dysbiosis, acute inflammatory episodes, and chronic low-grade inflammation are all implicated risk factors [5][6][7][8][9][10][11][12][13][14][15][16][17]. The specific mechanism(s) underlying inflammation and driving the immune component of this complex brain disorder, however, has been difficult to identify.…”

Section: Introductionmentioning

confidence: 99%

Prospects and Pitfalls of Plasma Complement C4 in Schizophrenia: Building a Better Biomarker

Severance,

Prandovszky,

Yang

et al. 2023

Dev Neurosci

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Complex brain disorders like schizophrenia may have multifactorial origins related to mis-timed heritable and environmental factors interacting during neurodevelopment. Infections, inflammation, and autoimmune diseases are over-represented in schizophrenia leading to immune system-centered hypotheses. Complement component C4 is genetically and neurobiologically associated with schizophrenia, and its dual activity peripherally and in the brain makes it an exceptional target for biomarker development. Studies to evaluate the biomarker potential of plasma or serum C4 in schizophrenia do so to understand how peripheral C4 might reflect central nervous system (CNS)-derived neuroinflammation, synapse pruning and other mechanisms. This effort, however, has produced mostly conflicting results, with peripheral C4 sometimes elevated, reduced or unchanged between comparison groups. We undertook a pilot biomarker development study to systematically identify sociodemographic, genetic, and immune-related variables (autoimmune, infection-related, gastrointestinal (GI), inflammatory), which may be associated with plasma C4 levels in schizophrenia (SCH; n=335) and/or in non-psychiatric comparison subjects (NCs; n=233). As with previously inconclusive studies, we detected no differences in plasma C4 levels between SCH and NCs. In contrast, levels of general inflammation, C-Reactive Protein (CRP), were significantly elevated in SCH compared to NCs (ANOVA, F=20.74, p<0.0001), suggestive that plasma C4 and CRP may reflect different sources or causes of inflammation. In multivariate regressions of C4 gene copy number variants (CNVs), plasma C4 levels were correlated only for C4A (not C4B, C4L, C4S) and only in NCs (R Coeff=0.39, CI=0.01-0.77, R2=0.18, p<0.01; not SCH). Other variables associated with plasma C4 levels only in NCs included sex, double-stranded DNA (dsDNA) IgG, tissue-transglutaminase (TTG) IgG, and cytomegalovirus (CMV) IgG. Toxoplasma gondii IgG was the only variable significantly correlated with plasma C4 in SCH but not in NCs. Many variables were associated with plasma C4 in both groups (body mass index (BMI), race, CRP, N-methyl-D-aspartate receptor (NMDAR) NR2 subunit IgG, TTG IgA, lipopolysaccharide (LPS)-binding protein (LBP), and soluble CD14 (sCD14). While the direction of most C4 associations was positive, autoimmune markers tended to be inverse, and associated with reduced plasma C4 levels. When NMDAR NR2 autoantibody-positive individuals were removed, plasma C4 was elevated in SCH versus NCs (ANOVA, F=5.16, p<0.02). Our study was exploratory and confirmation of the many variables associated with peripheral C4 require replication. Our preliminary results point toward autoimmune factors and exposure to the pathogen, T. gondii, as possibly significant contributors to variability of total C4 protein levels in plasma of individuals with schizophrenia.

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Infections, Inflammation, and Psychiatric Illness: Review of Postmortem Evidence

Cited by 9 publications

References 90 publications

Cognitive and inflammatory heterogeneity in severe mental illness: Translating findings from blood to brain

Cognitive and inflammatory heterogeneity in severe mental illness: Translating findings from blood to brain

Longitudinal course of inflammatory-cognitive subgroups across first treatment severe mental illness and healthy controls

Prospects and Pitfalls of Plasma Complement C4 in Schizophrenia: Building a Better Biomarker

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