Amisulpride withdrawal akathisia responding to aripiprazole with propranolol in first-onset psychosis: a case report.

BACKGROUND: Akathisia tends to develop as an early complication of antipsychotic treatment in a dose-dependent manner. Although withdrawal akathisia has been reported after the discontinuation or dose reduction of typical antipsychotic drugs, akathisia following atypical antipsychotic drug withdrawal remains a rare phenomenon. CASE PRESENTATION: A 24-year-old woman with an acute psychotic episode was admitted and initially treated with aripiprazole. The aripiprazole dose was titrated up to 30 mg/day over 9 days and maintained for the next 3 days; however, her psychotic symptoms persisted without change. She was switched to amisulpride, with the dose increased over 2 weeks to 1000 mg/day. Subsequently, although the patient's psychotic episode subsided, her serum prolactin levels increased markedly. After discharge, the amisulpride dose was increased to 1200 mg/day owing to auditory hallucinations and was maintained with quetiapine (100-200 mg/day) and benztropine (1 mg/day) for 13 weeks. Given the potential for hyperprolactinemia as a side effect, the amisulpride dose was reduced to 800 mg/day concurrently with the discontinuation of benztropine; however, these changes resulted in severe restlessness without other extrapyramidal symptoms. The withdrawal akathisia disappeared over 2 weeks after switching to aripiprazole (10 mg/day) with propranolol (40 mg/day) and the patient's prolactin levels had normalized after 6 months of aripiprazole monotherapy. CONCLUSIONS: The present case highlights the potential for the development of withdrawal akathisia when the dose of amisulpride is tapered abruptly. Thus, a slow tapering and careful monitoring are recommended when switching from amisulpride to other antipsychotic drugs. Furthermore, this case suggests that changing the regimen to aripiprazole with propranolol may be a potential option for amisulpride withdrawal akathisia superimposed on pre-existing hyperprolactinemia.

Ego-resiliency moderates the risk of depression and social anxiety symptoms on suicidal ideation in medical students.

BACKGROUND: Little is known about the role of protective factors in suicidal ideation among medical students. This study aimed to examine the association between suicidal ideation and protective (self-esteem/ego-resiliency/social support) and risk (depression/social anxiety) factors. METHODS: Data on sociodemographic factors, depression, social anxiety, self-esteem, ego-resiliency, social support, and current suicidal ideation were collected from 408 medical students. A logistic regression model was constructed to identify the independent impact of potential influencing factors on suicidal ideation. Potential moderating effects were also explored. RESULTS: Thirty-eight participants (9.3%) reported experiencing suicidal ideation. Younger age, higher levels of depression, social anxiety, and lower levels of self-esteem, ego-resiliency, and social support were found to be significantly correlated with suicidal ideation. In the final model, higher levels of depression and social anxiety were associated with an increased risk of suicidal ideation, while higher levels of self-esteem and social support were associated with a decreased risk of suicidal ideation. Although the independent effect was not significant, the interactions of ego-resiliency with both depression and social anxiety on suicidal ideation were significant. Higher levels of ego-resiliency acted as a buffer against suicidal ideation among those with higher levels of depression or social anxiety. CONCLUSIONS: In addition to risk factors, this study revealed the underlying protective and moderating factors of suicidal ideation among medical students. Mental health programs focusing on enhancing ego-resiliency, self-esteem, and social support may contribute to suicide prevention in medical students.

Tuberculum sellae meningioma with possible tacrolimus neurotoxicity manifesting as manic-like psychosis after kidney transplantation.

