{"paper_id":"2dce80ea-2856-4a2b-bce4-b24d8ee8a8f1","body_text":"Study on the Correlation between TDP-43, HDAC6, Prdx1 Proteins and Brain Oxygen Levels and Cognitive Function in Schizophrenia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Study on the Correlation between TDP-43, HDAC6, Prdx1 Proteins and Brain Oxygen Levels and Cognitive Function in Schizophrenia Ziling Tang, Han Zhang, Yanwen Lin, Ran Hu, Xiaoyue Hu, Xianlai Jin, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7125132/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Objective To analyze the expression levels of trans-activation regulatory DNA-binding protein 43 (TDP-43), histone deacetylase 6 (HDAC6), peroxiredoxin 1 (Prdx1), and brain-derived neurotrophic factor (BDNF) in patients with schizophrenia, and their correlation with oxida Brain Oxygen Levels and cognitive functions in schizophrenia. Methods According to the inclusion and exclusion criteria, seventy patients with schizophrenia were selected as the case group, while sixty-one healthy individuals undergoing physical examinations during the same period were recruited as the control group. The clinical symptoms of schizophrenia patients were assessed using the Positive and Negative Syndrome Scale (PANSS). Cognitive function was evaluated with the MATRICS Consensus Cognitive Battery (MCCB). Concentrations of TDP-43, HDAC6, Prdx1, and BDNF in peripheral blood were measured by enzyme-linked immunosorbent assay (ELISA) in both groups. Functional near-infrared spectroscopy was employed to measure the levels of oxy-hemoglobin (oxy-Hb) in the prefrontal cortex of the case and control groups. IBM SPSS 27.0 software was used to statistically analyze the correlations between the concentrations of TDP-43, HDAC6, Prdx1, and BDNF and clinical symptoms, cognitive function, and brain oxygen content in patients with schizophrenia. Results The serum levels of TDP-43 and HDAC6 in the case group were higher than those in the control group ( P < 0.05), while serum levels of Prdx1, oxy-Hb, and BDNF were lower ( P < 0.05). In the case group, TDP-43 expression was positively correlated with PANSS total score, PANSS negative symptoms ( P < 0.05); HDAC6 expression was positively correlated with positive symptoms ( P < 0.05); oxy-Hb levels were negatively correlated with PANSS negative symptoms and PANSS total score ( P < 0.01). TDP-43 concentration was negatively correlated with VEL-T scores ( P < 0.01), BDNF concentration is positively correlated with SOP-T scores( P < 0.05), and oxy-Hb levels were positively correlated with VEL-T scores ( P < 0.01). Negative scale scores were negatively correlated with VEL-T scores in the case group ( P < 0.05). Conclusion Abnormal expression of serum TDP-43, HDAC6, and Prdx1 may be involved in the Brain Oxygen Levels in schizophrenia and are correlated to varying degrees with clinical symptoms and cognitive dysfunctions in schizophrenia, though these findings should be confirmed by more detailed and longitudinal studies. Transactivation regulatory DNA-binding protein 43 Oxyhemoglobin Oxidative stress Schizophrenia Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction Schizophrenia is a mental disorder primarily characterized by cognitive dysfunction, and the study of its etiology and pathogenesis remains a challenge [ 1 ] . Oxidative stress has been proven to play a crucial role in the pathogenesis of schizophrenia [ 2 ] , thus assessing oxidative damage in schizophrenia is a current research focus. Trans-activation regulatory DNA-binding protein 43 (TAR DNA-binding Protein 43, TDP-43) is an RNA/DNA binding protein involved in RNA biogenesis and processing, with abnormal localization, accumulation, and expression implicated in various neurodegenerative and brain injury diseases. Previous studies have shown that overexpression of TDP-43 induces mitochondrial accumulation of TDP-43, which leads to the production of reactive oxygen species (ROS). Prolonged ROS production further causes oxidative stress in TDP-43 expressing cells and exacerbates other cellular dysfunctions [ 3 ] . Other research indicates that oxidative stress results in mitochondrial DNA degradation [ 4 ] , with mitochondrial DNA copy number positively correlating with cognitive function [ 5 ] . Research by Tann JY et al. suggests that decreased TDP-43 expression induces the production of Sortilin, a soluble Vps10p domain sorting receptor, which impairs the sorting and activity-dependent secretion of brain-derived neurotrophic factor (BDNF) in regulated pathways in mouse hippocampal neurons, indicating that TDP-43 may directly influence BDNF expression and secretion [ 6 ] . Particularly in the hippocampus, this neurotrophic factor is thought to act on pre- and post-synaptic compartments, regulating synaptic efficacy by altering presynaptic neurotransmitter release or by increasing the sensitivity of postsynaptic neurotransmitters to induce long-term increases in synaptic plasticity [ 7 ] . Histone deacetylase 6 (HDAC6) is part of the histone deacetylase family, and extensive research indicates that histone deacetylases (HDACs) have a significant regulatory function in neurological disorders, where their inhibitors can offer neuroprotection [ 8 ] . In pathological states, HDAC6 impairs synaptic function, resulting in decreased transcriptional regulation and BDNF expression, and lower BDNF levels have been proven to impact cognitive function in schizophrenia [ 9 ] . Fiesel FC's research group proposed in 2009 that reduced TDP-43 expression results in HDAC6 downregulation [ 10 ] . In human stem cell experiments, Fazal R and colleagues noted that pharmacological inhibition of HDAC6 ameliorated the observed reduction in TDP-43 mitochondrial transport and axonal transport defects [ 11 ] . These findings further suggest that HDAC6 might serve as a downstream target of TDP-43, involved in neural signal transduction through the regulation of mitochondria, axons, and other components. Peroxiredoxin 1 (Prdx1) belongs to the antioxidant enzyme protein family. Recent research has determined Prdx1's role in eliminating nuclear ROS and affecting aspartate metabolism through metabolic profiling of the DNA damage response, identifying Prdx1 as a critical factor in DNA damage monitoring. Aspartate levels are compromised in Prdx1-deficient cells, consequently reducing their capacity for new nucleotide synthesis, leading to replication stress and DNA damage [ 12 ] . In patients with irritable bowel syndrome, research by Zhang Y et al. found that high serum expression of Prdx1 is accompanied by low expression of serum BDNF [ 13 ] , which may indicate a certain correlation between Prdx1 and cognitive function. Earlier research has indicated that Prdx1 and Prdx2 are specific targets of HDAC6 deacetylase, with acetylated Prdx1 and Prdx2 accumulating in cells deficient in HDAC6 deacetylase activity [ 14 ] . We have also sought substantial theoretical evidence to support whether the peripheral blood concentrations of TDP-43, HDAC6, and Prdx1 can reflect central nervous system conditions. In a landmark study published in Nature Medicine last year, researchers proposed that although TDP-43 itself cannot cross the blood-brain barrier, certain extracellular vesicles (EVs) carrying TDP-43 can traverse the blood-brain barrier, and the TDP-43 protein within these EVs can directly reflect pathological changes in the central nervous system [ 15 ] , Therefore, we believe that the concentration of TDP-43 detected peripherally may, to some extent, reflect central TDP-43 status. Currently, there is no clear evidence that HDAC6 and Prdx1 can cross the blood-brain barrier, but numerous studies have confirmed their important roles in maintaining the physiological function of the blood-brain barrier [ 16 – 17 ] , Furthermore, previous studies have confirmed that in various pathological conditions, increased blood-brain barrier permeability may allow the entry of macromolecules [ 18 – 19 ] ,indicating that it is indeed possible for HDAC6 and Prdx1 to cross the blood-brain barrier, perhaps via encapsulation in exosomes or other mechanisms, though more experimental evidence is needed. Our previous study has demonstrated that serum levels of BDNF, PI3K, and CREB in first-episode schizophrenia patients are lower than in healthy controls, while AKT levels are higher than those in the control group [ 20 ] . It has been reported that the binding of BDNF to its high-affinity receptor, tropomyosin-related kinase B (TrkB), leads to TrkB phosphorylation, thereby activating three important downstream intracellular signaling cascades in neurons, including the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), phospholipase C-gamma (PLCγ), and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways [ 21 ] . In a recent study on cognitive impairment in schizophrenia, mice exposed to cuprizone were used as a schizophrenia model, and cognitive function was evaluated, leading to the conclusion that the MAPK and PI3K-Akt signaling pathways may be related to demyelination and cognitive deficits, respectively [ 22 ] . Synthesizing the above research findings, we can speculate that TDP-43, HDAC6, and Prdx1 may collectively participate in and regulate the expression of BDNF, thereby influencing the cellular signal transduction of the PI3K/AKT pathway. Hence, we propose a hypothesis that the pathophysiological mechanism of cognitive impairment in first-episode schizophrenia patients may be related to changes in BDNF, TDP-43, HDAC6, Prdx1, PI3K/AKT pathway, and blood oxygen levels in the corresponding cellular signaling pathways, as shown in Fig. 1 . As shown in the figure above, the TDP-43/HDAC6/Prdx1 pathway plays a role in regulating blood oxygen levels in schizophrenia. Through its influence on BDNF expression and PI3K/AKT pathway signal transduction, it indirectly affects the formation and development