The relationship between Urokinase-Plasminogen Activator Receptor (UPAR) and bipolar disorder: a case-control study, Egypt

The relationship between Urokinase-Plasminogen Activator Receptor (UPAR) and bipolar disorder: a case-control study, Egypt | 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 The relationship between Urokinase-Plasminogen Activator Receptor (UPAR) and bipolar disorder: a case-control study, Egypt Usama Mahmoud Youssef, Yasser Mohamed Raya, Mohammad Gamal Sehlo, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7947159/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Feb, 2026 Read the published version in Middle East Current Psychiatry → Version 1 posted 9 You are reading this latest preprint version Abstract Background Bipolar disorder (BD)- a leading cause of disability in young adults- lacks reliable biomarkers. This case-control study investigates soluble urokinase plasminogen activator receptor (suPAR), a protein bridging inflammation and neural repair, as a novel biomarker candidate among Egyptian patients with BD. Methods We compared 48 BD patients (DSM-5- diagnosis, confirmed via SCID-5-CV) and 48 age-/sex-matched controls. Sociodemographic data were collected from all participants using a standardized questionnaire, with additional clinical variables assessed exclusively in the bipolar disorder group. Symptom severity was assessed using Arabic-validated Hamilton Depression (HDRS-17) and Young Mania Rating Scale (YMRS). Fasting serum suPAR levels were quantified via ELISA. Results BD patients showed significantly lower suPAR versus controls, without significant associations with key clinical characteristics (as hospitalization, suicidality). ROC analysis identified suPAR ≤ 110.113 ng/ml with an optimal diagnostic cutoff (AUC = 0.758), with 83.3% sensitivity, 60.4% specificity, and 71.9% accuracy. Conclusions Reduced suPAR represents a potential trait biomarker in BD, reflecting impaired neural regeneration rather than episodic symptoms. Its strong diagnostic performance underscores clinical utility for early detection, while its role in axonal repair highlights new therapeutic targets. Bipolar disorder (BD) Urokinase-Plasminogen Activator Receptor (UPAR) Biomarker Egypt Figures Figure 1 Figure 2 Introduction BD is a complex, multifactorial neurodevelopmental disorder characterized by recurrent, fluctuating episodes of mood disturbance causing significant functional impairment and high suicide risk (15–17% lifetime attempt rate) (1). It is affecting 1–3% globally (40–50 million people), it ranks among the world's top causes of disability, with peak onset at ages 15–24 and substantial diagnostic delays (6–10 years) (2–4). According to DSM-5-TR and ICD-11 classifications, BD encompasses several subtypes: bipolar I disorder (defined by manic episodes often with psychosis or hospitalization), bipolar II disorder (marked by hypomanic and depressive episodes), cyclothymic disorder, and other specified variants (1). Etiologically, BD arises from gene-environment interactions: genome-wide studies implicate 298 risk loci (e.g., CACNA1C, ODZ4) and polygenic influences (70–90% heritability). At the same time, environmental triggers include childhood trauma (emotional abuse OR = 4.04), prenatal infections (Toxoplasma gondii OR = 1.52), and life stressors (5,6). Contemporary research prioritizes biomarker discovery, investigating inflammatory mediators (e.g., cytokines), neuroimaging correlates (such as prefrontal cortex thinning), and multi-omics approaches to elucidate the pathophysiology and enable precision diagnostics (7). Current biomarker investigations target pro-inflammatory agents (e.g., cytokines, acute-phase reactants), oxidative stress markers, neurotrophic factors, and neurophysiological indicators (1,8). For example, serum albumin-an inflammatory regulator-correlates inversely with symptom severity in mood episodes (8). The uPA system constitutes a protease system involving uPA, its receptor uPAR, and associated inhibitors (9). Soluble uPAR (suPAR)-a glycosylphosphatidylinositol (GPI)-anchored receptor derivative circulates in biofluids including plasma, serum, urine, and cerebrospinal fluid (CSF). This system critically modulates immune activation (10, 11) and exhibits biomarker potential, with elevated suPAR concentrations linked to neurological disorders (12), viral/bacterial infections (e.g., sepsis, tuberculosis), and systemic inflammation (13). Clinically, suPAR offers practical utility due to its minimal circadian fluctuation (14). Beyond inflammation, uPAR facilitates tissue regeneration (15) and central nervous system (CNS) repair by remodeling dendritic actin cytoskeletons post-ischemic injury (16). Neuropsychiatric research further implicates uPA polymorphisms in Alzheimer’s pathogenesis (17) and documents elevated suPAR in schizophrenia (18, 19) and mood disorders (1), underscoring its neuroimmunological significance. Given the well-established roles of uPA and its receptor uPAR system in neuroinflammation, neural regeneration, and CNS tissue remodeling, this study investigates whether serum soluble uPAR (suPAR) levels demonstrate significant alterations in patients with BD compared to healthy controls. This inquiry is motivated by: (1) robust evidence linking BD pathophysiology to inflammatory dysregulation, and (2) emerging reports of axonal protein damage in the disorder. Our work directly addresses this knowledge gap by evaluating uPAR as a novel biomarker candidate, which may reveal new immunoproteomic mechanisms underlying BD pathogenesis. This is probably among the very few studies conducted globally, and the first study performed in Arab countries. Subjects and methods 1- Subjects and study design : Using a case-control design, the current study compared 48 subjects diagnosed with BD using standard DSM-5 diagnostic criteria to 48 healthy controls. The two groups were similar in age, gender, and years of education. Participants were enrolled through the Psychiatry Department's outpatient clinic at a University Hospital in Egypt, using systematic random sampling between November 2020 and November 2021. The sample size was determined Open Epi software, with 95% confidence interval and 80% power, based on previous research examining inflammatory markers in mood disorders (20). Eligible BD patients met the following criteria: (1) DSM-5 diagnosis of BD (types I, II, or NOS) confirmed through clinical and psychometric evaluation; (2) Age between 18 and 60 years; and (3) Consent to participate. Controls had no history of diagnosed major mental or uncontrolled medical illness. Exclusion criteria for both groups included: (1) Secondary mood disorders or primary comorbid psychiatric conditions; (2) severe uncontrolled medical illnesses (e.g., diabetes, renal disease); (3) active infections or allergies; and (4) corticosteroid use. All subjects provided written consent prior to enrollment, and the data were collected during the period between November 1st, 2020, and October 31st, 2021. 2- Data Collection and Measures : All participants underwent a comprehensive assessment. First, a structured sociodemographic questionnaire was used to record the participants' age, gender, marital status, education, job, and residential details. For patients, diagnostic confirmation followed a two-stage process: initial clinical psychiatric evaluation and the Structured Clinical Interview for DSM-5, Clinician Version (SCID-5-CV) was then administered to definitively establish bipolar disorder diagnoses and screen for significant psychiatric comorbidities, utilizing this instrument's well-documented reliability and validity (21, 22). Finally, a targeted clinical questionnaire captured disease characteristics, including age of onset, first episode type/severity (noting hospitalization need), illness duration, frequency of manic/depressive episodes, rapid cycling patterns, hospitalization history, suicidality, and relevant family psychiatric and medical histories. 