Cognitive and inflammatory heterogeneity in severe mental illness: Translating findings from blood to brain
Abstract 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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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 08. Nov. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sæther, Linn Sofie [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.11.02.23297924 |
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| PPN (Katalog-ID): |
XBI041423038 |
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| 520 | |a Abstract 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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| 700 | 1 | |a Szabo, Attila |4 aut | |
| 700 | 1 | |a Akkouh, Ibrahim A. |4 aut | |
| 700 | 1 | |a Haatveit, Beathe |4 aut | |
| 700 | 1 | |a Mohn, Christine |4 aut | |
| 700 | 1 | |a Vaskinn, Anja |4 aut | |
| 700 | 1 | |a Aukrust, Pål |4 aut | |
| 700 | 1 | |a Ormerod, Monica B. E.G. |4 aut | |
| 700 | 1 | |a Steen, Nils Eiel |4 aut | |
| 700 | 1 | |a Melle, Ingrid |4 aut | |
| 700 | 1 | |a Djurovic, Srdjan |4 aut | |
| 700 | 1 | |a Andreassen, Ole A. |4 aut | |
| 700 | 1 | |a Ueland, Torill |4 aut | |
| 700 | 1 | |a Ueland, Thor |4 aut | |
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