of synapses, including dendrites and axons, ultimately reducing synaptic plasticity and leading to cognitive impairment. The study by OuY et al. found that in human microglial cells and peripheral blood of patients with obstructive sleep apnea syndrome, the expression level of TDP-43 is positively correlated with the expression level of HDAC6, while the expression levels of these two are negatively correlated with the expression level of Prdx1 and the overall cognitive function of patients [ 23 ] . However, there is no research reporting whether the TDP-43/HDAC6/Prdx1 pathway is associated with oxidative stress response and cognitive decline in schizophrenia. Based on this, this paper investigates the expression levels of TDP-43, HDAC6, and Prdx1 proteins in schizophrenia patients and their correlation with cognitive impairment, as reported below. Materials and Methods 1.1 Study Subjects 70 cases of first-episode, drug-naïve schizophrenia patients treated at our hospital from September 2022 to September 2024 were selected as the case group, with inclusion criteria as follows: (1) Meeting the diagnostic criteria for schizophrenia according to the International Classification of Diseases, Tenth Revision (ICD-10);(2) First-episode patients who have not taken medication or relapsed patients who have been off medication for over two months;(3) Male and female patients aged between 18 and 60 years, with good compliance and ability to cooperate with PANSS scale, MCCB test, and Functional Near-Infrared Spectroscopy(fNIRS) examination; (4) A PANSS scale total score of > 60; ; (5) No history of electroconvulsive therapy; (6) Informed consent obtained from the patient or their relatives. Exclusion criteria included: (1) Patients with past or current central nervous system diseases such as encephalitis or epilepsy; (2) Patients with past or current immune, endocrine, or metabolic disorders; (3) Patients with a history or current presence of substance abuse; (4) Women who are pregnant or breastfeeding; (5) Patients exhibiting significant impulsivity or lack of cooperation. Sixty-one healthy individuals undergoing physical examination during the same period were chosen as the healthy group, with no psychiatric disorders, all voluntarily participating in the study, and subject to the same exclusion criteria as the case group. All subjects in this study provided informed consent, conforming to medical ethical standards and approved by the Medical Ethics Committee of our hospital. 1.2 Research Methods 1.2.1 Determination of Serum TDP-43, HDAC6, Prdx1, BDNF: 4ml of fasting elbow venous blood was drawn from all subjects before treatment in the morning, centrifuged at 3000 r/min for 15 minutes to collect the serum, which was then stored at -80°C until analysis. The levels of serum TDP-43, HDAC6, Prdx1, and BDNF were determined using the ELISA method. A series of standard solutions were prepared following the kit instructions, and their absorbance at 450 nm was measured using a microplate reader to construct a standard curve. The absorbance of samples was measured, and the serum levels of TDP-43, HDAC6, Prdx1, and BDNF were calculated based on the standard curve. The kit was provided by Wuhan Huamei Bioengineering Co., Ltd. | The assay kits were supplied by Wuhan Huamei Bioengineering Co., Ltd. 1.2.2 Cognitive Assessment: All subjects were evaluated for cognitive ability using the MATRICS Consensus Cognitive Battery (MCCB) upon enrollment. The MCCB encompasses seven cognitive domains and nine dimensions. Given the subjects' cooperation and data completeness, this study focused on four cognitive domains and six dimensions from the MCCB: ① Speed of Processing (SOP) ② Verbal Learning (VEL) ③ Visual Learning (VIL) ④ Reasoning and Problem Solving (RPS), independently completed by two professionally trained psychiatrists, with the average of their scores taken as the final result. The results obtained from the assessment were raw scores, which were converted into standard T-scores. The higher the test scores, the better the cognitive ability. 1.2.3 Measurement of Oxidative Stress Indicators: A 37-channel near-infrared brain functional imaging device was used to detect changes in oxyhemoglobin (oxy-Hb) during tasks for all subjects upon enrollment, with a sampling frequency set at 20Hz. The testing task used a 150-second verbal fluency task (VFT) to induce changes in cerebral blood flow in the subjects. The specific design was: a 30-second pre-task period, a 60-second task period, and a 60-second recovery period. During the pre-task and recovery periods, subjects followed the system's voice prompts to count from 1 to 30. During the task period, subjects formed as many words as possible using the characters \"脸\" (face), \"半\" (half), \"妇\" (woman), and \"礼\" (ceremony), with each character given 15 seconds for word formation. The test was conducted in a quiet environment, with subjects seated on a chair, keeping their head and limbs as still as possible to minimize artifacts. The near-infrared brain functional imaging device was provided by Wuhan Union Rainbow Healthcare Technology Co., Ltd., as shown in Figs. 2 and 3 . 1.3 Statistical Methods Statistical analysis was performed using SPSS 27.0 software.The Shapiro-Wilk test was used to assess the normality of measurement data. Data conforming to a normal distribution were described as mean ± standard deviation (χ ± s), while non-normally distributed data were expressed as median ± interquartile range (M ± Q). The chi-square test (χ² test) was used for categorical data comparisons, and an independent samples t-test was applied to measurement data conforming to a normal distribution. Non-normally distributed measurement data were compared using the Wilcoxon signed-rank test to assess differences. Spearman correlation (for non-normally distributed variables) was used to analyze the relationships between PANSS scale scores, MCCB scale scores, oxy-Hb levels, and serum concentrations of TDP-43, HDAC6, and Prdx1, with graphs generated using GraphPad Prism 5.0 and Origin. A significance level of P < 0.05 was considered statistically significant. Results 2.1 Comparison of General Data Between the Two Groups : There were no statistically significant differences between the case group and the control group in terms of gender, age, education level, smoking status, and BMI ( P > 0.05), as shown in Table 1 . a, chi-square test; b, nonparametric test; c, t test. Table 1 Comparison of General Data Between the Two Groups Case Group(n = 70) Control Group (n = 61) t/Z/x² p Gender (Male/Female, n) 45/25 36/25 0.383 a 0.536 Age (years) 24.50 \\(\\:\\pm\\:4.50\\) 25.00 \\(\\:\\pm\\:3.00\\) 1.370 b 0.171 Education Level (years) 9.00 \\(\\:\\pm\\:\\) 3.00 9.00 \\(\\:\\pm\\:2.00\\) 1.804 b 0.071 Smoking Status (Yes/No, n) 28/42 24/37 0.006 a 0.939 BMI(kg/m²) 22.18 \\(\\:\\pm\\:\\) 5.04 23.44 \\(\\:\\pm\\:\\) 3.44 -1.695 c 0.093 2.2 Comparison of serum levels of TDP-43, HDAC6, and Prdx1 between the two groups : In the case group, serum TDP-43 and HDAC6 concentrations were higher (P < 0.05) and PRDX1 concentration was lower (P < 0.05) than in the control group, as demonstrated in Fig. 4 . 2.3 Comparison of oxyhemoglobin levels between the two groups : The oxyhemoglobin (oxy-Hb) in the case group was lower than in the control group (P < 0.01), as shown in Fig. 5 . 2.4 Comparison of brain-derived neurotrophic factor (BDNF) protein levels between the two groups : The BDNF in the case group was lower than in the control group (P < 0.01), as shown in Fig. 6 . 2.5 Correlation analysis of serum TDP-43, HDAC6, Prdx1 expression levels, oxy-Hb levels, and BDNF levels with PANSS in the case group : The total PANSS score and scores for positive symptoms, negative symptoms, and general psychopathology symptoms in the case group were (82.00 ± 8.00), (25.00 ± 6.25), (26.00 ± 6.00), and (32.00 ± 6.00) respectively. The results of Spearman correlation analysis showed that, at the clinical symptom level, the expression of TDP-43 in the serum of the case group was positively correlated with the total PANSS score and PANSS negative symptoms (P < 0.01), and the expression of HDAC6 was positively correlated with positive symptoms (P < 0.05). Meanwhile, the level of oxy-Hb was negatively correlated with the total PANSS score and PANSS negative symptoms (P < 0.01), and BDNF expression was negatively correlated with the total PANSS score (P < 0.05), with no other correlations observed. In terms of cognitive function, the concentration of TDP-43 in the case group was negatively correlated with the VEL-T score (P < 0.01), while the level of oxy-Hb was positively correlated with the VEL-T score (P < 0.01), and BDNF concentration was positively correlated with the SOP-T score (P < 0.05). The correlation analysis between clinical symptoms and cognitive function revealed that the negative scale score in the case group was negatively correlated with the VEL-T score (P < 0.05), as shown in Table 2 、Table 3 、Table 4 、Table 5 and Fig. 7 、Figure 8 . Table 2 Correlation of serum TDP-43, HDAC6 and Prdx1 expression levels with the PANSS scale TDP-43 rs P HDAC6 rs P Prdx1 rs P Total score 0.373 0.001 0.120 0.322 0.153 0.207 Positive scale score -0.016 0.898 0.237 0.048 * -0.033 0.789 Negative scale score 0.439 < 0.001 ** -0.023 0.849 0.216 0.072 General psychopathological scale score 0.162 0.181 -0.185 0.125 0.063 0.605 Table 3 Correlation of serum oxy-Hb levels, and BDNF levels with the PANSS scale oxy-Hb rs P BDNF rs P Total score -0.358 0.002 ** -0.244 0.040 * Positive scale score -0.021 0.860 -0.108 0.379 Negative scale score -0.358 0.002 ** 0.041 0.737 General psychopathological scale score -0.196 0.104 -0.159 0.191 Table 4 Correlation of serum TDP-43, HDAC6 and Prdx1 expression levels with the MCCB scale TDP-43 rs P HDAC6 rs P Prdx1 rs P SOP-T 0.126 0.298 0.021 0.862 0.008 0.951 VEL-T -0.316 