3- Severity assessment of the episodes in the case group : a- The Young Mania Rating Scale (YMRS) (23), which was developed by Young and colleagues in 1978. Clinicians widely use this scale in research settings to measure the intensity of manic. This 11-item scale primarily relies on patient-reported clinical status within the preceding 48 hours. Symptom domains are rated differentially: irritability, speech pattern, thought content, and disruptive/aggressive behavior are each scored on a 0–8 scale, whereas the remaining seven items employ a 0–4 scale. Consequently, the cumulative score can fall anywhere between 0 (lowest possible) and 60 (highest possible). Established cutoff interprets scores ≥ 13 as lower severity, ≥ 20 as mild, ≥ 26 as moderate, and ≥ 38 as severe manic episodes. YMRS demonstrates robust inter-rater reliability, evidenced by a total score intraclass correlation coefficient (ICC) of 0.93 and item-level ICCs ranging from 0.67 to 0.95 (23). At the start of the study, the scale was first translated into Arabic language for administration and then back into English by experts to ensure that the Arabic translation matches the English language. The Arabic version employed in this study has a good level of internal consistency (Cronbach's alpha = 0.81). b-The Hamilton Depression Rating Scale (HDRS-17) (24). It is a widely used objective tool designed to assess depressive symptom severity in adults. This 17-item scale assesses core depressive domains, including mood, guilt, psychomotor agitation/ retardation, anxiety, loss of weight, somatic symptoms, sleep disturbances, suicidal ideation, and evaluating experiences occurring predominantly within the preceding seven days. Each symptom is graded on a scale of either 3 or 5 points; total scores provide a metric of depression intensity, where values between 0 and 7 typically indicate remission or minimal symptomatology, while scores ≥ 20 suggest a moderately severe episode (24). In this research, the Arabic validated version of the HDRS-17(25) was used. 4- Investigation of the uPAR level in both groups : Venous blood samples were collected from a forearm vein at approximately 8:00 AM following an overnight fast of at least 8 hours. Serum was subsequently separated by centrifugation and stored for analysis. Serum suPAR levels were measured using an enzyme-linked immunosorbent assay (ELISA). Additionally, standard biochemistry profiles and complete blood count (CBC) parameters were analyzed from the collected blood samples for both bipolar disorder patients and healthy controls. Statistical analysis: Statistical processing was performed using the IBM SPSS software package (Statistical Package for the Social Sciences), specifically version 25.0 for Windows). Quantitative variables are presented as mean ± standard deviation or median (range), based on their distribution. Categorical variables are reported as frequencies (counts) and were compared using the Chi-square test or the Chi-square test for trend (for ordinal data between two groups). Assumptions of normality (Kolmogorov-Smirnov test) and homogeneity of variances (Levene's test) were assessed before parametric analyses. For comparing two groups, we used independent samples t-tests when data followed normal distributions and Mann-Whitney U tests for non-parametric data. We assessed variable relationships using Pearson's correlation for normally distributed continuous variables and Spearman's rank correlation for non-normal distributions. Diagnostic accuracy was evaluated through ROC curve analysis to identify optimal cutoff points for quantitative measures. Statistical significance was defined as p < 0.05, with p ≤ 0.001 indicating high significance. Results 1- Sociodemographic of the participants of both groups : The case-control study comprised 48 bipolar disorder patients (case group) and 48 age- and sex-matched healthy controls (control group). Demographic characteristics revealed no statistically significant differences between groups. Gender distribution was balanced in both groups, with females representing 50% of cases and 41.7% of controls (χ² = 0.664, p = 0.415). The mean age of patients (36.35 ± 11.76 years) was comparable to controls (33.9 ± 9.8 years; t = 1.113, p = 0.269). Marital status profiles were similar (Monte Carlo test, p = 0.594), with married participants constituting the majority in both groups (60.4% cases vs. 64.6% controls). Occupational distribution showed no significant variation (χ² = 1.468, p = 0.227), though housewives/unemployed/students were more prevalent in the case group (58.3% vs. 35.3%). Education levels (χ² = 0.073, p = 0.787) and residence patterns (urban: 68.7% cases vs. 54.2% controls; χ² = 2.155, p = 0.142) were also comparable. 2- Clinical characteristics of bipolar disorder patients (case group) : The clinical profile of the 48 bipolar disorder patients revealed significant disease burden and complexity. A majority (62.5%, n = 30) had a history of psychiatric hospitalization, while 12.5% (n = 6) reported prior suicidal risk (idea and/ or attempt). Medication adherence was evenly split (50% compliant, 50% non-compliant), while ECT was administered to 52.1% (n = 25) of participants. Family history of psychiatric disorder was positive in 52.1% (n = 25), though comorbid medical conditions were rare (4.2%, n = 2). The median illness duration was 12 years (range: 1 month–55 years), with a mean of 4 lifetime mood episodes (range: 1–28). Current symptom severity, assessed in relevant subgroups, demonstrated substantial impairment: depressive symptoms in 15 patients averaged 26.33 ± 6.23 on the Hamilton Rating Scale (range: 13–35), while manic symptoms in 13 patients scored 28.77 ± 5.21 on the YMRS (range: 21–39). 3- uPAR related findings among the studied group : - Our findings showed a highly significant reduction in serum uPAR levels among patients with bipolar disorder relative to healthy controls (p < 0.001; Table 1, Fig. 1). uPAR levels also showed no significant associations with key clinical characteristics such as history of hospitalization, suicide attempts, or ECT; treatment compliance; family history; and no significant correlation with age; illness duration; episode frequency; or scores on the Hamilton Depression or mania rating scales (Tables 2, 3). -Additionally, the valuation of uPAR as a diagnostic biomarker revealed an optimal serum concentration cutoff of ≤ 110.113 ng/ml (AUC = 0.758, p < 0.001). At this threshold, uPAR demonstrated good sensitivity (83.3%) and negative predictive value (78.4%), moderate specificity (60.4%) and positive predictive value (67.8%), and an overall accuracy of 71.9% in distinguishing bipolar cases from controls (Table 4, Fig. 2 ). Tables : Table (1) Comparison between the studied groups regarding Urokinase plasminogen activator receptor (uPAR) : Parameter Case group Control group Z P N = 48(%) N = 48(%) UPAR (ng/ml) Median (IQR) Range 87.56 (66.49–100.0) 133.69 (85.41–188.75) -4.356 < 0.001** Z: Mann Whitney test **p ≤ 0.001 is statistically highly significant Figure (1) Boxplot showing a comparison between the studied groups regarding Urokinase plasminogen activator receptor (uPAR) Table (2) Relation between clinical data and Urokinase plasminogen activator receptor (uPAR) among bipolar patients : Mean ± SD T P Hospitalization: No Yes 87.54 ± 29.13 88.43 ± 22.9 -0.118 0.907 Suicide: No Yes 88.19 ± 26.36 87.44 ± 15.09 0.067 0.947 ECT: No Yes 83.28 ± 28.47 92.52 ± 21.19 -1.282 0.206 Family history: Negative Positive 82.8 ± 26.32 92.97 ± 23.41 -1.416 0.163 Compliance: No Yes 86.27 ± 20.06 89.92 ± 29.65 -0.499 0.62 t independent sample t-test Table (3) Correlation between Urokinase plasminogen activator receptor (uPAR) and