Impact of transdermal trigeminal electrical neuromodulation on subjective and objective sleep parameters in patients with insomnia: a pilot study.

PURPOSE: Transcutaneous trigeminal electrical neuromodulation (TTEN) is a new treatment modality that has a potential to improve sleep through the suppression of noradrenergic activity. This study aimed to explore the changes of subjective and objective sleep parameters after 4-weeks of daily session of transcutaneous trigeminal electrical neuromodulation in a group of patients with insomnia. METHODS: In a group of patients with insomnia, TTEN targeting the ophthalmic division of the trigeminal nerve was utilized to test the effects of transcutaneous trigeminal electrical neuromodulation. Patients went through daily 20-min sessions of TTEN for 4 weeks. Polysomnography parameters, Pittsburgh sleep quality index, insomnia severity index, and Epworth sleepiness scale were obtained pre- and post-intervention. Changes in these parameters were compared and analyzed. RESULTS: Among 13 patients with insomnia there was a statistically significant reduction in Pittsburgh sleep quality index, insomnia severity index, and Epworth sleepiness scale scores after 4-week daily sessions of TTEN. There were no differences in polysomnography parameters pre- and post-intervention. CONCLUSION: This is the first study to demonstrate the effects of TTEN in a group of insomnia patients. TTEN may improve subjective parameters in patients with insomnia. Further replication studies are needed to support this finding. TRIAL REGISTRATION: The data presented in the study are from a study exploring the effect of TTEN on insomnia ( www. CLINICALTRIALS: gov , registration number: NCT04838067, date of registration: April 8, 2021, "retrospectively registered").

Alterations of Resting-State Locus Coeruleus Functional Connectivity After Transdermal Trigeminal Electrical Neuromodulation in Insomnia.

Background: Transdermal trigeminal electrical neuromodulation (TTEN) is a novel treatment modality that is known for noradrenergic modulation through the trigeminal nerve and locus coeruleus (LC). This study aimed to demonstrate the alterations of LC functional connectivity (FC) in patients with insomnia after a 4-week TTEN. Methods: The Cefaly device targeting the ophthalmic division of the trigeminal nerve was applied to a total of 12 patients with insomnia to monitor for the effects of TTEN. All the patients went through a 4-week daily 20 min TTEN sessions before bedtime. Baseline and post-TTEN demographic data, polysomnography (PSG) parameters, and insomnia severity index (ISI) were attained. Data from pre- and post-intervention resting-state functional magnetic resonance imaging (MRI) were collected. LC FC differences were measured between the pre-and post-TTEN groups through seed-to-voxel analysis. Correlation analyses were conducted between LC FC changes after TTEN, ISI score changes, and PSG parameter changes. Results: There was a significantly decreased LC FC with occipital and temporal cortices after a 4-week TTEN. However, there was no significant correlation between LC FC, ISI score changes, and PSG parameter changes. Conclusion: By targeting hyperarousal symptoms of insomnia, TTEN can be a promising intervention that can modulate LC FC in patients with insomnia patients. The data presented in the study are from a study exploring the effect of TTEN on insomnia (www.clinicaltrials.gov, NCT04838067).

Subcortical and Cerebellar Neural Correlates of Prodromal Alzheimer's Disease with Prolonged Sleep Latency.