0.008 ** 0.023 0.851 -0.041 0.737 VIL-T -0.111 0.360 0.001 0.995 -0.085 0.484 RPS-T -0.120 0.322 -0.041 0.737 -0.128 0.292 Table 5 Correlation of serum oxy-Hb levels, and BDNF levels with the MCCB scale oxy-Hb rs P BDNF rs P SOP-T 0.096 0.429 0.250 0.038 * VEL-T 0.330 0.005 ** 0.077 0.532 VIL-T 0.066 0.586 0.189 0.119 RPS-T 0.094 0.438 0.077 0.531 Discussion Current research has found that oxidative stress can affect cognitive impairment in schizophrenia through multiple pathways [ 24 – 25 ] . Our results showed that serum TDP-43 and HDAC6 levels were higher in the patient group than in the control group (P < 0.05), while serum Prdx1 and oxy-Hb levels were lower (P < 0.05). This suggests that significant oxidative stress responses may occur in both the peripheral and central systems of patients with schizophrenia, and that the hypoxic responses in these two systems may be consistent. These findings may indirectly support the notion that excessive reactive oxygen species can lead to blood-brain barrier damage [ 26 ] . Correlation analysis with the PANSS scale indicated that serum BDNF expression in the patient group was negatively correlated with the total PANSS score (P < 0.05). Previous studies have reported a significant negative correlation between BDNF and superoxide dismutase (SOD) in patients with schizophrenia [ 27 ] . This may reflect the interaction of oxidative damage, clinical symptoms, and neurotrophic factor dysfunction within the pathological mechanisms of schizophrenia. Previous studies have indicated that the disruption of the blood-brain barrier can enhance the interaction between the brain's innate immunity and peripheral adaptive immunity, thereby allowing harmful oxidative stress responses to persist in the body, which can continuously exacerbate the symptoms of schizophrenia [ 28 ] . However, the specific molecular biological mechanisms through which peripheral oxidative stress interacts with central oxidative stress still require further investigation. In the statistical analysis of MCCB test scores, we obtained the following results: In the case group, the concentration of TDP-43 was negatively correlated with the VEL-T score (P < 0.01), while the level of oxy-Hb was positively correlated with the VEL-T score (P < 0.01), which aligns with the research perspective proposed by Bryll A et al. that the imbalance of the antioxidant system in patients with schizophrenia leads to cognitive dysfunction [ 29 ] . Additionally, our findings indicate that the expression level of BDNF in the case group was lower than that in the control group in the statistical results, which may also reflect the cognitive impairment of patients with schizophrenia from another perspective. Our study has some limitations. This is a case-control study, which does not support the clarification of the causal relationship between serum protein factor indicators and cognitive impairment in patients with schizophrenia. Although the patient group only included treatment-naive patients with first-episode schizophrenia, there is still heterogeneity in the course of the illness, and future studies will consider appropriate stratification based on this. In our study, the number of included cases was limited, and only cross-sectional data were analyzed. In future studies, we will increase the sample size, conduct further longitudinal investigations, implement appropriate measures to minimize experimental errors, and monitor the improvement of cognitive function in patients. Conclusion Our research results indicate that first-episode schizophrenia patients exhibit significant signs of antioxidant system imbalance. TDP-43, HDAC6, and Prdx1 are not only associated with schizophrenia but also show varying degrees of correlation with cognitive impairment in schizophrenia. The interactions between serum protein factors may exacerbate the oxidative stress response. However, these findings should be validated through more detailed pathway studies and longitudinal research. In this study, our primary participants were first-episode schizophrenia patients, and we found that associated serum protein factors may help reduce the oxidative stress response, providing potential biomarkers for antioxidant therapy in schizophrenia. During clinical treatment, certain antipsychotic drugs like haloperidol and clozapine are commonly considered to worsen oxidative damage, which has led some researchers to explore antioxidant treatments for schizophrenia, such as N-acetylcysteine (NAC), ginkgo biloba, and vitamin E. These treatments have been confirmed to improve clinical symptoms and motor dysfunction in schizophrenia patients. However, since their mechanisms, applicability, and effectiveness remain uncertain, antioxidant treatments are currently considered only as adjunctive therapies [ 2 ] . In terms of improving the prognosis of schizophrenia and reducing the side effects of antipsychotic medications, further exploration of oxidative stress mechanisms in schizophrenia could lead to broader and more diverse therapeutic approaches. Declarations Funding This study was funded by Yunnan Health Training Projects of Highly Level Talents, China (Grant No. RLMY20200023), Sub-project of special fund of Yunnan Clinical Medical Research Center for Mental Disorders (Grant No. 202102AA100058) and Song Weihong Workstation, Yunnan Province (202305AF150180). Author Contribution Ziling Tang contributed to the conception and design of the project, data collection and analysis, and the writing and revision of the manuscript. Han Zhang, Yanwen Lin, Ran Hu, and Xiaoyue Hu contributed to data analysis. Xianlai Jin and Gaoxia Wen contributed to Investigation. All authors critically revised the draft version of the manuscript and approved the final manuscript. Peng Xiong participated in the conception and design, funding acquisition, resources, supervision, and interpretation of the research. Clinical trial number Not applicable. Data Availability The datasets presented in this article are not readily available because the data are currently part of a longitudinal study that is ongoing. However, they can be obtained by contacting the corresponding author. Requests to access the datasets should be directed to corresponding author [email protected] . Ethics approval and consent to participate All procedures have strictly followed the Declaration of Helsinki and other rules. And we also obtained the informed consent from all participants or their families. The studies involving human participants were reviewed and approved by the Ethics Review Board of Kunming Medical College First Affiliated Hospital [Ethics Review L No. 65(2022)]. Consent for publication Not applicable in this section. 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PMID: 28934193; PMCID: PMC5538118. Schreibelt G, Kooij G, Reijerkerk A, van Doorn R, Gringhuis SI, van der Pol S, Weksler BB, Romero IA, Couraud PO, Piontek J, Blasig IE, Dijkstra CD, Ronken E, de Vries HE. Reactive oxygen species alter brain endothelial tight junction dynamics via RhoA, PI3 kinase, and PKB signaling. FASEB J. 2007;21(13):3666–76. 10.1096/fj.07-8329com . Epub 2007 Jun 22. PMID: 17586731. Zhang XY, Chen DC, Tan YL, Tan SP, Wang ZR, Yang FD, Okusaga OO, Zunta-Soares GB, Soares JC. The interplay between BDNF and oxidative stress in chronic schizophrenia. Psychoneuroendocrinology. 2015;51:201–8. 10.1016/j.psyneuen.2014.09.029 . Epub 2014 Oct 7. PMID: 25462893. Shuvalova M, Dmitrieva A, Belousov V, Nosov G. The role of reactive oxygen species in the regulation of the blood-brain barrier. Tissue Barriers. 2024 May 29:2361202. doi: 10.1080/21688370.2024.2361202. Epub ahead of print. PMID: 3880858. Bryll A, Skrzypek J, Krzyściak W, Szelągowska M, Śmierciak N, Kozicz T, Popiela T. Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia. Biomolecules. 2020;10(3):384. 10.3390/biom10030384 . PMID: 32121669; PMCID: PMC7175146. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 08 Sep, 2025 Reviewers agreed at journal 17 Aug, 2025 Reviewers agreed at journal 14 Aug, 2025 Reviewers invited by journal 31 Jul, 2025 Editor invited by journal 29 Jul, 2025 Editor assigned by journal 28 Jul, 2025 Submission checks completed at journal 28 Jul, 2025 First submitted to journal 14 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-7125132\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":495194960,\"identity\":\"934b03c3-5773-42f8-9ee3-bb8f8cb2719d\",\"order_by\":0,\"name\":\"Ziling Tang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"First Affiliated Hospital of Kunming Medical University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ziling\",\"middleName\":\"\",\"lastName\":\"Tang\",\"suffix\":\"\"},{\"id\":495194961,\"identity\":\"33c00411-7aed-4eef-b5ac-e4a853f8ee92\",\"order_by\":1,\"name\":\"Han 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6\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":29909,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eComparison of BDNF levels\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage6.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7125132/v1/c41c8a25e2c7fab5f1006823.jpeg\"},{\"id\":88422579,\"identity\":\"f08bb6da-179e-4181-b769-8585cb29813e\",\"added_by\":\"auto\",\"created_at\":\"2025-08-06 09:37:03\",\"extension\":\"jpeg\",\"order_by\":7,\"title\":\"Figure 7\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":169659,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eCorrelation of serum TDP-43, HDAC6, Prdx1 expression levels, oxy-Hb levels, and BDNF levels with the PANSS 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10:01:03\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1344333,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7125132/v1/665baa81-c216-436f-8d48-5fa735065aa7.