BACKGROUND: Although kidney transplantation is the best treatment option for chronic kidney disease, the accompanying immunosuppressive treatment can induce severe neurotoxicity presenting, on rare occasions, as psychosis. However, a brain tumor synchronous with immunosuppressant neurotoxicity has never been reported in a kidney transplant recipient. Herein, we report the first case of possible tacrolimus neurotoxicity with a meningioma manifesting as manic-like psychosis after kidney transplantation. CASE PRESENTATION: A 63-year-old male presenting with acute psychotic mania was admitted to a psychiatric ward approximately 2 years after kidney transplantation. On brain magnetic resonance imaging, a tuberculum sellae meningioma was found, and hyperintense white matter lesions with possible tacrolimus-induced neurotoxicity were seen on fluid-attenuated inversion recovery images. Interestingly, the patient showed no visual field defects, and his blood tacrolimus concentration was within therapeutic ranges. After 3 weeks of adjunctive treatment with blonanserin, most of the symptoms had abated. CONCLUSIONS: The present case highlights the fact that neuroimaging studies are necessary to investigate underlying causes, as well as immunosuppressant neurotoxicity, which should all be considered when atypical psychiatric symptoms develop after organ transplantation. Further, this case suggests that the additional use of atypical antipsychotics while maintaining immunosuppressants may be effective for manic-like psychotic symptoms secondary to possible immunosuppressant neurotoxicity synchronous with a meningioma.

Psychotic mania as the solitary manifestation of neurosyphilis.

BACKGROUND: Neurosyphilis remains a diagnostic challenge in current psychiatric practice because of its pleomorphic psychiatric manifestations. Although neurosyphilis can present with a wide range of psychiatric symptoms, psychotic mania as its solitary manifestation is an unusual phenomenon. CASE PRESENTATION: A 46-year-old man, with no history of any psychiatric disorder, exhibited abruptly developed symptoms of psychotic mania. He was admitted to a psychiatric ward for further evaluation and treatment. Upon admission, his cognitive function was unimpaired, and the hyperactivity was not severe. Also, no abnormalities were found upon neurological examination and brain magnetic resonance imaging. He was initially diagnosed as bipolar disorder with psychotic features. On the 3rd day after admission, he was confirmed as having neurosyphilis by analysis of cerebrospinal fluid and treated with intravenous penicillin-in combination with blonanserin-an atypical antipsychotic drug. After 2 weeks of treatment, most of the symptoms had abated. CONCLUSIONS: The present case emphasizes that patients presenting with atypical psychiatric manifestation should be screened for possible syphilis, particularly in the absence of previous psychiatric history, and suggests that combination of blonanserin with antibiotic therapy may be effective in the treatment of the manic and psychotic symptoms secondary to neurosyphilis.

Life satisfaction and happiness associated with depressive symptoms among university students: a cross-sectional study in Korea.

BACKGROUND: This cross-sectional study investigated the impact of life satisfaction and happiness, as well as the prevalence and correlates of depressive symptoms in a large sample of university students. METHODS: We included 2338 students at 6 universities in 1 metropolitan city and 2 provinces of Korea. Depressive symptoms were assessed by the Beck Depression Inventory, and scores of 16 or higher were categorized as the presence of depression. Various sociodemographic, life satisfaction, happiness, and clinical factors (alcohol consumption and sleep quality) were measured. According to the presence of depression, sociodemographic, life satisfaction, happiness, and clinical characteristics were compared using statistical analyses. Further, a logistic regression model was constructed to examine the impact of life satisfaction, happiness, and clinical factors on depression. RESULTS: Among participants, 13.4% were identified as having depression. Life satisfaction and happiness were associated with a lower risk of depression, while hazardous alcohol drinking and poor sleep quality were related to a higher risk of depression. In addition, female gender, subjective body shape as obese, and insufficient pocket money were found to be significant correlates of depressive symptoms. CONCLUSIONS: This study demonstrated possible risk and protective factors of underlying depressive symptoms. Especially, our findings suggest that improvement in life satisfaction and happiness would be important in the prevention and management of depression. Our findings may contribute to developing specialized mental health programs for prevention, screening, and treatment of depression among university students.

Anxiety Symptoms and Associated Psychological and Job-Related Factors Among Hospital Nurses.