BACKGROUND: Despite the important associations among sleep, Alzheimer's disease (AD), subcortical structures, and the cerebellum, structural and functional magnetic resonance imaging (MRI) with regard to these regions and sleep on patients in AD trajectory are scarce. OBJECTIVE: This study aimed to evaluate the influence of prolonged sleep latency on the structural and functional alterations in the subcortical and cerebellar neural correlates in amyloid-ß positive amnestic mild cognitive impairment patients (Aß+aMCI). METHODS: A total of 60 patients with aMCI who were identified as amyloid positive ([18F] flutemetamol+) were recruited in the study, 24 patients with normal sleep latency (aMCI-n) and 36 patients prolonged sleep latency (aMCI-p). Cortical thickness and volumes between the two groups were compared. Volumetric analyses were implemented on the brainstem, thalamus, and hippocampus. Subcortical and cerebellar resting state functional connectivity (FC) differences were measured between the both groups through seed-to-voxel analysis. Additionally, group x Aß interactive effects on FC values were tested with a general linear model. RESULT: There was a significantly decreased brainstem volume in aMCI-p subjects. We observed a significant reduction of the locus coeruleus (LC) FC with frontal, temporal, insular cortices, hippocampus, and left thalamic FC with occipital cortex. Moreover, the LC FC with occipital cortex and left hippocampal FC with frontal cortex were increased in aMCI-p subjects. In addition, there was a statistically significant group by regional standardized uptake value ratio interactions discovered in cerebro-cerebellar networks. CONCLUSION: The aforementioned findings suggest that prolonged sleep latency may be a detrimental factor in compromising structural and functional correlates of subcortical structures and the cerebellum, which may accelerate AD pathophysiology.

Impact of APOE ε4 Carrier Status on Associations Between Subthreshold, Positive Amyloid-ß Deposition, Brain Function, and Cognitive Performance in Cognitively Normal Older Adults: A Prospective Study.

Background: A growing body of evidence suggests a deteriorating effect of subthreshold amyloid-beta (Aß) accumulation on cognition before the onset of clinical symptoms of Alzheimer's disease (AD). Despite the association between the Aß-dependent pathway and the APOE ε4 allele, the impact of this allele on the progression from the subthreshold Aß deposits to cognitive function impairment is unclear. Furthermore, the comparative analysis of positive Aß accumulation in the preclinical phase is lacking. Objective: This study aimed to explore the differential effect of the APOE ε4 carrier status on the association between Aß deposition, resting-state brain function, and cognitive performance in cognitively normal (CN) older adults, depending on the Aß burden status. Methods: One hundred and eighty-two older CN adults underwent resting-state functional magnetic resonance imaging, [18F] flutemetamol (FMM) positron emission tomography, a neuropsychological battery, and APOE genotyping. We evaluated the resting-state brain function by measuring the local and remote functional connectivity (FC) and measured the remote FC in the default-mode network (DMN), central-executive network (CEN), and salience network (SN). In addition, the subjects were dichotomized into those with subthreshold and positive Aß deposits using a neocortical standardized uptake value ratio with the cut-off value of 0.62, which was calculated with respect to the pons. Results: The present result showed that APOE ε4 carrier status moderated the relationship between Aß deposition, local and remote resting-state brain function, and cognitive performance in each CN subthreshold and positive Aß group. We observed the following: (i) the APOE ε4 carrier status-Aß deposition and APOE ε4 carrier status-local FC interaction for the executive and memory function; (ii) the APOE ε4 carrier status-regional Aß accumulation interaction for the local FC; and (iv) the APOE ε4 carrier status-local FC interaction for the remote inter-network FC between the DMN and CEN, contributing higher cognitive performance in the APOE ε4 carrier with higher inter-network FC. Finally, these results were modulated according to Aß positivity. Conclusion: This study is the first attempt to thoroughly examine the influence of the APOE ε4 carrier status from the subthreshold to positive Aß accumulation during the preclinical phase.

Associations Between Sub-Threshold Amyloid-ß Deposition, Cortical Volume, and Cognitive Function Modulated by APOE ɛ4 Carrier Status in Cognitively Normal Older Adults.

