Diagnostic model development for schizophrenia based on peripheral blood mononuclear cell subtype-specific expression of metabolic markers

Abstract

A significant proportion of the personal and economic burden of schizophrenia can be attributed to the late diagnosis or misdiagnosis of the disorder. A novel, objective diagnostic approaches could facilitate the early detection and treatment of schizophrenia and improve patient outcomes. In the present study, we aimed to identify robust schizophrenia-specific blood biomarkers, with the goal of developing an accurate diagnostic model. The levels of selected serum and peripheral blood mononuclear cell (PBMC) markers relevant to metabolic and immune function were measured in healthy controls (n = 26) and recent-onset schizophrenia patients (n = 36) using multiplexed immunoassays and flow cytometry. Analysis of covariance revealed significant upregulation of insulin receptor (IR) and fatty acid translocase (CD36) levels in T helper cells (F = 10.75, P = 0.002, Q = 0.024 and F = 21.58, P = 2.8 × 10−5, Q = 0.0004, respectively), as well as downregulation of glucose transporter 1 (GLUT1) expression in monocytes (F = 21.46, P = 2.9 × 10−5, Q = 0.0004). The most robust predictors, monocyte GLUT1 and T helper cell CD36, were used to develop a diagnostic model, which showed a leave-one-out cross-validated area under the receiver operating characteristic curve (AUC) of 0.78 (95% CI: 0.66–0.92). The diagnostic model was validated in two independent datasets. The model was able to distinguish first-onset, drug-naïve schizophrenia patients (n = 34) from healthy controls (n = 39) with an AUC of 0.75 (95% CI: 0.64–0.86), and also differentiated schizophrenia patients (n = 22) from patients with other neuropsychiatric conditions, including bipolar disorder, major depressive disorder and autism spectrum disorder (n = 68), with an AUC of 0.83 (95% CI: 0.75–0.92). These findings indicate that PBMC-derived biomarkers have the potential to support an accurate and objective differential diagnosis of schizophrenia.

Retinoid homeostasis in major depressive disorder

“…PBMC is a widely used model to study person-specific cell dynamics and is increasingly used as a source of biomarkers for diagnostics and prediction [ 35 – 37 ]. The crude microsomal fractions derived from the individual PBMC contain metabolic enzymes like CYPs that are involved in the turnover of drugs or endogenous substrates such as retinoids and are thus often used to study metabolic pathways.…”

Microglia and Other Cellular Mediators of Immunological Dysfunction in Schizophrenia: A Narrative Synthesis of Clinical Findings

“…Of potential clinical utility is the presence of various monocyte-specific markers for treatment response monitoring and differential diagnosis of SCZ. Specifically, reduced glucose transporter (GLUT1) expression in monocytes has been proposed as a key diagnostic feature to distinguish SCZ from BD, MDD, and autistic spectrum disorder [ 89 ], while soluble CD14, an identity marker of circulating monocytes, could accurately predict subsequent SCZ diagnosis [ 90 ]. A monocytic transcription signature was also proposed as a candidate marker for monitoring beneficial simvastatin response in patients with SCZ [ 91 ].…”

“…Monocytes Increased total monocyte counts [62][63][64] Increased classical monocyte counts [66] Increased pro-inflammatory monocyte counts [67] Increased monocyte to lymphocyte ratio [68] Increased monocyte to HDL ratio [72,73] Increased TREM1/2 [79,80] Increased ATF3/EGR3 [78] Increased HLA-DR [82] Increased phagocytosis [81] Increased IL-1, IL-6, TNF-α [83,85,86] Increased CD36 [93] Increased reactive oxygen species [92] Alterations in TLR4 signaling [84,87,88] Unique interferon gene signature [77] Reduced GLUT1 [89] Granulocytes Increased neutrophil counts [68,94-99] Increased neutrophil to lymphocyte ratio [100,101] Increased oxidative stress [108] Increased malonaldehyde [122] Increased superoxide anion [123,123] Increased phagocytosis [81,124] Natural killer cells Increased total counts [68] Decreased total counts [125][126][127] No change in total counts [128] Increased cytotoxicity [132] Decreased cytotoxicity [129,130] No change in cytotoxicity [121] Increased NKG2C [133] Increased S100B [134] Table 1. Cont.…”

Elevated SCN11A concentrations associated with lower serum lipid levels in patients with major depressive disorder

“…In addition, the absence of a specific molecular basis for diagnosis in psychiatry at this time prevents the creation of diagnostic tools, and diagnosis in MDD is still reliant on symptomatology. In recent years, peripheral tissues, such as blood, are gradually being used to study psychiatric illnesses [15][16][17][18], and some molecular mediators found in these studies may be used as possible biomarkers [19][20][21][22]. Thus, serum investigations are necessary to understand how they function in MDD and if they have potential as candidate biomarkers for the diagnosis of MDD.…”