A selective ER-phagy exerts neuroprotective effects via modulation of α-synuclein clearance in parkinsonian models.

The endoplasmic reticulum (ER) is selectively degraded by ER-phagy to maintain cell homeostasis. α-synuclein accumulates in the ER, causing ER stress that contributes to neurodegeneration in Parkinson's disease (PD), but the role of ER-phagy in α-synuclein modulation is largely unknown. Here, we investigated the mechanisms by which ER-phagy selectively recognizes α-synuclein for degradation in the ER. We found that ER-phagy played an important role in the degradation of α-synuclein and recovery of ER function through interaction with FAM134B, where calnexin is required for the selective FAM134B-mediated α-synuclein clearance via ER-phagy. Overexpression of α-synuclein in the ER of the substantia nigra (SN) resulted in marked loss of dopaminergic neurons and motor deficits, mimicking PD characteristics. However, enhancement of ER-phagy using FAM134B overexpression in the SN exerted neuroprotective effects on dopaminergic neurons and recovered motor performance. These data suggest that ER-phagy represents a specific ER clearance mechanism for the degradation of α-synuclein.

Immunosuppressive therapy in elderly patients with neuromyelitis optica spectrum disorder: a retrospective multicentre study.

BACKGROUND: The risk-benefit relationship of immunosuppressive therapies (ISTs) for elderly patients with neuromyelitis optica spectrum disorder (NMOSD) is not well established. This study aimed to investigate the safety and efficacy of IST in elderly patients with NMOSD. METHODS: This retrospective study analysed IST efficacy and safety in 101 patients with aquaporin-4 antibody-positive NMOSD aged over 65 years, treated for at least 6 months at five Korean referral centres, focusing on relapse rates, infection events and discontinuation due to adverse outcomes. RESULTS: The mean age at disease onset was 59.8 years, and female-to-male ratio was 4:1. Concomitant comorbidities at NMOSD diagnosis were found in 87 patients (86%). The median Expanded Disability Status Scale score at the initiation of IST was 3.5. The administered ISTs included azathioprine (n=61, 60%), mycophenolate mofetil (MMF) (n=48, 48%) and rituximab (n=41, 41%). Over a median of 5.8 years of IST, 58% of patients were relapse-free. The median annualised relapse rate decreased from 0.76 to 0 (p<0.001), and 81% experienced improved or stabilised disability. Patients treated with rituximab had a higher relapse-free rate than those treated with azathioprine or MMF (p=0.022). During IST, 21 patients experienced 25 severe infection events (SIEs) over the age of 65 years, and 3 died from pneumonia. 14 patients (14%) experienced 17 adverse events that led to switching or discontinuation of IST. When comparing the incidence rates of SIEs and adverse events, no differences were observed among patients receiving azathioprine, MMF and rituximab. CONCLUSION: In elderly patients with NMOSD, IST offers potential benefits in reducing relapse rates alongside a tolerable risk of adverse events.

Impact of COVID-19 Infection and Its Association With Previous Vaccination in Patients With Myasthenia Gravis in Korea: A Multicenter Retrospective Study.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, patients with myasthenia gravis (MG) were more susceptible to poor outcomes owing to respiratory muscle weakness and immunotherapy. Several studies conducted in the early stages of the COVID-19 pandemic reported higher mortality in patients with MG compared to the general population. This study aimed to investigate the clinical course and prognosis of COVID-19 in patients with MG and to compare these parameters between vaccinated and unvaccinated patients in South Korea. METHODS: This multicenter, retrospective study, which was conducted at 14 tertiary hospitals in South Korea, reviewed the medical records and identified MG patients who contracted COVID-19 between February 2022 and April 2022. The demographic and clinical characteristics associated with MG and vaccination status were collected. The clinical outcomes of COVID-19 infection and MG were investigated and compared between the vaccinated and unvaccinated patients. RESULTS: Ninety-two patients with MG contracted COVID-19 during the study. Nine (9.8%) patients required hospitalization, 4 (4.3%) of whom were admitted to the intensive care unit. Seventy-five of 92 patients were vaccinated before contracting COVID-19 infection, and 17 were not. During the COVID-19 infection, 6 of 17 (35.3%) unvaccinated patients were hospitalized, whereas 3 of 75 (4.0%) vaccinated patients were hospitalized (P < 0.001). The frequencies of ICU admission and mechanical ventilation were significantly lower in the vaccinated patients than in the unvaccinated patients (P = 0.019 and P = 0.032, respectively). The rate of MG deterioration was significantly lower in the vaccinated patients than in the unvaccinated patients (P = 0.041). Logistic regression after weighting revealed that the risk of hospitalization and MG deterioration after COVID-19 infection was significantly lower in the vaccinated patients than in the unvaccinated patients. CONCLUSION: This study suggests that the clinical course and prognosis of patients with MG who contracted COVID-19 during the dominance of the omicron variant of COVID-19 may be milder than those at the early phase of the COVID-19 pandemic when vaccination was unavailable. Vaccination may reduce the morbidity of COVID-19 in patients with MG and effectively prevent MG deterioration induced by COVID-19 infection.

