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. 2025 May 7;25(1):462.
doi: 10.1186/s12888-025-06905-1.

White matter hyperintensities, inflammation and cognitive impairments in drug-naïve first episode schizophrenia patients: a cross-sectional study

Yan Zhang  1   2   3 , Xiuxia Yuan  1   2   3 , Yu Zhang  1   2   3 , Yishao Chen  1   2   3 , Keju Su  1   2   3 , Kangkang Xue  4 , Suying Ding  5 , Jingfeng Chen  5 , Xiaoduo Fan  6 , Xueqin Song  7   8   9
Affiliations

White matter hyperintensities, inflammation and cognitive impairments in drug-naïve first episode schizophrenia patients: a cross-sectional study

Yan Zhang et al. BMC Psychiatry. .

Abstract

Background: Studies have reported that white matter hyperintensities (WMHs) are associated with disturbances in immune function, and the relationship between WMHs and cognitive impairments have been documented in various clinical populations. The present study was to examine the relationship between WMHs, immune function, and cognitive impairments in patients with schizophrenia (SCH) remains unknown.

Methods: A sample of 127 drug-naïve first episode SCH and 72 healthy controls (HCs) were included in this study. Serum levels of cytokines and oxidative stress indices were measured using enzyme-linked immunosorbent assay and microtiter plate method. WMHs were assessed using T2-weighted magnetic resonance imaging scanning, and cognitive performance was evaluated using the MATRICS Consensus Cognitive Battery.

Results: We found patients with SCH are more likely to present with WMHs compared with HCs (OR = 2.076, 95%CI 1.007-4.277, p = 0.048). SCH with WMHs displayed more pronounced cognitive deficits in domains including speed of processing, working memory, verbal learning, visual learning, reasoning, and problem-solving compared with patients without WMHs (p < 0.05). Correlation analysis showed that the volume of WMHs was negative correlated with the problem-solving score (r=-0.331, p = 0.042) in patients with SCH. Within the SCH group, patients with WMHs exhibited elevated levels of interleukin-2 (IL-2), reactive oxygen species (ROS), and superoxide dismutase (SOD), along with lower levels of serum interleukin-4 (IL-4) and interferon-γ (IFN-γ) compared with those without WMHs (p < 0.05). The mediation analyses demonstrated that serum levels of IFN-γ in SCH had fully indirect effects on cognitive function, mediated by the WMHs.

Conclusions: This study suggests that WMHs may play a vital mediating role in the relationship between inflammation, oxidative stress, and cognitive impairments in SCH. Future studies exploring the potential clinical utility of WMHs as biomarkers for early detection and intervention of SCH are warranted.

Keywords: Cognitive impairments; Inflammation; Oxidative stress indices; Schizophrenia; White matter hyperintensities.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The Ethics Committee of the First Affiliated Hospital of Zhengzhou University (Approval No. 2019-KY-0271) provided full ethical approval for this study, and written informed consent was obtained from all study participants before investigation. All studies were conducted in accordance with the Declaration of Helsinki, the Data Protection Act and other relevant guidelines and regulations. Written informed consent was obtained from all study participants and their parents or legal guardians. Consent for publication: The manuscript contains any information/images that the participant agrees to publish. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Relationship between the volume of WMHs and Cognitive performance in SCH Patients RPS: Problem-Solving; WMHV: the Volume of WMHs
Fig. 2
Fig. 2
Comparison of cytokines and Oxidative Stress Indices in SCH patients with and without WMHs A box-plot is a statistical graph for describing the discrete degree of a group of data. Box plot shows minimum (lower whiskers), maximum (upper whiskers), median (central line) and interquartile range (box margins). A: Serum levels of cytokines; IFN-γ: interferon-gamma; IL-4: Interleukin-4; IL-6: Interleukin-6; IL-2: Interleukin-2; B: oxidative stress indices; GSH: Reduced glutathione; SOD: Superoxide Dismutase; ROS: Reactive Oxygen Species; MDA: Malondialdehyde *p < 0.05;**p < 0.01
Fig. 3
Fig. 3
Mediation model of the interrelationships among serum levels of IFN-γ, presence of WMHs and Cognitive performance WM: Working Memory; Vis. Lrng: Visual Learning; RPS: Problem-solving *p < 0.05, **p < 0.01
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