Identification of schizophrenia by applying interpretable radiomics modeling with structural magnetic resonance imaging of the cerebellum.

AIMS: The cerebellum is involved in higher-order mental processing as well as sensorimotor functions. Although structural abnormalities in the cerebellum have been demonstrated in schizophrenia, neuroimaging techniques are not yet applicable to identify them given the lack of biomarkers. We aimed to develop a robust diagnostic model for schizophrenia using radiomic features from T1-weighted magnetic resonance imaging (T1-MRI) of the cerebellum. METHODS: A total of 336 participants (174 schizophrenia; 162 healthy controls [HCs]) were allocated to training (122 schizophrenia; 115 HCs) and test (52 schizophrenia; 47 HCs) cohorts. We obtained 2568 radiomic features from T1-MRI of the cerebellar subregions. After feature selection, a light gradient boosting machine classifier was trained. The discrimination and calibration of the model were evaluated. SHapley Additive exPlanations (SHAP) was applied to determine model interpretability. RESULTS: We identified 17 radiomic features to differentiate participants with schizophrenia from HCs. In the test cohort, the radiomics model had an area under the curve, accuracy, sensitivity, and specificity of 0.89 (95% confidence interval: 0.82-0.95), 78.8%, 88.5%, and 75.4%, respectively. The model explanation by SHAP suggested that the second-order size zone non-uniformity feature from the right lobule IX and first-order energy feature from the right lobules V and VI were highly associated with the risk of schizophrenia. CONCLUSION: The radiomics model focused on the cerebellum demonstrates robustness in diagnosing schizophrenia. Our results suggest that microcircuit disruption in the posterior cerebellum is a disease-defining feature of schizophrenia, and radiomics modeling has potential for supporting biomarker-based decision-making in clinical practice.

Multimodal neural correlates of dispositional resilience among healthy individuals.

Resilient individuals are less likely to develop psychiatric disorders despite extreme psychological distress. This study investigated the multimodal structural neural correlates of dispositional resilience among healthy individuals. Participants included 92 healthy individuals. The Korean version of the Connor-Davidson Resilience Scale and other psychological measures were used. Gray matter volumes (GMVs), cortical thickness, local gyrification index (LGI), and white matter (WM) microstructures were analyzed using voxel-based morphometry, FreeSurfer, and tract-based spatial statistics, respectively. Higher resilient individuals showed significantly higher GMVs in the inferior frontal gyrus (IFG), increased LGI in the insula, and lower fractional anisotropy values in the superior longitudinal fasciculus II (SLF II). These resilience's neural correlates were associated with good quality of life in physical functioning or general health and low levels of depression. Therefore, the GMVs in the IFG, LGI in the insula, and WM microstructures in the SLF II can be associated with resilience that contributes to emotional regulation, empathy, and social cognition.

Neural Correlates of Trait Impulsivity among Adult Healthy Individuals.

Objective: : Impulsivity can be observed in individuals with or without mental illness. The discovery of neural correlates responsible for trait impulsivity can therefore help to understand the severity of psychiatric symptoms, personality characteristics and social adjustment. In this study, we aimed to identify the gray matter substrates of trait impulsivity in healthy individuals. Methods: : Seventy-five healthy individuals were enrolled. At baseline, trait impulsivity was assessed using the Barratt Impulsiveness Scale (BIS) and all participants underwent T1-weighted magnetic resonance imaging scan. Beck Anxiety Inventory (BAI), World Health Organization Quality of Life (WHOQOL-BREF) and Connor-Davidson Resilience Scale (CD-RISC) were also assessed. Mean cortical thickness (CT) and the local gyrification index (LGI) were calculated to perform whole-brain vertex-wise correlation analysis, which were performed to investigate the relationship between BIS scores and CT or LGI in each brain region. We also revealed the relationship between brain regions and psychological measurements. Results: : Total BIS scores were significantly and negatively correlated with mean CT values in the left lateral occipital cortex (OC) and LGIs in the inferior frontal gyrus (IFG). Correlation analyses revealed that the lateral OC's mean CT values were negatively correlated with BAI scores and positively correlated with WHOQOL-BREF scores, while LGI in the IFG was positively correlated with CD-RISC scores. Conclusion: : Our study showed that trait impulsivity might be associated with the lateral OC and IFG in healthy individuals. Understanding the neural correlates of trait impulsivity could provide ways to expect high impulsivity, anxiety, and poor resilience in healthy adults.