BACKGROUND: There has been renewed interest in the deteriorating effects of sub-threshold amyloid-ß (Aß) accumulation in Alzheimer's disease (AD). Despite evidence suggesting a synergistic interaction between the APOE ɛ4 allele and Aß deposition in neurodegeneration, few studies have investigated the modulatory role of this allele in sub-threshold Aß deposition during the preclinical phase. OBJECTIVE: We aimed to explore the differential effect of the APOE ɛ4 carrier status on the association between sub-threshold Aß deposition, cortical volume, and cognitive performance in cognitively normal older adults (CN). METHODS: A total of 112 CN with sub-threshold Aß deposition was included in the study. Participants underwent structural magnetic resonance imaging, [18F] flutemetamol PET-CT, and a neuropsychological battery. Potential interactions between APOE ɛ4 carrier status, Aß accumulation, and cognitive function for cortical volume were assessed with whole-brain voxel-wise analysis. RESULTS: We found that greater cortical volume was observed with higher regional Aß deposition in the APOE ɛ4 carriers, which could be attributed to an interaction between the APOE ɛ4 carrier status and regional Aß deposition in the posterior cingulate cortex/precuneus. Finally, the APOE ɛ4 carrier status-neuropsychological test score interaction demonstrated a significant effect on the gray matter volume of the left middle occipital gyrus. CONCLUSION: There might be a compensatory response to initiating Aß in APOE ɛ4 carriers during the earliest AD stage. Despite its exploratory nature, this study offers some insight into recent interests concerning probabilistic AD modeling, focusing on the modulating role of the APOE ɛ4 carrier status during the preclinical period.

Differential Impact of Education on Gray Matter Volume According to Sex in Cognitively Normal Older Adults: Whole Brain Surface-Based Morphometry.

Background: The effect of educational status on brain structural measurements depends on demographic and clinical factors in cognitively healthy older adults. Objectives: The current study aimed to evaluate the impact of interaction between years of education and sex on gray matter volume and to investigate whether cortical volume has a differential impact on cognitive function according to sex. Methods: One hundred twenty-one subjects between 60 and 85 years old were included in this study. Gray matter volume was evaluated by whole brain surface-based morphometry. Multiple regression analysis was used to analyze the effects of sex-cortical volume interactions on cognitive functions. Results: There was a significant interaction between years of education and sex on the cortical volume of the left inferior temporal gyrus after adjusting for age, APOE ε4 allele prevalence, and total intracranial volume. In addition, we found a significant impact of the interaction between adjusted left inferior temporal volume and sex on CERAD-K total scores. Conclusion: These findings have significant implications for the understanding of how sex could affect the role of cognitive reserve for cortical atrophy in cognitively intact older adults.

Distinctive Association of the Functional Connectivity of the Posterior Cingulate Cortex on Memory Performances in Early and Late Amnestic Mild Cognitive Impairment Patients.

BACKGROUND: Attempts have been made to explore the biological basis of neurodegeneration in the amnestic mild cognitive impairment (MCI) stage, subdivided by memory performance. However, few studies have evaluated the differential impact of functional connectivity (FC) on memory performances in early- and late-MCI patients. OBJECTIVE: This study aims to explore the difference in FC of the posterior cingulate cortex (PCC) among healthy controls (HC) (n = 37), early-MCI patients (n = 30), and late-MCI patients (n = 35) and to evaluate a group-memory performance interaction against the FC of PCC. METHODS: The subjects underwent resting-state functional MRI scanning and a battery of neuropsychological tests. RESULTS: A significant difference among the three groups was found in FC between the PCC (seed region) and bilateral crus cerebellum, right superior medial frontal gyrus, superior temporal gyrus, and left middle cingulate gyrus (Monte Carlo simulation-corrected p < 0.01; cluster p < 0.05). Additionally, the early-MCI patients displayed higher FC values than the HC and late-MCI patients in the right superior medial frontal gyrus, cerebellum crus 1, and left cerebellum crus 2 (Bonferroni-corrected p < 0.05). Furthermore, there was a significant group-memory performance interaction (HC vs. early MCI vs. late MCI) for the FC between PCC and bilateral crus cerebellum, right superior medial frontal gyrus, superior temporal gyrus, and left middle cingulate gyrus (Bonferroni-corrected p < 0.05). CONCLUSION: These findings contribute to the biological implications of early- and late-MCI stages, categorized by evaluating the impairment of memory performance. Additionally, comprehensively analyzing the structural differences in the subdivided amnestic MCI (aMCI) stages could deepen our understanding of these biological meanings.