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Study on the Correlation between TDP-43, HDAC6, Prdx1 Proteins and Brain Oxygen Levels and Cognitive Function in Schizophrenia\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eSchizophrenia is a mental disorder primarily characterized by cognitive dysfunction, and the study of its etiology and pathogenesis remains a challenge\\u003csup\\u003e[\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]\\u003c/sup\\u003e. Oxidative stress has been proven to play a crucial role in the pathogenesis of schizophrenia\\u003csup\\u003e[\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]\\u003c/sup\\u003e, thus assessing oxidative damage in schizophrenia is a current research focus.\\u003c/p\\u003e\\u003cp\\u003eTrans-activation regulatory DNA-binding protein 43 (TAR DNA-binding Protein 43, TDP-43) is an RNA/DNA binding protein involved in RNA biogenesis and processing, with abnormal localization, accumulation, and expression implicated in various neurodegenerative and brain injury diseases. Previous studies have shown that overexpression of TDP-43 induces mitochondrial accumulation of TDP-43, which leads to the production of reactive oxygen species (ROS). Prolonged ROS production further causes oxidative stress in TDP-43 expressing cells and exacerbates other cellular dysfunctions\\u003csup\\u003e[\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]\\u003c/sup\\u003e. Other research indicates that oxidative stress results in mitochondrial DNA degradation\\u003csup\\u003e[\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]\\u003c/sup\\u003e, with mitochondrial DNA copy number positively correlating with cognitive function\\u003csup\\u003e[\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]\\u003c/sup\\u003e. Research by Tann JY et al. suggests that decreased TDP-43 expression induces the production of Sortilin, a soluble Vps10p domain sorting receptor, which impairs the sorting and activity-dependent secretion of brain-derived neurotrophic factor (BDNF) in regulated pathways in mouse hippocampal neurons, indicating that TDP-43 may directly influence BDNF expression and secretion\\u003csup\\u003e[\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]\\u003c/sup\\u003e. Particularly in the hippocampus, this neurotrophic factor is thought to act on pre- and post-synaptic compartments, regulating synaptic efficacy by altering presynaptic neurotransmitter release or by increasing the sensitivity of postsynaptic neurotransmitters to induce long-term increases in synaptic plasticity\\u003csup\\u003e[\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eHistone deacetylase 6 (HDAC6) is part of the histone deacetylase family, and extensive research indicates that histone deacetylases (HDACs) have a significant regulatory function in neurological disorders, where their inhibitors can offer neuroprotection\\u003csup\\u003e[\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]\\u003c/sup\\u003e. In pathological states, HDAC6 impairs synaptic function, resulting in decreased transcriptional regulation and BDNF expression, and lower BDNF levels have been proven to impact cognitive function in schizophrenia\\u003csup\\u003e[\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]\\u003c/sup\\u003e. Fiesel FC's research group proposed in 2009 that reduced TDP-43 expression results in HDAC6 downregulation\\u003csup\\u003e[\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]\\u003c/sup\\u003e. In human stem cell experiments, Fazal R and colleagues noted that pharmacological inhibition of HDAC6 ameliorated the observed reduction in TDP-43 mitochondrial transport and axonal transport defects\\u003csup\\u003e[\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e]\\u003c/sup\\u003e. These findings further suggest that HDAC6 might serve as a downstream target of TDP-43, involved in neural signal transduction through the regulation of mitochondria, axons, and other components.\\u003c/p\\u003e\\u003cp\\u003ePeroxiredoxin 1 (Prdx1) belongs to the antioxidant enzyme protein family. Recent research has determined Prdx1's role in eliminating nuclear ROS and affecting aspartate metabolism through metabolic profiling of the DNA damage response, identifying Prdx1 as a critical factor in DNA damage monitoring. Aspartate levels are compromised in Prdx1-deficient cells, consequently reducing their capacity for new nucleotide synthesis, leading to replication stress and DNA damage\\u003csup\\u003e[\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]\\u003c/sup\\u003e. In patients with irritable bowel syndrome, research by Zhang Y et al. found that high serum expression of Prdx1 is accompanied by low expression of serum BDNF\\u003csup\\u003e[\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]\\u003c/sup\\u003e, which may indicate a certain correlation between Prdx1 and cognitive function. Earlier research has indicated that Prdx1 and Prdx2 are specific targets of HDAC6 deacetylase, with acetylated Prdx1 and Prdx2 accumulating in cells deficient in HDAC6 deacetylase activity\\u003csup\\u003e[\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eWe have also sought substantial theoretical evidence to support whether the peripheral blood concentrations of TDP-43, HDAC6, and Prdx1 can reflect central nervous system conditions. In a landmark study published in Nature Medicine last year, researchers proposed that although TDP-43 itself cannot cross the blood-brain barrier, certain extracellular vesicles (EVs) carrying TDP-43 can traverse the blood-brain barrier, and the TDP-43 protein within these EVs can directly reflect pathological changes in the central nervous system\\u003csup\\u003e[\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]\\u003c/sup\\u003e, Therefore, we believe that the concentration of TDP-43 detected peripherally may, to some extent, reflect central TDP-43 status. Currently, there is no clear evidence that HDAC6 and Prdx1 can cross the blood-brain barrier, but numerous studies have confirmed their important roles in maintaining the physiological function of the blood-brain barrier\\u003csup\\u003e[\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e]\\u003c/sup\\u003e, Furthermore, previous studies have confirmed that in various pathological conditions, increased blood-brain barrier permeability may allow the entry of macromolecules\\u003csup\\u003e[\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e]\\u003c/sup\\u003e,indicating that it is indeed possible for HDAC6 and Prdx1 to cross the blood-brain barrier, perhaps via encapsulation in exosomes or other mechanisms, though more experimental evidence is needed.\\u003c/p\\u003e\\u003cp\\u003eOur previous study has demonstrated that serum levels of BDNF, PI3K, and CREB in first-episode schizophrenia patients are lower than in healthy controls, while AKT levels are higher than those in the control group\\u003csup\\u003e[\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]\\u003c/sup\\u003e. It has been reported that the binding of BDNF to its high-affinity receptor, tropomyosin-related kinase B (TrkB), leads to TrkB phosphorylation, thereby activating three important downstream intracellular signaling cascades in neurons, including the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), phospholipase C-gamma (PLCγ), and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways\\u003csup\\u003e[\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e]\\u003c/sup\\u003e. In a recent study on cognitive impairment in schizophrenia, mice exposed to cuprizone were used as a schizophrenia model, and cognitive function was evaluated, leading to the conclusion that the MAPK and PI3K-Akt signaling pathways may be related to demyelination and cognitive deficits, respectively\\u003csup\\u003e[\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e]\\u003c/sup\\u003e. Synthesizing the above research findings, we can speculate that TDP-43, HDAC6, and Prdx1 may collectively participate in and regulate the expression of BDNF, thereby influencing the cellular signal transduction of the PI3K/AKT pathway. Hence, we propose a hypothesis that the pathophysiological mechanism of cognitive impairment in first-episode schizophrenia patients may be related to changes in BDNF, TDP-43, HDAC6, Prdx1, PI3K/AKT pathway, and blood oxygen levels in the corresponding cellular signaling pathways, as shown in Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e.\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003eAs shown in the figure above, the TDP-43/HDAC6/Prdx1 pathway plays a role in regulating blood oxygen levels in schizophrenia. Through its influence on BDNF expression and PI3K/AKT pathway signal transduction, it indirectly affects the formation and development of synapses, including dendrites and axons, ultimately reducing synaptic plasticity and leading to cognitive impairment.\\u003c/p\\u003e\\u003cp\\u003eThe study by OuY et al. found that in human microglial cells and peripheral blood of patients with obstructive sleep apnea syndrome, the expression level of TDP-43 is positively correlated with the expression level of HDAC6, while the expression levels of these two are negatively correlated with the expression level of Prdx1 and the overall cognitive function of patients\\u003csup\\u003e[\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]\\u003c/sup\\u003e. However, there is no research reporting whether the TDP-43/HDAC6/Prdx1 pathway is associated with oxidative stress response and cognitive decline in schizophrenia. Based on this, this paper investigates the expression levels of TDP-43, HDAC6, and Prdx1 proteins in schizophrenia patients and their correlation with cognitive impairment, as reported below.