Peripheral inflammatory subgroup differences in anterior Default Mode network and multiplex functional network topology are associated with cognition in psychosis

Lizano, Paulo; Kiely, Chelsea; Mijalkov, Mite; Meda, Shashwath A.; Keedy, Sarah K.; Hoang, Dung; Zeng, Victor; Lutz, Olivia; Pereira, Joana B.; Ivleva, Elena I.; Volpe, Giovanni; Xu, Yanxun; Lee, Adam M.; Rubin, Leah H.; Hill, S. Kristian; Clementz, Brett A.; Tamminga, Carol A.; Pearlson, Godfrey D.; Sweeney, John A.; Gershon, Elliot S.; Keshavan, Matcheri S.; Bishop, Jeffrey R.

doi:10.1016/j.bbi.2023.07.014

Cited by 11 publications

(7 citation statements)

References 106 publications

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“…Nonetheless, the higher inflammation – lower cognition subgroup suggests some interaction with CRP and cognition, particularly in SZ participants that were overrepresented in this subgroup. This also aligns with previous findings that individuals with SMI in high-inflammatory subgroups have lower cognitive performance (Fillman et al, 2016; Lizano et al, 2023, 2020). Our findings suggest that there are trait-related cognitive-immune subgroups in SMI, which seems independent of state dependent fluctuations of immune markers.…”

Section: Discussionsupporting

confidence: 92%

“…This is also in line with genetic findings of mixed effect directions, which includes higher load of increasing and decreasing genetic variants for CRP in SMI (Hindley et al, 2023). Similar to findings on cognitive subgroups (Bora et al, 2023; Cowman et al, 2021; Lewandowski, 2020; Wenzel et al, 2023, 2021), the higher-inflammation subtype is associated with more adverse neurobiological and clinical outcomes, and is associated with lower cognitive functioning (Boerrigter et al, 2017; Fillman et al, 2016; Lizano et al, 2023, 2020; Millett et al, 2021; Nettis et al, 2019; Zhang et al, 2022). A common observation is that a larger proportion of individuals with SMI compared to control participants, belong to a higher-inflammation subtype (Boerrigter et al, 2017; Fillman et al, 2016; Lizano et al, 2020).…”

Section: Introductionsupporting

confidence: 64%

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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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Section: Discussionsupporting

confidence: 92%

Section: Introductionsupporting

confidence: 64%

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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“…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 (Saether 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, 2023aLizano et al, , 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.…”

Section: Discussionsupporting

confidence: 92%

“…Inflammation has long been associated with psychomotor slowing across SMI (Felger and Treadway, 2017; Goldsmith et al, 2016; Goldsmith et al, 2020; Larsen et al, 2021), and in experimentally induced inflammation (Brydon et al, 2008; Reichenberg et al, 2001). Reduced psychomotor processing speed and verbal learning performance have recently been linked to altered brain functional connectivity in high inflammation subgroups in SMI (Lizano et al, 2023a). This could indicate that these cognitive domains are particularly relevant in the context of inflammatory-immune dysregulation in SMI.…”

Section: Discussionmentioning

confidence: 99%

“…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). Similarly, there is evidence of transdiagnostic cognitive subgroups across SZ and BD spectrum disorders related to several negative outcomes (Carruthers et al, 2019; Vaskinn et al, 2020; Wenzel et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

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

Sæther,

Szabo,

Akkouh

et al. 2024

Brain, Behavior, and Immunity

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Peripheral inflammatory subgroup differences in anterior Default Mode network and multiplex functional network topology are associated with cognition in psychosis

Cited by 11 publications

References 106 publications

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

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

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

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