the studied parameters among bipolar patients : R P Age (year) -0.137 0.355 Duration of episodes 0.056 0.705 § Frequency of episodes -0.021 0.886 § Hamilton score 0.166 0.555 YMRS score -0.248 0.818 R Pearson correlation coefficient § Spearman rank correlation coefficient Table (4) Performance of uPAR in the prediction of the presence of bipolar disorder : Cutoff AUC Sensitivity Specificity PPV NPV Accuracy P ≤ 110.113 0.758 83.3% 60.4% 67.8% 78.4% 71.9% < 0.001** AUC area under curve, PPV positive predictive value, NPV negative predictive value. **p ≤ 0.001 is statistically highly significant Discussion BD affects over 1 in 100 people worldwide – cutting across cultural, economic, and social lines. For young adults, it is a leading cause of disability that significantly impacts daily functioning (2). its profound personal and societal burden underscores the urgency of elucidating its pathophysiology, which is essential for advancing targeted, effective treatments (1). To unravel the neurobiological underpinnings of bipolar disorder, research increasingly focuses on identifying endophenotypic/ biomarkers that may reflect core disease mechanisms. These markers may be detectable during different phases of the disorder (26). uPAR, implicated in neuroinflammation and axonal integrity, represents one such promising candidate Our study identified a pronounced reduction in circulating uPAR levels among a group with BD in comparison to healthy controls. This aligns with Özpercin et al. (2018), who reported significantly lower uPAR concentrations during manic and depressive episodes among patients, suggesting state-dependent alterations linked to acute mood pathophysiology (26). Mechanistically, this reduction may reflect impaired axonal regeneration, as uPAR promotes neural repair through interactions with integrins and extracellular proteases-a process dysregulated in BD-associated white matter deficits (27). While suPAR has been more extensively studied previously in schizophrenia (28, 29) relative to BD. Beyond inflammation, uPAR contributes to tissue homeostasis and neuroplasticity. It modulates extracellular matrix remodeling and axonal guidance during neural repair-functions particularly relevant in BD, where mitochondrial dysfunction and oxidative stress impair cellular resilience (30, 31). Following injury, uPAR expression increases rapidly. This upregulation activates signaling pathways that drive tissue healing, promoting inflammation, attracting immune cells, and accelerating cellular growth, adhesion, and migration through specific molecular pathways (15,32). uPAR also modulates integrin function (33). Given that integrins interact with extracellular matrix components- such as laminin, collagen, fibronectin, vitronectin, and tenascin (34), this modulation positions uPAR as a central regulator of axon growth and tissue repair within the central nervous system (CNS) (35). Supporting this role, Merino and colleagues (2017) (31) demonstrated that the uPA/uPAR system critically mediates the regeneration of neuronal axons within the CNS. Their findings indicate that uPA/uPAR signaling activates β1 integrins via LRP1 (low-density lipoprotein receptor-related protein-1). Further reinforcing the importance of uPAR in neural repair, Wu et al. (2014) (36) observed uPA secretion by cerebral cortical neurons during post-hypoxic or post-ischemic recovery. They proposed that uPAR facilitates CNS regeneration by promoting actin cytoskeleton reorganization following ischemic stroke. uPAR's significance extends to neurodevelopment. Powell et al. (2003) (37) identified substantial impairments in neocortical GABAergic interneuron development during embryonic and perinatal stages in uPAR-deficient mice, leading to persistent cortical dysfunction. This evidence underscores uPAR's essential role not only in biochemical signaling but also in cortical maturation. Additionally, uPA may contribute to neuronal plasticity during pathological states. Lahtinen et al. (2006) (38) documented a nearly sevenfold increase in uPA expression during epileptogenesis. In animal models, uPA expression remained elevated during recovery in hippocampal astrocytes, neurons, white matter, and vasculature (39). These findings suggest uPA involvement in the reorganization of the neural tissue throughout the epileptogenic process. Complementing our work, there is neuropathological evidence that suggests compromised axonal integrity in bipolar disorder (BD). Shao et al. (2016) (40) quantified six axonal transport proteins in prefrontal white matter via immunoblotting and ELISA, revealing significantly reduced levels in BD patients in comparison to the healthy group. This deficit in axon-related proteins aligns with our findings and implies structural CNS alterations in BD. Critically, uPAR’s established role in CNS regeneration-particularly through actin cytoskeletal reorganization post-injury (36) and its fundamental contribution to cortical development (37) provide a plausible explanation for our observed association between uPAR dysregulation and BD pathophysiology. Supporting uPAR’s trait-like stability, we found no significant correlations between uPAR concentrations and all measured parameters, including hospitalization frequency, suicidality, ECT history, illness duration, symptom severity or family history. This aligns with Özpercin et al (2018) (26), who reported no association with episode frequency or hospitalization. Importantly, ROC analysis identified serum uPAR ≤110.113 ng/ml as a robust discriminator of BD (AUC=0.758, *p*<0.001), with 83.3% sensitivity, 60.4% specificity, 67.8% PPV, 78.4% NPV, and 71.9% overall accuracy. This reinforces uPAR’s potential diagnostic utility in BD stratification. Conclusion This study demonstrates significantly reduced serum uPAR levels in BD patients compared to the control group, supporting uPAR's role as a potential trait biomarker. Unlike many BD biomarkers, uPAR levels remained consistently low regardless the clinical factors like prior hospitalizations and suicidality. This suggests that reduced uPAR may reflect persistent problems in the brain's self-repair mechanisms, particularly in rebuilding neural connections. Importantly, measuring uPAR could help identify BD with good accuracy (83% sensitivity), offering a new tool to support earlier diagnosis and in the future can offer a new treatment modality. Limitations of the study: There are some limitations in the study that should be taken into consideration. First, it is a cross-sectional study which affects cause effect relationship. Second, study participants were collected from one place, a single University hospital in Egypt, which limited the generalization of results. Although these limitations are present, this study had many strengths points, this study’s robust methodology strengthens confidence in its novel findings. First, we ensured rigorous comparability by matching 48 bipolar disorder patients with 48 healthy controls by age and sex-a design that minimizes confounding and clarifies uPAR’s specific association with BD. Second, diagnoses were meticulously confirmed using the validated SCID-5-CV, while symptom severity was captured via culturally adapted Arabic versions of the Hamilton Depression (HDRS-17) and Young Mania (YMRS) scales, enhancing clinical relevance. Third, analytical precision was prioritized: fasting serum samples quantified uPAR via standardized ELISA, and ROC analysis objectively established its diagnostic cutoff (≤110.113 ng/ml). Finally, as the first investigation of uPAR in an Egyptian cohort, our work addresses critical gap in regional biomarker research, offering unique insights into BD pathophysiology. Declarations List of abbreviations: Not applicable. Ethics approval and consent to participate: The study was approved by Zagazig University institutional review board (ZU-IRB#5911). All study procedures were conducted within the ethical guidelines as outlined in the Declaration of Helsinki and its later amendments. All the participants signed a written consent. Consent for publication: Not applicable Availability of data and material: All the data are included in the study. Competing interests: The authors declare that they have no competing interests. Funding: No funding. 