Association of hair cortisol concentration with brain-derived neurotrophic factor gene methylation: The role of sex as a moderator.

Hair cortisol concentration (HCC) reflects the long-term activity of the hypothalamus-pituitary-adrenal (HPA) axis in response to stress. Brain-derived neurotrophic factor DNA methylation (BDNF DNAM) may affect HCC, and sex and Val66Met may contribute to this association. Thus, the aim of this study was to investigate the associations between HCC and Brain-derived neurotrophic factor (BDNF) DNAM, and the moderating effects of Val66Met and sex. We recruited 191 healthy young participants (96 women, mean age 23.0 ± 2.6 years) and collected body samples to evaluate HCC, and to determine BDNF DNAM and Val66Met genotypes. We analyzed the effects of BDNF DNAM, sex, and Val66Met on HCC. We also evaluated the associations between BDNF DNAM and HCC in groups separated by sex and genotypes. We found a marked association of BDNF DNAM with HCC across men and women. After dividing the data by sex, a positive correlation of HCC with BDNF DNAM was found only in women. There was no substantial moderation effect of Val66Met genotypes on the association between BDNF DNAM and HCC. Therefore, BDNF DNAM was found to have positive association with HCC only in healthy young women, indicating that sex moderates the association of BDNF DNAM with long-term HPA axis activity.

Positive Effects of Uric Acid on White Matter Microstructures and Treatment Response in Patients With Schizophrenia.

BACKGROUND AND HYPOTHESIS: Schizophrenia involves microstructural changes in white matter (WM) tracts. Oxidative stress is a key factor causing WM damage by hindering oligodendrocyte development and myelin maturation. Uric acid (UA), an endogenous antioxidant, may protect against oxidative stress. We investigated the effect of UA on WM connectivity in antipsychotic-naive or -free patients with early- or chronic-stage schizophrenia. STUDY DESIGN: A total of 192 patients with schizophrenia (122 recent-onset [ROS] and 70 chronic [CS]) and 107 healthy controls (HCs) participated in this study. Diffusion tensor imaging data and serum UA levels at baseline were obtained. STUDY RESULTS: Fractional anisotropy was lower in the widespread WM regions across the whole brain, and diffusivity measures were higher in both schizophrenia groups than in HCs. The CS group showed lower diffusivity in some WM tracts than the ROS or HC groups. The linear relationship of serum UA levels with axial and mean diffusivity in the right frontal region was significantly different between schizophrenia stages, which was driven by a negative association in the CS group. WM diffusivity associated with serum UA levels correlated with 8-week treatment responses only in patients with CS, suggesting UA to be protective against long-term schizophrenia. CONCLUSIONS: UA may protect against the WM damage associated with the progression of schizophrenia by reducing oxidative stress and supporting WM repair against oxidative damage. These results provide insights into the positive role of UA and may facilitate the development of novel disease-modifying therapies.

Cerebro-cerebellar gray matter abnormalities associated with cognitive impairment in patients with recent-onset and chronic schizophrenia.

Although the role of the cerebellum in schizophrenia has gained attention, its contribution to cognitive impairment remains unclear. We aimed to investigate volumetric alterations in the cerebro-cerebellar gray matter (GM) in patients with recent-onset schizophrenia (ROS) and chronic schizophrenia (CS) compared with healthy controls (HCs). Seventy-two ROS, 43 CS, and 127 HC participants were recruited, and high-resolution T1-weighted structural magnetic resonance images of the brain were acquired. We compared cerebellar GM volumes among the groups using voxel-based morphometry and examined the cerebro-cerebellar GM volumetric correlations in participants with schizophrenia. Exploratory correlation analysis investigated the functional relevance of cerebro-cerebellar GM volume alterations to cognitive function in the schizophrenia group. The ROS and CS participants demonstrated smaller cerebellar GM volumes, particularly in Crus I and II, than HCs. Extracted cerebellar GM volumes demonstrated significant positive correlations with the cerebral GM volume in the fronto-temporo-parietal association areas engaged in higher-order association. The exploratory analysis showed that smaller cerebellar GM in the posterior lobe regions was associated with poorer cognitive performance in participants with schizophrenia. Our study suggests that cerebellar pathogenesis is present in the early stages of schizophrenia and interconnected with structural abnormalities in the cerebral cortex. Integrating the cerebellum into the pathogenesis of schizophrenia will help advance our understanding of the disease and identify novel treatment targets concerning dysfunctional cerebro-cerebellar interactions.

Altered cortical thickness of the superior frontal gyrus and fusiform gyrus in individuals with subthreshold social anxiety.

