A machine learning approach on whole blood immunomarkers to identify an inflammation-associated psychosis onset subgroup

Enrico, Paolo; Delvecchio, Giuseppe; Turtulici, Nunzio; Aronica, Rosario; Pigoni, Alessandro; Squarcina, Letizia; Villa, Filippo Maria; Rossetti, Maria Gloria; Scocco, Paolo; D’Agostino, Armando; Torresani, Stefano; Imbesi, Massimiliano; Bellini, F.; Veronese, Angelo; Bocchio-Chiavetto, L.; Balestrieri, Matteo; Colombo, Gualtiero I.; Finardi, Annamaria; Furlan, Roberto; Brambilla, Paolo; Ruggeri, Mirella; Bertani, Maria Elena; Bissoli, Sarah; Bonetto, Chiara; Cristofalo, Doriana; Santi, Katia De; Lasalvia, Antonio; Lunardi, Silvia; Poli, Sara; Tosato, Sarah; Zamboni, Maria Grazia; Ballarin, Mario; Girolamo, Giovanni de; Fioritti, Angelo; Neri, Giovanni; Pileggi, Francesca; Rucci, Paola; Gennarelli, Massimo; Bocchio-Chiavetto, Luisella; Scasselatti, Catia; Zanardini, Roberta; Brambilla, Paolo; Bertoldo, Alessandra; Marinelli, Veronica; Negretto, Valentina; Perlini, Cinzia; Rambaldelli, Gianluca

doi:10.1038/s41380-022-01911-1

Cited by 8 publications

(5 citation statements)

References 73 publications

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“…Disturbances of immune-regulatory processes have been observed during FEP, including the over-activation of complement system components 17 – 19 , altered immune cell functions 20 , and differences in the absolute number of circulating immune cells 7 , 21 . In accordance with the above observations, more recent evidence has shown that the exacerbation of inflammatory responses might constitute a key pathogenic mechanism predisposing to psychosis onset, at least in a subgroup of individuals with FEP or schizophrenia characterized by higher inflammatory profile 2 , 22 . Similarly, observations for centrally increased levels of immune-inflammatory markers in cerebrospinal fluid (CSF) of patients with FEP denote the concurrent occurrence of enhanced neuroinflammatory processes in the brain 18 , 23 , possibly with detrimental effects on neuronal function 1 , 3 .…”

Section: Introductionsupporting

confidence: 72%

Elevated serum kynurenic acid in individuals with first-episode psychosis and insufficient response to antipsychotics

Hatzimanolis,

Foteli,

Xenaki

et al. 2024

Schizophr

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The tryptophan-metabolizing kynurenine pathway (KP) can be activated by enhanced inflammatory responses and has been implicated in the pathophysiology of schizophrenia. However, there is little evidence for KP dysregulation in the early course of psychotic illness. We aimed to investigate the potential immune-mediated hyperactivity of KP in individuals with first-episode psychosis (FEP) and the relationship with symptom severity and treatment response outcomes. Serum immunoassays were performed to measure peripheral levels of inflammatory cytokines (IL-1β, IL-10, TNF-a), KP rate-limiting enzymes (IDO/TDO), and kynurenic acid (KYNA) metabolite in 104 antipsychotic-naïve patients with FEP and 80 healthy controls (HC). The Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning Scale (GAF) were administered to assess psychopathology and functioning status at admission and following 4-week treatment with antipsychotics. Cytokine and KP components levels were substantially increased in FEP patients compared to HC, before and after antipsychotic treatment. A significant positive correlation between pro-inflammatory IL-1β and KYNA levels was observed among FEP patients, but not in HC. Importantly, within-patient analysis revealed that those with higher baseline KYNA experienced more severe negative symptoms and poorer clinical improvement at follow-up. These findings suggest that KP is upregulated in early psychosis, likely through the induction of IL-1β-dependent pathways, and raised peripheral KYNA might represent a promising indicator of non-response to antipsychotic medication in patients with FEP.

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Section: Introductionsupporting

confidence: 72%

Elevated serum kynurenic acid in individuals with first-episode psychosis and insufficient response to antipsychotics

Hatzimanolis,

Foteli,

Xenaki

et al. 2024

Schizophr

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“…Moreover, while a meta-analysis by Pilinger et al (2019) on peripheral immune parameters in psychosis showed elevated cytokines, it did not support an immune subgroup hypothesis after adjusting for confounders (87). Contrarily, Enrico et al (2023) identified a subgroup of FEP patients with high expression of inflammatory and immune-activating genes (IL1B, CCR7, IL12A, and CXCR3), suggesting heterogeneity within the condition (88).…”

Section: Potential Biomarkers For Schizophrenia Diagnosis and Treatmentmentioning

confidence: 97%

“…Contrarily, Enrico et al. (2023) identified a subgroup of FEP patients with high expression of inflammatory and immune-activating genes (IL1B, CCR7, IL12A, and CXCR3), suggesting heterogeneity within the condition ( 88 ).…”

Section: Potential Biomarkers For Schizophrenia Diagnosis and Treatmentmentioning

confidence: 99%

Neuroinflammation and schizophrenia – is there a link?

Chaves,

Dursun,

Tusconi

et al. 2024

Front. Psychiatry

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“…Given not all SCZ patients show elevated inflammatory markers, the debate of inflammatory subgroups seems obvious. Using different methods such as machine learning ( Enrico et al, 2023 ) or principal component analysis, it was thought that about 30–50% of all patients suffering from psychosis can be in included in a subgroup with elevated inflammatory markers ( Tamminga et al, 2021 ; Bishop et al, 2022 ). These patients have shown to have a more impaired cognitive function than a comparable group with psychosis and a low inflammation status ( Sæther et al, 2023 ).…”

Section: Microglia-neuron Interactions In Schizophrenia Patientsmentioning

confidence: 99%

Microglia-neuron interactions in schizophrenia

Hartmann,

Heider,

Wüst

et al. 2024

Front. Cell. Neurosci.

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Multiple lines of evidence implicate increased neuroinflammation mediated by glial cells to play a key role in neurodevelopmental disorders such as schizophrenia. Microglia, which are the primary innate immune cells of the brain, are crucial for the refinement of the synaptic circuitry during early brain development by synaptic pruning and the regulation of synaptic plasticity during adulthood. Schizophrenia risk factors as genetics or environmental influences may further be linked to increased activation of microglia, an increase of pro-inflammatory cytokine levels and activation of the inflammasome resulting in an overall elevated neuroinflammatory state in patients. Synaptic loss, one of the central pathological hallmarks of schizophrenia, is believed to be due to excess removal of synapses by activated microglia, primarily affecting glutamatergic neurons. Therefore, it is crucial to investigate microglia-neuron interactions, which has been done by multiple studies focusing on post-mortem brain tissues, brain imaging, animal models and patient iPSC-derived 2D culture systems. In this review, we summarize the major findings in patients and in vivo and in vitro models in the context of neuron-microglia interactions in schizophrenia and secondly discuss the potential of anti-inflammatory treatments for the alleviation of positive, negative, and cognitive symptoms.

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A machine learning approach on whole blood immunomarkers to identify an inflammation-associated psychosis onset subgroup

Cited by 8 publications

References 73 publications

Elevated serum kynurenic acid in individuals with first-episode psychosis and insufficient response to antipsychotics

Elevated serum kynurenic acid in individuals with first-episode psychosis and insufficient response to antipsychotics

Neuroinflammation and schizophrenia – is there a link?

Microglia-neuron interactions in schizophrenia

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