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Powell, E. M., Campbell, D. B., Stanwood, G. D., Davis, C., Noebels, J. L., & Levitt, P. (2003). Genetic disruption of cortical interneuron development causes region- and GABA cell type-specific deficits, epilepsy, and behavioral dysfunction. Journal of Neuroscience , *23*, 622–631. Lahtinen, L., Lukasiuk, K., and Pitkänen, A. (2006): Increased expression and activity of urokinase-type plasminogen activator during epileptogenesis. Eur. J. Neurosci. 24,1935–1945. DOI: 10.1111/j.1460-9568.2006.05062.x Johnson, L., Chen, B., & Wang, Y. (2018). The role of brain-derived neurotrophic factor in epileptogenesis: An update. Frontiers in Pharmacology , *12*, 758232. https://doi.org/10.3389/fphar.2021.758232 Shao, L., Golbaz, K., Honer, W. G., & Beasley, C. L. (2016). Deficits in axon-associated proteins in prefrontal white matter in bipolar disorder but not schizophrenia. Bipolar Disorders , *18*(4), 342–351. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 04 Feb, 2026 Read the published version in Middle East Current Psychiatry → Version 1 posted Editorial decision: Revision requested 12 Nov, 2025 Reviews received at journal 11 Nov, 2025 Reviews received at journal 08 Nov, 2025 Reviewers agreed at journal 31 Oct, 2025 Reviewers agreed at journal 29 Oct, 2025 Reviewers invited by journal 29 Oct, 2025 Editor assigned by journal 29 Oct, 2025 Submission checks completed at journal 29 Oct, 2025 First submitted to journal 25 Oct, 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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1","display":"","copyAsset":false,"role":"figure","size":13650,"visible":true,"origin":"","legend":"\u003cp\u003eBoxplot showing a comparison between the studied groups regarding Urokinase plasminogen activator receptor (uPAR)\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7947159/v1/10537d5b7ab7571a01dce4a9.png"},{"id":95654352,"identity":"07a8b23c-23b2-471a-bda5-38d34e661bc4","added_by":"auto","created_at":"2025-11-11 16:11:12","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":20135,"visible":true,"origin":"","legend":"\u003cp\u003eROC curve showing the performance of Urokinase plasminogen activator receptor (uPAR) in the prediction of the presence of bipolar disorder\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7947159/v1/e997dbca591c4247e3134607.png"},{"id":102234219,"identity":"2a5632cb-c127-4fe7-8d2b-0a6ed6bf2638","added_by":"auto","created_at":"2026-02-09 16:07:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1720395,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7947159/v1/e2f387cc-47e9-437c-b5bc-fa6737f4cd8b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The relationship between Urokinase-Plasminogen Activator Receptor (UPAR) and bipolar disorder: a case-control study, Egypt","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBD is a complex, multifactorial neurodevelopmental disorder characterized by recurrent, fluctuating episodes of mood disturbance causing significant functional impairment and high suicide risk (15\u0026ndash;17% lifetime attempt rate) (1). It is affecting 1\u0026ndash;3% globally (40\u0026ndash;50\u0026nbsp;million people), it ranks among the world's top causes of disability, with peak onset at ages 15\u0026ndash;24 and substantial diagnostic delays (6\u0026ndash;10 years) (2\u0026ndash;4). According to DSM-5-TR and ICD-11 classifications, BD encompasses several subtypes: bipolar I disorder (defined by manic episodes often with psychosis or hospitalization), bipolar II disorder (marked by hypomanic and depressive episodes), cyclothymic disorder, and other specified variants (1). Etiologically, BD arises from gene-environment interactions: genome-wide studies implicate 298 risk loci (e.g., CACNA1C, ODZ4) and polygenic influences (70\u0026ndash;90% heritability). At the same time, environmental triggers include childhood trauma (emotional abuse OR\u0026thinsp;=\u0026thinsp;4.04), prenatal infections (Toxoplasma gondii OR\u0026thinsp;=\u0026thinsp;1.52), and life stressors (5,6). Contemporary research prioritizes biomarker discovery, investigating inflammatory mediators (e.g., cytokines), neuroimaging correlates (such as prefrontal cortex thinning), and multi-omics approaches to elucidate the pathophysiology and enable precision diagnostics (7). Current biomarker investigations target pro-inflammatory agents (e.g., cytokines, acute-phase reactants), oxidative stress markers, neurotrophic factors, and neurophysiological indicators (1,8). For example, serum albumin-an inflammatory regulator-correlates inversely with symptom severity in mood episodes (8).\u003c/p\u003e\u003cp\u003eThe uPA system constitutes a protease system involving uPA, its receptor uPAR, and associated inhibitors (9). Soluble uPAR (suPAR)-a glycosylphosphatidylinositol (GPI)-anchored receptor derivative circulates in biofluids including plasma, serum, urine, and cerebrospinal fluid (CSF). This system critically modulates immune activation (10, 11) and exhibits biomarker potential, with elevated suPAR concentrations linked to neurological disorders (12), viral/bacterial infections (e.g., sepsis, tuberculosis), and systemic inflammation (13). Clinically, suPAR offers practical utility due to its minimal circadian fluctuation (14). Beyond inflammation, uPAR facilitates tissue regeneration (15) and central nervous system (CNS) repair by remodeling dendritic actin cytoskeletons post-ischemic injury (16). Neuropsychiatric research further implicates uPA polymorphisms in Alzheimer\u0026rsquo;s pathogenesis (17) and documents elevated suPAR in schizophrenia (18, 19) and mood disorders (1), underscoring its neuroimmunological significance.\u003c/p\u003e\u003cp\u003eGiven the well-established roles of uPA and its receptor uPAR system in neuroinflammation, neural regeneration, and CNS tissue remodeling, this study investigates whether serum soluble uPAR (suPAR) levels demonstrate significant alterations in patients with BD compared to healthy controls. This inquiry is motivated by: (1) robust evidence linking BD pathophysiology to inflammatory dysregulation, and (2) emerging reports of axonal protein damage in the disorder. Our work directly addresses this knowledge gap by evaluating uPAR as a novel biomarker candidate, which may reveal new immunoproteomic mechanisms underlying BD pathogenesis. This is probably among the very few studies conducted globally, and the first study performed in Arab countries.\u003c/p\u003e"},{"header":"Subjects and methods","content":"\u003cp\u003e\u003cb\u003e1- Subjects and study design\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eUsing a case-control design, the current study compared 48 subjects diagnosed with BD using standard DSM-5 diagnostic criteria to 48 healthy controls. The two groups were similar in age, gender, and years of education. Participants were enrolled through the Psychiatry Department's outpatient clinic at a University Hospital in Egypt, using systematic random sampling between November 2020 and November 2021. The sample size was determined Open Epi software, with 95% confidence interval and 80% power, based on previous research examining inflammatory markers in mood disorders (20). Eligible BD patients met the following criteria: (1) DSM-5 diagnosis of BD (types I, II, or NOS) confirmed through clinical and psychometric evaluation; (2) Age between 18 and 60 years; and (3) Consent to participate. Controls had no history of diagnosed major mental or uncontrolled medical illness. Exclusion criteria for both groups included: (1) Secondary mood disorders or primary comorbid psychiatric conditions; (2) severe uncontrolled medical illnesses (e.g., diabetes, renal disease); (3) active infections or allergies; and (4) corticosteroid use. All subjects provided written consent prior to enrollment, and the data were collected during the period between November 1st, 2020, and October 31st, 2021.