Relationship Between Klotho, Neurotrophic Factors (Bdnf, Ngf, Gdnf) and Cognitive Functions in Patients With Bipolar Disorder

Relationship Between Klotho, Neurotrophic Factors (Bdnf, Ngf, Gdnf) and Cognitive Functions in Patients With Bipolar Disorder | 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 Relationship Between Klotho, Neurotrophic Factors (Bdnf, Ngf, Gdnf) and Cognitive Functions in Patients With Bipolar Disorder Zeynep Çelebi, Esra Yazici, Derya Güzel Erdoğan, Onur Davutoglu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5214269/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Jan, 2025 Read the published version in BMC Psychiatry → Version 1 posted 22 You are reading this latest preprint version Abstract Background Klotho and neurotrophic factors (BDNF, GDNF, NGF) are shown have role in cognitive functions but these molecules has not been investigated in bipolar disorder simultaneously to assess the interactions among these molecules and their relationship with cognitive functions. This study investigates the relationship between cognitive functions, klotho, and neurotrophic factors in patients with bipolar disorder in remission period. Methods Male, bipolar disorder dignosed patients (patient group, n = 48) in remission period and healthy volunteers (control group, n = 48) were included to the study. Stroop test and Wechsler Memory Scale – Visual Production Subtest was applied and Klotho, BDNF, GDNF, NGF serum levels were identified by ELISA reader. Results The klotho protein level (0,12 ± 0,15 and 0,17 ± 0,16) and NGF level (34,36 ± 41,99 and 48,54 ± 41,06) in the patient group were significantly lower compared to the control group (Z=-3.071, p = 0.002 and Z=-2.217, p = 0.027, respectively). In the patient group, there was a positive correlation between klotho and NGF levels (p = 0.003, r s =0.413) and a negative correlation was between NGF and GDNF levels (p = 0.013, r s =-0.355). Klotho and NGF were predictors of Weshler 40 minute test(Adjusted R2 = 0.467) and Klotho and BDNF were predictos of Stroop test colour word reading time (Adjusted R2 = 0.391)with other variables. Conclusion In BD, klotho, BDNF, GDNF and NGF are associated with cognitive functions and exhibit different characteristics from the control group. Nevertheless, the differences related to these molecules seem to be associated with a regulation system rather than merely indicating an increase or decrease in serum levels. Stroop Weshler Memory Bipolar neuroplasticity neurocognition Figures Figure 1 Figure 2 INTRODUCTION It is well known that patients diagnosed with Bipolar Disorder can exhibit residual symptoms even during remission periods, and these symptoms are particularly associated with impairments in cognitive functions. [ 1 ]. Studies on bipolar disorder and cognitive functions indicate significant heterogeneity in cognitive impairment within this population. While some patients do not exhibit any cognitive deficits, others show cognitive impairments similar to those observed in schizophrenia patients. [ 2 ]. Among the causes of impairment in cognitive functions, loss of neuroplasticity and neurodegeneration are significant factors. Neurodegeneration, which involves the progressive and irreversible loss of neurons in specific regions of the nervous system through various mechanisms, has also been demonstrated to occur in bipolar disorder.[ 3 ]. In bipolar disorder, neurodegeneration is associated with damage to neuronal networks. This damage can result from impaired neuroplasticity, while neurodegeneration itself can lead to disruptions in neuroplasticity, increased apoptosis, and alterations in synaptic transmission[ 4 ]. Research related to neuroplasticity has focused on neurotrophic factors such as BDNF, NGF, and GDNF. It has been reported that in individuals diagnosed with bipolar disorder, an increase in BDNF levels is associated with improved cognitive performance, enhanced verbal memory, and better executive functions. Conversely, a decrease in BDNF levels is linked to attention deficits and impairments in delayed memory [ 5 , 6 ] Numerous studies have investigated the correlation between peripheral BDNF levels and the mood phases of bipolar disorder, and a relationship has been demonstrated. However, the findings are not consistent across these studies. [ 5 , 7 – 9 ]. NGF regulates the plasticity, differentiation, pruning, and survival of basal forebrain cholinergic neurons in the cortex and hippocampus, thereby influencing processes associated with memory, learning, and attention. [ 10 ]. In the literature, there are conflicting results regarding NGF levels and their relationship with bipolar disorder. [ 11 ]. Animal studies have shown that GDNF plays a crucial role in cognitive functions such as learning and memory. Experiments on heterozygous mutant mice, such as the water maze test, have demonstrated that a deficiency in GDNF leads to impairments in cognitive functions. [ 12 ]. There are a limited number of studies in the literature that examine the correlation between GDNF levels and bipolar disorder, and there is no consensus on the findings of these studies. [ 11 ]. Another molecule that has recently been studied for its relationship with cognitive functions is klotho. Increased expression of the klotho gene is associated with enhanced memory, improved learning, and reduced oxidative stress. [ 13 , 14 ]. Klotho is one of the biomarkers that has recently been associated with various psychiatric disorders. [ 15 , 16 ]. In a study conducted on 42 patients with bipolar disorder during a manic episode, the klotho levels in the patient group were found to be significantly higher compared to healthy controls. [ 17 ]. In another study comparing patients with bipolar disorder during manic episodes and euthymic periods to healthy controls, klotho levels were found to be higher in the patient group than in the healthy controls. However, no significant difference was observed between the manic episode group and the remission group [ 15 ]. While separate studies have demonstrated relationships between klotho, neurotrophic factors (BDNF, GDNF, NGF), and bipolar disorder, there has not been a study designed to simultaneously assess the interactions among these molecules and their relationship with cognitive functions. This study investigates the relationship between cognitive functions, klotho, and neurotrophic factors in patients with bipolar disorder in remission period. Materials and Methods Study Location and Duration, and Ethical Approval This study was conducted from May 5, 2023, to December 31, 2023, at the the Sakarya Training and Research Hospital (SAEH) Psychiatry Clinic. All participants or legal guardians were provided with both verbal and written information about the study, and written consent forms were obtained. Ethical approval was obtained from the Sakarya University Faculty of Medicine Ethics Committee on December 16, 2022 (approval number: E-16214662-050.01.04-198306-150). Study Sample A priori power analysis was conducted using G*Power version 3.1.9.7 to estimate the required sample size for the study comparing schizophrenia patients and the control group[18]. According to the study mentioned above, the minimum effect size (calculated separately for four molecules) was determined to be (d = 0.91) using the criteria established by Cohen[19]. Given a significance criterion of α = 0.01 and a power of 0.95, the minimum sample size required with this effect size was determined to be n = 39 for each group for the independent sample t-test. The number of participants was increased to 48 bipolar disorder patients (patient group) and 48 healthy volunteers (control group) as a precaution against possible data loss. Participants For the study, male patients diagnosed with bipolar disorder who attended the outpatient psychiatry clinics of SEAH and healthy male volunteers with no active psychiatric diagnosis according to DSM-5 criteria were included. The selection of patients was guided by previous similar studies.[20] Thus, patients who had been in an euthymic mood for at least 3 months, were in the remission process, and had no major comorbid medical conditions were included in the study. Remission criteria included having a score of 7 or below on the Young Mania Rating Scale and the Hamilton Depression Scale, no history of hospitalization or acute symptoms during this period, and a stable medication regimen(figure 1). To eliminate the potential influence of factors such as gender, age, education level, and BMI on neuropsychiatric test and biomarker levels, the patient group was matched with participants who had similar characteristics in these aspects. 1.1 Data Collection For the bipolar disorder group, DSM-5-compatible SCID-1 interviews were conducted by a physician to include participants who met the inclusion and exclusion criteria. The bipolar disorder group underwent several assessments, including the Sociodemographic Data Form, Clinical Global Impressions Scale (CGI), Young Mania Rating Scale (YMRS), Global Assessment of Functioning Scale (GAF), Hamilton Depression Rating Scale (HDRS), and the Brief Psychiatric Rating Scale (BPRS). For the control group, a Sociodemographic Data Form was administered following the DSM-5-compatible SCID-1 interview. Both groups were assessed for cognitive functions using neuropsychiatric tests, including the Stroop Test and the Wechsler Memory Scale - Visual Reproduction subtest. To evaluate the levels of neurotrophic factors (BDNF, GDNF, NGF) and klotho, 4 cc of venous blood was collected from both groups during the interview. Clinical Evaluation Scales Sociodemographic and Clinical Data Form : The Sociodemographic and Clinical Data Form was prepared to collect sociodemographic data for both patient and control groups, as well as disease-specific data for the patient group. Young Mania Rating Scale (YMRS): Developed by Young and colleagues in 1978, the YMRS is designed to measure the severity of mania. [21]. The Turkish validity and reliability study of the scale was conducted by Karadağ and colleagues in 2001. [22]. Hamilton Depression Rating Scale (HDRS): The scale was developed by Max Hamilton in 1960 to rate the severity of depression in individuals diagnosed with depression[23]. The Turkish validity and reliability of the scale were established by Akdemir and colleagues in 1996 [24]. Neuropsychiatric Tests Stroop Test: The Stroop Test is an executive function test used to evaluate frontal lobe functions, including selective attention, information processing speed, inhibition, and cognitive flexibility.[25]. A validity and reliability study of Stroop Test, Çapa Form, has been conducted by Emek-Savaş and colleagues. Wechsler Memory Scale – Visual Production Subtest: This subtest, developed by Wechsler in 1987, is used to evaluate visual learning and memory functions. [26]. The validity and reliability study for the Turkish sample of this test was conducted by Karakaş and colleagues. [27]. Biochemical Tests Venous blood samples (4 cc) were collected from participants into non-anticoagulant tubes (BD Vacutainer SST™ 2 Advance plastic tubes, Silica Gel, UK). The samples were left at room temperature for 1 hour until coagulation was complete. Subsequently, they were centrifuged at 1000 g for 30 minutes at 6°C (Hettich Rotofix 32 A), and the serum was transferred to Eppendorf tubes and stored at -80°C. Once all samples were collected, they were thawed from -80°C and allowed to reach room temperature. To test the levels of klotho, GDNF, BDNF, and NGF, a double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) was used. The following commercial kits were used: klotho (Catalog No: E-EL-H5451, Elabscience®, Texas, USA), BDNF (Catalog No: E-EL-H0010, Elabscience®, Texas, USA), NGF (Catalog No: E-EL-H1205, Elabscience®, Texas, USA), and GDNF (Catalog No: E-EL-H1495, Elabscience®, Texas, USA). The assays were performed according to the test protocols. The readings were taken using an ELISA reader (Biotek, 800TS microplate reader, USA) at a wavelength of 450 nm. Based on the concentration of standards and the corresponding optical density values, a standard curve was constructed, and the concentration of each sample was calculated by applying the sample’s optical density values to the regression equation. Klotho, BDNF, and GDNF levels were expressed in ng/ml, while NGF was expressed in pg/ml. 2. Statistical Analysis Method Analyses in this study were conducted using IBM SPSS Statistics version 22 on a computer running Windows 10. When comparing variables, the distribution of the data was first examined. Values with skewness and kurtosis between +2 and -2 were considered to show a normal distribution[28]. The Independent Samples T-Test was employed as a parametric method for comparing two independent groups, and the Mann-Whitney U Test was used as a non-parametric method. For comparing categorical variables between two independent groups, chi-square and Fisher’s Exact tests were utilized. Levene's test was applied to assess the homogeneity of variances. Pearson correlation was used to examine correlations between normally distributed numerical variables, while Spearman correlation was used when at least one variable did not follow a normal distribution. A significance level of p<0.05 was considered for the study. The degree of correlation was categorized as follows: 0.01-0.19 as negligible, 0.20-0.49 as low, 0.50-0.69 as moderate, 0.70-0.85 as high, and 0.86-1 as very high. [29]. In the statistical comparison of correlation coefficients between the two groups, cocor analysis was used. [30]. In regression analyses, linear regression analysis using the backward method was employed. Calculation of Chlorpromazine Equivalent Dose The chlorpromazine equivalent doses of antipsychotics were calculated, and comparisons among patients using antipsychotic medications were made based on the equivalent doses. [31]. The chlorpromazine equivalent doses of depot antipsychotics were first converted to their oral form equivalent doses before being calculated. [32]. RESULTS The study sample consisted of two groups: patients and healthy controls. The patient group included 48 individuals diagnosed with bipolar disorder, and the control group comprised 48 healthy controls. All participants were male. When comparing the groups, no significant differences were found between the groups in terms of age (Patient group (37.31 ± 10.82 years) vs. Control group (36.89 ± 7.22 years); t = 0.222, p = 0.825); BMI (Patient group (29.00 ± 5.65 kg/m²) vs. Control group (27.24 ± 4.83 kg/m²); t = 1.645, p = 0.103), and years of education (Patient group (12.56 ± 3.76 years) vs. Control group (13.29 ± 3.16 years); t = -1.030, p = 0.305). Other descriptive information about the groups is provided in Table 1 . Table 1 Comparison