Distinct features of B cell receptors in neuromyelitis optica spectrum disorder among CNS inflammatory demyelinating diseases.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) stands out among CNS inflammatory demyelinating diseases (CIDDs) due to its unique disease characteristics, including severe clinical attacks with extensive lesions and its association with systemic autoimmune diseases. We aimed to investigate whether characteristics of B cell receptors (BCRs) differ between NMOSD and other CIDDs using high-throughput sequencing. METHODS: From a prospective cohort, we recruited patients with CIDDs and categorized them based on the presence and type of autoantibodies: NMOSD with anti-aquaporin-4 antibodies, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) with anti-myelin oligodendrocyte glycoprotein antibodies, double-seronegative demyelinating disease (DSN), and healthy controls (HCs). The BCR features, including isotype class, clonality, somatic hypermutation (SHM), and the third complementarity-determining region (CDR3) length, were analyzed and compared among the different disease groups. RESULTS: Blood samples from 33 patients with CIDDs (13 NMOSD, 12 MOGAD, and 8 DSN) and 34 HCs were investigated for BCR sequencing. Patients with NMOSD tended to have more activated BCR features compare to the other disease groups. They showed a lower proportion of unswitched isotypes (IgM and IgD) and a higher proportion of switched isotypes (IgG), increased clonality of BCRs, higher rates of SHM, and shorter lengths of CDR3. Notably, advanced age was identified as a clinical factor associated with these activated BCR features, including increased levels of clonality and SHM rates in the NMOSD group. Conversely, no such clinical factors were found to be associated with activated BCR features in the other CIDD groups. CONCLUSIONS: NMOSD patients, among those with CIDDs, displayed the most pronounced B cell activation, characterized by higher levels of isotype class switching, clonality, SHM rates, and shorter CDR3 lengths. These findings suggest that B cell-mediated humoral immune responses and characteristics in NMOSD patients are distinct from those observed in the other CIDDs, including MOGAD. Age was identified as a clinical factor associated with BCR activation specifically in NMOSD, implying the significance of persistent B cell activation attributed to anti-aquaporin-4 antibodies, even in the absence of clinical relapses throughout an individual's lifetime.

Early correction of synaptic long-term depression improves abnormal anxiety-like behavior in adult GluN2B-C456Y-mutant mice.

Extensive evidence links Glutamate receptor, ionotropic, NMDA2B (GRIN2B), encoding the GluN2B/NR2B subunit of N-methyl-D-aspartate receptors (NMDARs), with various neurodevelopmental disorders, including autism spectrum disorders (ASDs), but the underlying mechanisms remain unclear. In addition, it remains unknown whether mutations in GluN2B, which starts to be expressed early in development, induces early pathophysiology that can be corrected by early treatments for long-lasting effects. We generated and characterized Grin2b-mutant mice that carry a heterozygous, ASD-risk C456Y mutation (Grin2b+/C456Y). In Grin2b+/C456Y mice, GluN2B protein levels were strongly reduced in association with decreased hippocampal NMDAR currents and NMDAR-dependent long-term depression (LTD) but unaltered long-term potentiation, indicative of mutation-induced protein degradation and LTD sensitivity. Behaviorally, Grin2b+/C456Y mice showed normal social interaction but exhibited abnormal anxiolytic-like behavior. Importantly, early, but not late, treatment of young Grin2b+/C456Y mice with the NMDAR agonist D-cycloserine rescued NMDAR currents and LTD in juvenile mice and improved anxiolytic-like behavior in adult mice. Therefore, GluN2B-C456Y haploinsufficiency decreases GluN2B protein levels, NMDAR-dependent LTD, and anxiety-like behavior, and early activation of NMDAR function has long-lasting effects on adult mouse behavior.