Default mode network dissociation linking cerebral beta amyloid retention and depression in cognitively normal older adults.

Cerebral beta amyloid (Aß) deposition and late-life depression (LLD) are known to be associated with the trajectory of Alzheimer's disease (AD). However, their neurobiological link is not clear. Previous studies showed aberrant functional connectivity (FC) changes in the default mode network (DMN) in early Aß deposition and LLD, but its mediating role has not been elucidated. This study was performed to investigate the distinctive association pattern of DMN FC linking LLD and Aß retention in cognitively normal older adults. A total of 235 cognitively normal older adults with (n = 118) and without depression (n = 117) underwent resting-state functional magnetic resonance imaging and 18F-flutemetamol positron emission tomography to investigate the associations between Aß burden, depression, and DMN FC. Independent component analysis showed increased anterior DMN FC and decreased posterior DMN FC in the depression group compared with the no depression group. Global cerebral Aß retention was positively correlated with anterior and negatively correlated with posterior DMN FC. Anterior DMN FC was positively correlated with severity of depression, whereas posterior DMN FC was negatively correlated with cognitive function. In addition, the effects of global cerebral Aß retention on severity of depression were mediated by subgenual anterior cingulate FC. Our results of anterior and posterior DMN FC dissociation pattern may be pivotal in linking cerebral Aß pathology and LLD in the course of AD progression. Further longitudinal studies are needed to confirm the causal relationships between cerebral Aß retention and LLD.

Rapid Onset of Intranasal Esketamine in Patients with Treatment Resistant Depression and Major Depression with Suicide Ideation: A Meta-Analysis

Objective: We performed a meta-analysis of randomized double-blinded placebo controlled trials (DB-RCTs) to investigate efficacy and safety of intranasal esketamine in treating major depressive disorder (MDD) including treatment resistant depression (TRD) and major depression with suicide ideation (MDSI). Methods: Mean change in total scores on Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to different time-points were our primary outcome measure. Secondary efficacy measures included rate of remission of depression and resolution of suicidality. Results: Eight DB-RCTs (seven published and one un-published) covering 1,488 patients with MDD were included. Esketamine more significantly improved MADRS total scores than placebo starting from 2-4 hours after the first administration (standardized mean difference, -0.41 [95% CI, -0.58 to -0.25], p < 0.00001), and this superiority maintained until end of double-blinded period (28 days). Sub-group analysis showed that superior antidepressant effects of esketamine over placebo in TRD and MDSI was observed from 2-4 hours, which was maintained until 28 days. Resolution of suicide in MDSI was also greater for esketamine than for placebo at 2-4 hours (OR of 2.04, 95% CIs, 1.37 to 3.05, p = 0.0005), but two groups did not statistically differ at 24 hours and day 28. Total adverse events (AEs), and other common AEs including dissociation, blood pressure increment, nausea, vertigo, dysgeusia, dizziness, and somnolence were more frequent in esketamine than in placebo group. Conclusion: Esketamine showed rapid antidepressant effects in patients with MDD, including TRD and MDSI. The study also suggested that esketamine might be associated with rapid anti-suicidal effects for patients with MDSI.

Late-life depression, subjective cognitive decline, and their additive risk in incidence of dementia: A nationwide longitudinal study.