of Sociodemographic Characteristics Between Patient and Control Groups Sociodemographic and Clinical Data Patient Control n % n % Statistical analysis Marital status Single/Divorced 32 66,7 17 35,4 x 2 = 9,379 p = 0,002 Married 16 33,3 31 64,6 Co-Habitants Parents 25 52,1 8 16,7 x 2 = 13,548 p = 0,001 Spouse and Children 16 33,3 30 62,5 Alone 7 14,6 10 20,8 Place of Residence City Centre 33 68,8 35 72,9 x 2 = 0,202 p = 0,653 District 15 31,2 13 27,1 Employment Not working/retired 20 41,7 4 8,3 x 2 = 14,222 p˂0,001 Employed 28 58,3 44 91,7 Smoking Yes 32 66,7 25 52,1 x 2 = 2,116 p = 0,146 No 16 33,3 23 47,9 Comparison of Neurotrophic Factors and Klotho Levels between Patient and Control Groups The klotho protein level (0,12 ± 0,15 and 0,17 ± 0,16) and NGF level (34,36 ± 41,99 and 48,54 ± 41,06) in the patient group were significantly lower compared to the control group (Z=-3.071, p = 0.002 and Z=-2.217, p = 0.027, respectively). When comparing the patient and control groups, although BDNF (14,32 ± 6,71 and 12,03 ± 6,12) and GDNF ( 0,21 ± 0,28 and 0,16 ± 0,14) serum levels appeared higher in the patient group, the differences were not statistically significant ( t = 1.74 for BDNF, Z= -1.914 for GDNF p > 0.05 for both ) ( Fig. 2 ). Relationship between Neurotrophic Factors, Klotho Levels, and Variables Correlation between Neurotrophic Factors and Klotho Levels In the patient group, in the correlation analysis between klotho and the levels of BDNF, GDNF, and NGF; a positive correlation revealed between klotho and NGF levels (p = 0.003, r s =0.413). A negative correlation was found between NGF and GDNF levels (p = 0.013, r s =-0.355). In the control group, no significant correlations were detected between neurotrophic factors. Correlation between Neurotrophic Factors, Klotho Levels, and Wechsler Memory Scale Visual Production Subtest In the patient group, the Wechsler Visual Memory Test showed a positive, weak correlation between NGF levels and performance at the 40th minute (p = 0.043, r s =0.294). No significant relationship was found between performance at the 40th minute and other biomarkers. Additionally, no correlation was found between 1st minute performance and biomarkers (Table 2 ). Table 2 Correlation between Neurotrophic Factors, Klotho Levels, and Wechsler Visual Production Subtest in the Patient Group Patient Group (n = 48) Wechsler Visual Memory Scale Klotho BDNF NGF GDNF 1.minute r s= -0,031 r = 0,084 r s =0,203 r s =-0,094 p = 0,833 p = 0,572 p = 0,167 p = 0,523 40.minute r s =-0,003 r = 0,067 r s =0,294 r s =-0,173 p = 0,982 p = 0,650 p = 0,043* p = 0,239 r s : Spearman correlation coefficient, r: Pearson correlation coefficient, *p < 0,05 Correlation between Neurotrophic Factors, Klotho Levels, and Stroop Test In the patient group, the correlation between the stages of the Stroop test and biomarker levels revealed a positive, weak correlation between the number of errors in the black-and-white reading stage and klotho levels (r s =0.294, p = 0.043), as well as between the number of spontaneous corrections in the same stage and GDNF levels (r s =0.313, p = 0.030). Additionally, there was a positive correlation between the number of spontaneous corrections in the colour-word reading stage and GDNF levels (r s =0.338, p = 0.019). No significant correlations were found between other stages of the Stroop test and klotho, BDNF, NGF, or GDNF (Table 3 ). Table 3 Correlation between Neurotrophic Factors, Klotho Levels, and Stroop Test in the Patient Group Stages of Stroop test Patient Group (n = 48) Klotho BDNF NGF GDNF Stroop black and white reading Duration (sec) r s =,126 p=,394 r s =-,140 p=,342 r s =,101 p=,494 r s =-,040 p=,789 Incorrect reading r s =,294* p=,043 r s =,060 p=,685 r s =,029 p=,847 r s =,023 p=,877 Spontaneous Corrections r s =-,010 p=,946 r s =-,174 p=,236 r s =-,021 p=,889 r s =,313* p=,030 Stroop box colour naming Duration (sec) r s =,187 p=,202 r s =-,106 p=,474 r s =,095 p=,521 r s =-,165 p=,262 Incorrect naming r s =-,154 p=,295 r s =-,043 p=,769 r s =-,194 p=,187 r s = ,063 p=,671 Spontaneous Corrections r s =,213 p=,146 r=,244 p=,095 r s =,135 p=,360 r s =-,216 p=,141 Stroop reading coloured words Duration (sec) r s = ,212 p= ,148 r s =-,198 p=,178 r s = ,089 p= ,549 r s =-,044 p=,768 Incorrect Reading r s = ,181 p= ,218 r s =-,207 p=,159 r s = ,033 p= ,823 r s =,212 p= ,148 Spontaneous Correction r s =-,007 p=,962 r=-,084 p=,572 r s =-,034 p= ,821 r s =,338* p=,019 Stroop coloured Word colour naming Duration (sec) r s =-,059 p=,688 r=-,075 p=,610 r s =-,070 p=,638 r s =,003 p=,985 Incorrect Naming r s =,010 p=,948 r s =,057 p=,699 r s =,008 p=,955 r s =,056 p=,708 Spontaneous Correction r s =,145 p=,327 r s =,122 p=,408 r s =-,056 p=,707 r s =,017 p=,908 Interference r s =-,116 p=,434 r=-,024 p= ,871 r s =-,144 p=,328 r s =-,111 p=,454 r s : Spearman correlation coefficient, r: Pearson correlation coefficient, *p < 0,05 Correlation between Neurotrophic Factors, Klotho Levels, and Stroop Test in the Control Group In the control group, a negative, weak correlation was found between the Stroop colour naming time and BDNF levels (r=-0.316, p = 0.029). Positive, weak correlations were observed between BDNF levels and the time taken for the colour-word reading stage (r = 0.331, p = 0.022), between GDNF levels and the number of spontaneous corrections in the colour-word reading stage (r s =0.354, p = 0.014), and between klotho levels and the interference stage (r s =0.329, p = 0.022). No significant correlations were found between other stages of the Stroop test and BDNF, NGF, GDNF, or klotho (Table 4 ). Table 4 Correlation between Neurotrophic Factors, Klotho Levels, and Stroop Test in the Control Group Stages of Stroop Test Control Group (n = 48) Klotho BDNF NGF GDNF Stroop black and white reading Duration (sec) r s =-,092 p=,536 r=,257 p=,078 r s =,178 p=,227 r s =-,072 p=,628 Incorrect reading r s =,060 p=,685 r s =,192 p=,192 r s =,039 p=,792 r s =,067 p=,650 Spontaneous Corrections r s =-,037 p=,803 r s =-,027 p=,855 r s =-,278 p=,056 r s =,089 p=,547 Stroop box colour naming Duration (sec) r s =-,006 p=,966 r=-,316* p=,029 r s =,025 p=,865 r s =-,079 p=,592 Incorrect naming r s =-,109 p=,461 r s =-,023 p=,875 r s =-,240 p=,100 r s =-,111 p=,452 Spontaneous Corrections r s =,005 p=,973 r s =-,195 p=,184 r s =-,194 p=,187 r s =-,121 p=,413 Stroop reading coloured words Duration (sec) r s =-,056 p=,705 r=,331* p=,022 r s =,174 p=,236 r s =-,089 p=,549 Incorrect Reading r s =,083 p=,575 r s =-,071 p=,631 r s =-,169 p=,250 r s =-,174 p=,236 Spontaneous Correction r s =,055 p=,712 r s =,200 p=,173 r s =,077 p=,601 r s =,354* p=,014 Stroop coloured Word colour naming Duration (sec) r s =,252 p=,084 r=,145 p=,327 r s =-,024 p=,869 r s =-,192 p=,191 Incorrect Naming r s =,014 p=,926 r=-,017 p=,911 r s =-,256 p=,079 r s =-,248 p=,089 Spontaneous Correction r s =,095 p=,521 r=-,025 p=,868 r s =-,197 p=,180 r s =-,074 p=,604 Interference r s =,329* p=,022 r=,021 p=,889 r s =-,113 p=,445 r s =-,167 p=,257 r s : Spearman correlation coefficient, r: Pearson correlation coefficient, *p < 0,05 Correlation between Neurotrophic Factors, Klotho Levels, and Bipolar Disorder History In the patient group, a positive correlation was found between the duration of bipolar disorder and NGF levels (r s =0.357, p = 0.013), while a negative correlation was observed between disease duration and GDNF levels (r s =-0.455, p = 0.001). No significant correlations were found for other variables. Correlation between Neurotrophic Factors, Klotho Levels, and Chlorpromazine Equivalent Dose No significant correlations were found between BDNF, GDNF, NGF, and Klotho levels and the chlorpromazine equivalent dose (p > 0.05). Klotho, NGF and BDNF as predictors of cognitive scores Regression analyses were conducted to evaluate the predictive value of klotho and neurotrophic factors on cognitive test scores in the patient group. Various regression models were established. Weschler and Stroop test scores were used as dependent variables and 12–16 variables including klotho and neurotrophic factors and other factors related with the scores were used in models. After all this calculations klotho, and neurotrophic factors were identified as predictors in two models that are Wechsler 40-minute and Stroop Colour Word Reading Test scores. (Table 5 ). One; for the patient group, using Wechsler 40-minute performance as the dependent variable, a regression model was constructed that included 16 independent variables: age, education duration, age of disease onset, number of manic, depressive, and total episodes, time since the last episode, CGI-I, CGI-S, CGI-side effect, klotho, NGF, BDNF, GDNF, and chlorpromazine equivalent dose. SPSS proposed 12 different models. The most suitable model, which was statistically significant (F = 11.295, p < 0.001, CI = 95%), included four variables (education duration, CGI-S, klotho, NGF) and explained 46.7% of the variance (Adjusted R2 = 0.467). There was no autocorrelation among the independent variables, and the errors were found to be random (Durbin Watson = 2.167, VIF < 10). The other; for the patient group, using colour word reading time as the dependent variable, a regression model was constructed that included 12 independent variables: age, education duration, total number of episodes, duration of the illness, age of disease onset, CGI-I, CGI-S, chlorpromazine equivalent dose, klotho, BDNF, GDNF, and NGF. SPSS proposed 8 different models. The most suitable model, which was statistically significant (F = 8.540, p < 0.001, CI = 95%), included four independent variables (education duration, total number of episodes, BDNF, klotho) and explained 39.1% of the variance (Adjusted R2 = 0.391). There was no autocorrelation among the independent variables, and the errors were found to be random (Durbin Watson = 2.261, VIF < 10). Table 5 Linear regression table for cognitive tests predictors. Dependent Independent B Std. error Beta t p %95 CI for B Lower Lower Wechsler 40.min Constant 40.285 10.969 20.176 0.035 0.315 80.255 Education years 0.457 0.114 0.456 40.011 0.000 0.227 0.687 CGI- SS -10.564 0.450 -0.396 -30.474 0.001 -20.472 -0.656 Klotho -60.520 20.682 -0.264 -20.431 0.019 -110.928 -10.112 NGF 0.023 0.010 0.261 20.371 0.022 0.004 0.043 Colored Word reading Constant 560.913 40.773 110.924 0.000 470.287 660.539 Education years -10.291 0.278 -0.519 -40.642 0.000 -10.852 -0.730 Total number of episodes -10.323 0.421 -0.355 -30.142 0.003 -20.172 -0.474 Klotho 170.942 60.819 0.293 20.631 0.012 40.191 310.693 BDNF -0.357 0.155 -0.256 -20.306 0.026 -0.669 -0.045 DISCUSSION This study aimed to investigate the correlation between cognitive functions and levels of BDNF, GDNF, NGF, and klotho in patients diagnosed with bipolar disorder (BD) during remission and in healthy individuals. To this end, 48 euthymic male patients diagnosed with bipolar disorder and 48 healthy male controls were included in the study. Initially, we examined the levels of neuroplasticity markers klotho, BDNF, GDNF, and NGF, which we hypothesized to be associated with cognitive functions. We found that klotho and NGF levels were higher in the control group compared to the patient group. BDNF and GDNF levels were higher in the patient group, but the difference was not statistically significant. Then, we examined the correlations among biomarkers, and a positive relationship was found between NGF and klotho in the patient group. There were no existing studies in the literature that evaluated klotho and NGF together in patients with bipolar disorder. However, a study conducted on patients with schizophrenia found a positive correlation between klotho and NGF levels. [ 33 ]. Additionally, a study on cannabinoid users also reported a positive correlation between klotho and NGF [ 18 ]. In our study, a negative correlation was found between NGF and GDNF levels in the patient group. This differs from the findings of Yazıcı et al. and Türkmen et al., where a positive correlation between NGF and GDNF was reported in their patient groups [ 18 , 33 ]. This discrepancy suggests that the relationships between neurotrophic factors in bipolar disorder may differ from those observed in cannabinoid users and schizophrenia patients. BDNF and related Factors In this study BDNF levels did not show significant results in comparison BDNF levels of groups and in correlations with cognitive performance. When examining studies comparing BDNF levels between patients diagnosed with bipolar disorder and healthy controls, conflicting results were found in the literature. [ 5 , 7 , 34 ]. In this study regression analysis revealed the predictor role of BDNF levels for duration to read coloured words of stroop test. In our study, although the patient group performed worse on most neuropsychiatric tests, the association with duration suggested that BDNF might be effective in information processing speed. Söğüt et al. also reported an association between BDNF levels and the first stage of the Stroop test.