Spatiotemporal association between air pollution and stroke mortality in South Korea.

BACKGROUND: Air pollutant concentrations in South Korea vary greatly by region and time. To assess temporal and spatial associations of stroke subtypes with long-term air pollution effects on stroke mortality, we studied ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). METHODS: This was an observational study conducted in South Korea from 2001-2018. Concentrations of carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2), and particulate matter ≤10 µm in diameter (PM10) were determined from 332 stations. Average air pollutant concentrations in each district were determined by distance-weighted linear interpolation. The nationwide stroke mortality rates in 249 districts were obtained from the Korean Statistical Information Service. Time intervals were divided into three consecutive 6-year periods: 2001-2006, 2007-2012, and 2013-2018. RESULTS: The concentrations of air pollutants gradually decreased from 2001-2018, along with decreases in IS and ICH mortality rates. However, mortality rates associated with SAH remained constant. From 2001-2006, NO2 (adjusted odds ratio [aOR]:1.13, 95% confidence interval: 1.08-1.19), SO2 (aOR: 1.10, 1.07-1.13), and PM10 (aOR: 1.12, 1.06-1.18) concentrations were associated with IS mortality, and SO2 (aOR: 1.07, 1.02-1.13) and PM10 (aOR:1.11,1.06-1.22) concentrations were associated with SAH-associated mortality. Air pollution was no longer associated with stroke mortality from 2007 onward, as the air pollution concentration continued to decline. Throughout the entire 18-year period, ICH-associated mortality was not associated with air pollution. CONCLUSIONS: Considering temporal and spatial trends, high concentrations of air pollutants were most likely to be associated with IS mortality. Our results strengthen the existing evidence of the deleterious effects of air pollution on IS mortality.

Inhibition Effect of Adipogenesis and Lipogenesis via Activation of AMPK in Preadipocytes Treated with Canavalia gladiata Extract.

The aim of this study was to investigate the effect of Canavalia gladiata extract (CGE) on the regulation of AMP-activated protein kinase (AMPK) in 3T3-L1 preadipocytes and evaluate the adipogenesis and lipogenesis mechanisms. In 3T3-L1 preadipocytes, lipid accumulation and differentiation were suppressed by 1.1, 1.3, and 1.4 times under the CGE treatment at 0.25, 0.5, and 1.0 mg/mL, respectively. The expression of the main genes involved in the inhibition of adipogenesis was evaluated at the mRNA level via a transcription-polymerase chain reaction. The extract at 1.0 mg/mL increased the mRNA expressions of AMPK and carnitine palmitoyl transferase-1 (CPT-1) by 1.9 and 1.2 times, respectively, while it decreased the expression of sterol regulatory element binding proteins-1c (SREBP-1c), peroxisome proliferator activated receptor-γ (PPAR-γ), CCAAT enhancer binding protein-α (C/EBP-α), and fatty acid synthase (FAS) by 1.1, 1.2, 1.8, and 1.5 times, respectively, indicating inhibition of the adipogenesis and lipogenesis potential of CGE. Gallic acid (4.02 mg/g) was identified as the main component of the CGE via LC-MS/MS and HPLC analysis. The results of this study suggested that CGE can be utilized as an anti-obesity food additive or medication by activating the AMPK-induced regulation and suppressing adipogenesis transcription factors.

Longitudinal follow-up of serum biomarkers in patients with neuromyelitis optica spectrum disorder.