OBJECTIVE: Recently, burnout and mental health issues regarding nurses are reported increasingly. This study aimed to investigate the prevalence of anxiety symptoms among hospital nurses and determine their association with psychological and job-related factors. METHODS: Data on demographics, job-related characteristics, burnout, Type A behavior patterns, self-esteem, and happiness were collected from 515 nurses working at a university hospital in Korea. Anxiety symptoms were assessed using the anxiety subscale of the Hospital Anxiety and Depression Scale, with scores of 8 or higher indicating the presence of anxiety symptoms. Demographic, job-related, and psychological factors were compared according to the presence of anxiety. Logistic regression was conducted to identify factors associated with anxiety symptoms. RESULTS: Two hundred and four (39.6%) participants had anxiety symptoms. Self-esteem and happiness were associated with a lower risk of anxiety symptoms, whereas burnout was associated with a higher risk of anxiety symptoms. Furthermore, being female, having a career of less than five years, and requiring counseling due to stress were associated with a higher risk of anxiety symptoms. Being younger, female, or a basic nurse; having a career of less than five years; partaking in shift work; experiencing job dissatisfaction; requiring counseling due to stress; being exposed to higher levels of burnout; and having lower levels of self-esteem and happiness were all found to be significantly correlated with anxiety symptoms. CONCLUSION: These findings suggest that promoting self-esteem and happiness while reducing burnout may be beneficial in preventing and managing anxiety symptoms among hospital nurses.

Suicidality is most centrally situated within network of depression symptom criteria in unipolar depression patients with mood stabilizer in Asia.

Lithium and mood stabilizers are considered effective augmentation agents of antidepressants for treatment-resistant depression. Thus, this study aimed to estimate the network structure of depression symptom criteria among unipolar depression patients with mood stabilizers, using data from the Research on Asian Psychotropic Prescription Patterns for mood stabilizers (REAP-MS). We estimated a network of the 9 depression symptom criteria among 411 unipolar depression patients in Asia. Each of the depression symptom criteria was considered to be a dichotomous categorical variable. Suicidality (suicidal ideation or attempt) was the most centrally situated within the network of depression symptoms, followed by depressed mood, loss of energy, anhedonia and weight loss or gain. Contrastingly, concentration problem was the least interconnected. The depression symptom criteria were organized into 4 clusters by the community detection method. The findings suggest that suicidality may be one of the significant therapeutic target symptoms in unipolar depression patients with mood stabilizers.

Efficacy and safety of haloperidol versus atypical antipsychotic medications in the treatment of delirium.

BACKGROUND: Most previous studies on the efficacy of antipsychotic medication for the treatment of delirium have reported that there is no significant difference between typical and atypical antipsychotic medications. It is known, however, that older age might be a predictor of poor response to antipsychotics in the treatment of delirium. The objective of this study was to compare the efficacy and safety of haloperidol versus three atypical antipsychotic medications (risperidone, olanzapine, and quetiapine) for the treatment of delirium with consideration of patient age. METHODS: This study was a 6-day, prospective, comparative clinical observational study of haloperidol versus atypical antipsychotic medications (risperidone, olanzapine, and quetiapine) in patients with delirium at a tertiary level hospital. The subjects were referred to the consultation-liaison psychiatric service for management of delirium and were screened before enrollment in this study. A total of 80 subjects were assigned to receive either haloperidol (N = 23), risperidone (N = 21), olanzapine (N = 18), or quetiapine (N = 18). The efficacy was evaluated using the Korean version of the Delirium Rating Scale-Revised-98 (DRS-K) and the Korean version of the Mini Mental Status Examination (K-MMSE). The safety was evaluated by the Udvalg Kliniske Undersogelser side effect rating scale. RESULTS: There were no significant differences in mean DRS-K severity or K-MMSE scores among the four groups at baseline. In all groups, the DRS-K severity score decreased and the K-MMSE score increased significantly over the study period. However, there were no significant differences in the improvement of DRS-K or K-MMSE scores among the four groups. Similarly, cognitive and non-cognitive subscale DRS-K scores decreased regardless of the treatment group. The treatment response rate was lower in patients over 75 years old than in patients under 75 years old. Particularly, the response rate to olanzapine was poorer in the older age group. Fifteen subjects experienced a few adverse events, but there were no significant differences in adverse event profiles among the four groups. CONCLUSIONS: Haloperidol, risperidone, olanzapine, and quetiapine were equally efficacious and safe in the treatment of delirium. However, age is a factor that needs to be considered when making a choice of antipsychotic medication for the treatment of delirium. TRIAL REGISTRATION: Clinical Research Information Service, Republic of Korea, (http://cris.nih.go.kr/cris/en/search/basic_search.jsp, Registered Trial No. KCT0000632).