\\u003c/p\\u003e\"},{\"header\":\"Materials and Methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e1.1 Study Subjects\\u003c/h2\\u003e\\u003cp\\u003e70 cases of first-episode, drug-na\\u0026iuml;ve schizophrenia patients treated at our hospital from September 2022 to September 2024 were selected as the case group, with inclusion criteria as follows: (1) Meeting the diagnostic criteria for schizophrenia according to the International Classification of Diseases, Tenth Revision (ICD-10);(2) First-episode patients who have not taken medication or relapsed patients who have been off medication for over two months;(3) Male and female patients aged between 18 and 60 years, with good compliance and ability to cooperate with PANSS scale, MCCB test, and Functional Near-Infrared Spectroscopy(fNIRS) examination; (4) A PANSS scale total score of \\u0026gt;\\u0026thinsp;60; ; (5) No history of electroconvulsive therapy; (6) Informed consent obtained from the patient or their relatives. Exclusion criteria included: (1) Patients with past or current central nervous system diseases such as encephalitis or epilepsy; (2) Patients with past or current immune, endocrine, or metabolic disorders; (3) Patients with a history or current presence of substance abuse; (4) Women who are pregnant or breastfeeding; (5) Patients exhibiting significant impulsivity or lack of cooperation. Sixty-one healthy individuals undergoing physical examination during the same period were chosen as the healthy group, with no psychiatric disorders, all voluntarily participating in the study, and subject to the same exclusion criteria as the case group. All subjects in this study provided informed consent, conforming to medical ethical standards and approved by the Medical Ethics Committee of our hospital.\\u003c/p\\u003e\\u003c/div\\u003e\\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e1.2 Research Methods\\u003c/h2\\u003e\\u003cp\\u003e1.2.1 Determination of Serum TDP-43, HDAC6, Prdx1, BDNF: 4ml of fasting elbow venous blood was drawn from all subjects before treatment in the morning, centrifuged at 3000 r/min for 15 minutes to collect the serum, which was then stored at -80\\u0026deg;C until analysis. The levels of serum TDP-43, HDAC6, Prdx1, and BDNF were determined using the ELISA method. A series of standard solutions were prepared following the kit instructions, and their absorbance at 450 nm was measured using a microplate reader to construct a standard curve. The absorbance of samples was measured, and the serum levels of TDP-43, HDAC6, Prdx1, and BDNF were calculated based on the standard curve. The kit was provided by Wuhan Huamei Bioengineering Co., Ltd. | The assay kits were supplied by Wuhan Huamei Bioengineering Co., Ltd.\\u003c/p\\u003e\\u003cp\\u003e1.2.2 Cognitive Assessment: All subjects were evaluated for cognitive ability using the MATRICS Consensus Cognitive Battery (MCCB) upon enrollment. The MCCB encompasses seven cognitive domains and nine dimensions. Given the subjects' cooperation and data completeness, this study focused on four cognitive domains and six dimensions from the MCCB: ① Speed of Processing (SOP) ② Verbal Learning (VEL) ③ Visual Learning (VIL) ④ Reasoning and Problem Solving (RPS), independently completed by two professionally trained psychiatrists, with the average of their scores taken as the final result. The results obtained from the assessment were raw scores, which were converted into standard T-scores. The higher the test scores, the better the cognitive ability.\\u003c/p\\u003e\\u003cp\\u003e1.2.3 Measurement of Oxidative Stress Indicators: A 37-channel near-infrared brain functional imaging device was used to detect changes in oxyhemoglobin (oxy-Hb) during tasks for all subjects upon enrollment, with a sampling frequency set at 20Hz. The testing task used a 150-second verbal fluency task (VFT) to induce changes in cerebral blood flow in the subjects. The specific design was: a 30-second pre-task period, a 60-second task period, and a 60-second recovery period. During the pre-task and recovery periods, subjects followed the system's voice prompts to count from 1 to 30. During the task period, subjects formed as many words as possible using the characters \\\"脸\\\" (face), \\\"半\\\" (half), \\\"妇\\\" (woman), and \\\"礼\\\" (ceremony), with each character given 15 seconds for word formation. The test was conducted in a quiet environment, with subjects seated on a chair, keeping their head and limbs as still as possible to minimize artifacts. The near-infrared brain functional imaging device was provided by Wuhan Union Rainbow Healthcare Technology Co., Ltd., as shown in Figs.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e and \\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e.\\u003c/p\\u003e\\u003c/div\\u003e\\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e1.3 Statistical Methods\\u003c/h2\\u003e\\u003cp\\u003eStatistical analysis was performed using SPSS 27.0 software.The Shapiro-Wilk test was used to assess the normality of measurement data. Data conforming to a normal distribution were described as mean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;standard deviation (χ\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;s), while non-normally distributed data were expressed as median\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;interquartile range (M\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;Q). The chi-square test (χ\\u0026sup2; test) was used for categorical data comparisons, and an independent samples t-test was applied to measurement data conforming to a normal distribution. Non-normally distributed measurement data were compared using the Wilcoxon signed-rank test to assess differences. Spearman correlation (for non-normally distributed variables) was used to analyze the relationships between PANSS scale scores, MCCB scale scores, oxy-Hb levels, and serum concentrations of TDP-43, HDAC6, and Prdx1, with graphs generated using GraphPad Prism 5.0 and Origin. A significance level of \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05 was considered statistically significant.\\u003c/p\\u003e\\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003e\\u003cb\\u003e2.1 Comparison of General Data Between the Two Groups\\u003c/b\\u003e: There were no statistically significant differences between the case group and the control group in terms of gender, age, education level, smoking status, and BMI (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026gt;\\u0026thinsp;0.05), as shown in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e. a, chi-square test; b, nonparametric test; c, t test.\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eComparison of General Data Between the Two Groups\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"12\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c9\\\" colnum=\\\"9\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c10\\\" colnum=\\\"10\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c11\\\" colnum=\\\"11\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c12\\\" colnum=\\\"12\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e\\u003cp\\u003eCase Group(n\\u0026thinsp;=\\u0026thinsp;70)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e\\u003cp\\u003eControl Group (n\\u0026thinsp;=\\u0026thinsp;61)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c7\\\" namest=\\\"c6\\\"\\u003e\\u003cp\\u003et/Z/x\\u0026sup2;\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c9\\\" namest=\\\"c8\\\"\\u003e\\u003cp\\u003e\\u003cem\\u003ep\\u003c/em\\u003e\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c12\\\" namest=\\\"c10\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e\\u003cp\\u003eGender\\u003c/p\\u003e\\u003cp\\u003e(Male/Female, n)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c4\\\" namest=\\\"c3\\\"\\u003e\\u003cp\\u003e45/25\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c6\\\" namest=\\\"c5\\\"\\u003e\\u003cp\\u003e36/25\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e\\u003cp\\u003e0.383\\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"4\\\" nameend=\\\"c12\\\" namest=\\\"c9\\\"\\u003e\\u003cp\\u003e0.536\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e\\u003cp\\u003eAge (years)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c4\\\" namest=\\\"c3\\\"\\u003e\\u003cp\\u003e24.50\\u003cspan class=\\\"InlineEquation\\\"\\u003e\\u003cspan class=\\\"mathinline\\\"\\u003e\\\\(\\\\:\\\\pm\\\\:4.50\\\\)\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c6\\\" namest=\\\"c5\\\"\\u003e\\u003cp\\u003e25.00\\u003cspan class=\\\"InlineEquation\\\"\\u003e\\u003cspan class=\\\"mathinline\\\"\\u003e\\\\(\\\\:\\\\pm\\\\:3.00\\\\)\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e\\u003cp\\u003e1.370\\u003csup\\u003eb\\u003c/sup\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"4\\\" nameend=\\\"c12\\\" namest=\\\"c9\\\"\\u003e\\u003cp\\u003e0.171\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e\\u003cp\\u003eEducation Level (years)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c4\\\" namest=\\\"c3\\\"\\u003e\\u003cp\\u003e9.00\\u003cspan class=\\\"InlineEquation\\\"\\u003e\\u003cspan class=\\\"mathinline\\\"\\u003e\\\\(\\\\:\\\\pm\\\\:\\\\)\\u003c/span\\u003e\\u003c/span\\u003e3.00\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c6\\\" namest=\\\"c5\\\"\\u003e\\u003cp\\u003e9.00\\u003cspan class=\\\"InlineEquation\\\"\\u003e\\u003cspan class=\\\"mathinline\\\"\\u003e\\\\(\\\\:\\\\pm\\\\:2.00\\\\)\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e\\u003cp\\u003e1.804\\u003csup\\u003eb\\u003c/sup\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c11\\\" namest=\\\"c9\\\"\\u003e\\u003cp\\u003e0.071\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c12\\\" namest=\\\"c12\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e\\u003cp\\u003eSmoking Status (Yes/No, n)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c4\\\" namest=\\\"c3\\\"\\u003e\\u003cp\\u003e28/42\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c6\\\" namest=\\\"c5\\\"\\u003e\\u003cp\\u003e24/37\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e\\u003cp\\u003e0.006\\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"4\\\" nameend=\\\"c12\\\" namest=\\\"c9\\\"\\u003e\\u003cp\\u003e0.939\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e\\u003cp\\u003eBMI(kg/m\\u0026sup2;)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c4\\\" namest=\\\"c3\\\"\\u003e\\u003cp\\u003e22.18\\u003cspan class=\\\"InlineEquation\\\"\\u003e\\u003cspan class=\\\"mathinline\\\"\\u003e\\\\(\\\\:\\\\pm\\\\:\\\\)\\u003c/span\\u003e\\u003c/span\\u003e5.04\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c6\\\" namest=\\\"c5\\\"\\u003e\\u003cp\\u003e23.44\\u003cspan class=\\\"InlineEquation\\\"\\u003e\\u003cspan class=\\\"mathinline\\\"\\u003e\\\\(\\\\:\\\\pm\\\\:\\\\)\\u003c/span\\u003e\\u003c/span\\u003e3.44\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e\\u003cp\\u003e-1.695\\u003csup\\u003ec\\u003c/sup\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c10\\\" namest=\\\"c9\\\"\\u003e\\u003cp\\u003e0.093\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c12\\\" namest=\\\"c11\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003e2.2 Comparison of serum levels of TDP-43, HDAC6, and Prdx1 between the two groups\\u003c/b\\u003e: In the case group, serum TDP-43 and HDAC6 concentrations were higher (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05) and PRDX1 concentration was lower (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05) than in the control group, as demonstrated in Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e.\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003e2.3 Comparison of oxyhemoglobin levels between the two groups\\u003c/b\\u003e: The oxyhemoglobin (oxy-Hb) in the case group was lower than in the control group (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01), as shown in Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig5\\\" class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003e.\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003e2.4 Comparison of brain-derived neurotrophic factor (BDNF) protein levels between the two groups\\u003c/b\\u003e: The BDNF in the case group was lower than in the control group (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01), as shown in Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig6\\\" class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003e.\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003e2.5 Correlation analysis of serum TDP-43, HDAC6, Prdx1 expression levels, oxy-Hb levels, and BDNF levels with PANSS in the case group\\u003c/b\\u003e: The total PANSS score and scores for positive symptoms, negative symptoms, and general psychopathology symptoms in the case group were (82.00\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;8.00), (25.00\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;6.25), (26.00\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;6.00), and (32.00\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;6.00) respectively. The results of Spearman correlation analysis showed that, at the clinical symptom level, the expression of TDP-43 in the serum of the case group was positively correlated with the total PANSS score and PANSS negative symptoms (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01), and the expression of HDAC6 was positively correlated with positive symptoms (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05). Meanwhile, the level of oxy-Hb was negatively correlated with the total PANSS score and PANSS negative symptoms (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01), and BDNF expression was negatively correlated with the total PANSS score (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05), with no other correlations observed. In terms of cognitive function, the concentration of TDP-43 in the case group was negatively correlated with the VEL-T score (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01), while the level of oxy-Hb was positively correlated with the VEL-T score (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01), and BDNF concentration was positively correlated with the SOP-T score (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05). The correlation analysis between clinical symptoms and cognitive function revealed that the negative scale score in the case group was negatively correlated with the VEL-T score (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05), as shown in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e、Table\\u0026nbsp;\\u003cspan refid=\\\"Tab3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e、Table\\u0026nbsp;\\u003cspan refid=\\\"Tab4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e、Table\\u0026nbsp;\\u003cspan refid=\\\"Tab5\\\" class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003e and Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig7\\\" class=\\\"InternalRef\\\"\\u003e7\\u003c/span\\u003e 、Figure \\u003cspan refid=\\\"Fig8\\\" class=\\\"InternalRef\\\"\\u003e8\\u003c/span\\u003e.\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eCorrelation of serum TDP-43, HDAC6 and Prdx1 expression levels with the PANSS scale\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"31\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c9\\\" colnum=\\\"9\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c10\\\" colnum=\\\"10\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c11\\\" colnum=\\\"11\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c12\\\" colnum=\\\"12\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c13\\\" colnum=\\\"13\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c14\\\" colnum=\\\"14\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c15\\\" colnum=\\\"15\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c16\\\" colnum=\\\"16\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c17\\\" colnum=\\\"17\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c18\\\" colnum=\\\"18\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c19\\\" colnum=\\\"19\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c20\\\" colnum=\\\"20\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c21\\\" colnum=\\\"21\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c22\\\" colnum=\\\"22\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c23\\\" colnum=\\\"23\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c24\\\" colnum=\\\"24\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c25\\\" colnum=\\\"25\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c26\\\" colnum=\\\"26\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c27\\\" colnum=\\\"27\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c28\\\" colnum=\\\"28\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c29\\\" colnum=\\\"29\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c30\\\" colnum=\\\"30\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c31\\\" colnum=\\\"31\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colspan=\\\"8\\\" nameend=\\\"c9\\\" namest=\\\"c2\\\"\\u003e\\u003cp\\u003eTDP-43\\u003c/p\\u003e\\u003cp\\u003ers \\u003cem\\u003eP\\u003c/em\\u003e\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colspan=\\\"13\\\" nameend=\\\"c22\\\" namest=\\\"c10\\\"\\u003e\\u003cp\\u003eHDAC6\\u003c/p\\u003e\\u003cp\\u003ers \\u003cem\\u003eP\\u003c/em\\u003e\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c27\\\" namest=\\\"c23\\\"\\u003e\\u003cp\\u003ePrdx1\\u003c/p\\u003e\\u003cp\\u003ers \\u003cem\\u003eP\\u003c/em\\u003e\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colspan=\\\"4\\\" nameend=\\\"c31\\\" namest=\\\"c28\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c3\\\" namest=\\\"c1\\\"\\u003e\\u003cp\\u003eTotal score\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c6\\\" namest=\\\"c4\\\"\\u003e\\u003cp\\u003e0.373\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c11\\\" namest=\\\"c7\\\"\\u003e\\u003cp\\u003e0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c14\\\" namest=\\\"c12\\\"\\u003e\\u003cp\\u003e0.120\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c19\\\" namest=\\\"c15\\\"\\u003e\\u003cp\\u003e0.322\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"4\\\" nameend=\\\"c23\\\" namest=\\\"c20\\\"\\u003e\\u003cp\\u003e0.153\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"6\\\" nameend=\\\"c29\\\" namest=\\\"c24\\\"\\u003e\\u003cp\\u003e0.207\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c31\\\" namest=\\\"c30\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c3\\\" namest=\\\"c1\\\"\\u003e\\u003cp\\u003ePositive scale score\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"4\\\" nameend=\\\"c7\\\" namest=\\\"c4\\\"\\u003e\\u003cp\\u003e-0.016\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c12\\\" namest=\\\"c8\\\"\\u003e\\u003cp\\u003e0.898\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c15\\\" namest=\\\"c13\\\"\\u003e\\u003cp\\u003e0.237\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c20\\\" namest=\\\"c16\\\"\\u003e\\u003cp\\u003e0.048\\u003csup\\u003e*\\u003c/sup\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"4\\\" nameend=\\\"c24\\\" namest=\\\"c21\\\"\\u003e\\u003cp\\u003e-0.033\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"7\\\" nameend=\\\"c31\\\" namest=\\\"c25\\\"\\u003e\\u003cp\\u003e0.789\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e\\u003cp\\u003eNegative scale score\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c5\\\" namest=\\\"c3\\\"\\u003e\\u003cp\\u003e0.439\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c10\\\" namest=\\\"c6\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003csup\\u003e**\\u003c/sup\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"6\\\" nameend=\\\"c16\\\" namest=\\\"c11\\\"\\u003e\\u003cp\\u003e-0.023\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c18\\\" namest=\\\"c17\\\"\\u003e\\u003cp\\u003e0.849\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"7\\\" nameend=\\\"c25\\\" namest=\\\"c19\\\"\\u003e\\u003cp\\u003e0.216\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c30\\\" namest=\\\"c26\\\"\\u003e\\u003cp\\u003e0.072\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c31\\\" namest=\\\"c31\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"4\\\" nameend=\\\"c4\\\" namest=\\\"c1\\\"\\u003e\\u003cp\\u003eGeneral