Subthreshold social anxiety (SSA) is a condition in which individuals experience social anxiety that does not reach the threshold required for a clinical diagnosis of a social anxiety disorder (SAD). Although SSA may not impair lives as severely as SAD, it can affect social functioning. However, only a few studies focused on structural neural correlates of SSA. We recruited 65 individuals with SSA and used the Leibowitz Social Anxiety Scale to assess their social and performance anxiety levels and other relevant measures of social anxiety. Voxel-wise whole-brain correlational analyses showed a positive association between the cortical thickness (CT) of the superior frontal gyrus (SFG) and social anxiety levels and a negative correlation between the CT of the fusiform gyrus (FG) and performance anxiety levels in individuals with SSA. Exploratory Pearson's correlation analyses showed significant positive correlations between the CT of the SFG and Generalized Anxiety Disorder-7 total scores and negative associations between the CT of the FG and Beck Anxiety Inventory total scores. Our study provides insight into the neural basis of SSA, particularly performance anxiety, by highlighting the association between CT in specific brain regions and SSA characteristics.

Fibronectin Type III Domain Containing 3B as a Potential Prognostic and Therapeutic Biomarker for Glioblastoma.

Glioblastoma (GBM) is a representative malignant brain tumor characterized by a dismal prognosis, with survival rates of less than 2 years and high recurrence rates. Despite surgical resection and several alternative treatments, GBM remains a refractory disease due to its aggressive invasiveness and resistance to anticancer therapy. In this report, we explore the role of fibronectin type III domain containing 3B (FNDC3B) and its potential as a prognostic and therapeutic biomarker in GBM. GBM exhibited a significantly higher cancer-to-normal ratio compared to other organs, and patients with high FNDC3B expression had a poor prognosis (p < 0.01). In vitro studies revealed that silencing FNDC3B significantly reduced the expression of Survivin, an apoptosis inhibitor, and also reduced cell migration, invasion, extracellular matrix adhesion ability, and stem cell properties in GBM cells. Furthermore, we identified that FNDC3B regulates PTEN/PI3K/Akt signaling in GBM cells using MetaCore integrated pathway bioinformatics analysis and a proteome profiler phospho-kinase array with sequential western blot analysis. Collectively, our findings suggest FNDC3B as a potential biomarker for predicting GBM patient survival and for the development of treatment strategies for GBM.

Potential Risk of Choline Alfoscerate on Isoflurane-Induced Toxicity in Primary Human Astrocytes.

Objective: Isoflurane, a widely used common inhalational anesthetic agent, can induce brain toxicity. The challenge lies in protecting neurologically compromised patients from neurotoxic anesthetics. Choline alfoscerate (L-α-Glycerophosphorylcholine, α-GPC) is recognized for its neuroprotective properties against oxidative stress and inflammation, but its optimal therapeutic window and indications are still under investigation. This study explores the impact of α-GPC on human astrocytes, the most abundant cells in the brain that protect against oxidative stress, under isoflurane exposure. Methods: This study was designed to examine changes in factors related to isoflurane-induced toxicity following α-GPC administration. Primary human astrocytes were pretreated with varying doses of α-GPC (ranging from 0.1 to 10.0 µM) for 24 hours prior to 2.5% isoflurane exposure. In vitro analysis of cell morphology, water-soluble tetrazolium salt-1 assay, quantitative real-time polymerase chain reaction, proteome profiler array, and transcriptome sequencing were conducted. Results: A significant morphological damage to human astrocytes was observed in the group that had been pretreated with 10.0 mM of α-GPC and exposed to 2.5% isoflurane. A decrease in cell viability was identified in the group pretreated with 10.0 µM of α-GPC and exposed to 2.5% isoflurane compared to the group exposed only to 2.5% isoflurane. Quantitative real-time polymerase chain reaction revealed that mRNA expression of heme-oxygenase 1 and hypoxia-inducible factor-1α, which were reduced by isoflurane, was further suppressed by 10.0 µM α-GPC pretreatment. The proteome profiler array demonstrated that α-GPC pretreatment influenced a variety of factors associated with apoptosis induced by oxidative stress. Additionally, transcriptome sequencing identified pathways significantly related to changes in isoflurane-induced toxicity caused by α-GPC pretreatment. Conclusion: The findings suggest that α-GPC pretreatment could potentially enhance the vulnerability of primary human astrocytes to isoflurane-induced toxicity by diminishing the expression of antioxidant factors, potentially leading to amplified cell damage.