Successful Early Lamotrigine and Aripiprazole Augmentation of Clomipramine in Severe Obsessive-compulsive Disorder.

Lamotrigine and aripiprazole have shown efficacy as augmentation agents of serotonin reuptake inhibitors for treatment-resistant obsessive-compulsive disorder (OCD). To date, the efficacy of lamotrigine/aripiprazole augmentation has not been reported in OCD treatment. Herein, we report the case of a 37-year-old male with severe OCD and comorbid depression whose symptoms markedly improved after low-dose lamotrigine/aripiprazole augmentation to clomipramine. Our report suggests that early glutamatergic/antipsychotic augmentation contributes to rapid remission of OCD symptoms.

Automating Rey Complex Figure Test scoring using a deep learning-based approach: a potential large-scale screening tool for cognitive decline.

BACKGROUND: The Rey Complex Figure Test (RCFT) has been widely used to evaluate the neurocognitive functions in various clinical groups with a broad range of ages. However, despite its usefulness, the scoring method is as complex as the figure. Such a complicated scoring system can lead to the risk of reducing the extent of agreement among raters. Although several attempts have been made to use RCFT in clinical settings in a digitalized format, little attention has been given to develop direct automatic scoring that is comparable to experienced psychologists. Therefore, we aimed to develop an artificial intelligence (AI) scoring system for RCFT using a deep learning (DL) algorithm and confirmed its validity. METHODS: A total of 6680 subjects were enrolled in the Gwangju Alzheimer's and Related Dementia cohort registry, Korea, from January 2015 to June 2021. We obtained 20,040 scanned images using three images per subject (copy, immediate recall, and delayed recall) and scores rated by 32 experienced psychologists. We trained the automated scoring system using the DenseNet architecture. To increase the model performance, we improved the quality of training data by re-examining some images with poor results (mean absolute error (MAE) [Formula: see text] 5 [points]) and re-trained our model. Finally, we conducted an external validation with 150 images scored by five experienced psychologists. RESULTS: For fivefold cross-validation, our first model obtained MAE = 1.24 [points] and R-squared ([Formula: see text]) = 0.977. However, after evaluating and updating the model, the performance of the final model was improved (MAE = 0.95 [points], [Formula: see text] = 0.986). Predicted scores among cognitively normal, mild cognitive impairment, and dementia were significantly different. For the 150 independent test sets, the MAE and [Formula: see text] between AI and average scores by five human experts were 0.64 [points] and 0.994, respectively. CONCLUSION: We concluded that there was no fundamental difference between the rating scores of experienced psychologists and those of our AI scoring system. We expect that our AI psychologist will be able to contribute to screen the early stages of Alzheimer's disease pathology in medical checkup centers or large-scale community-based research institutes in a faster and cost-effective way.

Psychosocial Factors Influencing Quality of Life Among Medical Students.