BACKGROUND: Recently, several serum biomarkers have been proposed in Neuromyelitis Optica Spectrum Disorders (NMOSD) to monitor disease activity. OBJECTIVE: The objective of the study is to evaluate the longitudinal clinical value of serum biomarkers in patients with NMOSD. METHODS: We prospectively recruited consecutive NMOSD patients with anti-aquaporin-4 antibody and obtained serum samples at enrollment, after 6-12 months of follow-up (main period), and at attacks. Using single-molecule array assays, we evaluated longitudinal changes of serum neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and GFAP/NfL levels. RESULTS: Overall, 64 patients (58 women) were enrolled (age: 51 years, disease duration: 6.7 years) and 133 samples were obtained. Among patients who did not develop new attacks during the main period (n = 62), serum levels of NfL, GFAP, and GFAP/NfL were significantly decreased over time in patients with attacks (<2 months) at enrollment (n = 14 (23%)), whereas serum NfL and GFAP levels gradually increased in the others (n = 48 (77%)). During the study, five (8%) patients developed new attacks; only serum GFAP levels increased consistently upon these events compared with baseline levels. To differentiate attacks from remissions, serum GFAP levels showed the largest area under the receiver operating characteristic curve (0.876, 95% confidence interval: 0.801-0.951). CONCLUSION: Among NfL, GFAP, and GFAP/NfL, serum GFAP might be the most appropriate for monitoring NMOSD longitudinally, which warrants future confirming studies.

NGL-3 in the regulation of brain development, Akt/GSK3b signaling, long-term depression, and locomotive and cognitive behaviors.

Netrin-G ligand-3 (NGL-3) is a postsynaptic adhesion molecule known to directly interact with the excitatory postsynaptic scaffolding protein postsynaptic density-95 (PSD-95) and trans-synaptically with leukocyte common antigen-related (LAR) family receptor tyrosine phosphatases to regulate presynaptic differentiation. Although NGL-3 has been implicated in the regulation of excitatory synapse development by in vitro studies, whether it regulates synapse development or function, or any other features of brain development and function, is not known. Here, we report that mice lacking NGL-3 (Ngl3-/- mice) show markedly suppressed normal brain development and postnatal survival and growth. A change of the genetic background of mice from pure to hybrid minimized these developmental effects but modestly suppressed N-methyl-D-aspartate (NMDA) receptor (NMDAR)-mediated synaptic transmission in the hippocampus without affecting synapse development, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR)-mediated basal transmission, and presynaptic release. Intriguingly, long-term depression (LTD) was near-completely abolished in Ngl3-/- mice, and the Akt/glycogen synthase kinase 3ß (GSK3ß) signaling pathway, known to suppress LTD, was abnormally enhanced. In addition, pharmacological inhibition of Akt, but not activation of NMDARs, normalized the suppressed LTD in Ngl3-/- mice, suggesting that Akt hyperactivity suppresses LTD. Ngl3-/- mice displayed several behavioral abnormalities, including hyperactivity, anxiolytic-like behavior, impaired spatial memory, and enhanced seizure susceptibility. Among them, the hyperactivity was rapidly improved by pharmacological NMDAR activation. These results suggest that NGL-3 regulates brain development, Akt/GSK3ß signaling, LTD, and locomotive and cognitive behaviors.

Safety and Efficacy of Otaplimastat in Patients with Acute Ischemic Stroke Requiring tPA (SAFE-TPA): A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2 Study.

OBJECTIVE: Otaplimastat is a neuroprotectant that inhibits matrix metalloprotease pathway, and reduces edema and intracerebral hemorrhage induced by recombinant tissue plasminogen activator (rtPA) in animal stroke models. We aimed to assess the safety and efficacy of otaplimastat in patients receiving rtPA. METHODS: This was a phase 2, 2-part, multicenter trial in stroke patients (19-80 years old) receiving rtPA. Intravenous otaplimastat was administered <30 minutes after rtPA. Stage 1 was a single-arm, open-label safety study in 11 patients. Otaplimastat 80 mg was administered twice daily for 3 days. Stage 2 was a randomized, double-blind, placebo-controlled study involving 69 patients, assigned (1:1:1) to otaplimastat 40 mg, otaplimastat 80 mg, or a placebo. The primary endpoint was the occurrence of parenchymal hematoma (PH) on day 1. Secondary endpoints included serious adverse events (SAEs), mortality, and modified Rankin scale (mRS) distribution at 90 days (clinicaltrials.gov identifier: NCT02787278). RESULTS: No safety issues were encountered in stage 1. The incidence of PH during stage 2 was comparable: 0 of 22 with the placebo, 0 of 22 with otaplimastat 40 mg, and 1 of 21 with the 80 mg dose. No differences in SAEs (13%, 17%, 14%) or death (8.3%, 4.2%, 4.8%) were observed among the 3 groups. Three adverse events (chills, muscle rigidity, hepatotoxicity) were judged to be related to otaplimastat. INTERPRETATION: Intravenous otaplimastat adjunctive therapy in patients receiving rtPA is feasible and generally safe. The functional efficacy of otaplimastat needs to be investigated with further large trials. ANN NEUROL 2020;87:233-245.