Self-compassion is associated with the superior longitudinal fasciculus in the mirroring network in healthy individuals.

Self-compassion (SC) involves taking an emotionally positive attitude towards oneself when suffering. Although SC has positive effects on mental well-being as well as a protective role in preventing symptoms in healthy individuals, few studies on white matter (WM) microstructures in neuroimaging studies of SC has been studied. Brain imaging data were acquired from 71 healthy participants. WM regions of mirroring network were analyzed using tract-based spatial statistics. After the WM regions associated with SC were extracted, exploratory correlation analysis with the self-forgiveness scale, the coping scale, and the world health organization quality of life scale abbreviated version was performed. We found that self-compassion scale total scores were negatively correlated with the fractional anisotropy (FA) values of the superior longitudinal fasciculus (SLF) in healthy individuals. The self-kindness and mindfulness subscale scores were also negatively correlated with FA values of the same regions. These FA values were negatively correlated with the total scores of self-forgiveness scale, and self-control coping strategy and confrontation coping strategy. Our findings suggest levels of SC may be associated with WM microstructural changes of SLF in healthy individuals. These lower WM microstructures may be associated with positive personal attitudes, such as self-forgiveness, self-control and active confrontational strategies.

Network analysis of plasma proteomes in affective disorders.

The conventional differentiation of affective disorders into major depressive disorder (MDD) and bipolar disorder (BD) has insufficient biological evidence. Utilizing multiple proteins quantified in plasma may provide critical insight into these limitations. In this study, the plasma proteomes of 299 patients with MDD or BD (aged 19-65 years old) were quantified using multiple reaction monitoring. Based on 420 protein expression levels, a weighted correlation network analysis was performed. Significant clinical traits with protein modules were determined using correlation analysis. Top hub proteins were determined using intermodular connectivity, and significant functional pathways were identified. Weighted correlation network analysis revealed six protein modules. The eigenprotein of a protein module with 68 proteins, including complement components as hub proteins, was associated with the total Childhood Trauma Questionnaire score (r = -0.15, p = 0.009). Another eigenprotein of a protein module of 100 proteins, including apolipoproteins as hub proteins, was associated with the overeating item of the Symptom Checklist-90-Revised (r = 0.16, p = 0.006). Functional analysis revealed immune responses and lipid metabolism as significant pathways for each module, respectively. No significant protein module was associated with the differentiation between MDD and BD. In conclusion, childhood trauma and overeating symptoms were significantly associated with plasma protein networks and should be considered important endophenotypes in affective disorders.

Altered DNA Methylation of the Serotonin Transporter Gene Associated with Early Life Stress and White Matter Microalterations in Korean Patients with Panic Disorder.

INTRODUCTION: Changes in the DNA methylation of 5-HTTLPR are associated with the pathophysiology of panic disorder (PD). This study was conducted to investigate the association between stressful life events and the level of 5-HTTLPR methylation in patients with PD. We also examined whether these factors were associated with white matter alterations in psychological trauma-related regions. METHODS: The participants comprised 232 patients with PD and 93 healthy adults of Korean descent. DNA methylation levels of five cytosine-phosphate-guanine (CpG) sites in the 5-HTTLPR region were analyzed. Voxel-wise statistical analysis of diffusion tensor imaging data was performed within the trauma-related regions. RESULTS: PD patients showed significantly lower levels of the DNA methylation at 5-HTTLPR 5 CpG sites than healthy controls. In patients with PD, the DNA methylation levels at 5-HTTLPR 5 CpG sites showed significant negative association with the parental separation-related psychological distress, and positive correlations with the fractional anisotropy values of the superior longitudinal fasciculus (SLF) which might be related to trait anxiety. CONCLUSION: Early life stress was significantly associated with DNA methylation levels at 5-HTTLPR related to the decreased white matter integrity in the SLF region in PD. Decreased white matter connectivity in the SLF might be related to trait anxiety and is vital to the pathophysiology of PD.

Performance Degradation in Static Random Access Memory of 10 nm Node FinFET Owing to Displacement Defects.

We comprehensively investigate displacement-defect-induced current and static noise margin variations in six-transistor (6T) static random access memory (SRAM) based on a 10 nm node fin field-effect transistor (FinFET) using technology computer-aided design (TCAD). Various defect cluster conditions and fin structures are considered as variables to estimate the worst-case scenario for displacement defects. The rectangular defect clusters capture more widely distributed charges at the fin top, reducing the on- and off-current. The read static noise margin (RSNM) is the most degraded in the pull-down transistor during the read operation. The increased fin width decreases the RSNM due to the gate field. The current per cross-sectional area increases when the fin height decreases, but the energy barrier lowering by the gate field is similar. Therefore, the reduced fin width and increased fin height structure suit the 10 nm node FinFET 6T SRAMs with high radiation hardness.