OBJECTIVE: This study investigated the influence of psychosocial factors on medical students' quality of life (QOL). METHODS: A total of 408 medical students participated in this study. We collected data on participants' sociodemographic details, symptoms of depression and Internet addiction, self-esteem, social support, and QOL. QOL was assessed using the World Health Organization Quality of Life-Abbreviated form, which has four domains (physical health, psychological health, social relationships, and environment). A stepwise multiple linear regression model was constructed to identify factors' independent impact on QOL. RESULTS: Higher levels of depression and Internet addiction were associated with lower scores in all domains of QOL, whereas higher levels of self-esteem and social support were associated with higher scores. Being in third-year versus first-year was associated with higher scores in the physical health and environment domains. Living alone or in dormitories, low or middle socioeconomic status, and insufficient or moderate pocket money were associated with lower scores in the environment domain. Additionally, female students displayed significantly lower scores for physical health, psychological health, and environment than male students, but not for social relationships. There were significant differences in certain domains of QOL due to sociodemographic factors. CONCLUSION: This study demonstrates the psychosocial factors influencing medical students' QOL. Educational strategies focusing on strengthening self-esteem and social support as well as preventing depression and Internet addiction may contribute to improving medical students' QOL.

The association between adverse childhood experiences and self-harm among South Korean children and adolescents: a cross-sectional study.

PURPOSE: Adolescent self-harm is a public health problem. Research suggests a link between adverse childhood experiences (ACEs) and self-destructive behaviors. Few studies, however, have examined the effects of ACEs on self-harm among Asian adolescents. This study explored the association between lifetime ACEs and a history of self-harm among Korean children and adolescents in elementary, middle, and high schools. METHODS: A cross-sectional, retrospective medical record review was conducted on a dataset of a national psychiatrist advisory service for school counselors who participated in the Wee Doctor Service from January 1 to December 31, 2020. The data were analyzed using multiple logistic regression to predict self-harm. RESULTS: Student cases (n=171) were referred to psychiatrists by school counselors for remote consultation. Multiple logistic regression analyses revealed that the odds of self-harm were higher among high school students (adjusted odds ratio [aOR]=4.97; 95% confidence interval [CI]=1.94-12.76), those with two or more ACEs (aOR=3.27; 95% CI=1.43-7.47), and those with depression (aOR=3.06; 95% CI=1.32-7.10). CONCLUSION: The study's findings provide compelling evidence that exposure to ACEs can increase vulnerability to self-harm among Korean students. Students with a history of ACEs and depression, as well as high school students, require increased attention during counseling. School counselors can benefit from incorporating screening assessment tools that include questions related to ACEs and depression. Establishing a systematic referral system to connect students with experts can enhance the likelihood of identifying self-harm tendencies and offering the essential support to prevent self-harm.

Network Analysis-Based Disentanglement of the Symptom Heterogeneity in Asian Patients with Schizophrenia: Findings from the Research on Asian Psychotropic Prescription Patterns for Antipsychotics.

The symptom heterogeneity of schizophrenia is consistent with Wittgenstein's analogy of a language game. From the perspective of precision medicine, this study aimed to estimate the symptom presentation and identify the psychonectome in Asian patients, using data obtained from the Research on Asian Psychotropic Prescription Patterns for Antipsychotics. We constructed a network structure of the Brief Psychiatric Rating Scale (BPRS) items in 1438 Asian patients with schizophrenia. Furthermore, all the BPRS items were considered to be an ordered categorical variable ranging in value from 1-7. Motor retardation was situated most centrally within the BPRS network structure, followed by depressive mood and unusual thought content. Contrastingly, hallucinatory behavior was situated least centrally within the network structure. Using a community detection algorithm, the BPRS items were organized into positive, negative, and general symptom clusters. Overall, DSM symptoms were not more central than non-DSM symptoms within the symptom network of Asian patients with schizophrenia. Thus, motor retardation, which results from the unmet needs associated with current antipsychotic medications for schizophrenia, may be a tailored treatment target for Asian patients with schizophrenia. Based on these findings, targeting non-dopamine systems (glutamate, γ-aminobutyric acid) may represent an effective strategy with respect to precision medicine for psychosis.