Post-Stroke Depressive Symptoms: Varying Responses to Escitalopram by Individual Symptoms and Lesion Location.

OBJECTIVE: The efficacy of antidepressants in post-stroke depressive symptoms (PSD) varies. We aimed to examine whether the effect of escitalopram on PSD differs according to individual depressive symptoms and stroke lesion location. METHODS: This is a post hoc analysis of EMOTION (ClinicalTrials.gov, NCT01278498), a randomized, placebo-controlled, double-blind trial that examined the efficacy of escitalopram on depression in acute stroke patients (237 with placebo, 241 with escitalopram). Depressive symptoms were evaluated with the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS). Changes in MADRS and individual item scores at 12 weeks were compared between the treatment groups and among the stroke lesion location groups. Stroke lesion locations were grouped according to the anatomical distribution of serotonin fibers that originate from the midbrain/pons and spread to the forebrain via subcortical structures: "Midbrain-Pons," "Frontal-Subcortical," and "Others." Least-squares means were calculated to demonstrate the independent effect of lesion location. RESULTS: Total MADRS scores decreased more significantly in the escitalopram than in the placebo group, while a significant effect of escitalopram was observed in only 3 items: apparent sadness, reported sadness, pessimistic thoughts. In the lesion location analyses, escitalopram users in the Frontal-Subcortical group showed significant improvement in total MADRS scores (placebo [n = 130] vs. escitalopram [n = 148], least-square mean [95% CI]: -2.3 [-3.5 to -0.2] vs. -4.5 [-5.5 to -3.4], p = .005), while those in the Midbrain-Pons and Others groups did not. CONCLUSIONS: The effect of escitalopram on PSD may be more prominent in patients with particular depressive symptoms and stroke lesion locations, suggesting the need for tailored treatment strategies.

Neuro-Ophthalmologic Features and Outcomes of Thalamic Infarction: A Single-Institutional 10-Year Experience.

BACKGROUND: Neuro-ophthalmologic deficit after thalamic infarction has been of great concern to ophthalmologists because of its debilitating impacts on patients' daily living. We aimed to describe the visual and oculomotor features of thalamic infarction and to delineate clinical outcomes and prognostic factors of the oculomotor deficits from an ophthalmologic point of view. METHODS: Clinical and neuroimaging data of all participants were retrospectively reviewed. Among the 12,755 patients with first-ever ischemic stroke, who were registered in our Stroke Data Bank between January 2009 and December 2018, 342 were found to have acute thalamic infarcts on MRI, from whom we identified the patients exhibiting neuro-ophthalmologic manifestations including visual, oculomotor, pupillary, and eyelid anomalies. RESULTS: Forty (11.7%) of the 342 patients with thalamic infarction demonstrated neuro-ophthalmologic manifestations, consisting of vertical gaze palsy (n = 19), skew deviation with an invariable hypotropia of the contralesional eye (n = 18), third nerve palsy (n = 11), pseudoabducens palsy (n = 9), visual field defects (n = 7), and other anomalies such as isolated ptosis and miosis (n = 7). Paramedian infarct was the most predominant lesion of neuro-ophthalmologic significance, accounting for 84.8% (n = 28) of all patients sharing the oculomotor features. Although most of the patients with oculomotor abnormalities rapidly improved without sequelae, 6 (18.2%) patients showed permanent oculomotor deficits. Common clinical features of patients with permanent oculomotor deficits included the following: no improvement within 3 months, combined upgaze and downgaze palsy, and the involvement of the paramedian tegmentum of the rostral midbrain. CONCLUSIONS: Thalamic infarction, especially in paramedian territory, can cause a wide variety of neuro-ophthalmologic manifestations, including vertical gaze palsy, skew deviation, and third nerve palsy. Although most oculomotor abnormalities resolve spontaneously within a few months, some may persist for years when the deficits remain unimproved for more than 3 months after stroke.