[ 20 ]. NGF and related factors In our study, a positive correlation was found between NGF levels and age in the patient group. However, there was no correlation between age and NGF levels in the control group. Yazıcı and colleagues reported a negative correlation between NGF levels and age in cannabinoid users in their study[ 18 ]. In our study, a positive correlation was observed between the duration of the illness and NGF levels. Barbosa et al. reported that when manic and euthymic patients were considered as a single group, there was a positive relationship between illness duration and NGF levels. However, when the groups were analyzed separately, this relationship lost its significance. [ 35 ]. In our study, NGF levels were positively correlated with the Wechsler 40-minute score, which measures delayed memory. Linear regression analysis indicated that NGF was a predictor of this score. No significant relationship was found between Stroop test results and NGF levels. There were no studies in the literature examining the relationship between NGF and cognitive functions in bipolar disorder. However, research in Alzheimer’s disease reported that patients who had NGF-secreting cells implanted into the basal forebrain showed improved Mini-Mental State Examination results[ 36 ]. Our study was consistent with this finding. GDNF and related factors In our study, there was no difference in GDNF levels between patients with bipolar disorder and healthy controls. Thera are studies that report no difference in GDNF levels when comparing manic, depressive, and euthymic phases of bipolar disorder patients with healthy controlsor elevated GDNF levels in during manic and depressive episodes [ 37 , 38 ]. Another study investigating mood disorders and GDNF levels found that GDNF levels were lower in patients with major depressive disorder and bipolar disorder compared to healthy controls. [ 39 ]. The differences between studies might be attributed to heterogeneous patient groups and small sample sizes in the research. Additionally, there is ongoing debate in the literature about whether serum GDNF levels accurately reflect brain GDNF levels as well as other neurotrophic factors [ 40 ]. In a study conducted on Alzheimer's patients, it was observed that levels of GDNF in cerebrospinal fluid were elevated compared to healthy controls, while serum GDNF levels were decreased. [ 41 ]. In our study, GDNF levels were assessed only in serum. We found a negative correlation between age and GDNF levels in the patient group, which was not observed in the control group. Previously, studies evaluating bipolar disorder and GDNF levels have not discussed the relationship with age. Yazıcı and colleagues, in their study on patients using cannabinoids, reported a negative correlation between GDNF levels and age in the patient group, while no association was found between age and GDNF in the control group. [ 18 ]. In our study, we observed that as GDNF levels increased, the number of spontaneous corrections in the Stroop black-and-white reading and colour-word reading tasks in the patient group, and the number of spontaneous corrections in the colour-word reading task in the control group also increased. No relationship was found between Wechsler performance and GDNF levels. In a study conducted by Türkmen and colleagues, a negative relationship was found between GDNF levels and Wechsler Visual Memory Test scores in the healthy control group. Additionally, a positive relationship was observed between GDNF levels and the time taken for the colour-word reading and colour-naming tasks in the Stroop test. Türkmen’s study also reported a positive correlation between GDNF levels and the number of errors in naming the ink colour of colour words, indicating that as GDNF levels increased, the number of errors also increased[ 33 ]. In a study on late-onset depression, the patient group exhibited poorer cognitive performance compared to healthy controls, and the GDNF levels in the patient group were found to be significantly higher[ 42 ]. According to the literature, high serum GDNF levels appear to be associated with poorer cognitive functions. This relationship may be due to GDNF potentially having a negative impact on cognitive functions, or it could be a compensatory increase in GDNF levels secondary to a reduction in receptor numbers. Klotho and Related Factors In our study, klotho levels were found to be lower in the patient group compared to the control group. Barbosa et al. conducted a study comparing klotho levels in 20 patients with bipolar disorder (BD) in manic and euthymic states with 30 healthy controls. Their study demonstrated that BD patients had higher klotho levels compared to healthy controls, regardless of mood state. This study included participants with a disease duration of over 20 years. Additionally, the study noted that conditions affecting klotho levels, such as hypertension and diabetes, were more prevalent in the control group. The findings of the study suggest that elevated klotho levels in long-term bipolar disorder patients might be associated with the progression of the disorder [ 15 ]. In our study, the remission period was 12 weeks, whereas in the study where higher klotho levels were observed in the euthymic state, the remission period was set at 8 weeks. Differences in remission periods and disease duration, as well as the compensatory effect of klotho, might account for the differing results between the two studies. Other studies in the literature have compared manic periods with healthy controls, but euthymic patients were not included in these studies. In those studies, klotho levels in manic patients were found to be higher than in healthy controls. [ 43 ]. No studies were found that evaluated klotho levels and cognitive function in patients with bipolar disorder during the remission period. Some studies in the literature have found a positive relationship between klotho levels and cognitive performance in other diseases. [ 44 , 45 ]. A cross-sectional and observational study conducted with 94 subjects at the Oregon Alzheimer's Disease Center reported that serum and cerebrospinal fluid levels of klotho protein were correlated with Mini-Mental State Examination (MMSE) scores. Additionally, the study indicated that serum klotho levels significantly reflect cerebrospinal fluid klotho levels[ 46 ]. In a study conducted with healthy older adults, the relationship between klotho levels and Mini-Mental State Examination (MMSE) scores as well as the Trail Making Test was examined. It was found that a decrease in klotho levels over the annual observation period was associated with a decline in MMSE scores, but there was no association with the executive function tests represented by the Trail Making Test. The study emphasized that klotho may affect domain-specific cognitive changes.[ 47 ]. In a study by Türkmen and colleagues involving patients with schizophrenia, it was reported that in healthy controls, the times to name the colour of coloured words and to read coloured words increased with higher levels of klotho. [ 33 ]. In our study, an increase in klotho levels was associated with an increase in the number of errors in black-and-white reading in the patient group on the Stroop test. Regression analyses revealed that klotho was a predictor and a factor extending the duration for both black-and-white reading and coloured word reading times. In the control group, an increase in klotho levels was associated with an increase in interference. No relationship was found with other parameters of the Stroop test. Linear regression analysis showed that klotho was a negative predictor for Wechsler 40th-minute performance. These findings suggest a negative relationship between klotho and cognitive functions in our study, which aligns with the study by Türkmen and colleagues. This indicates that it may not be possible to interpret the relationship between klotho and cognitive functions in a single direction, suggesting that heterogenous subgroups, regional, and genetic effects may be factors. The limited number of tests used in our study might have restricted the assessment of the relationship between klotho and cognitive functions. There were some limitations in our study. Access to tests validated in Turkish for assessing cognitive functions was challenging, and patients' willingness to dedicate time to such studies was short. Although tests commonly used in the literature were selected, this allowed for the assessment of cognitive functions in limited areas. Only whole blood serum samples were used for evaluating BDNF, NGF, GDNF, and klotho levels; cerebrospinal fluid samples were not collected. Due to the passage through the blood-brain barrier and peripheral production, it could not be assessed whether blood levels truly reflect the actual levels. Due to the confounding effect of gender on neurotrophic factors, individuals of female gender were excluded from the study. While this reduced confounding factors in our study, it limited the generalizability of the sample representation. Strengths of our study include the similarity in age, BMI, substance use, and gender factors, as well as factors affecting neuropsychological test evaluations, such as age and education level, between the patient and control groups. This was important in excluding confounding factors. The diagnoses of the patients were confirmed by a physician through DSM-5-oriented interviews, which was a significant advantage for the reliability of the data. The fact that neuropsychological tests were administered to all participants by the same physician was another advantage for the reliability and standardization of the data. Our study is valuable as it is the first in the literature to simultaneously evaluate BDNF, GDNF, NGF, and klotho levels in bipolar disorder patients and investigate their relationship with cognitive functions. CONCLUSION As a conclusion, when comparing patients diagnosed with euthymic bipolar disorder (BD) in remission to healthy controls, there were no differences in BDNF and GDNF levels; however, klotho and NGF levels were lower in the patient group. In BD, klotho, BDNF, GDNF and NGF are associated with cognitive functions and exhibit different characteristics from the control group. Nevertheless, the differences related to these molecules seem to be associated with a regulation system rather than merely indicating an increase or decrease in serum levels. Considering the literature and the limitations of our study, it is recommended to increase the representativeness of the sample and the generalizability of the results by including female participants in new samples, measuring biomarker samples not only from blood but also from cerebrospinal fluid, and expanding the study to include other mood phases of the illness. Additionally, examining the sub-parameters of the biochemical cascade related to klotho and neurotrophic factors, as well as investigating genetic and epigenetic levels that could influence all these factors, which were not examined in this study but are relevant in the literature, are suggested for future research. Declarations ACKNOWLEDGEMENTS We want to say thank you for their valuable supports to Dr Betul Aslan Turkmen and Sakarya Community Counselling Center (Sakarya TRSM) members. Ethics approval and consent to participate; We confirm that ethical approval has been granted approval number: E-16214662-050.01.04-198306-150, reference number is and we obtained written informed consent of participants accordingly. Consent for publication; Not applicable Availability of data and materials; The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests; The authors declare that they have no competing interest. Funding; This study is funded by Sakarya University Scientific Research Projects Unit with the project number 2023-19-44-11. Author contributions; ZÇ and EY developed the theoretical background and literature check, ZÇ and OD worked with the subject and collected data. ABY and ZÇ performed the statistical analysis. EY and ABY write draft of manuscript. All authors contributed to the final version of the manuscript. ABY supervised the project. 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Alterations in BDNF (brain derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) serum levels in bipolar disorder: The role of lithium. J Affect Disord. 2014;166:193–200. Rosa AR, Frey BN, Andreazza AC, Ceresér KM, Cunha AB, Quevedo J, Santin A, Gottfried C, Gonçalves CA, Vieta E, et al. Increased serum glial cell line-derived neurotrophic factor immunocontent during manic and depressive episodes in individuals with bipolar disorder. Neurosci Lett. 2006;407(2):146–50. Takebayashi M, Hisaoka K, Nishida A, Tsuchioka M, Miyoshi I, Kozuru T, Hikasa S, Okamoto Y, Shinno H, Morinobu S, et al. Decreased levels of whole blood glial cell line-derived neurotrophic factor (GDNF) in remitted patients with mood disorders. Int J Neuropsychopharmacol. 2006;9(5):607–12. Kastin AJ, Akerstrom V, Pan W. Glial cell line-derived neurotrophic factor does not enter normal mouse brain. Neurosci Lett. 2003;340(3):239–41. Straten G, Eschweiler GW, Maetzler W, Laske C, Leyhe T. Glial cell-line derived neurotrophic factor (GDNF) concentrations in cerebrospinal fluid and serum of patients with early Alzheimer's disease and normal controls. J Alzheimers Dis. 2009;18(2):331–7. Wang X, Hou Z, Yuan Y, Hou G, Liu Y, Li H, Zhang Z. Association study between plasma GDNF and cognitive function in late-onset depression. J Affect Disord. 2011;132(3):418–21. Sirlier Emir B, Yildiz S, Kazğan Kiliçaslan A, Kiliç F, Uğur K, Aydin S, Atmaca M. The roles of Klotho and FGF-23 in bipolar manic episode. Eur Rev Med Pharmacol Sci. 2023;27(5 Suppl):101–8. Sanz B, Arrieta H, Rezola-Pardo C, Fernández-Atutxa A, Garin-Balerdi J, Arizaga N, Rodriguez-Larrad A, Irazusta J. Low serum klotho concentration is associated with worse cognition, psychological components of frailty, dependence, and falls in nursing home residents. Sci Rep. 2021;11(1):9098. Abraham CR, Mullen PC, Tucker-Zhou T, Chen CD, Zeldich E. Klotho Is a Neuroprotective and Cognition-Enhancing Protein. Vitam Horm. 2016;101:215–38. Kundu P, Zimmerman B, Quinn JF, Kaye J, Mattek N, Westaway SK, Raber J. Serum Levels of α-Klotho Are Correlated with Cerebrospinal Fluid Levels and Predict Measures of Cognitive Function. J Alzheimers Dis. 2022;86(3):1471–81. Shardell M, Semba RD, Rosano C, Kalyani RR, Bandinelli S, Chia CW, Ferrucci L. Plasma Klotho and Cognitive Decline in Older Adults: Findings From the InCHIANTI Study. J Gerontol Biol Sci Med Sci. 2016;71(5):677–82. Additional Declarations No competing interests reported. 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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-5214269","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":387007291,"identity":"a0b95e9f-ddfa-4bff-a486-66f1b622b035","order_by":0,"name":"Zeynep Çelebi","email":"","orcid":"","institution":"Sakarya University Medical Faculty","correspondingAuthor":false,"prefix":"","firstName":"Zeynep","middleName":"","lastName":"Çelebi","suffix":""},{"id":387007294,"identity":"50097a29-4e85-4877-9e1c-aacb3deac9ae","order_by":1,"name":"Esra Yazici","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7klEQVRIiWNgGAWjYDCCAzAGM5D9AUizsZOi5eAMkBZmorWAdPFA9eIFfLcPH/5cUXNYXr6d+eFhm1/b5PmYGRg/fMzBrUXyXFqa5Jljhw0bm9kMDuf23TZsY2Zglpy5DbcWgzM8ZowNbIcZm4GuOpzbc5sRqIWNmRevFv7PHxv+HbZvA2mx7LltT4QWHgbJxrbDiT0gLQw/bicS1CJ5hs1MsrEvPXkGM5vBwd6G28ltzIzNeP3Cd4b58ceGb9a28/sPP/7w489t2/ntzQc/fMSjBQqaIRRjG5hsIKgeCOqg9B9iFI+CUTAKRsFIAwA54FHB4veXhAAAAABJRU5ErkJggg==","orcid":"","institution":"Sakarya University Medical Faculty","correspondingAuthor":true,"prefix":"","firstName":"Esra","middleName":"","lastName":"Yazici","suffix":""},{"id":387007296,"identity":"cf077870-d7e9-4300-a0d1-3b6631a47eeb","order_by":2,"name":"Derya Güzel Erdoğan","email":"","orcid":"","institution":"Sakarya University Medical Faculty","correspondingAuthor":false,"prefix":"","firstName":"Derya","middleName":"Güzel","lastName":"Erdoğan","suffix":""},{"id":387007298,"identity":"7aec6ba0-7189-48f4-a5b4-38e4350ad8b1","order_by":3,"name":"Onur Davutoglu","email":"","orcid":"","institution":"Sakarya University Medical Faculty","correspondingAuthor":false,"prefix":"","firstName":"Onur","middleName":"","lastName":"Davutoglu","suffix":""},{"id":387007299,"identity":"41d3aecf-2b81-468e-8f80-48b53d9d3db3","order_by":4,"name":"Ahmet Bulent Yazıcı","email":"","orcid":"","institution":"Sakarya University Medical Faculty","correspondingAuthor":false,"prefix":"","firstName":"Ahmet","middleName":"Bulent","lastName":"Yazıcı","suffix":""}],"badges":[],"createdAt":"2024-10-06 19:08:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5214269/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5214269/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12888-025-06469-0","type":"published","date":"2025-01-20T15:58:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":72333696,"identity":"7a785b70-455e-49a2-8db7-477d2d565fb6","added_by":"auto","created_at":"2024-12-25 15:24:41","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":101674,"visible":true,"origin":"","legend":"\u003cp\u003eSample selection flowchart\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5214269/v1/9adc504952f54fbb81d58dc1.png"},{"id":72334118,"identity":"701a7783-7400-43e3-8bc5-4cf0b6045a1e","added_by":"auto","created_at":"2024-12-25 15:32:41","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":35389,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of neurotrophic factor and klotho levels in patient and control groups\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5214269/v1/a2cdc9b01741bb7c173b9979.png"},{"id":74859398,"identity":"3fead6ea-63b9-4176-9447-e2cc38ee9380","added_by":"auto","created_at":"2025-01-27 16:14:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1719147,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5214269/v1/9375f50d-2611-43bf-8f16-8309415cdc20.