Self-forgiveness is associated with increased volumes of fusiform gyrus in healthy individuals.

Self-forgiveness (SF) involves a process through which negative moral emotions directed at the self are replaced by benevolence and acceptance. Lower SF scores can be associated with less self-compassion, higher psychological distress, and lower life dissatisfaction. However, neural correlates of SF have not been investigated yet. We enrolled a total of 79 healthy individuals. The Self-Forgiveness Scale (SFS), Self-Compassion Scale (SCS), Connor-Davidson Resilience Scale (CD-RISC), Beck Depression Inventory-II (BDI-II), and Beck Anxiety Inventory (BAI) were evaluated. Voxel-wise correlational analyses showed a significant positive correlation between the total SFS scores and gray matter volumes (GMVs) in the fusiform gyrus (FG). In addition, the GMVs in the FG were significantly positively associated with the total SCS and CD-RISC scores and negatively correlated with the total BDI-II and BAI scores. These findings suggest that the FG related to the mirror neuron system might be a neural correlate of SF. Furthermore, its increased volumes of FG in healthy individuals can be associated with the capacity to overcome stressful life events.

Differences in Functional Level and Central Symptom of Network Structures in the Patients Seeking Treatment for Panic Disorder Before and During the COVID-19 Pandemic.

OBJECTIVE: Mental health problems such as anxiety, panic, and depression have been exacerbated by the coronavirus disease-2019 (COVID-19). This study aimed to compare the symptom severities and overall function before and during the COVID-19 pandemic among patients with panic disorder (PD) seeking treatment compared to healthy controls (HCs). METHODS: Baseline data were collected from the two groups (patients with PD and HCs) in two separate periods: before COVID-19 (Jan 2016-Dec 2019) and during COVID-19 (Mar 2020-Jul 2022). A total 453 participants (before COVID-19: 246 [139 patients with PD and 107 HCs], during COVID-19: 207 [86 patients with PD and 121 HCs]) was included. Scales for panic and depressive symptoms and overall function were administered. Additionally, network analyses were performed to compare the two groups within the patients with PD. RESULTS: The results of two-way analysis of variance analyses showed that patients with PD enrolled during COVID-19 showed higher levels of interoceptive fear and lower overall functioning. In addition, a network comparison test revealed that a significantly high strength and expected influence for agoraphobia and avoidance in patients with PD during COVID-19. CONCLUSION: This study suggested that the overall function could have worsened, and the importance of agoraphobia and avoidance as a central symptom may have increased in patients with PD seeking treatment during COVID-19.

Long-term benefits of mindfulness on white matter tracts underlying the cortical midline structures in panic disorder: A 2-year longitudinal study.

AIMS: We aimed to examine the long-term benefits of mindfulness-based cognitive therapy (MBCT) on white matter plasticity in the cortical midline structures (CMS) for a period of 2 years in patients with panic disorder and the relationships between white matter changes in the CMS and severity of state and trait symptoms. METHODS: Seventy-one participants were enrolled and underwent diffusion tensor imaging at baseline and after 2 years (26 who received MBCT as an adjunct to pharmacotherapy [MBCT+PT], 20 treated with pharmacotherapy alone [PT-alone], and 25 healthy controls [HCs]). The severity of symptoms and fractional anisotropy (FA) in white matter regions underlying the CMS were assessed at baseline and 2-year follow-up. RESULTS: The MBCT+PT group showed better outcomes after 2 years than the PT-alone group. The groups showed different FA changes: the MBCT+PT group showed decreased FA in the left anterior cingulate cortex (ACC); the PT-alone group showed increased FA in the bilateral dorsomedial prefrontal cortex, posterior cingulate cortex (PCC), and precuneus. Decreased white matter FA in the ACC, PCC, and precuneus was associated with improvements in the severity of state and trait symptoms in patients with panic disorder. CONCLUSION: Alleviation of excessive white matter connectivity in the CMS after MBCT leads to improvements in clinical symptoms and trait vulnerability in patients with panic disorder. Our study provides new evidence for the long-term benefits of MBCT on white matter plasticity and its clinical applicability as a robust treatment for panic disorder.