Associations between Brain Reserve Proxies and Clinical Progression in Alzheimer's Disease Dementia.

The purpose of this study was to investigate whether brain and cognitive reserves were associated with the clinical progression of AD dementia. We included participants with AD dementia from the Alzheimer's Disease Neuroimaging Initiative, provided they were followed up at least once, and candidate proxies for cognitive (education for early-life reserve and Adult Reading Test for late-life reserve) or brain reserve (intracranial volume [ICV] for early-life reserve and the composite value of [18F] fluorodeoxyglucose positron emission tomography regions of interest (FDG-ROIs) for late-life reserve) were available. The final analysis included 120 participants. Cox proportional hazards model revealed that FDG-ROIs were the only significant predictor of clinical progression. Subgroup analysis revealed a significant association between FDG-ROIs and clinical progression only in the larger ICV group (HR = 0.388, p = 0.028, 95% CI 0.167-0.902). Our preliminary findings suggest that relatively preserved cerebral glucose metabolism might delay further clinical progression in AD dementia, particularly in the greater ICV group. In addition to ICV, cerebral glucose metabolism could play an important role as a late-life brain reserve in the process of neurodegeneration. Distinguishing between early- and late-life reserves, and considering both proxies simultaneously, would provide a wider range of factors associated with the prognosis of AD dementia.

Internet Addiction and Its Associations with Clinical and Psychosocial Factors in Medical Students.

OBJECTIVE: Excessive internet use has been associated with various psychiatric symptoms and psychosocial factors. This study aimed to investigate the prevalence of internet addiction (IA) and its associations with clinical (depression/social anxiety) and psychosocial (self-esteem/perceived social support) factors in medical students. METHODS: In total, 408 medical students at one university in Korea were included in this study. IA symptoms were assessed with Young's Internet Addiction Test, and scores of 50 or higher were considered to indicate IA. Participants were asked to complete the Beck Depression Inventory, Social Phobia Inventory, Rosenberg Self-Esteem Scale, and Duke-University of North Carolina Functional Social Support Questionnaire. A logistic regression model was constructed to examine the impact of clinical and psychosocial factors on IA. RESULTS: Forty-seven participants (11.5%) were identified as having IA. Self-esteem was associated with a lower risk of IA, whereas depression and social anxiety were associated with a higher risk of IA. Depression, social anxiety, low self-esteem, and low perceived social support were found to be significant correlates of IA. Young's Internet Addiction Test score positively correlated with Beck Depression Inventory and Social Phobia Inventory scores, but negatively correlated with Rosenberg Self-Esteem Scale and Duke-University of North Carolina Functional Social Support Questionnaire scores. Furthermore, the prevalence of IA was highest in first-year medical students. CONCLUSION: This study revealed the possible risk and protective factors of IA. Our findings indicate that strengthening self-esteem and reducing depression and social anxiety may contribute to the prevention and management of IA in medical students.

A Literature Review on the Efficacy and Related Neural Effects of Pharmacological and Psychosocial Treatments in Individuals With Internet Gaming Disorder.

OBJECTIVE: Internet gaming disorder (IGD) has attracted considerable attention as a serious mental and public health issue worldwide. Currently, there are no established treatment guidelines for IGD. Herein, we review the latest findings on the efficacy and related neural effects of pharmacological and psychosocial treatments for individuals with IGD. METHODS: A database search of relevant studies published between 2007 and 2020 was conducted using PubMed and Google Scholar. Twenty-seven studies were reviewed for current evidence related to the efficacy and neural effects of pharmacological and psychosocial IGD treatments. RESULTS: Pharmacological studies suggest that bupropion may play a significant role in IGD. Additionally, nuclear imaging studies on IGD have demonstrated functional impairment of the dopamine system, providing a neurobiological basis for the efficacy of dopamineenhancing drugs. Among the various psychosocial interventions, current evidence suggests that cognitive behavioral therapy may be an effective intervention for IGD. Cognitive behavioral therapy and bupropion were found to influence resting-state functional connectivity within the cortico-subcortical circuit and default mode network, suggesting a possible neural mechanism. Innovative approaches, including virtual reality treatment, residential camps, voluntary abstinence, and transcranial direct current stimulation, have shown promising results. However, methodological limitations, such as the absence of proper controls, small sample sizes, short duration, inconsistency of inclusion criteria across studies, and self-report measures of outcome, hamper conclusions regarding the efficacy of treatments. CONCLUSION: Ongoing basic research and clinical trials overcoming these limitations could add to the existing knowledge on IGD and contribute to the development of evidence-based treatments.