\u003c/p\u003e\u003cp\u003e\u003cb\u003e2- Data Collection and Measures\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eAll participants underwent a comprehensive assessment. First, a structured sociodemographic questionnaire was used to record the participants' age, gender, marital status, education, job, and residential details. For patients, diagnostic confirmation followed a two-stage process: initial clinical psychiatric evaluation and the Structured Clinical Interview for DSM-5, Clinician Version (SCID-5-CV) was then administered to definitively establish bipolar disorder diagnoses and screen for significant psychiatric comorbidities, utilizing this instrument's well-documented reliability and validity (21, 22). Finally, a targeted clinical questionnaire captured disease characteristics, including age of onset, first episode type/severity (noting hospitalization need), illness duration, frequency of manic/depressive episodes, rapid cycling patterns, hospitalization history, suicidality, and relevant family psychiatric and medical histories.\u003c/p\u003e\u003cp\u003e\u003cb\u003e3- Severity assessment of the episodes in the case group\u003c/b\u003e:\u003c/p\u003e\u003cp\u003ea- The Young Mania Rating Scale (YMRS) (23), which was developed by Young and colleagues in 1978. Clinicians widely use this scale in research settings to measure the intensity of manic. This 11-item scale primarily relies on patient-reported clinical status within the preceding 48 hours. Symptom domains are rated differentially: irritability, speech pattern, thought content, and disruptive/aggressive behavior are each scored on a 0\u0026ndash;8 scale, whereas the remaining seven items employ a 0\u0026ndash;4 scale. Consequently, the cumulative score can fall anywhere between 0 (lowest possible) and 60 (highest possible). Established cutoff interprets scores\u0026thinsp;\u0026ge;\u0026thinsp;13 as lower severity, \u0026ge;\u0026thinsp;20 as mild, \u0026ge;\u0026thinsp;26 as moderate, and \u0026ge;\u0026thinsp;38 as severe manic episodes. YMRS demonstrates robust inter-rater reliability, evidenced by a total score intraclass correlation coefficient (ICC) of 0.93 and item-level ICCs ranging from 0.67 to 0.95 (23). At the start of the study, the scale was first translated into Arabic language for administration and then back into English by experts to ensure that the Arabic translation matches the English language. The Arabic version employed in this study has a good level of internal consistency (Cronbach's alpha\u0026thinsp;=\u0026thinsp;0.81).\u003c/p\u003e\u003cp\u003eb-The Hamilton Depression Rating Scale (HDRS-17) (24). It is a widely used objective tool designed to assess depressive symptom severity in adults. This 17-item scale assesses core depressive domains, including mood, guilt, psychomotor agitation/ retardation, anxiety, loss of weight, somatic symptoms, sleep disturbances, suicidal ideation, and evaluating experiences occurring predominantly within the preceding seven days. Each symptom is graded on a scale of either 3 or 5 points; total scores provide a metric of depression intensity, where values between 0 and 7 typically indicate remission or minimal symptomatology, while scores\u0026thinsp;\u0026ge;\u0026thinsp;20 suggest a moderately severe episode (24). In this research, the Arabic validated version of the HDRS-17(25) was used.\u003c/p\u003e\u003cp\u003e\u003cb\u003e4- Investigation of the uPAR level in both groups\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eVenous blood samples were collected from a forearm vein at approximately 8:00 AM following an overnight fast of at least 8 hours. Serum was subsequently separated by centrifugation and stored for analysis. Serum suPAR levels were measured using an enzyme-linked immunosorbent assay (ELISA). Additionally, standard biochemistry profiles and complete blood count (CBC) parameters were analyzed from the collected blood samples for both bipolar disorder patients and healthy controls.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis:\u003c/h2\u003e\u003cp\u003eStatistical processing was performed using the IBM SPSS software package (Statistical Package for the Social Sciences), specifically version 25.0 for Windows). Quantitative variables are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median (range), based on their distribution. Categorical variables are reported as frequencies (counts) and were compared using the Chi-square test or the Chi-square test for trend (for ordinal data between two groups). Assumptions of normality (Kolmogorov-Smirnov test) and homogeneity of variances (Levene's test) were assessed before parametric analyses. For comparing two groups, we used independent samples t-tests when data followed normal distributions and Mann-Whitney U tests for non-parametric data. We assessed variable relationships using Pearson's correlation for normally distributed continuous variables and Spearman's rank correlation for non-normal distributions. Diagnostic accuracy was evaluated through ROC curve analysis to identify optimal cutoff points for quantitative measures. Statistical significance was defined as p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, with p\u0026thinsp;\u0026le;\u0026thinsp;0.001 indicating high significance.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003e1- Sociodemographic of the participants of both groups\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eThe case-control study comprised 48 bipolar disorder patients (case group) and 48 age- and sex-matched healthy controls (control group). Demographic characteristics revealed no statistically significant differences between groups. Gender distribution was balanced in both groups, with females representing 50% of cases and 41.7% of controls (χ\u0026sup2; = 0.664, p\u0026thinsp;=\u0026thinsp;0.415). The mean age of patients (36.35\u0026thinsp;\u0026plusmn;\u0026thinsp;11.76 years) was comparable to controls (33.9\u0026thinsp;\u0026plusmn;\u0026thinsp;9.8 years; t\u0026thinsp;=\u0026thinsp;1.113, p\u0026thinsp;=\u0026thinsp;0.269). Marital status profiles were similar (Monte Carlo test, p\u0026thinsp;=\u0026thinsp;0.594), with married participants constituting the majority in both groups (60.4% cases vs. 64.6% controls). Occupational distribution showed no significant variation (χ\u0026sup2; = 1.468, p\u0026thinsp;=\u0026thinsp;0.227), though housewives/unemployed/students were more prevalent in the case group (58.3% vs. 35.3%). Education levels (χ\u0026sup2; = 0.073, p\u0026thinsp;=\u0026thinsp;0.787) and residence patterns (urban: 68.7% cases vs. 54.2% controls; χ\u0026sup2; = 2.155, p\u0026thinsp;=\u0026thinsp;0.142) were also comparable.