Exploring the Association Between Heavy Metals, TNF-α Regulation, and Cognitive Dysfunction in Schizophrenia

The presence of hazardous heavy metals (HMs) in the environment is well established, and numerous studies have explored their involvement in brain-related disorders. However, their potential impact on neuroinflammation, disease severity, and cognitive function in schizophrenia (SZ) remains largely unexplored. Therefore, this study aimed to investigate the potential pathophysiological role of environmental HMs in SZ. A total of 40 SZ patients and 40 healthy controls (HCs) were recruited from AIIMS Jodhpur, India. Blood samples were analyzed for lead (Pb), cadmium (Cd), arsenic (As), aluminium (Al), and TNF-α using atomic absorption spectroscopy and ELISA, while TNF-α gene expression was quantified using RT-qPCR. Patients exhibited notably elevated concentrations of Cd and Pb while decreased levels of As with median (IQR), 0.9 (0.40-1.72); 1.11 (0.59-1.26); and 0.73 (0.46-0.89) compared to HCs with median (IQR), 0.75 (0.46-1.06); 0.11 (0.04-0.18); and 0.92 (0.65-1.60) respectively. A significant positive relationship between TNF-α gene expression and blood As (ρ = 0.33, p < 0.05) and a negative association between Pb and Al (ρ = -0.34; p < 0.05) were reported in the patient group. Cognitive focus test scores were significantly lower in patients than in controls (p < 0.001). Cd levels negatively correlated with Stroop Word, Stroop Color, Color-Word, and Stroop Total scores (ρ =  - 0.28, - 0.36, - 0.28, - 0.33), indicating cognitive dysfunction. Additionally, PANSS score correlated negatively with Stroop Word (ρ =  - 0.36) and Stroop Total (ρ =  - 0.35), while PANSS Total scores showed negative correlations with Stroop Total (ρ =  - 0.33) and Stroop Color (ρ =  - 0.34), linking higher disease severity to poorer cognitive performance. In conclusion, these findings provide novel insights into SZ pathophysiology, highlighting the neurotoxic impact of heavy metals on TNF-α regulation, neuroinflammation, and cognition. The relationship between cognitive function with Cd and disease severity underscores the importance of early intervention and environmental risk mitigation to protect brain function and overall health.