Visuospatial memory impairment as a potential neurocognitive marker to predict tau pathology in Alzheimer's continuum.

BACKGROUND: Given that tau accumulation, not amyloid-ß (Aß) burden, is more closely connected with cognitive impairment in Alzheimer's disease (AD), a detailed understanding of the tau-related characteristics of cognitive function is critical in both clinical and research settings. We investigated the association between phosphorylated tau (p-Tau) level and cognitive impairment across the AD continuum and the mediating role of medial temporal lobe (MTL) atrophy. We also developed a prediction model for abnormal tau accumulation. METHODS: We included participants from the Gwangju Alzheimer's Disease and Related Dementia Cohort in Korea, who completed cerebrospinal fluid analysis and clinical evaluation, and corresponded to one of three groups according to the biomarkers of A and T profiles based on the National Institute on Aging and Alzheimer's Association research framework. Multiple linear and logistic regression analyses were performed to examine the association between p-Tau and cognition and to develop prediction models. Receiver operating characteristic curve analysis was performed to examine the discrimination ability of the models. RESULTS: Among 185 participants, 93 were classified as A-T-, 23 as A+T-, and 69 as A+T+. There was an association between decreased visuospatial delayed memory performance and p-Tau level (B = - 0.754, ß = - 0.363, p < 0.001), independent of other relevant variables (e.g., Aß). MTL neurodegeneration was found to mediate the association between the two. Prediction models with visuospatial delayed memory alone (area under the curve [AUC] = 0.872) and visuospatial delayed memory and entorhinal thickness (AUC = 0.921) for abnormal tau accumulation were suggested and they were validated in an independent sample (AUC = 0.879 and 0.891, respectively). CONCLUSION: It is crucial to identify sensitive cognitive measures that capture subtle cognitive impairment associated with underlying pathological changes. Preliminary findings from the current study might suggest that abnormal tau accumulation underlies episodic memory impairment, particularly visuospatial modality, in the AD continuum. Suggested models are potentially useful in predicting tau pathology, and might be utilized practically in the field.

Promoted migration of fibroblast cells on low aspect ratio isotropic nanopore surface by reduced maturation of focal adhesion at peripheral region.

Cell migration plays fundamental roles in the development and maintenance of organisms such as wound healing and embryonic development, and cell migration is affected by the surrounding nanostructure of the extracellular matrix. Many researchers have developed various nanotopographical structures to investigate cell migration behaviors in response to the nanostructures, however, it is hard to draw firm conclusions about a relationship between surface topography and cell migration due to the contradictory results. Here, as one of the possible approaches to investigate the cell migration behaviors on the nanotopographies, we developed isotropic nanopore surfaces with high and low aspect ratios to have decreased and increased adherable areas, respectively. The nanopore surface with high aspect ratio had decreased adherable area of 86 % by providing the cells to adhere only on the top surface of the nanopores, while the nanopore surface with low aspect ratio had increased adherable area of 130 % by providing the cells to perceive both on the top surface and the bottom surface of the nanopores. In contrast to our expectation, the migration speeds of fibroblast cells were both promoted on the nanopore surfaces compared to the flat surface, regardless of the increase or decrease in adherable area. We found that the maturation of the focal adhesions (FAs) at the peripheral region is a key factor determining the adhesion strength of the fibroblast cells, which in turn affects cell migration. Our findings may widen our understanding of the cell migration behaviors on the nanostructured surface according to the formation of the FAs.

