Association of salivary testosterone levels during the post-awakening period with age and symptoms suggestive of late-onset hypogonadism in men.

BACKGROUND: The lack of association between serum testosterone levels and symptoms suggestive of hypogonadism is a significant barrier in the determination of late-onset hypogonadism (LOH) in men. This study explored whether testosterone levels increase after morning awakening, likewise the cortisol awakening response (CAR) in the hypothalamic-pituitary-adrenal (HPA) axis, and whether testosterone levels during the post-awakening period are associated with age and symptoms suggestive of late-onset hypogonadism (LOH) in men. METHODS: Testosterone and cortisol levels were determined in saliva samples collected immediately upon awakening and 30 and 60 min after awakening, and scores of the Aging Males' Symptoms (AMS) questionnaire were obtained from 225 healthy adult men. RESULTS: A typical CAR (an increase in cortisol level ≥ 2.5 nmol/L above individual baseline) was observed in 155 participants (the subgroup exhibiting typical CAR). In the subgroup exhibiting CAR, testosterone levels sharply increased during the post-awakening period, showing a significant negative correlation with age, total AMS score, and the scores of 11 items on the somatic, psychological, and sexual AMS subscales. Of these items, three sexual items (AMS items #15-17) were correlated with age. Meanwhile, there was no notable increase in testosterone levels and no significant correlation of testosterone levels with age and AMS score in the subgroup exhibiting no typical CAR (n = 70). CONCLUSIONS: The results indicate that the hypothalamus-pituitary-gonad (HPG) axis responds to morning awakening, and determining testosterone levels during the post-awakening period in men with typical CAR may be useful for assessing HPG axis function and LOH.

The present study found that the HPG axis in healthy adult men responds to the morning awakening, characterized by increased salivary testosterone levels after the awakening period.The levels of salivary testosterone during the first hour after awakening are negatively associated with age and the severity of symptoms suggestive of LOH in adult men with typical CAR.

Comparative analysis of salivary cortisol measurements using different assay methods in relation to serum-free cortisol measurement.

Objectives: Salivary cortisol reflects the biologically active form of serum cortisol, offering a noninvasive evaluation method for the diurnal rhythm of the hypothalamic-pituitary-adrenal (HPA) axis. While liquid chromatography-tandem mass spectrometry (LC-MS/MS) is known for its specificity, immunoassays (IA) are commonly used because of their simplicity. This study aimed to assess the performance of salivary cortisol measurement using both IA and LC-MS/MS in comparison to serum-free cortisol measurement. Methods: Assay results for 188 saliva and 94 serum samples from 47 participants were analyzed. Salivary samples collected at different time points were analyzed using IA and LC-MS/MS. Serum samples were analyzed for cortisol, cortisol-binding globulin, and free cortisol. The statistical analyses included correlations and method comparisons. Results: The diurnal salivary cortisol profiles exhibited a comparable circadian rhythm pattern; however, the concentrations measured using IA were consistently higher than those measured using LC-MS/MS. The correlation analysis revealed robust associations among salivary cortisol (IA), salivary cortisol (LC-MS/MS), and serum-free cortisol levels (LC-MS/MS). However, the method comparison revealed a systematic bias between IA and LC-MS/MS in salivary cortisol measurement. Conclusions: This study contributes to the ongoing debate on assay techniques by affirming the suitability of IA and LC-MS/MS for salivary cortisol measurement to assess dynamic changes in HPA axis activity. The identified systematic bias emphasizes the importance of selecting methods based on specific research or clinical requirements.

Exploratory Clinical Trial of a Depression Diagnostic Software That Integrates Stress Biomarkers and Composite Psychometrics.