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eRelationship Between Klotho, Neurotrophic Factors (Bdnf, Ngf, Gdnf) and Cognitive Functions in Patients With Bipolar Disorder\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eIt is well known that patients diagnosed with Bipolar Disorder can exhibit residual symptoms even during remission periods, and these symptoms are particularly associated with impairments in cognitive functions. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Studies on bipolar disorder and cognitive functions indicate significant heterogeneity in cognitive impairment within this population. While some patients do not exhibit any cognitive deficits, others show cognitive impairments similar to those observed in schizophrenia patients. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Among the causes of impairment in cognitive functions, loss of neuroplasticity and neurodegeneration are significant factors. Neurodegeneration, which involves the progressive and irreversible loss of neurons in specific regions of the nervous system through various mechanisms, has also been demonstrated to occur in bipolar disorder.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In bipolar disorder, neurodegeneration is associated with damage to neuronal networks. This damage can result from impaired neuroplasticity, while neurodegeneration itself can lead to disruptions in neuroplasticity, increased apoptosis, and alterations in synaptic transmission[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eResearch related to neuroplasticity has focused on neurotrophic factors such as BDNF, NGF, and GDNF. It has been reported that in individuals diagnosed with bipolar disorder, an increase in BDNF levels is associated with improved cognitive performance, enhanced verbal memory, and better executive functions. Conversely, a decrease in BDNF levels is linked to attention deficits and impairments in delayed memory [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] Numerous studies have investigated the correlation between peripheral BDNF levels and the mood phases of bipolar disorder, and a relationship has been demonstrated. However, the findings are not consistent across these studies. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. NGF regulates the plasticity, differentiation, pruning, and survival of basal forebrain cholinergic neurons in the cortex and hippocampus, thereby influencing processes associated with memory, learning, and attention. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In the literature, there are conflicting results regarding NGF levels and their relationship with bipolar disorder. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Animal studies have shown that GDNF plays a crucial role in cognitive functions such as learning and memory. Experiments on heterozygous mutant mice, such as the water maze test, have demonstrated that a deficiency in GDNF leads to impairments in cognitive functions. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. There are a limited number of studies in the literature that examine the correlation between GDNF levels and bipolar disorder, and there is no consensus on the findings of these studies. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAnother molecule that has recently been studied for its relationship with cognitive functions is klotho. Increased expression of the klotho gene is associated with enhanced memory, improved learning, and reduced oxidative stress. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Klotho is one of the biomarkers that has recently been associated with various psychiatric disorders. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In a study conducted on 42 patients with bipolar disorder during a manic episode, the klotho levels in the patient group were found to be significantly higher compared to healthy controls. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In another study comparing patients with bipolar disorder during manic episodes and euthymic periods to healthy controls, klotho levels were found to be higher in the patient group than in the healthy controls. However, no significant difference was observed between the manic episode group and the remission group [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile separate studies have demonstrated relationships between klotho, neurotrophic factors (BDNF, GDNF, NGF), and bipolar disorder, there has not been a study designed to simultaneously assess the interactions among these molecules and their relationship with cognitive functions. This study investigates the relationship between cognitive functions, klotho, and neurotrophic factors in patients with bipolar disorder in remission period.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy Location and Duration, and Ethical Approval\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;This study was conducted from May 5, 2023, to December 31, 2023, at the the Sakarya Training and Research Hospital (SAEH) Psychiatry Clinic. All participants or legal guardians were provided with both verbal and written information about the study, and written consent forms were obtained. Ethical approval was obtained from the Sakarya University Faculty of Medicine Ethics Committee on December 16, 2022 (approval number: E-16214662-050.01.04-198306-150).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Sample\u003c/strong\u003e\u003cbr\u003eA priori power analysis was conducted using G*Power version 3.1.9.7 to estimate the required sample size for the study comparing schizophrenia patients and the control group[18]. According to the study mentioned above, the minimum effect size (calculated separately for four molecules) was determined to be (d = 0.91) using the criteria established by Cohen[19]. Given a significance criterion of \u0026alpha; = 0.01 and a power of 0.95, the minimum sample size required with this effect size was determined to be n = 39 for each group for the independent sample t-test. The number of participants was increased to 48 bipolar disorder patients (patient group) and 48 healthy volunteers (control group) as a precaution against possible data loss.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003cbr\u003eFor the study, male patients diagnosed with bipolar disorder who attended the outpatient psychiatry clinics of SEAH and healthy male volunteers with no active psychiatric diagnosis according to DSM-5 criteria were included. The selection of patients was guided by previous similar studies.[20] Thus, patients who had been in an euthymic mood for at least 3 months, were in the remission process, and had no major comorbid medical conditions were included in the study. Remission criteria included having a score of 7 or below on the Young Mania Rating Scale and the Hamilton Depression Scale, no history of hospitalization or acute symptoms during this period, and a stable medication regimen(figure 1).\u003c/p\u003e\n\u003cp\u003eTo eliminate the potential influence of factors such as gender, age, education level, and BMI on neuropsychiatric test and biomarker levels, the patient group was matched with participants who had similar characteristics in these aspects.\u003c/p\u003e\n\u003ch2\u003e1.1 Data Collection\u003c/h2\u003e\n\u003cp\u003eFor the bipolar disorder group, DSM-5-compatible SCID-1 interviews were conducted by a physician to include participants who met the inclusion and exclusion criteria. The bipolar disorder group underwent several assessments, including the Sociodemographic Data Form, Clinical Global Impressions Scale (CGI), Young Mania Rating Scale (YMRS), Global Assessment of Functioning Scale (GAF), Hamilton Depression Rating Scale (HDRS), and the Brief Psychiatric Rating Scale (BPRS).\u003c/p\u003e\n\u003cp\u003eFor the control group, a Sociodemographic Data Form was administered following the DSM-5-compatible SCID-1 interview.\u003c/p\u003e\n\u003cp\u003eBoth groups were assessed for cognitive functions using neuropsychiatric tests, including the Stroop Test and the Wechsler Memory Scale - Visual Reproduction subtest. To evaluate the levels of neurotrophic factors (BDNF, GDNF, NGF) and klotho, 4 cc of venous blood was collected from both groups during the interview.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Evaluation Scales\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSociodemographic and Clinical Data Form\u003c/strong\u003e: The Sociodemographic and Clinical Data Form was prepared to collect sociodemographic data for both patient and control groups, as well as disease-specific data for the patient group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYoung Mania Rating Scale (YMRS):\u003c/strong\u003e Developed by Young and colleagues in 1978, the YMRS is designed to measure the severity of mania. [21]. The Turkish validity and reliability study of the scale was conducted by Karadağ and colleagues in 2001. [22].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHamilton Depression Rating Scale (HDRS):\u003c/strong\u003eThe scale was developed by Max Hamilton in 1960 to rate the severity of depression in individuals diagnosed with depression[23]. The Turkish validity and reliability of the scale were established by Akdemir and colleagues in 1996 [24].\u003c/p\u003e\n\u003ch3\u003eNeuropsychiatric Tests\u003c/h3\u003e\n\u003cp\u003eStroop Test: The Stroop Test is an executive function test used to evaluate frontal lobe functions, including selective attention, information processing speed, inhibition, and cognitive flexibility.[25]. A validity and reliability study of \u0026nbsp;Stroop Test, \u0026Ccedil;apa Form, has been conducted by Emek-Savaş and colleagues.\u003c/p\u003e\n\u003cp\u003eWechsler Memory Scale \u0026ndash; Visual Production Subtest: This subtest, developed by Wechsler in 1987, is used to evaluate visual learning and memory functions. [26]. The validity and reliability study for the Turkish sample of this test was conducted by Karakaş and colleagues. [27].\u003c/p\u003e\n\u003ch3\u003eBiochemical Tests\u003c/h3\u003e\n\u003cp\u003eVenous blood samples (4 cc) were collected from participants into non-anticoagulant tubes (BD Vacutainer SST\u0026trade; 2 Advance plastic tubes, Silica Gel, UK). The samples were left at room temperature for 1 hour until coagulation was complete. Subsequently, they were centrifuged at 1000 g for 30 minutes at 6\u0026deg;C (Hettich Rotofix 32 A), and the serum was transferred to Eppendorf tubes and stored at -80\u0026deg;C.\u003c/p\u003e\n\u003cp\u003eOnce all samples were collected, they were thawed from -80\u0026deg;C and allowed to reach room temperature. To test the levels of klotho, GDNF, BDNF, and NGF, a double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) was used. The following commercial kits were used: klotho (Catalog No: E-EL-H5451, Elabscience\u0026reg;, Texas, USA), BDNF (Catalog No: E-EL-H0010, Elabscience\u0026reg;, Texas, USA), NGF (Catalog No: E-EL-H1205, Elabscience\u0026reg;, Texas, USA), and GDNF (Catalog No: E-EL-H1495, Elabscience\u0026reg;, Texas, USA). The assays were performed according to the test protocols. The readings were taken using an ELISA reader (Biotek, 800TS microplate reader, USA) at a wavelength of 450 nm. Based on the concentration of standards and the corresponding optical density values, a standard curve was constructed, and the concentration of each sample was calculated by applying the sample\u0026rsquo;s optical density values to the regression equation. Klotho, BDNF, and GDNF levels were expressed in ng/ml, while NGF was expressed in pg/ml.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. Statistical Analysis Method\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalyses in this study were conducted using IBM SPSS Statistics version 22 on a computer running Windows 10. When comparing variables, the distribution of the data was first examined. Values with skewness and kurtosis between +2 and -2 were considered to show a normal distribution[28]. The Independent Samples T-Test was employed as a parametric method for comparing two independent groups, and the Mann-Whitney U Test was used as a non-parametric method. For comparing categorical variables between two independent groups, chi-square and Fisher\u0026rsquo;s Exact tests were utilized. Levene\u0026apos;s test was applied to assess the homogeneity of variances.\u003c/p\u003e\n\u003cp\u003ePearson correlation was used to examine correlations between normally distributed numerical variables, while Spearman correlation was used when at least one variable did not follow a normal distribution. A significance level of p\u0026lt;0.05 was considered for the study. The degree of correlation was categorized as follows: 0.01-0.19 as negligible, 0.20-0.49 as low, 0.50-0.69 as moderate, 0.70-0.85 as high, and 0.86-1 as very high. [29]. In the statistical comparison of correlation coefficients between the two groups, cocor analysis was used. [30]. In regression analyses, linear regression analysis using the backward method was employed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCalculation of Chlorpromazine Equivalent Dose\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe chlorpromazine equivalent doses of antipsychotics were calculated, and comparisons among patients using antipsychotic medications were made based on the equivalent doses. [31]. The chlorpromazine equivalent doses of depot antipsychotics were first converted to their oral form equivalent doses before being calculated. [32].