Rapid harvesting of stem cell sheets by thermoresponsive bulk poly(N-isopropylacrylamide) (PNIPAAm) nanotopography.

To date, cell sheet engineering-based technologies have actualized diverse scaffold-free bio-products to revitalize unintentionally damaged tissues/organs, including cardiomyopathy, corneal defects, and periodontal damage. Although substantial interest is now centered on the practical utilization of these bio-products for patients, the long harvest period of stem cells- or other primary cell-sheets has become a huge hurdle. Here, we dramatically reduce the total harvest period of a cell sheet (from cell layer formation to cell sheet detachment) composed of human bone marrow mesenchymal stem cells (hBMSCs) down to 2 d with the help of bulk thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm) substrate nanotopography, which is not achievable via the previous grafting methods using PNIPAAm. We directly replicated an isotropic 400 nm-nanopore-array pattern on a bulk PNIPAAm substrate through UV polymerization of highly concentrated NIPAAm monomers, which was achieved using a remarkably increased Young's modulus of bulk PNIPAAm that was 1500 times higher than conventional PNIPAAm. The rapid harvesting of the hBMSC sheet on the bulk PNIPAAm substrate nanotopography was not only based on the accelerated formation and maturation of the hBMSC layer, but also the easy detachment of the hBMSC sheet induced by the abrupt change in the surface roughness of the substrate below the lower critical solution temperature (LCST) owing to the enlarged surface area of the substrate. Our findings may contribute to reverse presumptions about the limitations regarding the grafting methods for the cell sheet harvest and could broaden the practical utilization of cell sheets for patients in the near future.

Bulk poly(N-isopropylacrylamide) (PNIPAAm) thermoresponsive cell culture platform: toward a new horizon in cell sheet engineering.

Although a conventional method of utilizing thermoresponsive grafted poly(N-isopropylacrylamide) (PNIPAAm) enables the harvest of a healthy confluent cell-to-cell junction preserved cell sheet while limiting the use of the trypsin enzyme, the absolute necessity in the delicate control of a sensitive nm-scale PNIPAAm chain length inevitably decelerates the advancement of cell sheet engineering. In this study, we demonstrate, for the first time, a thermoresponsive cell culture platform composed only of a 'bulk' form of a PNIPAAm hydrogel with the Young's modulus being increased up to the MPa scale. The surface roughness of the bulk PNIPAAm hydrogel initially modulated by the cross-linker concentration was altered from the nm- to µm-scale in response to a change in temperature above/below the low critical solution temperature (LCST) of 32 °C. The appropriate control of the surface roughness allowed the stable attachment (above the LCST) and easy detachment (below the LCST) of diverse cells and enabled the harvest of cell sheets composed of cell lines (C2C12 and NIH3T3) or even primary cells (human umbilical vein endothelial cells and keratinocytes). During their incubation at 37 °C, the cell lines were able to be attached on every surface of the prepared PNIPAAm cell culture platforms, whereas the primary cells were found to be only attached on a surface having a roughness below ∼30 nm. Furthermore, in the aspect of cell sheet detachment at the incubation temperature of 20 °C, the cell sheets composed of cell lines were fully detached from the surface of the platform having a roughness of ∼10 µm or higher, while the cell sheets composed of primary cells were entirely detached from the surface with a roughness of ∼19 µm or higher. Based on such behaviors of the diverse cells at a given surface roughness, this study further suggests a universal thermoresponsive cell culture platform which allows the harvest of all types of cells from cell lines to primary cells in a desired shape. Our suggested universal cell culture platform could play a powerful and versatile role in accelerating the advancement of cell sheet engineering.