OBJECTIVE: Late-life depression and subjective cognitive decline (SCD) are significant risk factors for dementia. However, studies with a large sample size are needed to clarify their independent and combined risks for subsequent dementia. METHODS: This nationwide population-based cohort study included all individuals aged 66 years who participated in the National Screening Program between 2009 and 2013 (N = 939,099). Subjects were followed from the day they underwent screening to the diagnosis of dementia, death, or the last follow-up day (December 31, 2017). RESULTS: Depressive symptom presentation, recent depressive disorder, and SCD independently increased dementia incidence with adjusted hazard ratio (aHR) of 1.286 (95% CI:1.255-1.318), 1.697 (95% CI:1.621-1.776), and 1.748 (95% CI: 689-1.808) respectively. Subjects having both SCD and depression had a higher risk (aHR = 2.466, 95% CI:2.383-2.551) of dementia than having depression (aHR = 1.402, 95% CI:1.364-1.441) or SCD (aHR = 1.748, 95% CI:1.689-1.808) alone. CONCLUSIONS: Depressive symptoms, depressive disorder, and SCD are independent risk factors for dementia. Co-occurring depression and SCD have an additive effect on the risk of dementia; thus, early intervention and close follow up are necessary for patients with co-occurring SCD and depression.

Association between Dementia and Clinical Outcome after COVID-19: A Nationwide Cohort Study with Propensity Score Matched Control in South Korea.

OBJECTIVE: Despite a high prevalence of dementia in older adults hospitalized with severe acute respiratory syndrome coronavirus 2 infection (SARS-CoV-2), or so called COVID-19, research investigating association between preexisting diagnoses of dementia and prognosis of COVID-19 is scarce. We aimed to investigate treatment outcome of patients with dementia after COVID-19. METHODS: We explored a nationwide cohort with a total of 2,800 subjects older than 50 years who were diagnosed with COVID-19 between January and April 2020. Among them, 223 patients had underlying dementia (dementia group). We matched 1:1 for each dementia- non-dementia group pair yielding 223 patients without dementia (no dementia group) using propensity score matching. RESULTS: Mortality rate after COVID-19 was higher in dementia group than in no dementia group (33.6% vs. 20.2%, p=0.002). Dementia group had higher proportion of patients requiring invasive ventilatory support than no dementia group (34.1% vs. 22.0%, p=0.006). Multivariable analysis showed that dementia group had a higher risk of mortality than no dementia group (odds ratio=3.05, p<0.001). We also found that patients in dementia group had a higher risk of needing invasive ventilatory support than those in no dementia group. CONCLUSION: Our results suggest that system including strengthen quarantines are required for patients with dementia during the COVID- 19 pandemic.

Semi-Supervised Learning in Medical MRI Segmentation: Brain Tissue with White Matter Hyperintensity Segmentation Using FLAIR MRI.

White-matter hyperintensity (WMH) is a primary biomarker for small-vessel cerebrovascular disease, Alzheimer's disease (AD), and others. The association of WMH with brain structural changes has also recently been reported. Although fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) provide valuable information about WMH, FLAIR does not provide other normal tissue information. The multi-modal analysis of FLAIR and T1-weighted (T1w) MRI is thus desirable for WMH-related brain aging studies. In clinical settings, however, FLAIR is often the only available modality. In this study, we thus propose a semi-supervised learning method for full brain segmentation using FLAIR. The results of our proposed method were compared with the reference labels, which were obtained by FreeSurfer segmentation on T1w MRI. The relative volume difference between the two sets of results shows that our proposed method has high reliability. We further evaluated our proposed WMH segmentation by comparing the Dice similarity coefficients of the reference and the results of our proposed method. We believe our semi-supervised learning method has a great potential for use for other MRI sequences and will encourage others to perform brain tissue segmentation using MRI modalities other than T1w.

A Comparative Study on the Predictive Value of Different Resting-State Functional Magnetic Resonance Imaging Parameters in Preclinical Alzheimer's Disease.