\u003c/p\u003e\u003cp\u003e\u003cb\u003e2- Clinical characteristics of bipolar disorder patients (case group)\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eThe clinical profile of the 48 bipolar disorder patients revealed significant disease burden and complexity. A majority (62.5%, n\u0026thinsp;=\u0026thinsp;30) had a history of psychiatric hospitalization, while 12.5% (n\u0026thinsp;=\u0026thinsp;6) reported prior suicidal risk (idea and/ or attempt). Medication adherence was evenly split (50% compliant, 50% non-compliant), while ECT was administered to 52.1% (n\u0026thinsp;=\u0026thinsp;25) of participants. Family history of psychiatric disorder was positive in 52.1% (n\u0026thinsp;=\u0026thinsp;25), though comorbid medical conditions were rare (4.2%, n\u0026thinsp;=\u0026thinsp;2). The median illness duration was 12 years (range: 1 month\u0026ndash;55 years), with a mean of 4 lifetime mood episodes (range: 1\u0026ndash;28). Current symptom severity, assessed in relevant subgroups, demonstrated substantial impairment: depressive symptoms in 15 patients averaged 26.33\u0026thinsp;\u0026plusmn;\u0026thinsp;6.23 on the Hamilton Rating Scale (range: 13\u0026ndash;35), while manic symptoms in 13 patients scored 28.77\u0026thinsp;\u0026plusmn;\u0026thinsp;5.21 on the YMRS (range: 21\u0026ndash;39).\u003c/p\u003e\u003cp\u003e\u003cb\u003e3- uPAR related findings among the studied group\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e- Our findings showed a highly significant reduction in serum uPAR levels among patients with bipolar disorder relative to healthy controls (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Table\u0026nbsp;1, Fig.\u0026nbsp;1).\u003c/p\u003e\u003cp\u003euPAR levels also showed no significant associations with key clinical characteristics such as history of hospitalization, suicide attempts, or ECT; treatment compliance; family history; and no significant correlation with age; illness duration; episode frequency; or scores on the Hamilton Depression or mania rating scales (Tables\u0026nbsp;2, 3).\u003c/p\u003e\u003cp\u003e-Additionally, the valuation of uPAR as a diagnostic biomarker revealed an optimal serum concentration cutoff of \u0026le;\u0026thinsp;110.113 ng/ml (AUC\u0026thinsp;=\u0026thinsp;0.758, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). At this threshold, uPAR demonstrated good sensitivity (83.3%) and negative predictive value (78.4%), moderate specificity (60.4%) and positive predictive value (67.8%), and an overall accuracy of 71.9% in distinguishing bipolar cases from controls (Table\u0026nbsp;4, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eTables\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u003cb\u003eTable\u0026nbsp;(1) Comparison between the studied groups regarding Urokinase plasminogen activator receptor (uPAR)\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"5\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eParameter\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCase group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eControl group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eZ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eP\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eN\u0026thinsp;=\u0026thinsp;48(%)\u003c/b\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eN\u0026thinsp;=\u0026thinsp;48(%)\u003c/b\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUPAR (ng/ml)\u003c/p\u003e\u003cp\u003eMedian (IQR)\u003c/p\u003e\u003cp\u003eRange\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e87.56 (66.49\u0026ndash;100.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e133.69 (85.41\u0026ndash;188.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-4.356\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001**\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\u003eZ: Mann Whitney test **p\u0026thinsp;\u0026le;\u0026thinsp;0.001 is statistically highly significant\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFigure (1) Boxplot showing a comparison between the studied groups regarding Urokinase plasminogen activator receptor (uPAR)\u003c/p\u003e\u003cp\u003e\u003cb\u003eTable\u0026nbsp;(2) Relation between clinical data and Urokinase plasminogen activator receptor (uPAR) among bipolar patients\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e\u003ccolgroup cols=\"4\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eT\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHospitalization:\u003c/p\u003e\u003cp\u003eNo\u003c/p\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e87.54\u0026thinsp;\u0026plusmn;\u0026thinsp;29.13\u003c/p\u003e\u003cp\u003e88.43\u0026thinsp;\u0026plusmn;\u0026thinsp;22.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.118\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.907\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSuicide:\u003c/p\u003e\u003cp\u003eNo\u003c/p\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e88.19\u0026thinsp;\u0026plusmn;\u0026thinsp;26.36\u003c/p\u003e\u003cp\u003e87.44\u0026thinsp;\u0026plusmn;\u0026thinsp;15.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.067\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.947\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eECT:\u003c/p\u003e\u003cp\u003eNo\u003c/p\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e83.28\u0026thinsp;\u0026plusmn;\u0026thinsp;28.47\u003c/p\u003e\u003cp\u003e92.52\u0026thinsp;\u0026plusmn;\u0026thinsp;21.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-1.282\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.206\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFamily history:\u003c/p\u003e\u003cp\u003eNegative\u003c/p\u003e\u003cp\u003ePositive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e82.8\u0026thinsp;\u0026plusmn;\u0026thinsp;26.32\u003c/p\u003e\u003cp\u003e92.97\u0026thinsp;\u0026plusmn;\u0026thinsp;23.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-1.416\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.163\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCompliance:\u003c/p\u003e\u003cp\u003eNo\u003c/p\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e86.27\u0026thinsp;\u0026plusmn;\u0026thinsp;20.06\u003c/p\u003e\u003cp\u003e89.92\u0026thinsp;\u0026plusmn;\u0026thinsp;29.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.499\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.62\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003et independent sample t-test\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eTable\u0026nbsp;(3) Correlation between Urokinase plasminogen activator receptor (uPAR) and the studied parameters among bipolar patients\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabc\" border=\"1\"\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eP\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (year)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.137\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.355\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuration of episodes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.056\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.705\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFrequency of episodes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.886\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHamilton score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.166\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.555\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYMRS score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.248\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.818\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\u003eR Pearson correlation coefficient \u003csup\u003e\u0026sect;\u003c/sup\u003eSpearman rank correlation coefficient\u003c/p\u003e\u003cp\u003e\u003cb\u003eTable\u0026nbsp;(4) Performance of uPAR in the prediction of the presence of bipolar disorder\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabd\" border=\"1\"\u003e\u003ccolgroup