psychopathological scale score\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"4\\\" nameend=\\\"c8\\\" namest=\\\"c5\\\"\\u003e\\u003cp\\u003e0.162\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c13\\\" namest=\\\"c9\\\"\\u003e\\u003cp\\u003e0.181\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"4\\\" nameend=\\\"c17\\\" namest=\\\"c14\\\"\\u003e\\u003cp\\u003e-0.185\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"4\\\" nameend=\\\"c21\\\" namest=\\\"c18\\\"\\u003e\\u003cp\\u003e0.125\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c26\\\" namest=\\\"c22\\\"\\u003e\\u003cp\\u003e0.063\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c28\\\" namest=\\\"c27\\\"\\u003e\\u003cp\\u003e0.605\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c31\\\" namest=\\\"c29\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab3\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 3\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eCorrelation of serum oxy-Hb levels, and BDNF levels with the PANSS scale\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"18\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c9\\\" colnum=\\\"9\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c10\\\" colnum=\\\"10\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c11\\\" colnum=\\\"11\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c12\\\" colnum=\\\"12\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c13\\\" colnum=\\\"13\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c14\\\" colnum=\\\"14\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c15\\\" colnum=\\\"15\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c16\\\" colnum=\\\"16\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c17\\\" colnum=\\\"17\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c18\\\" colnum=\\\"18\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colspan=\\\"9\\\" nameend=\\\"c10\\\" namest=\\\"c2\\\"\\u003e\\u003cp\\u003eoxy-Hb\\u003c/p\\u003e\\u003cp\\u003ers \\u003cem\\u003eP\\u003c/em\\u003e\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c15\\\" namest=\\\"c11\\\"\\u003e\\u003cp\\u003eBDNF\\u003c/p\\u003e\\u003cp\\u003ers \\u003cem\\u003eP\\u003c/em\\u003e\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c18\\\" namest=\\\"c16\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c3\\\" namest=\\\"c1\\\"\\u003e\\u003cp\\u003eTotal score\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e\\u003cp\\u003e-0.358\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c8\\\" namest=\\\"c6\\\"\\u003e\\u003cp\\u003e0.002\\u003csup\\u003e**\\u003c/sup\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c13\\\" namest=\\\"c9\\\"\\u003e\\u003cp\\u003e-0.244\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c18\\\" namest=\\\"c14\\\"\\u003e\\u003cp\\u003e0.040\\u003csup\\u003e*\\u003c/sup\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c3\\\" namest=\\\"c1\\\"\\u003e\\u003cp\\u003ePositive scale score\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e\\u003cp\\u003e-0.021\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c7\\\" namest=\\\"c6\\\"\\u003e\\u003cp\\u003e0.860\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c12\\\" namest=\\\"c8\\\"\\u003e\\u003cp\\u003e-0.108\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c17\\\" namest=\\\"c13\\\"\\u003e\\u003cp\\u003e0.379\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c18\\\" namest=\\\"c18\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c3\\\" namest=\\\"c1\\\"\\u003e\\u003cp\\u003eNegative scale 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align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e-0.196\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c6\\\" namest=\\\"c5\\\"\\u003e\\u003cp\\u003e0.104\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c11\\\" namest=\\\"c7\\\"\\u003e\\u003cp\\u003e-0.159\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c16\\\" namest=\\\"c12\\\"\\u003e\\u003cp\\u003e0.191\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c18\\\" namest=\\\"c17\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab4\\\" border=\\\"1\\\"\\u003e\\u003ccaption 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align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e\\u003cp\\u003e0.038\\u003csup\\u003e*\\u003c/sup\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c9\\\" namest=\\\"c9\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eVEL-T\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e\\u003cp\\u003e0.330\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e0.005\\u003csup\\u003e**\\u003c/sup\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c6\\\" namest=\\\"c5\\\"\\u003e\\u003cp\\u003e0.077\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e\\u003cp\\u003e0.532\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c9\\\" namest=\\\"c9\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eVIL-T\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e\\u003cp\\u003e0.066\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e0.586\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c6\\\" namest=\\\"c5\\\"\\u003e\\u003cp\\u003e0.189\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.119\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c9\\\" namest=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eRPS-T\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c3\\\" namest=\\\"c2\\\"\\u003e\\u003cp\\u003e0.094\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e0.438\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c6\\\" namest=\\\"c5\\\"\\u003e\\u003cp\\u003e0.077\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c9\\\" namest=\\\"c7\\\"\\u003e\\u003cp\\u003e0.531\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eCurrent research has found that oxidative stress can affect cognitive impairment in schizophrenia through multiple pathways\\u003csup\\u003e[\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e]\\u003c/sup\\u003e. Our results showed that serum TDP-43 and HDAC6 levels were higher in the patient group than in the control group (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05), while serum Prdx1 and oxy-Hb levels were lower (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05). This suggests that significant oxidative stress responses may occur in both the peripheral and central systems of patients with schizophrenia, and that the hypoxic responses in these two systems may be consistent. These findings may indirectly support the notion that excessive reactive oxygen species can lead to blood-brain barrier damage\\u003csup\\u003e[\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e]\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eCorrelation analysis with the PANSS scale indicated that serum BDNF expression in the patient group was negatively correlated with the total PANSS score (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05). Previous studies have reported a significant negative correlation between BDNF and superoxide dismutase (SOD) in patients with schizophrenia\\u003csup\\u003e[\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e]\\u003c/sup\\u003e. This may reflect the interaction of oxidative damage, clinical symptoms, and neurotrophic factor dysfunction within the pathological mechanisms of schizophrenia. Previous studies have indicated that the disruption of the blood-brain barrier can enhance the interaction between the brain's innate immunity and peripheral adaptive immunity, thereby allowing harmful oxidative stress responses to persist in the body, which can continuously exacerbate the symptoms of schizophrenia\\u003csup\\u003e[\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e]\\u003c/sup\\u003e. However, the specific molecular biological mechanisms through which peripheral oxidative stress interacts with central oxidative stress still require further investigation.\\u003c/p\\u003e\\u003cp\\u003eIn the statistical analysis of MCCB test scores, we obtained the following results: In the case group, the concentration of TDP-43 was negatively correlated with the VEL-T score (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01), while the level of oxy-Hb was positively correlated with the VEL-T score (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01), which aligns with the research perspective proposed by Bryll A et al. that the imbalance of the antioxidant system in patients with schizophrenia leads to cognitive dysfunction\\u003csup\\u003e[\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e]\\u003c/sup\\u003e. Additionally, our findings indicate that the expression level of BDNF in the case group was lower than that in the control group in the statistical results, which may also reflect the cognitive impairment of patients with schizophrenia from another perspective.\\u003c/p\\u003e\\u003cp\\u003eOur study has some limitations. This is a case-control study, which does not support the clarification of the causal relationship between serum protein factor indicators and cognitive impairment in patients with schizophrenia. Although the patient group only included treatment-naive patients with first-episode schizophrenia, there is still heterogeneity in the course of the illness, and future studies will consider appropriate stratification based on this. In our study, the number of included cases was limited, and only cross-sectional data were analyzed. In future studies, we will increase the sample size, conduct further longitudinal investigations, implement appropriate measures to minimize experimental errors, and monitor the improvement of cognitive function in patients.