CSF total tau/α-synuclein ratio improved the diagnostic performance for Alzheimers disease as an indicator of tau phosphorylation

Abstract Background Recently, several studies suggested potential involvements of α-synuclein in Alzheimers disease (AD) pathophysiology. Higher concentrations of α-synuclein were reported in cerebrospinal fluid (CSF) of AD patients with a positive correlation towards CSF tau, indicating its possible role in AD. We analyzed the CSF biomarkers to verify whether α-synuclein could be an additional supported biomarker in AD diagnosis. Methods In this cross-sectional study, CSF samples of 71 early-onset AD, 34 late-onset AD, 11 mild cognitive impairment, 17 subjective cognitive decline, 45 Parkinsons disease, and 32 healthy control (HC) were collected. CSF amyloid-β1-42 (A), total tau (N), and phosphorylated tau181 (T) were measured by commercial ELISA kits, and in-house ELISA kit was developed to quantify α-synuclein. The cognitive assessments and amyloid-PET imaging were also performed. Results CSF α-synuclein manifested a tendency to increase in AD and to decreased in Parkinsons disease compared to HC. The equilibrium states of total tau and α-synuclein concentrations were changed significantly in AD, and the ratio of total tau/α-synuclein (N/αS) was dramatically increased in AD than HC. Remarkably, N/αS revealed a strong positive correlation with tau phosphorylation rate. Also, the combination of N/αS with amyloid-β1-42/phosphorylated tau181ratio had the best diagnosis performance (AUC = 0.956, sensitivity = 96%, specificity = 87%). In concordance analysis, N/αS showed the higher diagnostic agreement with amyloid-β1-42 and amyloid-PET. Analysis of biomarker profiling with N/αS had distinctive characteristics and clustering of each group. Especially, among the group of suspected non-Alzheimers disease pathophysiology, all A−T+N+ patients with N/αS+ were reintegrated into AD. Conclusions The high correlation of α-synuclein with tau and the elevated N/αS in AD supported the involvement of α-synuclein in AD pathophysiology. Importantly, N/αS improved the diagnostic performance, confirming the needs of incorporating α-synuclein as a biomarker for neurodegenerative disorders. The incorporation of a biomarker group [N/αS] could contribute to provide better understanding and diagnosis of neurodegenerative disorders

Change in cognitive function according to cholinesterase inhibitor use and amyloid PET positivity in patients with mild cognitive impairment

Background Cholinesterase inhibitors (ChEIs) are an FDA-approved symptomatic treatment for patients with Alzheimers disease (AD). Its efficacy in patients with mild cognitive impairment (MCI), however, is controversial. Nonetheless, ChEIs have often been used in patients with MCI. From the perspective that ChEIs were developed based on the pathomechanism of AD, the effect of ChEIs in MCI patients could be different depending on the amyloid burden. In this retrospective observational study, we aimed to investigate the influence of ChEIs and amyloid burden on cognitive change for 1 year in patients with MCI. Methods We included 111 patients with MCI with a Clinical Dementia Rating (CDR) score of 0.5, a 1-year follow-up cognitive assessment, and amyloid positron emission tomography (PET) performed within 6 months before or after the baseline cognitive assessment (73 ChEI users and 38 ChEI non-users) from the Neurocognitive Behavior Center of Seoul National University Bundang Hospital. Additionally, those who had a positive amyloid PET scan more than 6 months before the baseline cognitive assessment and those who had a negative amyloid PET scan more than 6 months after the 1-year follow-up cognitive assessment were also included. Among the total 111 patients, 25 ChEI users and 25 ChEI non-users were matched by baseline Mini-Mental State Examination (MMSE) score, age, educational level, CDR Sum of Boxes, and amyloid PET positivity using propensity score matching. Multiple linear regression analysis was performed to assess the influence of ChEI use and amyloid PET positivity on cognitive change for 1 year. Univariate and multivariate logistic regression analyses were performed to evaluate the association between ChEI use and disease progression to CDR 1 at the 1-year follow-up visit. Results ChEI use or non-use was not associated with cognitive change for 1 year. Amyloid PET positivity or negativity did not change this non-association. Furthermore, progression to CDR 1 was related to low baseline MMSE score (OR 0.606, CI 0.381–0.873), but not with ChEI use or non-use, and not with amyloid PET result. Conclusion ChEI use or non-use was not related to cognitive change at a 1-year follow-up visit in patients with or without amyloid burden. In addition, ChEI use or non-use could not predict disease progression to CDR 1 at 1-year follow-up visit

Prediction of amyloid PET positivity via machine learning algorithms trained with EDTA-based blood amyloid-β oligomerization data

Background The tendency of amyloid-β to form oligomers in the blood as measured with Multimer Detection System-Oligomeric Amyloid-β (MDS-OAβ) is a valuable biomarker for Alzheimer’s disease and has been verified with heparin-based plasma. The objective of this study was to evaluate the performance of ethylenediaminetetraacetic acid (EDTA)-based MDS-OAβ and to develop machine learning algorithms to predict amyloid positron emission tomography (PET) positivity. Methods The performance of EDTA-based MDS-OAβ in predicting PET positivity was evaluated in 312 individuals with various machine learning models. The models with various combinations of features (i.e., MDS-OAβ level, age, apolipoprotein E4 alleles, and Mini-Mental Status Examination [MMSE] score) were tested 50 times on each dataset. Results The random forest model best-predicted amyloid PET positivity based on MDS-OAβ combined with other features with an accuracy of 77.14 ± 4.21% and an F1 of 85.44 ± 3.10%. The order of significance of predictive features was MDS-OAβ, MMSE, Age, and APOE. The Support Vector Machine using the MDS-OAβ value only showed an accuracy of 71.09 ± 3.27% and F−1 value of 80.18 ± 2.70%. Conclusions The Random Forest model using EDTA-based MDS-OAβ combined with the MMSE and apolipoprotein E status can be used to prescreen for amyloid PET positivity.This study was supported by the Ministry of Education of the Republic of Korea and National Research Foundation of Korea (NRF‑2017S1A6A3A01078538) and funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF) and the Ministry of Education (NRF‑2021R1A2C2013359)

