Alterations of plasma cytokine biomarkers for identifying age at onset of schizophrenia with neurological soft signs

Abstract

Several studies have been suggested that immunity plays a part in neurodevelopment and schizophrenia pathogenesis. Early age of onset in schizophrenia is associated with genetic factors which affect neurodevelopment. This study aims to identify immune abnormalities associated with neurodevelopmental impairments in early-onset schizophrenia (EOS) and adult-onset schizophrenia (AOS) patients. We determined the plasma levels of six cytokines (IL-1β, IL-4, IL-6, IL-10, IL-12 and TNF-α) in schizophrenia patients and healthy controls. Measurements included neurological soft signs (NSS) to distinguish and subgroup those with neurodevelopmental impairments. The study included 210 schizophrenia patients, which were divided into 84 EOS and 126 AOS patients, as well as 122 healthy controls. We observed significant differences in levels of IL-4, IL-6 and IL-10 between EOS and AOS patients. The results demonstrated the area under ROC curve (AUC) of the IL-4 in EOS and healthy controls was 0.81. Moreover, these results indicated that AUC of the IL-4 and the combination of IL-4, IL-6 and IL-12 in EOS with NSS and healthy controls were 0.91 and 0.95. These cytokines are altered in EOS and schizophrenia patients with neurodevelopmental impairments and demonstrated good classification abilities. These findings manifested that both pro-and anti-inflammatory cytokines are contributed to the clinical and pathophysiological features of schizophrenia. Future works are expected to explore potential genetic effectors and predictors as well as therapeutic directions in personalized medicine for early-onset schizophrenia.

The Role of Cytokines in the Pathogenesis of Schizophrenia

“…Similarly, peripheral levels of IL-10 also appear to be unchanged relative to HC in the CHR and UHR populations [38,39]. Interestingly, reduced IL-10 peripheral levels relative to both other adult AChRs and HCs were demonstrated in AChR patients with early-onset psychosis [40], which is inconsistent with the results reported in other works [12,14].…”

“…No alterations of IL-4 levels were found in the blood of Sch [14] or CHR populations [38]. In addition, decreased IL-4 levels were observed in the chronic EOP population compared to adult AChR and HC, which may indicate that reduced peripheral levels of IL-4 are typical only of AChR patients with early-onset psychosis and comorbid minor neurological disorders [40].…”

“…There is evidence of reduced IL-1β levels in the CHR population as compared to HC [38], but a more recent meta-analysis by Misiak et al, including a larger sample of CHR and UHR patients, did not confirm such findings [39]. As regards chronic EOP patients, no significant differences in IL-1β levels were found compared to HC [40]. The results of meta-analyses concerning IL-1β CSF levels are also vastly inconclusive, showing their decreased [12], increased [41] or unaltered [42,43] values compared to HC, although some observations are based on rather small research samples [12].…”

“…Among others, its role is to promote the differentiation of Th into Th2 lymphocytes, and it also increases their cytotoxicity [34]. It is particularly important that it is also known to affect macrophages and microglial cells, and may have a neuroprotective effect by reducing their ability to induce oxidative stress [40]. In addition, it also plays a role in cognitive processes [11].…”

“…IL-6 is one of the most extensively investigated cytokines in schizophrenia research, and with the exception of the meta-analysis by Miller et al, which reported its unaltered levels in SCh patients [12], there are consistent reports of elevated peripheral and CSF levels compared to HC in all patient populations [13,14,[41][42][43], including chronic EOP, CHR and UHR patients [38][39][40]. Additionally, evidence suggests a significantly reduced variability in its levels compared to HC, which may indicate that elevated levels of IL-6 is a key element of the schizophrenia immunophenotype [37].…”