Neutrophil Count Is Associated With Reduced Gray Matter and Enlarged Ventricles in First-Episode Psychosis

Abstract

Although there is recent evidence that cells from the peripheral immune system can gain access to the central nervous system in certain conditions such as multiple sclerosis, their role has not been assessed in psychosis. Here, we aimed to explore whether blood cell count was associated with brain volume and/or clinical symptomatology. A total of 218 participants (137 first-episode psychosis patients [FEP] and 81 healthy controls [HC]) were included in the study. For each participant, a T1 structural image was acquired, from which brain tissue volumes were calculated. We found that, in FEP, neutrophil count was associated with reduced gray matter (GM) volume (β = -0.117, P < .001) and increased cerebrospinal fluid volume (β = 0.191, P = .007). No associations were observed in HC. GM reduction was generalized but more prominent in certain regions, notably the thalamus, the anterior insula, and the left Heschl's gyrus, among many others. Neutrophil count was also associated with the total PANSS score (β = 0.173, P = .038), including those items assessing hallucinations (β = 0.182, P = .028) and avolition (β = 0.197, P = .018). Several confounders, such as antipsychotic medication, body mass index, and smoking, were controlled for. Overall, the present study may represent the first indirect evidence of brain tissue loss associated with neutrophils in psychosis, and lends support to the hypothesis of a dysregulated immune system. Higher neutrophil count was also associated with more severe clinical symptomatology, which renders it a promising indicator of schizophrenia severity and could even give rise to new therapies.

Large-scale analysis of DNA methylation identifies cellular alterations in blood from psychosis patients and molecular biomarkers of treatment-resistant schizophrenia

“…Of note, because we can only derive proportion of cell types from whole blood DNA methylation data, and not actual counts, an increase in one or more cell types must be balanced by a decrease in one or more other cell types and an apparrent change in the proportion of one specific cell type does not mean that the actual abundance of that cell type is altered. Despite this, the results from DNA methylation-derived cell proportions are consistent with previous studies based on empirical cell abundance measures which have reported increased monocyte counts 67,68 , increased neutrophil counts 69,70 , increased monocyte to lymphocyte ratio 71,72 and increased neutrophil to lymphocyte ratio 71,73 in both schizophrenia and FEP patients compared to controls. Studies have also shown that higher neutrophil counts in schizophrenia patients correlate with a greater burden of positive symptoms 69 suggesting that variations in the number of neutrophils is a potential marker of disease severity 72 .…”

“…Despite this, the results from DNA methylation-derived cell proportions are consistent with previous studies based on empirical cell abundance measures which have reported increased monocyte counts 67,68 , increased neutrophil counts 69,70 , increased monocyte to lymphocyte ratio 71,72 and increased neutrophil to lymphocyte ratio 71,73 in both schizophrenia and FEP patients compared to controls. Studies have also shown that higher neutrophil counts in schizophrenia patients correlate with a greater burden of positive symptoms 69 suggesting that variations in the number of neutrophils is a potential marker of disease severity 72 . Our sub-analysis of treatment-resistant schizophrenia, which is associated with a higher number of positive symptoms 65 , found that the increase in granulocytes was primary driven by those with the more severe phenotype, supporting this hypothesis.…”

Innate Immune Cells and C-Reactive Protein in Acute First-Episode Psychosis and Schizophrenia: Relationship to Psychopathology and Treatment

“…A recent cross-sectional study combined magnetic resonance imaging of the brain and differential blood analyses and observed significantly increased neutrophil granulocytes in FEP patients ( n = 137) vs controls ( n = 81). 9 Neutrophil granulocytes were associated with reduced total brain gray matter. Their counts correlated with clinical symptom severity, namely total, positive and general Positive and Negative Syndrome Scale (PANSS) subscores, but not with PANSS negative scores.…”

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

“…The probable mechanism of the observed changes in psychosis may be associated with inflammatory disorders, dysregulation of the immune system [3,10], neurodevelopmental disorders, including genetic abnormalities, i.e., 22q11.2 (22q11DS) deletion [11,12], or neutrophil functioning in the severe forms of mental disorders [10]. Their higher levels strongly correlate with positive clinical symptoms, constituting a promising marker of disease progression [13]. In turn, the mentioned genetic disorders (22q11DS) are the cause of the limited growth of axons and dendrites, which impair the integrity of mitochondria and functioning of synapses in productive neurons [11].…”