cols=\"8\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCutoff\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAUC\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSensitivity\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSpecificity\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePPV\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNPV\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eAccuracy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eP\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026le;\u0026thinsp;110.113\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.758\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e83.3%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e60.4%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e67.8%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e78.4%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e71.9%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001**\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\u003eAUC area under curve, PPV positive predictive value, NPV negative predictive value. **p\u0026thinsp;\u0026le;\u0026thinsp;0.001 is statistically highly significant\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eBD affects over 1 in 100 people worldwide \u0026ndash; cutting across cultural, economic, and social lines. For young adults, it is a leading cause of disability that significantly impacts daily functioning (2). its profound personal and societal burden underscores the urgency of elucidating its pathophysiology, which is essential for advancing targeted, effective treatments (1). To unravel the neurobiological underpinnings of bipolar disorder, research increasingly focuses on identifying endophenotypic/ biomarkers that may reflect core disease mechanisms. These markers may be detectable during different phases of the disorder (26). uPAR, implicated in neuroinflammation and axonal integrity, represents one such promising candidate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study identified a pronounced reduction in circulating uPAR levels among a group with BD in comparison to healthy controls. This aligns with \u0026Ouml;zpercin et al. (2018), who reported significantly lower uPAR concentrations during manic and depressive episodes among patients, suggesting state-dependent alterations linked to acute mood pathophysiology (26). Mechanistically, this reduction may reflect impaired axonal regeneration, as uPAR promotes neural repair through interactions with integrins and extracellular proteases-a process dysregulated in BD-associated white matter deficits (27). \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;While suPAR has been more extensively studied previously in schizophrenia (28, 29) relative to BD.\u003c/p\u003e\n\u003cp\u003eBeyond inflammation, uPAR contributes to tissue homeostasis and neuroplasticity. It modulates extracellular matrix remodeling and axonal guidance during neural repair-functions particularly relevant in BD, where mitochondrial dysfunction and oxidative stress impair cellular resilience (30, 31).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFollowing injury, uPAR expression increases rapidly. This upregulation activates signaling pathways that drive tissue healing, promoting inflammation, attracting immune cells, and accelerating cellular growth, adhesion, and migration through specific molecular pathways (15,32). uPAR also modulates integrin function (33). Given that integrins interact with extracellular matrix components- such as laminin, collagen, fibronectin, vitronectin, and tenascin (34), this modulation positions uPAR as a central regulator of axon growth and tissue repair within the central nervous system (CNS) (35). Supporting this role, Merino and colleagues (2017) (31) demonstrated that the uPA/uPAR system critically mediates the regeneration of neuronal axons within the CNS. Their findings indicate that uPA/uPAR signaling activates \u0026beta;1 integrins via LRP1 (low-density lipoprotein receptor-related protein-1). Further reinforcing the importance of uPAR in neural repair, Wu et al. (2014) (36) observed uPA secretion by cerebral cortical neurons during post-hypoxic or post-ischemic recovery. They proposed that uPAR facilitates CNS regeneration by promoting actin cytoskeleton reorganization following ischemic stroke.\u003c/p\u003e\n\u003cp\u003euPAR\u0026apos;s significance extends to neurodevelopment. Powell et al. (2003) (37) identified substantial impairments in neocortical GABAergic interneuron development during embryonic and perinatal stages in uPAR-deficient mice, leading to persistent cortical dysfunction. This evidence underscores uPAR\u0026apos;s essential role not only in biochemical signaling but also in cortical maturation.\u003c/p\u003e\n\u003cp\u003eAdditionally, uPA may contribute to neuronal plasticity during pathological states. Lahtinen et al. (2006) (38) documented a nearly sevenfold increase in uPA expression during epileptogenesis. In animal models, uPA expression remained elevated during recovery in hippocampal astrocytes, neurons, white matter, and vasculature (39). These findings suggest uPA involvement in the reorganization of the neural tissue throughout the epileptogenic process.\u003c/p\u003e\n\u003cp\u003eComplementing our work, there is neuropathological evidence that suggests compromised axonal integrity in bipolar disorder (BD). Shao et al. (2016) (40) quantified six axonal transport proteins in prefrontal white matter via immunoblotting and ELISA, revealing significantly reduced levels in BD patients in comparison to the healthy group. This deficit in axon-related proteins aligns with our findings and implies structural CNS alterations in BD.\u003c/p\u003e\n\u003cp\u003eCritically, uPAR\u0026rsquo;s established role in CNS regeneration-particularly through actin cytoskeletal reorganization post-injury (36) and its fundamental contribution to cortical development (37) provide a plausible explanation for our observed association between uPAR dysregulation and BD pathophysiology.\u003c/p\u003e\n\u003cp\u003eSupporting uPAR\u0026rsquo;s trait-like stability, we found no significant correlations between uPAR concentrations and all measured parameters, including hospitalization frequency, suicidality, ECT history, illness duration, symptom severity or family history. \u0026nbsp;This aligns with \u0026Ouml;zpercin et al (2018) (26), who reported no association with episode frequency or hospitalization.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eImportantly, ROC analysis identified serum uPAR \u0026le;110.113 ng/ml as a robust discriminator of BD (AUC=0.758,\u0026nbsp;*p*\u0026lt;0.001), with 83.3% sensitivity, 60.4% specificity, 67.8% PPV, 78.4% NPV, and 71.9% overall accuracy. This reinforces uPAR\u0026rsquo;s potential diagnostic utility in BD stratification.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study demonstrates significantly reduced serum uPAR levels in BD patients compared to the control group, supporting uPAR\u0026apos;s role as a potential trait biomarker. Unlike many BD biomarkers, uPAR levels remained consistently low regardless the clinical factors like prior hospitalizations and suicidality. This suggests that reduced uPAR may reflect persistent problems in the brain\u0026apos;s self-repair mechanisms, particularly in rebuilding neural connections. Importantly, measuring uPAR could help identify BD with good accuracy (83% sensitivity), offering a new tool to support earlier diagnosis and in the future can offer a new treatment modality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations of the study:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are some limitations in the study that should be taken into consideration. First, it is a cross-sectional study which affects cause effect relationship. Second, study participants were collected from one place, a single University hospital in Egypt, which limited the generalization of results. Although these limitations are present, this study had many strengths points, this study\u0026rsquo;s robust methodology strengthens confidence in its novel findings. First, we ensured rigorous comparability by matching 48 bipolar disorder patients with 48 healthy controls by age and sex-a design that minimizes confounding and clarifies uPAR\u0026rsquo;s specific association with BD. Second, diagnoses were meticulously confirmed using the validated SCID-5-CV, while symptom severity was captured via culturally adapted Arabic versions of the Hamilton Depression (HDRS-17) and Young Mania (YMRS) scales, enhancing clinical relevance. Third, analytical precision was prioritized: fasting serum samples quantified uPAR via standardized ELISA, and ROC analysis objectively established its diagnostic cutoff (\u0026le;110.113 ng/ml). Finally, as the first investigation of uPAR in an Egyptian cohort, our work addresses critical gap in regional biomarker research, offering unique insights into BD pathophysiology.