OBJECTIVE: This study evaluated the clinical effectiveness of Minds.NAVI, a depression screening kit combining psychometric measures and stress hormone biomarkers, in a prospective clinical trial. The objective was to assess its potential as a depression screening tool and investigate the associations between psychological assessments, salivary hormone staging, and depression severity. METHODS: Thirty-five participants with major depressive disorder and 12 healthy controls (HCs) were included. The Minds.NAVI software, utilizing the PROtective and Vulnerable factors battEry Test (PROVE) and salivary cortisol/dehydroepiandrosterone (DHEA) analysis, was employed. The PROVE test is a comprehensive self-report questionnaire that assesses depressive symptoms, suicide risk, attachment style, adverse childhood experiences, mentalization capacity, and resilience. In addition, salivary cortisol and DHEA levels were measured to evaluate the functional stage of the hypothalamic-pituitary-adrenal (HPA) axis. RESULTS: Minds.NAVI exhibited 100% sensitivity, 91.7% specificity, and 97.9% accuracy in distinguishing depression from HCs within an exploratory small group. Salivary stress hormone phases showed changes with depression stage (p=0.030), and the proportion of patients with "adrenal exhaustion stage" was higher in the moderate/severe depression group (p=0.038). Protective/vulnerable factors differed significantly between controls and depressed groups (p<0.001). Cortisol awakening response inversely correlated with depressive symptom severity (r=-0.31, p=0.034). CONCLUSION: This study suggested possible clinical effectiveness of Minds.NAVI, a depression screening tool that integrates psychometric measures and stress hormone biomarkers. The findings support the potential association between depression, chronic stress, and HPA axis hyporesponsiveness.

Relationship of Resilience Factors With Biopsychosocial Markers Using a Comprehensive Home Evaluation Kit for Depression and Suicide Risk: A Real-World Data Analysis.

Objectives: Adverse childhood experiences (ACEs) are fundamental factors in developing depression with increased suicide risk. Resilience is considered an important protective factor that can prevent trauma survivors from developing depression. We developed a home evaluation kit for a comprehensive assessment of bio-psycho-social factors related to depression and suicide. This kit contained a psycho-social evaluation battery, named the Protective and Vulnerable factors battery questionnaire (PROVE) comprising depressive symptoms and suicide risk, as well as various depression-related psychosocial factors, such as ACE, resilience, mentalization capacity, and attachment, via online survey tools. Furthermore, salivary cortisol levels were used as biological indicators to assess the hypothalamus-pituitary-adrenal axis function. Methods: Real-world data analysis was made out of data collected from participants who visited CHEEU Counseling center or Gangnam Severance hospital for mental health check-ups. The participants were put into three mental state groups (green-normal, yellow-borderline, and red-risk) depending on the result of PROVE battery. The difference between psychosocial factors and salivary cortisol indicators by the group was identified by analysis of covariance with sex and age as covariates. Linear regression analysis was conducted to find a significant association of resilience score with other bio-psycho-social variables, such as ACE, attachment, mentalization, or post-awakening cortisol concentrations (area under the curve with respect to ground, AUCg). A partial correlation analysis was performed to evaluate the relationship of AUCg with psychosocial factors. Results: Depression-related psycho-social indicators were significantly different among groups. Insecure attachment and the mentalization problem are negatively influencing factors to resilience. Furthermore, the severity of depression in participants with ACE was also influenced by mentalization problems. AUCg was different according to the PROVE group, presence of ACE, or resilience level. In addition, AUCg showed a positive correlation with resilience score but negative correlations with depressive symptoms, ACE, mentalization problems, and anxiety or avoidance attachment. Conclusion: This study suggests that there are some key factors negatively affecting resilience: insecure attachment and mentalization problems. In groups with ACE, a mentalization problem was suggested as a factor that can increase depressive symptoms. AUCg was associated with resilience as well as several other vulnerable factors of depression, showing its potential as a promising biomarker.

Virtual reality-based monitoring test for MCI: A multicenter feasibility study.

Objectives: As the significance of the early diagnosis of mild cognitive impairment (MCI) has emerged, it is necessary to develop corresponding screening tools with high ecological validity and feasible biomarkers. Virtual reality (VR)-based cognitive assessment program, which is close to the daily life of the older adults, can be suitable screening tools for MCI with ecological validity and accessibility. Meanwhile, dehydroepiandrosterone (DHEA) has been observed at a low concentration in the older adults with dementia or cognitive decline, indicating its potential as a biomarker of MCI. This study aimed to determine the efficacy and usability of a VR cognitive assessment program and salivary DHEA for screening MCI. Methods: The VR cognitive assessment program and the traditional Montreal Cognitive Assessment (MOCA) test were performed on 12 patients with MCI and 108 healthy older adults. The VR program operates in a situation of caring for a grandchild, and evaluates the memory, attention, visuospatial, and executive functions. An analysis of covariance (ANCOVA), a partial correlation analysis, and receiving operating characteristic (ROC) curve analysis were conducted for statistical analysis. Results: According to the ANCOVA, no significant difference in MOCA scores was found between the normal and MCI groups (F = 2.36, p = 0.127). However, the VR total score of the MCI group was significantly lower than that of the normal group (F = 8.674, p = 0.004). There was a significant correlation between the MOCA and VR scores in the total and matched subdomain scores. The ROC curve analysis also showed a larger area under the curve (AUC) for the VR test (0.765) than for the MOCA test (0.598), and the sensitivity and specificity of the VR program were 0.833 and 0.722, respectively. Salivary DHEA was correlated with VR total (R 2 = 0.082, p = 0.01) and attention scores (R 2 = 0.086, p = 0.009). Conclusion: The VR cognitive test was as effective as the traditional MOCA test in the MCI classification and safe enough for older adults to perform, indicating its potential as a diagnostic tool. It has also been shown that salivary DHEA can be used as a biomarker for MCI.

