Inflammation and cognition in severe mental illness: patterns of covariation and subgroups

Abstract

A potential relationship between dysregulation of immune/inflammatory pathways and cognitive impairment has been suggested in severe mental illnesses (SMI), such as schizophrenia (SZ) and bipolar (BD) spectrum disorders. However, multivariate relationships between peripheral inflammatory/immune-related markers and cognitive domains are unclear, and many studies do not account for inter-individual variance in both cognitive functioning and inflammatory/immune status. This study aimed to investigate covariance patterns between inflammatory/immune-related markers and cognitive domains and further elucidate heterogeneity in a large SMI and healthy control (HC) cohort (SZ = 343, BD = 289, HC = 770). We applied canonical correlation analysis (CCA) to identify modes of maximum covariation between a comprehensive selection of cognitive domains and inflammatory/immune markers. We found that poor verbal learning and psychomotor processing speed was associated with higher levels of interleukin-18 system cytokines and beta defensin 2, reflecting enhanced activation of innate immunity, a pattern augmented in SMI compared to HC. Applying hierarchical clustering on covariance patterns identified by the CCA revealed a high cognition—low immune dysregulation subgroup with predominantly HC (24% SZ, 45% BD, 74% HC) and a low cognition—high immune dysregulation subgroup predominantly consisting of SMI patients (76% SZ, 55% BD, 26% HC). These subgroups differed in IQ, years of education, age, CRP, BMI (all groups), level of functioning, symptoms and defined daily dose (DDD) of antipsychotics (SMI cohort). Our findings suggest a link between cognitive impairment and innate immune dysregulation in a subset of individuals with severe mental illness.

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

“…Based on covariance patterns in our main sample we identified a more compromised low cognition – high inflammatory-immune dysregulation subgroup, consisting primarily of individuals with SMI. This is a consistent pattern also observed in our previous work using a different inflammatory-immune marker panel (Sæther et al, 2023), and is in line with evidence that individuals with SMI in high inflammatory subgroups tend to have lower cognitive functioning (Fillman et al, 2016; Lizano et al, 2023a, 2020). We also found that individuals with SMI with co-occurring inflammation and cognitive impairment have more symptoms and lower functioning, which may be important to consider in future clinical trials.…”

“…We also found that individuals with SMI with co-occurring inflammation and cognitive impairment have more symptoms and lower functioning, which may be important to consider in future clinical trials. Interestingly, we found the same cognitive domains as in our previous work (Sæther et al, 2023), i.e. measures of speed and verbal learning, shared variance with inflammatory-immune markers.…”

“…Case-control studies may mask clinically relevant characteristics of subgroups of individuals with SMI. Recent studies using a comprehensive selection of inflammatory and immune-related markers in SMI have revealed considerable variation in the degree of dysregulation (Bishop et al, 2022; Boerrigter et al, 2017; Enrico et al, 2023; Fillman et al, 2016, 2014; Hoang et al, 2022; Lizano et al, 2023a, 2020; Sæther et al, 2023; Tamminga et al, 2021; Zhang et al, 2022). A consistent finding is that 30-50% of individuals with SMI show inflammatory-immune dysregulation (Bishop et al, 2022; Boerrigter et al, 2017; Lizano et al, 2023a, 2020; Zhang et al, 2022), which is associated with several unfavorable outcomes, including cognitive impairment (Fillman et al, 2016; Lizano et al, 2023a, 2020).…”

“…Identifying peripheral markers sharing variance with cognitive phenotypes, rather than diagnostic categories, in combination with investigating the regulation of these molecules in CNS cells using iPSC-technology, may improve our understanding of their pathogenic role in cognitive functioning in SMI. We recently identified transdiagnostic subgroups based on the shared variance between peripheral inflammatory-immune pathways and cognitive functioning, particularly measures of verbal learning and processing speed (Sæther et al, 2023). The current study aimed to use a translational approach to shed light on the relationship between peripheral and central inflammatory-immune activity related to cognitive functioning in SMI.…”

“…We included nine core cognitive domains: fine-motor speed, psychomotor processing speed, mental processing speed, attention, verbal learning, verbal memory, semantic fluency, working memory and cognitive control. While we previously investigated markers reflecting BBB integrity and trafficking, chemokines, cell adhesion molecules and mediators of innate immune activity (Sæther et al, 2023), we now included a novel set of markers capturing a more comprehensive range of peripheral inflammation and immune activity reflecting i) immune activation of different leukocyte subsets, ii) general upstream inflammatory markers, iii) vascular and endothelial-related inflammation, iv) extracellular matrix (ECM) remodelling, v) Wnt signalling pathway and vi) neuroinflammation. Following identification of candidate markers sharing variance with cognitive domains, we assessed the potential dysregulation of these candidates in CNS cells, by in vitro inflammatory modulation of iPSC-derived astrocytes and neural progenitor cells (NPCs).…”