Latent class analysis of psychotic-affective disorders with data-driven plasma proteomics.

Data-driven approaches to subtype transdiagnostic samples are important for understanding heterogeneity within disorders and overlap between disorders. Thus, this study was conducted to determine whether plasma proteomics-based clustering could subtype patients with transdiagnostic psychotic-affective disorder diagnoses. The study population included 504 patients with schizophrenia, bipolar disorder, and major depressive disorder and 160 healthy controls, aged 19 to 65 years. Multiple reaction monitoring was performed using plasma samples from each individual. Pathologic peptides were determined by linear regression between patients and healthy controls. Latent class analysis was conducted in patients after peptide values were stratified by sex and divided into tertile values. Significant demographic and clinical characteristics were determined for the latent clusters. The latent class analysis was repeated when healthy controls were included. Twelve peptides were significantly different between the patients and healthy controls after controlling for significant covariates. Latent class analysis based on these peptides after stratification by sex revealed two distinct classes of patients. The negative symptom factor of the Brief Psychiatric Rating Scale was significantly different between the classes (t = -2.070, p = 0.039). When healthy controls were included, two latent classes were identified, and the negative symptom factor of the Brief Psychiatric Rating Scale was still significant (t = -2.372, p = 0.018). In conclusion, negative symptoms should be considered a significant biological aspect for understanding the heterogeneity and overlap of psychotic-affective disorders.

A molecular characterization and clinical relevance of microglia-like cells derived from patients with panic disorder.

Few studies report the microglia involvement in the pathogenesis of panic disorder (PD), although the crucial role of microglia in other neuropsychiatric diseases is being emphasized. In addition, there is no report to characterize the phenotypic and functional levels of PD patient-derived microglia to find their clinical relevance. Herein, we used a model to induce patient-derived microglia-like cells (iMGs) to clarify the molecular characteristics and function of PD-iMGs. We established iMGs from 17 PD patients and 16 healthy controls (non-psychiatric controls, HC). PD-iMGs showed increased T-cell death-associated gene-8 expression per the proposal of a previous in vivo study. In addition, we found that patient-derived iMGs showed reduced phagocytosis and increased TREM2 expression. We analyzed the phenotype of the PD-iMGs by RNA sequencing. The PD-iMGs clustered together distinct from HC-iMGs. Gene set enrichment analysis revealed the involvement of cholesterol biosynthesis and steroid metabolism in PD-iMGs. Regarding the cholesterol synthesis pathway, we discovered ACAT2 and DHCR7 as the most impacted genes related to a character of PD-iMGs compared to HC-iMGs. The ACAT2, a major cholesterol esterifier, was increased in PD-iMGs. Nevertheless, PD-iMGs did not show lipid droplet accumulation. Interestingly, ACAT2 expression was inversely correlated with the severity of depression and anxiety sensitivity to publicly observable anxiety reactions. We propose that microglia of PD patients have unique characteristics with dysregulation of cholesterol biosynthesis pathway and impaired phagocytosis, reflecting clinical phenotype.

Minoxidil Regulates Aging-Like Phenotypes in Rat Cortical Astrocytes In Vitro.

Mainly due to the slanted focus on the mechanism and regulation of neuronal aging, research on astrocyte aging and its modulation during brain aging is scarce. In this study, we established aged astrocyte culture model by long-term culturing. Cellular senescence was confirmed through SA-ß-gal staining as well as through the examination of morphological, molecular, and functional markers. RNA sequencing and functional analysis of astrocytes were performed to further investigate the detailed characteristics of the aged astrocyte model. Along with aged phenotypes, decreased astrocytic proliferation, migration, mitochondrial energetic function and support for neuronal survival and differentiation has been observed in aged astrocytes. In addition, increased expression of cytokines and chemokine-related factors including plasminogen activator inhibitor -1 (PAI-1) was observed in aged astrocytes. Using the RNA sequencing results, we searched potential drugs that can normalize the dysregulated gene expression pattern observed in long-term cultured aged astrocytes. Among several candidates, minoxidil, a pyrimidine-derived anti-hypertensive and anti-pattern hair loss drug, normalized the increased number of SA-ß-gal positive cells and nuclear size in aged astrocytes. In addition, minoxidil restored up-regulated activity of PAI-1 and increased mitochondrial superoxide production in aged astrocytes. We concluded that long term culture of astrocytes can be used as a reliable model for the study of astrocyte senescence and minoxidil can be a plausible candidate for the regulation of brain aging.