\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThe study sample consisted of two groups: patients and healthy controls. The patient group included 48 individuals diagnosed with bipolar disorder, and the control group comprised 48 healthy controls. All participants were male.\u003c/p\u003e \u003cp\u003eWhen comparing the groups, no significant differences were found between the groups in terms of age (Patient group (37.31\u0026thinsp;\u0026plusmn;\u0026thinsp;10.82 years) vs. Control group (36.89\u0026thinsp;\u0026plusmn;\u0026thinsp;7.22 years); t\u0026thinsp;=\u0026thinsp;0.222, p\u0026thinsp;=\u0026thinsp;0.825); BMI (Patient group (29.00\u0026thinsp;\u0026plusmn;\u0026thinsp;5.65 kg/m\u0026sup2;) vs. Control group (27.24\u0026thinsp;\u0026plusmn;\u0026thinsp;4.83 kg/m\u0026sup2;); t\u0026thinsp;=\u0026thinsp;1.645, p\u0026thinsp;=\u0026thinsp;0.103), and years of education (Patient group (12.56\u0026thinsp;\u0026plusmn;\u0026thinsp;3.76 years) vs. Control group (13.29\u0026thinsp;\u0026plusmn;\u0026thinsp;3.16 years); t = -1.030, p\u0026thinsp;=\u0026thinsp;0.305). Other descriptive information about the groups is provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\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 Sociodemographic Characteristics Between Patient and Control Groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSociodemographic and Clinical Data\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eStatistical analysis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMarital status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingle/Divorced\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66,7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e35,4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003ex\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;9,379\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ep\u0026thinsp;=\u0026thinsp;0,002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMarried\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33,3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e64,6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCo-Habitants\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52,1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16,7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003ex\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;13,548\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ep\u0026thinsp;=\u0026thinsp;0,001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpouse and Children\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33,3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62,5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14,6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20,8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlace of Residence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCity Centre\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68,8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e72,9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ex\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0,202\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0,653\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistrict\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31,2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27,1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmployment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot working/retired\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41,7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8,3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003ex\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;14,222\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ep˂0,001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmployed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58,3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e91,7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66,7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e52,1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ex\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;2,116\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0,146\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33,3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e47,9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eComparison of Neurotrophic Factors and Klotho Levels between Patient and Control Groups\u003c/h2\u003e \u003cp\u003eThe klotho protein level (0,12\u0026thinsp;\u0026plusmn;\u0026thinsp;0,15 and 0,17\u0026thinsp;\u0026plusmn;\u0026thinsp;0,16) and NGF level (34,36\u0026thinsp;\u0026plusmn;\u0026thinsp;41,99 and 48,54\u0026thinsp;\u0026plusmn;\u0026thinsp;41,06) in the patient group were significantly lower compared to the control group (Z=-3.071, p\u0026thinsp;=\u0026thinsp;0.002 and Z=-2.217, p\u0026thinsp;=\u0026thinsp;0.027, respectively).\u003c/p\u003e \u003cp\u003eWhen comparing the patient and control groups, although BDNF (14,32\u0026thinsp;\u0026plusmn;\u0026thinsp;6,71 and 12,03\u0026thinsp;\u0026plusmn;\u0026thinsp;6,12) and GDNF ( 0,21\u0026thinsp;\u0026plusmn;\u0026thinsp;0,28 and 0,16\u0026thinsp;\u0026plusmn;\u0026thinsp;0,14) serum levels appeared higher in the patient group, the differences were not statistically significant ( t\u0026thinsp;=\u0026thinsp;1.74 for BDNF, Z= -1.914 for GDNF p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for both ) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eRelationship between Neurotrophic Factors, Klotho Levels, and Variables\u003c/h2\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003eCorrelation between Neurotrophic Factors and Klotho Levels\u003c/h2\u003e \u003cp\u003eIn the patient group, in the correlation analysis between klotho and the levels of BDNF, GDNF, and NGF; a positive correlation revealed between klotho and NGF levels (p\u0026thinsp;=\u0026thinsp;0.003, r\u003csub\u003es\u003c/sub\u003e=0.413). A negative correlation was found between NGF and GDNF levels (p\u0026thinsp;=\u0026thinsp;0.013, r\u003csub\u003es\u003c/sub\u003e=-0.355). In the control group, no significant correlations were detected between neurotrophic factors.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation between Neurotrophic Factors, Klotho Levels, and Wechsler Memory Scale Visual Production Subtest\u003c/h2\u003e \u003cp\u003eIn the patient group, the Wechsler Visual Memory Test showed a positive, weak correlation between NGF levels and performance at the 40th minute (p\u0026thinsp;=\u0026thinsp;0.043, r\u003csub\u003es\u003c/sub\u003e=0.294). No significant relationship was found between performance at the 40th minute and other biomarkers. Additionally, no correlation was found between 1st minute performance and biomarkers (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\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 between Neurotrophic Factors, Klotho Levels, and Wechsler Visual Production Subtest in the Patient Group\u003c/p\u003e \u003c/div\u003e \u003c/caption\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\"\u003e \u003cp\u003ePatient Group (n\u0026thinsp;=\u0026thinsp;48)\u003c/p\u003e \u003cp\u003eWechsler Visual Memory Scale\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKlotho\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBDNF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNGF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGDNF\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1.minute\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es=\u003c/sub\u003e-0,031\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er\u0026thinsp;=\u0026thinsp;0,084\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=0,203\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-0,094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0,833\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0,572\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0,167\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0,523\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e40.minute\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-0,003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er\u0026thinsp;=\u0026thinsp;0,067\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003er\u003c/b\u003e\u003csub\u003e\u003cb\u003es\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e=0,294\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e =-0,173\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0,982\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0,650\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003ep\u0026thinsp;=\u0026thinsp;0,043*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0,239\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003er\u003csub\u003es\u003c/sub\u003e: Spearman correlation coefficient, r: Pearson correlation coefficient, *p\u0026thinsp;\u0026lt;\u0026thinsp;0,05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation between Neurotrophic Factors, Klotho Levels, and Stroop Test\u003c/h2\u003e \u003cp\u003eIn the patient group, the correlation between the stages of the Stroop test and biomarker levels revealed a positive, weak correlation between the number of errors in the black-and-white reading stage and klotho levels (r\u003csub\u003es\u003c/sub\u003e =0.294, p\u0026thinsp;=\u0026thinsp;0.043), as well as between the number of spontaneous corrections in the same stage and GDNF levels (r\u003csub\u003es\u003c/sub\u003e =0.313, p\u0026thinsp;=\u0026thinsp;0.030). Additionally, there was a positive correlation between the number of spontaneous corrections in the colour-word reading stage and GDNF levels (r\u003csub\u003es\u003c/sub\u003e =0.338, p\u0026thinsp;=\u0026thinsp;0.019). No significant correlations were found between other stages of the Stroop test and klotho, BDNF, NGF, or GDNF (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\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 between Neurotrophic Factors, Klotho Levels, and Stroop Test in the Patient Group\u003c/p\u003e \u003c/div\u003e \u003c/caption\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\u003eStages of Stroop test\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003ePatient Group (n\u0026thinsp;=\u0026thinsp;48)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKlotho\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBDNF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNGF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGDNF\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStroop black and white reading\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration (sec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,126\u003c/p\u003e \u003cp\u003ep=,394\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,140\u003c/p\u003e \u003cp\u003ep=,342\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,101\u003c/p\u003e \u003cp\u003ep=,494\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,040\u003c/p\u003e \u003cp\u003ep=,789\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncorrect reading\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003er\u003c/b\u003e\u003csub\u003e\u003cb\u003es\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e=,294*\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ep=,043\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,060\u003c/p\u003e \u003cp\u003ep=,685\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,029\u003c/p\u003e \u003cp\u003ep=,847\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,023\u003c/p\u003e \u003cp\u003ep=,877\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpontaneous Corrections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,010\u003c/p\u003e \u003cp\u003ep=,946\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,174\u003c/p\u003e \u003cp\u003ep=,236\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,021\u003c/p\u003e \u003cp\u003ep=,889\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003er\u003c/b\u003e\u003csub\u003e\u003cb\u003es\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e=,313*\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ep=,030\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStroop box colour naming\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration (sec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,187\u003c/p\u003e \u003cp\u003ep=,202\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,106\u003c/p\u003e \u003cp\u003ep=,474\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,095\u003c/p\u003e \u003cp\u003ep=,521\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,165\u003c/p\u003e \u003cp\u003ep=,262\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncorrect naming\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,154\u003c/p\u003e \u003cp\u003ep=,295\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,043\u003c/p\u003e \u003cp\u003ep=,769\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,194\u003c/p\u003e \u003cp\u003ep=,187\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e= ,063\u003c/p\u003e \u003cp\u003ep=,671\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpontaneous Corrections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,213\u003c/p\u003e \u003cp\u003ep=,146\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er=,244\u003c/p\u003e \u003cp\u003ep=,095\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,135\u003c/p\u003e \u003cp\u003ep=,360\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,216\u003c/p\u003e \u003cp\u003ep=,141\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStroop reading coloured words\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration (sec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e= ,212\u003c/p\u003e \u003cp\u003ep= ,148\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,198\u003c/p\u003e \u003cp\u003ep=,178\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e= ,089\u003c/p\u003e \u003cp\u003ep= ,549\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,044\u003c/p\u003e \u003cp\u003ep=,768\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncorrect Reading\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e= ,181\u003c/p\u003e \u003cp\u003ep= ,218\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,207\u003c/p\u003e \u003cp\u003ep=,159\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e= ,033\u003c/p\u003e \u003cp\u003ep= ,823\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,212\u003c/p\u003e \u003cp\u003ep= ,148\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpontaneous Correction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,007\u003c/p\u003e \u003cp\u003ep=,962\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er=-,084\u003c/p\u003e \u003cp\u003ep=,572\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,034\u003c/p\u003e \u003cp\u003ep= ,821\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003er\u003c/b\u003e\u003csub\u003e\u003cb\u003es\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e=,338*\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ep=,019\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStroop coloured Word colour naming\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration (sec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,059\u003c/p\u003e \u003cp\u003ep=,688\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er=-,075\u003c/p\u003e \u003cp\u003ep=,610\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,070\u003c/p\u003e \u003cp\u003ep=,638\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,003\u003c/p\u003e \u003cp\u003ep=,985\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncorrect Naming\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,010\u003c/p\u003e \u003cp\u003ep=,948\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,057\u003c/p\u003e \u003cp\u003ep=,699\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,008\u003c/p\u003e \u003cp\u003ep=,955\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,056\u003c/p\u003e \u003cp\u003ep=,708\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpontaneous Correction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,145\u003c/p\u003e \u003cp\u003ep=,327\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,122\u003c/p\u003e \u003cp\u003ep=,408\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,056\u003c/p\u003e \u003cp\u003ep=,707\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,017\u003c/p\u003e \u003cp\u003ep=,908\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,116\u003c/p\u003e \u003cp\u003ep=,434\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er=-,024\u003c/p\u003e \u003cp\u003ep= ,871\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,144\u003c/p\u003e \u003cp\u003ep=,328\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,111\u003c/p\u003e \u003cp\u003ep=,454\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003er\u003csub\u003es\u003c/sub\u003e: Spearman correlation coefficient, r: Pearson correlation coefficient, *p\u0026thinsp;\u0026lt;\u0026thinsp;0,05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation between Neurotrophic Factors, Klotho Levels, and Stroop Test in the Control Group\u003c/h2\u003e \u003cp\u003eIn the control group, a negative, weak correlation was found between the Stroop colour naming time and BDNF levels (r=-0.316, p\u0026thinsp;=\u0026thinsp;0.029). Positive, weak correlations were observed between BDNF levels and the time taken for the colour-word reading stage (r\u0026thinsp;=\u0026thinsp;0.331, p\u0026thinsp;=\u0026thinsp;0.022), between GDNF levels and the number of spontaneous corrections in the colour-word reading stage (r\u003csub\u003es\u003c/sub\u003e =0.354, p\u0026thinsp;=\u0026thinsp;0.014), and between klotho levels and the interference stage (r\u003csub\u003es\u003c/sub\u003e =0.329, p\u0026thinsp;=\u0026thinsp;0.022). No significant correlations were found between other stages of the Stroop test and BDNF, NGF, GDNF, or klotho (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCorrelation between Neurotrophic Factors, Klotho Levels, and Stroop Test in the Control Group\u003c/p\u003e \u003c/div\u003e \u003c/caption\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\u003eStages of Stroop Test\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eControl Group (n\u0026thinsp;=\u0026thinsp;48)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKlotho\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBDNF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNGF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGDNF\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStroop black and white reading\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration (sec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,092\u003c/p\u003e \u003cp\u003ep=,536\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er=,257\u003c/p\u003e \u003cp\u003ep=,078\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,178\u003c/p\u003e \u003cp\u003ep=,227\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,072\u003c/p\u003e \u003cp\u003ep=,628\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncorrect reading\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,060\u003c/p\u003e \u003cp\u003ep=,685\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,192\u003c/p\u003e \u003cp\u003ep=,192\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,039\u003c/p\u003e \u003cp\u003ep=,792\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,067\u003c/p\u003e \u003cp\u003ep=,650\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpontaneous Corrections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,037\u003c/p\u003e \u003cp\u003ep=,803\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,027\u003c/p\u003e \u003cp\u003ep=,855\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,278\u003c/p\u003e \u003cp\u003ep=,056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,089\u003c/p\u003e \u003cp\u003ep=,547\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStroop box colour naming\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration (sec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,006\u003c/p\u003e \u003cp\u003ep=,966\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003er=-,316*\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ep=,029\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,025\u003c/p\u003e \u003cp\u003ep=,865\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,079\u003c/p\u003e \u003cp\u003ep=,592\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncorrect naming\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,109\u003c/p\u003e \u003cp\u003ep=,461\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,023\u003c/p\u003e \u003cp\u003ep=,875\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,240\u003c/p\u003e \u003cp\u003ep=,100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,111\u003c/p\u003e \u003cp\u003ep=,452\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpontaneous Corrections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,005\u003c/p\u003e \u003cp\u003ep=,973\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,195\u003c/p\u003e \u003cp\u003ep=,184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,194\u003c/p\u003e \u003cp\u003ep=,187\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,121\u003c/p\u003e \u003cp\u003ep=,413\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStroop reading coloured words\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration (sec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,056\u003c/p\u003e \u003cp\u003ep=,705\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003er=,331*\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ep=,022\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,174\u003c/p\u003e \u003cp\u003ep=,236\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,089\u003c/p\u003e \u003cp\u003ep=,549\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncorrect Reading\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,083\u003c/p\u003e \u003cp\u003ep=,575\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,071\u003c/p\u003e \u003cp\u003ep=,631\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,169\u003c/p\u003e \u003cp\u003ep=,250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,174\u003c/p\u003e \u003cp\u003ep=,236\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpontaneous\u003c/p\u003e \u003cp\u003eCorrection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,055\u003c/p\u003e \u003cp\u003ep=,712\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,200\u003c/p\u003e \u003cp\u003ep=,173\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,077\u003c/p\u003e \u003cp\u003ep=,601\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003er\u003c/b\u003e\u003csub\u003e\u003cb\u003es\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e=,354*\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ep=,014\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStroop coloured Word colour naming\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration (sec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,252\u003c/p\u003e \u003cp\u003ep=,084\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er=,145\u003c/p\u003e \u003cp\u003ep=,327\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,024\u003c/p\u003e \u003cp\u003ep=,869\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,192\u003c/p\u003e \u003cp\u003ep=,191\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncorrect Naming\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,014\u003c/p\u003e \u003cp\u003ep=,926\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er=-,017\u003c/p\u003e \u003cp\u003ep=,911\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,256\u003c/p\u003e \u003cp\u003ep=,079\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,248\u003c/p\u003e \u003cp\u003ep=,089\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpontaneous Correction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=,095\u003c/p\u003e \u003cp\u003ep=,521\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er=-,025\u003c/p\u003e \u003cp\u003ep=,868\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,197\u003c/p\u003e \u003cp\u003ep=,180\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,074\u003c/p\u003e \u003cp\u003ep=,604\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003er\u003c/b\u003e\u003csub\u003e\u003cb\u003es\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e=,329*\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ep=,022\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003er=,021\u003c/p\u003e \u003cp\u003ep=,889\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,113\u003c/p\u003e \u003cp\u003ep=,445\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003er\u003csub\u003es\u003c/sub\u003e=-,167\u003c/p\u003e \u003cp\u003ep=,257\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003er\u003csub\u003es\u003c/sub\u003e: Spearman correlation coefficient, r: Pearson correlation coefficient, *p\u0026thinsp;\u0026lt;\u0026thinsp;0,05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation between Neurotrophic Factors, Klotho Levels, and Bipolar Disorder History\u003c/h2\u003e \u003cp\u003eIn the patient group, a positive correlation was found between the duration of bipolar disorder and NGF levels (r\u003csub\u003es\u003c/sub\u003e =0.357, p\u0026thinsp;=\u0026thinsp;0.013), while a negative correlation was observed between disease duration and GDNF levels (r\u003csub\u003es\u003c/sub\u003e =-0.455, p\u0026thinsp;=\u0026thinsp;0.001). No significant correlations were found for other variables.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation between Neurotrophic Factors, Klotho Levels, and Chlorpromazine Equivalent Dose\u003c/h2\u003e \u003cp\u003eNo significant correlations were found between BDNF, GDNF, NGF, and Klotho levels and the chlorpromazine equivalent dose (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eKlotho, NGF and BDNF as predictors of cognitive scores\u003c/h2\u003e \u003cp\u003eRegression analyses were conducted to evaluate the predictive value of klotho and neurotrophic factors on cognitive test scores in the patient group. Various regression models were established. Weschler and Stroop test scores were used as dependent variables and 12\u0026ndash;16 variables including klotho and neurotrophic factors and other factors related with the scores were used in models. After all this calculations klotho, and neurotrophic factors were identified as predictors in two models that are Wechsler 40-minute and Stroop Colour Word Reading Test scores. (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOne; for the patient group, using Wechsler 40-minute performance as the dependent variable, a regression model was constructed that included 16 independent variables: age, education duration, age of disease onset, number of manic, depressive, and total episodes, time since the last episode, CGI-I, CGI-S, CGI-side effect, klotho, NGF, BDNF, GDNF, and chlorpromazine equivalent dose. SPSS proposed 12 different models. The most suitable model, which was statistically significant (F\u0026thinsp;=\u0026thinsp;11.295, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, CI\u0026thinsp;=\u0026thinsp;95%), included four variables (education duration, CGI-S, klotho, NGF) and explained 46.7% of the variance (Adjusted R2\u0026thinsp;=\u0026thinsp;0.467). There was no autocorrelation among the independent variables, and the errors were found to be random (Durbin Watson\u0026thinsp;=\u0026thinsp;2.167, VIF\u0026thinsp;\u0026lt;\u0026thinsp;10).\u003c/p\u003e \u003cp\u003eThe other; for the patient group, using colour word reading time as the dependent variable, a regression model was constructed that included 12 independent variables: age, education duration, total number of episodes, duration of the illness, age of disease onset, CGI-I, CGI-S, chlorpromazine equivalent dose, klotho, BDNF, GDNF, and NGF. SPSS proposed 8 different models. The most suitable model, which was statistically significant (F\u0026thinsp;=\u0026thinsp;8.540, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, CI\u0026thinsp;=\u0026thinsp;95%), included four independent variables (education duration, total number of episodes, BDNF, klotho) and explained 39.1% of the variance (Adjusted R2\u0026thinsp;=\u0026thinsp;0.391). There was no autocorrelation among the independent variables, and the errors were found to be random (Durbin Watson\u0026thinsp;=\u0026thinsp;2.261, VIF\u0026thinsp;\u0026lt;\u0026thinsp;10).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLinear regression table for cognitive tests predictors.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\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 \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDependent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIndependent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eStd. error\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBeta\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003et\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e%95 CI for B\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLower\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eLower\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eWechsler\u003c/p\u003e \u003cp\u003e40.min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eConstant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.285\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.969\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20.176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.315\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e80.255\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEducation years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.457\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.456\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e40.