Objective: Diverse resting-state functional magnetic resonance imaging (rs-fMRI) studies showed that rs-fMRI might be able to reflect the earliest detrimental effect of cerebral beta-amyloid (Aß) pathology. However, no previous studies specifically compared the predictive value of different rs-fMRI parameters in preclinical AD. Methods: A total of 106 cognitively normal adults (Aß+ group = 66 and Aß- group = 40) were included. Three different rs-fMRI parameter maps including functional connectivity (FC), fractional amplitude of low-frequency fluctuations (fALFF), and regional homogeneity (ReHo) were calculated. Receiver operating characteristic (ROC) curve analyses were utilized to compare classification performance of the three rs-fMRI parameters. Results: FC maps showed the best classifying performance in ROC curve analysis (AUC, 0.915, p < 0.001). Good but weaker performance was achieved by using ReHo maps (AUC, 0.836, p < 0.001) and fALFF maps (AUC, 0.804, p < 0.001). The brain regions showing the greatest discriminative power included the left angular gyrus for FC, left anterior cingulate for ReHo, and left middle frontal gyrus for fALFF. However, among the three measurements, ROI-based FC was the only measure showing group difference in voxel-wise analysis. Conclusion: Our results strengthen the idea that rs-fMRI might be sensitive to earlier changes in spontaneous brain activity and FC in response to cerebral Aß retention. However, further longitudinal studies with larger sample sizes are needed to confirm their utility in predicting the risk of AD.

Impact of Transcranial Direct Current Stimulation on Cognitive Function, Brain Functional Segregation, and Integration in Patients with Mild Cognitive Impairment According to Amyloid-Beta Deposition and APOE ε4-Allele: A Pilot Study.

Anodal transcranial direct current stimulation (anodal-tDCS) is known to improve cognition and normalize abnormal network configuration during resting-state functional magnetic resonance imaging (fMRI) in patients with mild cognitive impairment (MCI). We aimed to evaluate the impact of sequential anodal-tDCS on cognitive functions, functional segregation, and integration parameters in patients with MCI, according to high-risk factors for Alzheimer's disease (AD): amyloid-beta (Aß) deposition and APOE ε4-allele status. In 32 patients with MCI ([18 F] flutemetamol-: n = 10, [18 F] flutemetamol+: n = 22; APOE ε4-: n = 13, APOE ε4+: n = 19), we delivered anodal-tDCS (2 mA/day, five times/week, for 2 weeks) over the left dorsolateral prefrontal cortex and assessed the neuropsychological test battery and resting-state fMRI measurements before and after 2 weeks stimulation. We observed a non-significant impact of an anodal-tDCS on changes in neuropsychological battery scores between MCI patients with and without high-risk factors of AD, Aß retention and APOE ε4-allele. However, there was a significant difference in brain functional segregation and integration parameters between MCI patients with and without AD high-risk factors. We also found a significant effect of tDCS-by-APOE ε4-allele interaction on changes in the functional segregation parameter of the temporal pole. In addition, baseline Aß deposition significantly associated negatively with change in global functional integrity of hippocampal formation. Anodal-tDCS might help to enhance restorative and compensatory intrinsic functional changes in MCI patients, modulated by the presence of Aß retention and the APOE ε4-allele.

Pre-transplant Dementia is Associated with Poor Survival After Hematopoietic Stem Cell Transplantation: A Nationwide Cohort Study with Propensity Score Matched Control.

OBJECTIVE: No previous study examined impact of dementia in the outcome of allogeneic hematopoietic stem cell transplantation (HSCT). We aimed to investigate overall survival (OS) of patients with dementia after receiving HSCT. METHODS: Among 8,230 patients who underwent HSCT between 2002 and 2018, 5,533 patients younger than 50 years were first excluded. Remaining patients were divided into those who were and were not diagnosed with dementia before HSCT (dementia group: n = 31; no dementia: n = 2,666). Thereafter, among 2,666 participants without dementia, 93 patients were selected via propensity-matched score as non-dementia group. Patients were followed from the day they received HSCT to the occurrence of death or the last follow-up day (December 31, 2018), whichever came first. RESULTS: With median follow-up of 621 days for dementia group and 654 days for non-dementia group, 2 year-OS of dementia group was lower than that of non-dementia group (53.3% [95% confidence interval, 95% CI, 59.0-80.2%] vs. 68.8% [95% CI, 38.0-68.2%], p = 0.076). In multivariate analysis, dementia had significant impacts on OS (hazard risk = 2.539, 95% CI, 1.166-4.771, p = 0.017). CONCLUSION: Our results indicated that patients diagnosed with dementia before HSCT have 2.539 times higher risk of mortality after transplantation than those not having dementia. With number of elderly needing HSCT is increasing, further work to establish treatment guidelines for the management of HSCT in people with dementia is needed.