Mobile app-based chatbot to deliver cognitive behavioral therapy and psychoeducation for adults with attention deficit: A development and feasibility/usability study.

BACKGROUND: Attention deficit is a growing problem in adults, and early diagnosis and treatment are needed. Previous studies have shown that cognitive behavioral therapy (CBT) is effective in improving attention deficit symptoms. However, many patients are not receiving adequate treatment due to time, space, and cost constraints. Recently, in other mental illnesses, mobile-based chatbots delivering CBT and psychoeducation have been used for symptom mitigation and treatment. OBJECTIVE: This study aimed to investigate the feasibility and usability of a short-term intervention, specifically a mobile-based interactive chatbot application, in alleviating attention deficit symptoms. METHODS: This was a randomized, non-blind parallel-group pilot study conducted from September 2019 to March 2020. Forty-six individuals with attention deficit aged 19-60 were randomly allocated to the chatbot (n = 23) and information-only control groups (n = 23) for 4 weeks. The former group was instructed to use the chatbot application "Todaki," while the latter group was provided with a book on managing attention deficit symptoms. Participants were administered questionnaires to assess their symptoms of attention deficit, depression, and anxiety and evaluated at baseline and 4 weeks after the intervention. The post-intervention survey assessed the chatbot's usability, acceptability, and side effects. RESULTS: The average age of the participants was 25.1 years (standard deviation [SD] 7.5 years), and 56.5 % (26/46) participants were female. Intention-to-treat analysis (chatbot, n = 23; control, n = 23) revealed a significant reduction of attention deficit symptoms only in the chatbot group, which is represented by group-by-time interaction in Conner's Adult ADHD Rating Scale subscales of Diagnostic and Statistical Manual-IV Attention-Deficit/Hyperactivity Disorder (ADHD) Hyperactive-Impulsive symptoms (F = 4.39; p = .04) and ADHD symptoms total (F = 6.74, p = .01). Further, the results of the paired t-test were significant only in the chatbot group. The average number of times the chatbots were used in 4 weeks was 20.32 (SD 12.89). The total average usage time was 1 h 15 min (SD 1 h 20 min). The degree of improvement in the ADHD symptoms total score was correlated with the number of times the psychoeducation program was used. According to the participants, the empathic/friendly character and unnatural flow of conversation were the best and worst features of the chatbot, respectively. CONCLUSIONS: This study identified the feasibility and usability of using the mobile-based chatbot to improve attention deficit and its associated psychiatric symptoms. Using this novel intervention to conduct CBT would provide a useful digital therapeutic tool that allows easy accessibility and self-guided management for people with attention deficit, which should be verified through the large scale randomized controlled trial.

Efficacy of mobile app-based interactive cognitive behavioral therapy using a chatbot for panic disorder.

BACKGROUND: Cognitive behavioral therapy (CBT) is a well-established treatment for panic disorder, but many fewer patients receive this treatment compared to medication-based therapy. Mobile app-based interactive CBT using a chatbot can increase patient access to CBT. We performed a preliminary study to determine whether short-term use of a newly developed chatbot is feasible and effective for relieving panic symptoms. METHOD: Forty-one patients were randomly assigned to either a chatbot group (n = 21) or control group (n = 20) for a period of 4 weeks. The chatbot group was guided in the use of the chatbot application, while the control group was provided with a book on panic disorder. MAIN RESULTS: The severity of panic disorder was significantly decreased in the chatbot group, but not in the control group. The social phobia score was significantly decreased and the control helplessness score was significantly increased in the chatbot group compared to the control group. DISCUSSION AND CONCLUSION: We found that mobile app-based interactive CBT using the chatbot was feasible and effective for reducing the severity of panic symptoms. Using this novel approach to provide CBT would allow clinicians to effect positive therapeutic outcomes with easy accessibility, interactivity, and self-management for patients with panic symptoms.