\\u003c/p\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003eOur research results indicate that first-episode schizophrenia patients exhibit significant signs of antioxidant system imbalance. TDP-43, HDAC6, and Prdx1 are not only associated with schizophrenia but also show varying degrees of correlation with cognitive impairment in schizophrenia. The interactions between serum protein factors may exacerbate the oxidative stress response. However, these findings should be validated through more detailed pathway studies and longitudinal research. In this study, our primary participants were first-episode schizophrenia patients, and we found that associated serum protein factors may help reduce the oxidative stress response, providing potential biomarkers for antioxidant therapy in schizophrenia. During clinical treatment, certain antipsychotic drugs like haloperidol and clozapine are commonly considered to worsen oxidative damage, which has led some researchers to explore antioxidant treatments for schizophrenia, such as N-acetylcysteine (NAC), ginkgo biloba, and vitamin E. These treatments have been confirmed to improve clinical symptoms and motor dysfunction in schizophrenia patients. However, since their mechanisms, applicability, and effectiveness remain uncertain, antioxidant treatments are currently considered only as adjunctive therapies\\u003csup\\u003e[\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]\\u003c/sup\\u003e. In terms of improving the prognosis of schizophrenia and reducing the side effects of antipsychotic medications, further exploration of oxidative stress mechanisms in schizophrenia could lead to broader and more diverse therapeutic approaches.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study was funded by Yunnan Health Training Projects of Highly Level Talents, China (Grant No. RLMY20200023), Sub-project of special fund of Yunnan Clinical Medical Research Center for Mental Disorders (Grant No. 202102AA100058) and Song Weihong Workstation, Yunnan Province (202305AF150180).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor Contribution\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eZiling Tang\\u0026nbsp;contributed to the conception and design of the project, data collection and analysis, and the writing and revision of the manuscript.\\u0026nbsp;Han Zhang,\\u0026nbsp;Yanwen Lin,\\u0026nbsp;Ran Hu, and\\u0026nbsp;Xiaoyue Hu\\u0026nbsp;contributed to data analysis.\\u0026nbsp;Xianlai Jin\\u0026nbsp;and\\u0026nbsp;Gaoxia Wen\\u0026nbsp;contributed to Investigation. All authors critically revised the draft version of the manuscript and approved the final manuscript.\\u0026nbsp;Peng Xiong\\u0026nbsp;participated in the conception and design, funding acquisition, resources, supervision, and interpretation of the research.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eClinical trial number\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eData Availability\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe datasets presented in this article are not readily available because the data are currently part of a longitudinal study that is ongoing. However, they can be obtained by contacting the corresponding author. Requests to access the datasets should be directed to corresponding author xp6945399@163.com.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEthics approval and consent to participate\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAll procedures have strictly followed the Declaration of Helsinki and other rules. And we also obtained the informed consent from all participants or their families.\\u003c/p\\u003e\\n\\u003cp\\u003eThe studies involving human participants were reviewed and approved by the Ethics Review Board of Kunming Medical College First Affiliated Hospital [Ethics Review L No. 65(2022)].\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable in this section.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAuthors declare that they have no competing interests.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eJauhar S, Johnstone M, McKenna PJ, Schizophrenia. 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PMID: 32121669; PMCID: PMC7175146.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-psychiatry\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"bpsy\",\"sideBox\":\"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/bpsy/default.aspx\",\"title\":\"BMC Psychiatry\",\"twitterHandle\":\"@BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Transactivation regulatory DNA-binding protein 43, Oxyhemoglobin, Oxidative stress, Schizophrenia\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7125132/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7125132/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eObjective\\u003c/h2\\u003e\\u003cp\\u003eTo analyze the expression levels of trans-activation regulatory DNA-binding protein 43 (TDP-43), histone deacetylase 6 (HDAC6), peroxiredoxin 1 (Prdx1), and brain-derived neurotrophic factor (BDNF) in patients with schizophrenia, and their correlation with oxida Brain Oxygen Levels and cognitive functions in schizophrenia.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e\\u003cp\\u003eAccording to the inclusion and exclusion criteria, seventy patients with schizophrenia were selected as the case group, while sixty-one healthy individuals undergoing physical examinations during the same period were recruited as the control group. The clinical symptoms of schizophrenia patients were assessed using the Positive and Negative Syndrome Scale (PANSS). Cognitive function was evaluated with the MATRICS Consensus Cognitive Battery (MCCB). Concentrations of TDP-43, HDAC6, Prdx1, and BDNF in peripheral blood were measured by enzyme-linked immunosorbent assay (ELISA) in both groups. Functional near-infrared spectroscopy was employed to measure the levels of oxy-hemoglobin (oxy-Hb) in the prefrontal cortex of the case and control groups. IBM SPSS 27.0 software was used to statistically analyze the correlations between the concentrations of TDP-43, HDAC6, Prdx1, and BDNF and clinical symptoms, cognitive function, and brain oxygen content in patients with schizophrenia.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e\\u003cp\\u003eThe serum levels of TDP-43 and HDAC6 in the case group were higher than those in the control group (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05), while serum levels of Prdx1, oxy-Hb, and BDNF were lower (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05). In the case group, TDP-43 expression was positively correlated with PANSS total score, PANSS negative symptoms (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05); HDAC6 expression was positively correlated with positive symptoms (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05); oxy-Hb levels were negatively correlated with PANSS negative symptoms and PANSS total score (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01). TDP-43 concentration was negatively correlated with VEL-T scores (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01), BDNF concentration is positively correlated with SOP-T scores(\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05), and oxy-Hb levels were positively correlated with VEL-T scores (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01). Negative scale scores were negatively correlated with VEL-T scores in the case group (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05).\\u003c/p\\u003e\\u003ch2\\u003eConclusion\\u003c/h2\\u003e\\u003cp\\u003eAbnormal expression of serum TDP-43, HDAC6, and Prdx1 may be involved in the Brain Oxygen Levels in schizophrenia and are correlated to varying degrees with clinical symptoms and cognitive dysfunctions in schizophrenia, though these findings should be confirmed by more detailed and longitudinal studies.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Study on the Correlation between TDP-43, HDAC6, Prdx1 Proteins and Brain Oxygen Levels and Cognitive Function in Schizophrenia\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-08-06 09:36:57\",\"doi\":\"10.21203/rs.3.rs-7125132/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-09-08T15:53:10+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"325876649993436743857117354521545058004\",\"date\":\"2025-08-17T07:41:12+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"325516733115565290727153988296091280810\",\"date\":\"2025-08-14T14:11:57+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2025-07-31T18:36:45+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvited\",\"content\":\"\",\"date\":\"2025-07-29T17:36:10+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2025-07-28T13:07:12+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2025-07-28T13:06:40+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"BMC Psychiatry\",\"date\":\"2025-07-15T01:37:01+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-psychiatry\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"bpsy\",\"sideBox\":\"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/bpsy/default.aspx\",\"title\":\"BMC Psychiatry\",\"twitterHandle\":\"@BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"4dd2755e-bebf-4c48-8524-95c510814224\",\"owner\":[],\"postedDate\":\"August 6th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"under-review\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-08-06T09:36:57+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-08-06 09:36:57\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7125132\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7125132\",\"identity\":\"rs-7125132\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}