Development of Random Forest Algorithm Based Prediction Model of Alzheimer's Disease Using Neurodegeneration Pattern.

OBJECTIVE: Alzheimer's disease (AD) is the most common type of dementia and the prevalence rapidly increased as the elderly population increased worldwide. In the contemporary model of AD, it is regarded as a disease continuum involving preclinical stage to severe dementia. For accurate diagnosis and disease monitoring, objective index reflecting structural change of brain is needed to correctly assess a patient's severity of neurodegeneration independent from the patient's clinical symptoms. The main aim of this paper is to develop a random forest (RF) algorithm-based prediction model of AD using structural magnetic resonance imaging (MRI). METHODS: We evaluated diagnostic accuracy and performance of our RF based prediction model using newly developed brain segmentation method compared with the Freesurfer's which is a commonly used segmentation software. RESULTS: Our RF model showed high diagnostic accuracy for differentiating healthy controls from AD and mild cognitive impairment (MCI) using structural MRI, patient characteristics, and cognitive function (HC vs. AD 93.5%, AUC 0.99; HC vs. MCI 80.8%, AUC 0.88). Moreover, segmentation processing time of our algorithm (<5 minutes) was much shorter than of Freesurfer's (6-8 hours). CONCLUSION: Our RF model might be an effective automatic brain segmentation tool which can be easily applied in real clinical practice.

Agomelatine for the Treatment of Generalized Anxiety Disorder: A Meta-Analysis.

OBJECTIVE: Despite multiple drugs available, a large proportion of patients with generalized anxiety disorder (GAD) do not show adequate response and remission. Thus, additional novel pharmacological agents are needed to increase treatment option for GAD. We aimed to investigate efficacy and safety of agomelatine in the treatment of GAD by conducting a meta-analysis. METHODS: An extensive search of multiple databases and clinical trial registries were conducted. Mean change in total scores on Hamilton Anxiety Rating Scale (HAM-A) from baseline to endpoint was our primary outcome measure. Secondary efficacy measures included response and remission rates, as defined by a 50% or greater reduction in HAM-A total scores and a score of 7 or less in HAM-A total scores at study endpoint respectively. RESULTS: Four published double blinded, randomized, placebo-controlled trials were included in this meta-analysis. Agomelatine more significantly (standardized mean difference = -0.56, p = 0.004) improved HAM-A total scores than placebo. The odds ratios (ORs) of agomelatine over placebo for response and remission rates were 3.75 (p < 0.00001) and 2.74 (p < 0.00001), respectively. Agomelatine was generally well tolerated with insignificance in dropout rate, somnolence, headache, nasopharyngitis, and dizziness compared with placebo. However, agomelatine showed significantly higher incidence of liver function increment (OR = 3.13, p = 0.01) and nausea (OR = 3.27, p = 0.02). CONCLUSION: We showed that agomelatine may be another treatment option in patients with GAD. However, the results should be interpreted and translated into clinical practice with caution because the meta-analysis was based on limited numbers of clinical trials.

Effects of Moderate Intensity Exercise on the Cortical Thickness and Subcortical Volumes of Preclinical Alzheimer's Disease Patients: A Pilot Study.