Use of Virtual Reality Working Memory Task and Functional Near-Infrared Spectroscopy to Assess Brain Hemodynamic Responses to Methylphenidate in ADHD Children.

Virtual reality (VR) neuropsychological tests have emerged as a method to explore drug effects in real-life contexts in attention deficit hyperactivity disorder (ADHD) children. Functional near-infrared spectroscopy (fNIRS) is a useful tool to measure brain activity during VR tasks in ADHD children with motor restlessness. The present study aimed to explore the acute effects of methylphenidate (MPH) on behavioral performance and brain activity during a VR-based working memory task simulating real-life classroom settings in ADHD children. In total, 23 children with ADHD performed a VR n-back task before and 2 h after MPH administration concurrent with measurements of oxygenated hemoglobin signal changes with fNIRS. Altogether, 12 healthy control (HC) subjects participated in the same task but did not receive MPH treatment. Reaction time (RT) was shortened after MPH treatment in the 1-back condition, but changes in brain activation were not observed. In the 2-back condition, activation of the left dorsolateral prefrontal cortex (DLPFC) and bilateral medial prefrontal cortex (mPFC) was decreased alongside behavioral changes such as shorter RT, lower RT variability, and higher accuracy after MPH administration. Bilateral mPFC activation in the 2-back condition inversely correlated with task accuracy in the pre-MPH condition; this inverse correlation was not observed after MPH administration. In ADHD children, deactivation of the default mode network mediated by mPFC reduced during high working memory load, which was restored through MPH treatment. Our results suggest that the combination of VR classroom tasks and fNIRS examination makes it easy to assess drug effects on brain activity in ADHD children in settings simulating real-life.

Particulate matter increases beta-amyloid and activated glial cells in hippocampal tissues of transgenic Alzheimer's mouse: Involvement of PARP-1.

Exposure to air pollutants, such as particulate matter (PM), has been implicated in neurodegenerative disorders including Alzheimer's disease (AD). However, direct effects of PM on production of ß-amyloid (Aß), a key pathogenic molecule in AD, and its underlying mechanism are still elusive. Given PM's potential to induce oxidative stress in other tissues, we hypothesized that poly(ADP-ribose) polymerase (PARP-1) might be involved in PM-induced neurotoxicity. To address this, we used an ex vivo model of AD, the organotypic hippocampal slice tissue culture from old (12-14 months-of-age) triple transgenic 3xTg-AD mice. First, we observed that fine PM (aerodynamic diameter < 4 µm) can dose-dependently activate PARP-1 and decrease NAD+ levels in Neuro2A cells. PARP-1 activation did occur under concentrations of PM which did not affect cell viability. Next, we observed that direct treatment of PM increased Aß levels and activated glial cells in the ex vivo hippocampal tissues of 3xTg-AD mice. PM-induced glial activation was most prominent in CA1 region of the hippocampal tissue. Notably, we found that pharmacological inhibition of PARP-1 reversed both PM-induced Aß increase and glial activation, arguing the possible involvement of PARP-1 in PM-induced AD pathogenesis. Our findings suggest that PARP-1 might be a potential molecular target, responsible for mediating negative effects of PM on the brain. Modulating PARP-1 activity could be a promising approach to prevent or alleviate PM-related environmental neurotoxicity which could initiate AD pathogenesis.

Long-Term Culture of Organotypic Hippocampal Slice from Old 3xTg-AD Mouse: An ex vivo Model of Alzheimer's Disease.