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.227\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.687\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCGI- SS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-10.564\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.450\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.396\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-30.474\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-20.472\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-0.656\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKlotho\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-60.520\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20.682\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.264\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-20.431\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-110.928\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-10.112\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNGF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.261\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20.371\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.043\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eColored Word reading\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eConstant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e560.913\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40.773\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e110.924\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e470.287\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e660.539\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEducation years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-10.291\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.278\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.519\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-40.642\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-10.852\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-0.730\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal number of episodes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-10.323\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.421\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.355\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-30.142\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-20.172\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-0.474\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKlotho\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e170.942\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60.819\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.293\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20.631\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e40.191\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e310.693\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBDNF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.357\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.155\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-20.306\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.669\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-0.045\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study aimed to investigate the correlation between cognitive functions and levels of BDNF, GDNF, NGF, and klotho in patients diagnosed with bipolar disorder (BD) during remission and in healthy individuals. To this end, 48 euthymic male patients diagnosed with bipolar disorder and 48 healthy male controls were included in the study.\u003c/p\u003e \u003cp\u003eInitially, we examined the levels of neuroplasticity markers klotho, BDNF, GDNF, and NGF, which we hypothesized to be associated with cognitive functions. We found that klotho and NGF levels were higher in the control group compared to the patient group. BDNF and GDNF levels were higher in the patient group, but the difference was not statistically significant. Then, we examined the correlations among biomarkers, and a positive relationship was found between NGF and klotho in the patient group. There were no existing studies in the literature that evaluated klotho and NGF together in patients with bipolar disorder. However, a study conducted on patients with schizophrenia found a positive correlation between klotho and NGF levels. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Additionally, a study on cannabinoid users also reported a positive correlation between klotho and NGF [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In our study, a negative correlation was found between NGF and GDNF levels in the patient group. This differs from the findings of Yazıcı et al. and T\u0026uuml;rkmen et al., where a positive correlation between NGF and GDNF was reported in their patient groups [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. This discrepancy suggests that the relationships between neurotrophic factors in bipolar disorder may differ from those observed in cannabinoid users and schizophrenia patients.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section2\"\u003e \u003ch2\u003eBDNF and related Factors\u003c/h2\u003e \u003cp\u003eIn this study BDNF levels did not show significant results in comparison BDNF levels of groups and in correlations with cognitive performance. When examining studies comparing BDNF levels between patients diagnosed with bipolar disorder and healthy controls, conflicting results were found in the literature. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study regression analysis revealed the predictor role of BDNF levels for duration to read coloured words of stroop test. In our study, although the patient group performed worse on most neuropsychiatric tests, the association with duration suggested that BDNF might be effective in information processing speed. S\u0026ouml;ğ\u0026uuml;t et al. also reported an association between BDNF levels and the first stage of the Stroop test.[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eNGF and related factors\u003c/h2\u003e \u003cp\u003eIn our study, a positive correlation was found between NGF levels and age in the patient group. However, there was no correlation between age and NGF levels in the control group. Yazıcı and colleagues reported a negative correlation between NGF levels and age in cannabinoid users in their study[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our study, a positive correlation was observed between the duration of the illness and NGF levels. Barbosa et al. reported that when manic and euthymic patients were considered as a single group, there was a positive relationship between illness duration and NGF levels. However, when the groups were analyzed separately, this relationship lost its significance. [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our study, NGF levels were positively correlated with the Wechsler 40-minute score, which measures delayed memory. Linear regression analysis indicated that NGF was a predictor of this score. No significant relationship was found between Stroop test results and NGF levels. There were no studies in the literature examining the relationship between NGF and cognitive functions in bipolar disorder. However, research in Alzheimer\u0026rsquo;s disease reported that patients who had NGF-secreting cells implanted into the basal forebrain showed improved Mini-Mental State Examination results[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Our study was consistent with this finding.\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eGDNF and related factors\u003c/h2\u003e \u003cp\u003eIn our study, there was no difference in GDNF levels between patients with bipolar disorder and healthy controls. Thera are studies that report no difference in GDNF levels when comparing manic, depressive, and euthymic phases of bipolar disorder patients with healthy controlsor elevated GDNF levels in during manic and depressive episodes [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Another study investigating mood disorders and GDNF levels found that GDNF levels were lower in patients with major depressive disorder and bipolar disorder compared to healthy controls. [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. The differences between studies might be attributed to heterogeneous patient groups and small sample sizes in the research. Additionally, there is ongoing debate in the literature about whether serum GDNF levels accurately reflect brain GDNF levels as well as other neurotrophic factors [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. In a study conducted on Alzheimer's patients, it was observed that levels of GDNF in cerebrospinal fluid were elevated compared to healthy controls, while serum GDNF levels were decreased. [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. In our study, GDNF levels were assessed only in serum.\u003c/p\u003e \u003cp\u003eWe found a negative correlation between age and GDNF levels in the patient group, which was not observed in the control group. Previously, studies evaluating bipolar disorder and GDNF levels have not discussed the relationship with age. Yazıcı and colleagues, in their study on patients using cannabinoids, reported a negative correlation between GDNF levels and age in the patient group, while no association was found between age and GDNF in the control group. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our study, we observed that as GDNF levels increased, the number of spontaneous corrections in the Stroop black-and-white reading and colour-word reading tasks in the patient group, and the number of spontaneous corrections in the colour-word reading task in the control group also increased. No relationship was found between Wechsler performance and GDNF levels.\u003c/p\u003e \u003cp\u003eIn a study conducted by T\u0026uuml;rkmen and colleagues, a negative relationship was found between GDNF levels and Wechsler Visual Memory Test scores in the healthy control group. Additionally, a positive relationship was observed between GDNF levels and the time taken for the colour-word reading and colour-naming tasks in the Stroop test. T\u0026uuml;rkmen\u0026rsquo;s study also reported a positive correlation between GDNF levels and the number of errors in naming the ink colour of colour words, indicating that as GDNF levels increased, the number of errors also increased[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In a study on late-onset depression, the patient group exhibited poorer cognitive performance compared to healthy controls, and the GDNF levels in the patient group were found to be significantly higher[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. According to the literature, high serum GDNF levels appear to be associated with poorer cognitive functions. This relationship may be due to GDNF potentially having a negative impact on cognitive functions, or it could be a compensatory increase in GDNF levels secondary to a reduction in receptor numbers.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003eKlotho and Related Factors\u003c/h2\u003e \u003cp\u003eIn our study, klotho levels were found to be lower in the patient group compared to the control group. Barbosa et al. conducted a study comparing klotho levels in 20 patients with bipolar disorder (BD) in manic and euthymic states with 30 healthy controls. Their study demonstrated that BD patients had higher klotho levels compared to healthy controls, regardless of mood state. This study included participants with a disease duration of over 20 years. Additionally, the study noted that conditions affecting klotho levels, such as hypertension and diabetes, were more prevalent in the control group. The findings of the study suggest that elevated klotho levels in long-term bipolar disorder patients might be associated with the progression of the disorder [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In our study, the remission period was 12 weeks, whereas in the study where higher klotho levels were observed in the euthymic state, the remission period was set at 8 weeks. Differences in remission periods and disease duration, as well as the compensatory effect of klotho, might account for the differing results between the two studies. Other studies in the literature have compared manic periods with healthy controls, but euthymic patients were not included in these studies. In those studies, klotho levels in manic patients were found to be higher than in healthy controls. [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNo studies were found that evaluated klotho levels and cognitive function in patients with bipolar disorder during the remission period. Some studies in the literature have found a positive relationship between klotho levels and cognitive performance in other diseases. [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. A cross-sectional and observational study conducted with 94 subjects at the Oregon Alzheimer's Disease Center reported that serum and cerebrospinal fluid levels of klotho protein were correlated with Mini-Mental State Examination (MMSE) scores. Additionally, the study indicated that serum klotho levels significantly reflect cerebrospinal fluid klotho levels[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn a study conducted with healthy older adults, the relationship between klotho levels and Mini-Mental State Examination (MMSE) scores as well as the Trail Making Test was examined. It was found that a decrease in klotho levels over the annual observation period was associated with a decline in MMSE scores, but there was no association with the executive function tests represented by the Trail Making Test. The study emphasized that klotho may affect domain-specific cognitive changes.[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. In a study by T\u0026uuml;rkmen and colleagues involving patients with schizophrenia, it was reported that in healthy controls, the times to name the colour of coloured words and to read coloured words increased with higher levels of klotho. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In our study, an increase in klotho levels was associated with an increase in the number of errors in black-and-white reading in the patient group on the Stroop test. Regression analyses revealed that klotho was a predictor and a factor extending the duration for both black-and-white reading and coloured word reading times. In the control group, an increase in klotho levels was associated with an increase in interference. No relationship was found with other parameters of the Stroop test. Linear regression analysis showed that klotho was a negative predictor for Wechsler 40th-minute performance. These findings suggest a negative relationship between klotho and cognitive functions in our study, which aligns with the study by T\u0026uuml;rkmen and colleagues. This indicates that it may not be possible to interpret the relationship between klotho and cognitive functions in a single direction, suggesting that heterogenous subgroups, regional, and genetic effects may be factors. The limited number of tests used in our study might have restricted the assessment of the relationship between klotho and cognitive functions.\u003c/p\u003e \u003cp\u003eThere were some limitations in our study. Access to tests validated in Turkish for assessing cognitive functions was challenging, and patients' willingness to dedicate time to such studies was short. Although tests commonly used in the literature were selected, this allowed for the assessment of cognitive functions in limited areas. Only whole blood serum samples were used for evaluating BDNF, NGF, GDNF, and klotho levels; cerebrospinal fluid samples were not collected. Due to the passage through the blood-brain barrier and peripheral production, it could not be assessed whether blood levels truly reflect the actual levels. Due to the confounding effect of gender on neurotrophic factors, individuals of female gender were excluded from the study. While this reduced confounding factors in our study, it limited the generalizability of the sample representation.\u003c/p\u003e \u003cp\u003eStrengths of our study include the similarity in age, BMI, substance use, and gender factors, as well as factors affecting neuropsychological test evaluations, such as age and education level, between the patient and control groups. This was important in excluding confounding factors. The diagnoses of the patients were confirmed by a physician through DSM-5-oriented interviews, which was a significant advantage for the reliability of the data. The fact that neuropsychological tests were administered to all participants by the same physician was another advantage for the reliability and standardization of the data. Our study is valuable as it is the first in the literature to simultaneously evaluate BDNF, GDNF, NGF, and klotho levels in bipolar disorder patients and investigate their relationship with cognitive functions.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eAs a conclusion, when comparing patients diagnosed with euthymic bipolar disorder (BD) in remission to healthy controls, there were no differences in BDNF and GDNF levels; however, klotho and NGF levels were lower in the patient group. In BD, klotho, BDNF, GDNF and NGF are associated with cognitive functions and exhibit different characteristics from the control group. Nevertheless, the differences related to these molecules seem to be associated with a regulation system rather than merely indicating an increase or decrease in serum levels.\u003c/p\u003e \u003cp\u003eConsidering the literature and the limitations of our study, it is recommended to increase the representativeness of the sample and the generalizability of the results by including female participants in new samples, measuring biomarker samples not only from blood but also from cerebrospinal fluid, and expanding the study to include other mood phases of the illness. Additionally, examining the sub-parameters of the biochemical cascade related to klotho and neurotrophic factors, as well as investigating genetic and epigenetic levels that could influence all these factors, which were not examined in this study but are relevant in the literature, are suggested for future research.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe want to say thank you for their valuable supports to Dr Betul Aslan Turkmen and Sakarya Community Counselling Center (Sakarya TRSM) members.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate;\u0026nbsp;\u003c/strong\u003eWe confirm that ethical approval has been granted approval number: E-16214662-050.01.04-198306-150, reference number is and we obtained written informed consent of participants accordingly.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication;\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials;\u0026nbsp;\u003c/strong\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests; The authors declare that they have no competing interest.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding;\u0026nbsp;\u003c/strong\u003eThis study is funded by Sakarya University Scientific Research Projects Unit with the project number 2023-19-44-11.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions;\u0026nbsp;\u003c/strong\u003eZ\u0026Ccedil; and EY developed the theoretical background and literature check, Z\u0026Ccedil; and OD worked with the subject and collected data. ABY and Z\u0026Ccedil; performed the statistical analysis. EY and ABY write draft of manuscript. All authors contributed to the final version of the manuscript. ABY supervised the project.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNehra R, Chakrabarti S, Pradhan BK, Khehra N. Comparison of cognitive functions between first- and multi-episode bipolar affective disorders. J Affect Disord. 2006;93(1\u0026ndash;3):185\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBora E. Neurocognitive features in clinical subgroups of bipolar disorder: A meta-analysis. J Affect Disord. 2018;229:125\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCeylan MF, Tural Hesapcioglu S, Kanoğlu Y\u0026uuml;ksekkaya S, Er\u0026ccedil;in G, Yavas CP, Neşelіoğlu S, Erel O. 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BMC Med. 2015;13:289.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarbosa IG, Huguet RB, Neves FS, Reis HJ, Bauer ME, Janka Z, Palot\u0026aacute;s A, Teixeira AL. Impaired nerve growth factor homeostasis in patients with bipolar disorder. World J Biol Psychiatry. 2011;12(3):228\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerreira D, Westman E, Eyjolfsdottir H, Almqvist P, Lind G, Linderoth B, Seiger A, Blennow K, Karami A, Darreh-Shori T, et al. Brain changes in Alzheimer's disease patients with implanted encapsulated cells releasing nerve growth factor. J Alzheimers Dis. 2015;43(3):1059\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTunca Z, Ozerdem A, Ceylan D, Yal\u0026ccedil;ın Y, Can G, Resmi H, Akan P, Erg\u0026ouml;r G, Aydemir O, Cengisiz C, et al. 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Int J Neuropsychopharmacol. 2006;9(5):607\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKastin AJ, Akerstrom V, Pan W. Glial cell line-derived neurotrophic factor does not enter normal mouse brain. Neurosci Lett. 2003;340(3):239\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStraten G, Eschweiler GW, Maetzler W, Laske C, Leyhe T. Glial cell-line derived neurotrophic factor (GDNF) concentrations in cerebrospinal fluid and serum of patients with early Alzheimer's disease and normal controls. J Alzheimers Dis. 2009;18(2):331\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang X, Hou Z, Yuan Y, Hou G, Liu Y, Li H, Zhang Z. Association study between plasma GDNF and cognitive function in late-onset depression. J Affect Disord. 2011;132(3):418\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSirlier Emir B, Yildiz S, Kazğan Kili\u0026ccedil;aslan A, Kili\u0026ccedil; F, Uğur K, Aydin S, Atmaca M. The roles of Klotho and FGF-23 in bipolar manic episode. Eur Rev Med Pharmacol Sci. 2023;27(5 Suppl):101\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSanz B, Arrieta H, Rezola-Pardo C, Fern\u0026aacute;ndez-Atutxa A, Garin-Balerdi J, Arizaga N, Rodriguez-Larrad A, Irazusta J. Low serum klotho concentration is associated with worse cognition, psychological components of frailty, dependence, and falls in nursing home residents. Sci Rep. 2021;11(1):9098.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbraham CR, Mullen PC, Tucker-Zhou T, Chen CD, Zeldich E. Klotho Is a Neuroprotective and Cognition-Enhancing Protein. Vitam Horm. 2016;101:215\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKundu P, Zimmerman B, Quinn JF, Kaye J, Mattek N, Westaway SK, Raber J. Serum Levels of α-Klotho Are Correlated with Cerebrospinal Fluid Levels and Predict Measures of Cognitive Function. J Alzheimers Dis. 2022;86(3):1471\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShardell M, Semba RD, Rosano C, Kalyani RR, Bandinelli S, Chia CW, Ferrucci L. Plasma Klotho and Cognitive Decline in Older Adults: Findings From the InCHIANTI Study. J Gerontol Biol Sci Med Sci. 2016;71(5):677\u0026ndash;82.\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":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","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":"Stroop, Weshler Memory, Bipolar, neuroplasticity, neurocognition","lastPublishedDoi":"10.21203/rs.3.rs-5214269/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5214269/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eKlotho and neurotrophic factors (BDNF, GDNF, NGF) are shown have role in cognitive functions but these molecules has not been investigated in bipolar disorder simultaneously to assess the interactions among these molecules and their relationship with cognitive functions. This study investigates the relationship between cognitive functions, klotho, and neurotrophic factors in patients with bipolar disorder in remission period.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eMale, bipolar disorder dignosed patients (patient group, n\u0026thinsp;=\u0026thinsp;48) in remission period and healthy volunteers (control group, n\u0026thinsp;=\u0026thinsp;48) were included to the study. Stroop test and Wechsler Memory Scale \u0026ndash; Visual Production Subtest was applied and Klotho, BDNF, GDNF, NGF serum levels were identified by ELISA reader.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe klotho protein level (0,12\u0026thinsp;\u0026plusmn;\u0026thinsp;0,15 and 0,17\u0026thinsp;\u0026plusmn;\u0026thinsp;0,16) and NGF level (34,36\u0026thinsp;\u0026plusmn;\u0026thinsp;41,99 and 48,54\u0026thinsp;\u0026plusmn;\u0026thinsp;41,06) in the patient group were significantly lower compared to the control group (Z=-3.071, p\u0026thinsp;=\u0026thinsp;0.002 and Z=-2.217, p\u0026thinsp;=\u0026thinsp;0.027, respectively). In the patient group, there was a positive correlation between klotho and NGF levels (p\u0026thinsp;=\u0026thinsp;0.003, r\u003csub\u003es\u003c/sub\u003e=0.413) and a negative correlation was between NGF and GDNF levels (p\u0026thinsp;=\u0026thinsp;0.013, r\u003csub\u003es\u003c/sub\u003e=-0.355). Klotho and NGF were predictors of Weshler 40 minute test(Adjusted R2\u0026thinsp;=\u0026thinsp;0.467) and Klotho and BDNF were predictos of Stroop test colour word reading time (Adjusted R2\u0026thinsp;=\u0026thinsp;0.391)with other variables.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIn BD, klotho, BDNF, GDNF and NGF are associated with cognitive functions and exhibit different characteristics from the control group. Nevertheless, the differences related to these molecules seem to be associated with a regulation system rather than merely indicating an increase or decrease in serum levels.\u003c/p\u003e","manuscriptTitle":"Relationship Between Klotho, Neurotrophic Factors (Bdnf, Ngf, Gdnf) and Cognitive Functions in Patients With Bipolar Disorder","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-25 15:24:36","doi":"10.21203/rs.3.rs-5214269/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-06T07:54:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-06T06:18:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"32909692194490111359477700691944746911","date":"2024-12-05T11:04:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-04T08:35:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"1879403912742756742440673530753006832","date":"2024-12-04T07:19:39+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-03T09:03:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-03T08:18:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"185283379655511609052592322409962543620","date":"2024-12-03T08:14:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"23533029077558798796496870021699557930","date":"2024-12-02T05:55:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"272879834412004380809187819538875823680","date":"2024-12-02T05:48:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"144074318933886564191871417814575047132","date":"2024-12-02T01:56:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-02T01:24:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"60208589793996270886164845804913047636","date":"2024-12-02T00:28:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"189301571402169006911462408824408496515","date":"2024-12-01T23:47:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"286161561702449144867736560492450328530","date":"2024-12-01T23:15:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"325516733115565290727153988296091280810","date":"2024-10-28T13:38:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"124576207423964083876826629862330036256","date":"2024-10-28T06:24:06+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-25T11:29:25+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-10-09T06:05:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-08T10:13:30+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-08T10:13:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Psychiatry","date":"2024-10-06T18:59:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","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":"9e17a263-0f2a-4e02-8da4-f47dafafdee3","owner":[],"postedDate":"December 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-27T16:12:30+00:00","versionOfRecord":{"articleIdentity":"rs-5214269","link":"https://doi.org/10.1186/s12888-025-06469-0","journal":{"identity":"bmc-psychiatry","isVorOnly":false,"title":"BMC Psychiatry"},"publishedOn":"2025-01-20 15:58:02","publishedOnDateReadable":"January 20th, 2025"},"versionCreatedAt":"2024-12-25 15:24:36","video":"","vorDoi":"10.1186/s12888-025-06469-0","vorDoiUrl":"https://doi.org/10.1186/s12888-025-06469-0","workflowStages":[]},"version":"v1","identity":"rs-5214269","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5214269","identity":"rs-5214269","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}