OBJECTIVE: We aimed to explore the impact of moderate intensity exercise on the cortical thickness and subcortical volumes of preclinical Alzheimer's disease (AD) patients. METHODS: Sixty-three preclinical AD patients with magnetic resonance imaging (MRI) and 18-florbetaben positron emission tomography (PET) data were enrolled in the study. Information on demographic characteristics, cognitive battery scores, self-reported exercise habits were attained. Structural magnetic resonance images were analyzed and processed using Freesurfer v6.0. RESULTS: Compared to Exercise group, Non-Exercise group demonstrated reduced cortical thickness in left parstriangularis, rostral middle frontal, entorhinal, superior frontal, lingual, superior parietal, lateral occipital, inferior parietal gyrus, temporal pole, precuneus, insula, fusiform gyrus, right precuneus, superiorparietal, lateral orbitofrontal, rostral middle frontal, medial orbitofrontal, superior frontal, lingual, middle temporal gyrus, insula, supramarginal, parahippocampal, paracentral gyrus. Volumes of right thalamus, caudate, putamen, pallidum, hippocampus, amygdala were also reduced in Non-Exercise group. CONCLUSION: Moderate intensity exercise affects cortical and subcortical structures in preclinical AD patients. Thus, physical exercise has a potential to be an effective intervention to prevent future cognitive decline in those at high risk of AD.

Pre-transplant depression decreased overall survival of patients receiving allogeneic hematopoietic stem cell transplantation: a nationwide cohort study.

Studies investigating association of depression with overall survival (OS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) yielded conflicting results. A nationwide cohort study, which included all adult patients [n = 7,170; depression group, 13.3% (N = 956); non-depression group, 86.7% (N = 6,214)] who received allo-HSCT from 2002 to 2018 in South Korea, analyzed risk of pre-transplant depression in OS of allo-HSCT. Subjects were followed from the day they received allo-HSCT, to occurrence of death, or last follow-up day (December 31, 2018). Median age at allo-HSCT for depression and non-depression groups were 50 and 45 (p < 0.0001), respectively. Two groups also differed in rate of females (depression group, 55.8%; non-depression group, 43.8%; p < 0.0001) and leukemia (depression group, 61.4%; non-depression group, 49.7%; p < 0.0001). After a median follow-up of 29.1 months, 5-year OS rate was 63.1%. Cox proportional-hazard regression evaluated an adjusted risk of post-transplant mortality related to depression: OS decreased sequentially from no depression (adjusted hazard ratio [aHR] = 1) to pre-transplant depression only (aHR = 1.167, CI: 1.007-1.352, p = 0.04), and to having both depression and anxiety disorder (aHR = 1.202, CI: 1.038-1.393, p = 0.014) groups. Pre-transplant anxiety (anxiety only) did not have significant influence in OS. Additional medical and psychiatric care might be necessary in patients who experienced depression, especially with anxiety, before allo-HSCT.

Association of Alcohol Intake and Fracture Risk in Elderly Varied by Affected Bones: A Nationwide Longitudinal Study.

OBJECTIVE: Previous studies investigating association of alcohol intake and fracture risk in elderly yielded conflicting results. We first examined the association between alcohol intake and total fracture risk in elderly subjects and further analyzed whether the association varied by fracture locations. METHODS: This is a nationwide population-based cohort study which included all people aged 66 (n=1,431,539) receiving the National Screening Program during 2009-2014. Time-to-event were defined as duration from study recruitment, the day they received health screening, to the occurrence of fracture. RESULTS: Total fracture was significantly lower in mild drinkers [adjusted hazard ratio (aHR)=0.952; 95% confidence interval (95% CI) =0.931-0.973] and higher in heavy drinkers (aHR=1.246; 95% CI=1.201-1.294) than non-drinkers. Risk pattern of alcohol consumption and fracture differed according to affected bones. Similar J-shaped trends were observed for vertebra fractures, but risk of limb fracture showed a linear relationship with alcohol intake. For hip fracture, risk decrement was more pronounced in mild and moderate drinkers, and significant increment was noted only in very severe drinkers [≥60 g/day; (aHR)=1.446; 1.162-1.801]. CONCLUSION: Light to moderate drinking generally lowered risk of fractures, but association between alcohol and fracture risk varied depending on the affected bone lesions.