OBJECTIVE: Conventional methods for organotypic hippocampal tissue slice culture (OHSC) have shown several disadvantages or limitations regarding age of animals used, duration of culture and difficulty using neurodegenerative models. Therefore, we tried to establish OHSC from old 3xTg-Alzheimer's disease (AD) mice for longer period (over 4 weeks) and to validate utility of this system as a valid platform for translational neuroscience of AD. METHODS: OHSC was performed with old 3xTg-AD mice (12-14 months), old wild type mice (12-14 months) and young 3xTg-AD mice (2-4 months) using serum-free medium for 4 weeks. Hippocampal structure was evaluated by 4', 6-diamidino-2-phenylindole (DAPI) intensity and neuronal metabolism was measured by Alamarblue assay. Pathologic characteristics of AD were also investigated; ß-amyloid levels by ELISA, amyloid plaque deposition by Thioflavin-S staining, and glial activation by immunohistochemistry. RESULTS: Following 4-week culture in serum-free media, hippocampal cells and layers were well preserved in cultured slices from old AD mice as was in those from young AD and old wild type mice. On the contrary, excessive regression of total visible cells was observed in conventional serum-containing medium regardless of genotype of mice. In parallel with this well preserved structure, major pathologic characteristics of AD were also well manifested in hippocampal slices from old AD mice. CONCLUSION: Our findings suggest that long-term OHSC from old 3xTg-AD mouse can serve as a promising ex vivo system for studies on pathophysiology of AD, especially with the minimum number of sacrifice of experimental animals.

Suppression of AIMP1 protects cognition in Alzheimer's disease model mice 3xTg-AD.

Neuroinflammation has been raised as a candidate of unifying pathogenesis and a target of a disease-modifying strategy for Alzheimer's disease (AD). Aminoacyl-tRNA synthetase complex (ARS)-interacting multifunctional protein 1 (AIMP1) is a cytokine that is known to amplify the actions of tumor necrosis factor-α and to be involved in microglial activation and neuronal death. In this respect, AIMP1 could be a plausible target for the treatment of AD. Therefore, we aimed to examine whether anti-AIMP1 antibody could exert therapeutic effects against cognitive impairment using 3xTg-AD mice. Through the passive avoidance test, we found that an intraperitoneal injection of anti-AIMP1 antibody over 4 weeks was effective in protecting memory function in 3xTg-AD mice (16 weeks old). In addition, to address the translational implications of AIMP1, we measured blood AIMP1 levels in patients with AD (n=22), mild cognitive impairment (n=25), and normal cognition (n=23). Blood AIMP1 levels were associated negatively with global cognitive function and were significantly higher in individuals with a higher degree of medial temporal lobe atrophy, which is one of the representative clinical markers of AD. Our results suggested a possible association of AIMP1 with AD pathogenesis, as well as the potential of the anti-AIMP1 antibody as a novel therapeutic option for AD.

Blunted response of hippocampal AMPK associated with reduced neurogenesis in older versus younger mice.

The rate of hippocampal neurogenesis declines with aging. This is partly explained by decreased neural responsiveness to various cues stimulating metabolism. AMP-activated protein kinase (AMPK), a pivotal enzyme regulating energy homeostasis in response to metabolic demands, showed the diminished sensitivity in peripheral tissues during aging. AMPK is also known to be involved in neurogenesis. We aimed to see whether AMPK reactivity is also blunted in the aged hippocampus, and thus is associated with aging-related change in neurogenesis. Following subchronic (7days) intraperitoneal and acute intracerebroventricular (i.c.v.) administration of either 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR; AMPK activator) or saline (sham) to young (16-week-old) and old (72-week-old) mice, we measured changes in AMPK activity, brain-derived neurotrophic factor (BDNF) expression or neurogenesis in the hippocampus. AICAR-induced changes in AMPK activity were observed in the hippocampus of young mice after acute i.c.v. injection. However, neither subchronic nor acute treatment induced significant changes in AMPK activity in old mice. Intriguingly, directions of AICAR-induced changes in AMPK activity were opposite between the hippocampus (decrease) and skeletal muscle (increase). ATP levels were inversely correlated with hippocampal AMPK activity, suggesting that the higher energy levels achieved by AICAR treatment might deactivate neuronal AMPK in young mice. The blunted response of AMPK to AICAR in old age was also indicated by the observations that the levels of neurogenesis and BDNF expression were significantly changed only in young mice upon AICAR treatment. Our findings suggest that the blunted response of neuronal AMPK in old age might be responsible for aging-associated decline in neurogenesis. Therefore, in addition to activation of AMPK, recovering its sensitivity may be necessary to enhance hippocampal neurogenesis in old age.