Korean Validation of the Short Version of the TEMPS-A (Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire) in Patients with Mood Disorders

Background and Objectives: The Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire (TEMPS-A) is designed to assess affective temperaments. The short version of the TEMPS-A (TEMPS-A-SV) has been translated into various languages for use in research and clinical settings. However, no research has been conducted to validate the Korean version of the TEMPS-A-SV in patients with mood disorders. The goal of this study is to evaluate the reliability and validity of the TEMPS-A-SV in Korean mood disorder patients. Materials and Methods: In this cross-sectional retrospective study, a total of 715 patients (267 patients with major depressive disorder, 94 patients with bipolar disorder I, and 354 patients with bipolar disorder II) completed the Korean TEMPS-A-SV. Cronbach’s alpha and McDonald’s omega were used to assess the reliability. Exploratory factor analysis (EFA) was also performed. Spearman’s correlation coefficient was used to examine associations between the five temperaments. The difference in five temperament scores between the gender or diagnosis groups was analyzed, and the correlation between five temperament scores and age was tested. Results: The Korean TEMPS-A-SV displayed good internal consistency (α = 0.65–0.88, ω = 0.66–0.9) and significant correlations between the subscales except one (the correlation between hyperthymic and anxious). Using EFA, a two-factor structure was produced: Factor I (cyclothymic, depressive, irritable, and anxious) and Factor II (hyperthymic). The cyclothymic temperament score differed by gender and the anxious temperament score was significantly correlated with age. All the temperaments, except for irritable temperament, showed significant differences between diagnosis groups. Conclusions: Overall, the results show that the TEMPS-A-SV is a reliable and valid measurement that can be used for estimating Koreans’ affective temperaments. However, more research is required on affective temperaments and associated characteristics in people with mood disorders

Development and Validation of the Mood Instability Questionnaire-Trait (MIQ-T)

Background and objectives: Mood instability (MI) is a stable trait associated with psychiatric disorders, yet there is a lack of tools to measure MI. The purpose of this study was to develop and validate the Mood Instability Questionnaire-Trait (MIQ-T) to evaluate MI in mood disorder patients. Material and methods: Items were taken from various established questionnaires to create an initial list of MIQ-T questions. Data from 309 psychiatric patients (n = 309; 62 major depressive disorder, 58 bipolar I disorder, and 189 bipolar II disorder) were gathered from their medical records and were utilized in an exploratory factor analysis to clarify the underlying components of MI. Then, anonymous survey data from 288 individuals from the general population were included in the analysis as a comparison group. Associations between MIQ-T and other previously validated clinical instruments for mood disorders were examined to test external validity. Results: The exploratory factor analysis demonstrated that the five-factor structure (Lability, Upward Tendency, Downward Tendency, Childhood Instability, and Seasonality) of 59 items was the most appropriate with clear, cohesive features. MIQ-T exhibited high internal consistency (α = 0.96) and moderate to strong correlations with other previously validated clinical instruments, which were consistent with theoretical predictions, providing evidence of criterion validity. Short forms were also created to address the high internal consistency value, which can indicate redundancy, and to increase the approachability of the measure. We found that the patients with bipolar II disorder had higher MIQ-T scores than the patients with bipolar I disorder or major depressive disorder and the comparison group. Conclusion: Together, these findings validate the newly developed MIQ-T as an instrument of mood instability. MIQ-T can be a potential research tool for mood disorder

Data_Sheet_1_Efficacy and safety of daily home-based transcranial direct current stimulation as adjunct treatment for bipolar depressive episodes: Double-blind sham-controlled randomized clinical trial.doc

BackgroundAlthough transcranial direct current stimulation (tDCS) is known to be a promising therapeutic modality for unipolar depression, the efficacy and safety of tDCS for bipolar depressive episodes (BD) are still unknown and clinical trials of home-based tDCS treatment are scarce. As a result, we set out to investigate the efficacy and safety of home-based tDCS for the treatment BD.MethodsParticipants (n = 64), diagnosed as bipolar disorder as per the diagnostic and statistical manual of mental disorders (DSM-5), were randomly assigned to receive tDCS. Hamilton Depression Rating Scale (HDRS-17) scores were measured at the baseline, week 2, 4, and 6, and home-based tDCS (for 30 min with 2 mA) was self-administered daily.ResultsOf the 64 patients (15.6% bipolar disorder I, 84.4% bipolar disorder II), 41 patients completed the entire assessment. In the intention-to-treat analysis, time-group interaction for the HDRS-17 [F(3, 146.36) = 2.060; p = 0.108] and adverse effect differences between two groups were not statistically significant, except the pain score, which was higher in the active group than the sham group (week 0–2: p ConclusionEven though we found no evidence for the efficacy of home-based tDCS for patients with BD, this tool was found to be a safe and tolerable treatment modality for BD.Clinical trial registration[https://clinicaltrials.gov/show/NCT03974815], identifier [NCT03974815].</p