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eList of abbreviations:\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by Zagazig University institutional review board (ZU-IRB#5911). All study procedures were conducted within the ethical guidelines as outlined in the Declaration of Helsinki and its later amendments. All the participants signed a written consent. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material:\u003c/strong\u003e All the data are included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e No funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u003c/strong\u003e UY, YR, MS, OG, FH and MS: share the design, data collection and interpretation of the data, writing of the draft. All the authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eThe authors would like to thank all the participants in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cstrong\u003eOliva, V., Fico, G., De Prisco, M., Gonda, X., Rosa, A. R., \u0026amp; Vieta, E.\u003c/strong\u003e (2024). Bipolar disorders: An update on critical aspects. \u003cem\u003eThe Lancet Regional Health - Europe\u003c/em\u003e, *48*, 101135. https://doi.org/10.1016/j.lanepe.2024.101135 *(Note: PMCID/PMID omitted per APA 7th)*\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eWorld Health Organization.\u003c/strong\u003e (2024). \u003cem\u003eBipolar disorder\u003c/em\u003e.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eGlobal Burden of Disease Collaborators.\u003c/strong\u003e (2024). 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Genetic disruption of cortical interneuron development causes region- and GABA cell type-specific deficits, epilepsy, and behavioral dysfunction. \u003cem\u003eJournal of Neuroscience\u003c/em\u003e, *23*, 622\u0026ndash;631.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eLahtinen, L., Lukasiuk, K., and Pitk\u0026auml;nen, A. (2006):\u003c/strong\u003e Increased expression and activity of urokinase-type plasminogen activator during epileptogenesis. Eur. J. Neurosci. 24,1935\u0026ndash;1945. DOI: 10.1111/j.1460-9568.2006.05062.x\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eJohnson, L., Chen, B., \u0026amp; Wang, Y.\u003c/strong\u003e (2018). The role of brain-derived neurotrophic factor in epileptogenesis: An update. \u003cem\u003eFrontiers in Pharmacology\u003c/em\u003e, *12*, 758232. https://doi.org/10.3389/fphar.2021.758232\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eShao, L., Golbaz, K., Honer, W. G., \u0026amp; Beasley, C. L.\u003c/strong\u003e (2016). Deficits in axon-associated proteins in prefrontal white matter in bipolar disorder but not schizophrenia. \u003cem\u003eBipolar Disorders\u003c/em\u003e, *18*(4), 342\u0026ndash;351.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"middle-east-current-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mecp","sideBox":"Learn more about [Middle East Current Psychiatry](http://mecp.springeropen.com)","snPcode":"43045","submissionUrl":"https://submission.nature.com/new-submission/43045/3","title":"Middle East Current Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Bipolar disorder (BD), Urokinase-Plasminogen Activator Receptor (UPAR), Biomarker, Egypt","lastPublishedDoi":"10.21203/rs.3.rs-7947159/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7947159/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eBipolar disorder (BD)- a leading cause of disability in young adults- lacks reliable biomarkers. This case-control study investigates soluble urokinase plasminogen activator receptor (suPAR), a protein bridging inflammation and neural repair, as a novel biomarker candidate among Egyptian patients with BD.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe compared 48 BD patients (DSM-5- diagnosis, confirmed via SCID-5-CV) and 48 age-/sex-matched controls. Sociodemographic data were collected from all participants using a standardized questionnaire, with additional clinical variables assessed exclusively in the bipolar disorder group. Symptom severity was assessed using Arabic-validated Hamilton Depression (HDRS-17) and Young Mania Rating Scale (YMRS). Fasting serum suPAR levels were quantified via ELISA.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eBD patients showed significantly lower suPAR versus controls, without significant associations with key clinical characteristics (as hospitalization, suicidality). ROC analysis identified suPAR\u0026thinsp;\u0026le;\u0026thinsp;110.113 ng/ml with an optimal diagnostic cutoff (AUC\u0026thinsp;=\u0026thinsp;0.758), with 83.3% sensitivity, 60.4% specificity, and 71.9% accuracy.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eReduced suPAR represents a potential trait biomarker in BD, reflecting impaired neural regeneration rather than episodic symptoms. Its strong diagnostic performance underscores clinical utility for early detection, while its role in axonal repair highlights new therapeutic targets.\u003c/p\u003e","manuscriptTitle":"The relationship between Urokinase-Plasminogen Activator Receptor (UPAR) and bipolar disorder: a case-control study, Egypt","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-10 10:39:30","doi":"10.21203/rs.3.rs-7947159/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-12T12:39:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-11T14:48:56+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-08T18:48:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"196973754274943940552227743213985995725","date":"2025-10-31T17:36:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"214310933411462273680317333232198029924","date":"2025-10-29T14:44:46+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-29T14:38:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-29T09:15:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-29T09:13:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"Middle East Current Psychiatry","date":"2025-10-25T14:11:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"middle-east-current-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mecp","sideBox":"Learn more about [Middle East Current Psychiatry](http://mecp.springeropen.com)","snPcode":"43045","submissionUrl":"https://submission.nature.com/new-submission/43045/3","title":"Middle East Current Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"2d0e84e8-d1ad-4f77-ba3c-855cd87f372b","owner":[],"postedDate":"November 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-09T16:03:34+00:00","versionOfRecord":{"articleIdentity":"rs-7947159","link":"https://doi.org/10.1186/s43045-026-00617-2","journal":{"identity":"middle-east-current-psychiatry","isVorOnly":false,"title":"Middle East Current Psychiatry"},"publishedOn":"2026-02-04 15:58:24","publishedOnDateReadable":"February 4th, 2026"},"versionCreatedAt":"2025-11-10 10:39:30","video":"","vorDoi":"10.1186/s43045-026-00617-2","vorDoiUrl":"https://doi.org/10.1186/s43045-026-00617-2","workflowStages":[]},"version":"v1","identity":"rs-7947159","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7947159","identity":"rs-7947159","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}