Machine Learning Approach to Identify Stroke Within 4.5 Hours.

Background and Purpose- We aimed to investigate the ability of machine learning (ML) techniques analyzing diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging to identify patients within the recommended time window for thrombolysis. Methods- We analyzed DWI and FLAIR images of consecutive patients with acute ischemic stroke within 24 hours of clear symptom onset by applying automatic image processing approaches. These processes included infarct segmentation, DWI, and FLAIR imaging registration and image feature extraction. A total of 89 vector features from each image sequence were captured and used in the ML. Three ML models were developed to estimate stroke onset time for binary classification (≤4.5 hours): logistic regression, support vector machine, and random forest. To evaluate the performance of ML models, the sensitivity and specificity for identifying patients within 4.5 hours were compared with the sensitivity and specificity of human readings of DWI-FLAIR mismatch. Results- Data from a total of 355 patients were analyzed. DWI-FLAIR mismatch from human readings identified patients within 4.5 hours of symptom onset with 48.5% sensitivity and 91.3% specificity. ML algorithms had significantly greater sensitivities than human readers (75.8% for logistic regression, P=0.020; 72.7% for support vector machine, P=0.033; 75.8% for random forest, P=0.013) in detecting patients within 4.5 hours, but their specificities were comparable (82.6% for logistic regression, P=0.157; 82.6% for support vector machine, P=0.157; 82.6% for random forest, P=0.157). Conclusions- ML algorithms using multiple magnetic resonance imaging features were feasible even more sensitive than human readings in identifying patients with stroke within the time window for acute thrombolysis.

Depressive Symptoms in Stroke Patients: Are There Sex Differences?

BACKGROUND: We aimed to examine sex differences in symptom characteristics and pharmacological responses in post-stroke depressive (PSD) symptoms. METHODS: This is a post hoc analysis of EMOTION (ClinicalTrials.gov, NCT01278498), a randomized, placebo-controlled, double-blind trial that examined the efficacy of escitalopram for 3 months on depression in patients with acute stroke. Depressive symptoms were evaluated using the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS). Baseline characteristics, clinical variables, and treatment responses to escitalopram were compared between male and female patients. Treatment responses were defined as changes in MADRS (total score and its components) between baseline and 3 months and were compared between the escitalopram and placebo groups within each sex group. The least square mean was calculated to determine the independent effect of escitalopram, of which interaction was evaluated with patient sex. RESULTS: Of the 478 patients (intention-to-treat population), 187 (39%) were female. Female patients were significantly older than male patients and demonstrated more severe depressive symptoms at baseline (male vs. female, MADRS score, mean [SD]: 9.7 ± 8.0 vs. 12.2 ± 8.4, p = 0.001), especially in apparent sadness, reported sadness, and reduced appetite items. These differences were significant after adjustment for age and the severity of neurologic deficits. The female escitalopram group showed a significant 3-month improvement in MADRS scores (placebo [n = 86] vs. escitalopram [n = 101], least square mean [95% CI] -2.7 [-4.1 to -1.2] vs. -5.0 [-6.4 to -3.6], p = 0.007), and this efficacy was prominent in apparent sadness, reported sadness, and pessimistic thoughts items. However, there was no significant effect of escitalopram on depressive symptoms in the male group. The treatment responses of escitalopram tended to be more pronounced in the female group, particularly in alleviating a subset of depressive symptoms such as apparent sadness (p for interaction = 0.009). CONCLUSION: PSD may differ according to sex in its symptom characteristics and treatment responses to escitalopram, and tailored treatment strategies for PSD may therefore be needed.

Serotonin transporter gene polymorphisms may be associated with poststroke neurological recovery after escitalopram use.

OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) putatively improve neurological recovery after stroke. We aimed to investigate whether serotonin transporter (SERT) gene polymorphisms are related to the responsiveness to SSRIs in the poststroke neurological recovery. METHODS: This was a post hoc analysis of the EMOTION study (ClinicalTrials.gov NCT01278498), a randomised, placebo-controlled, double-blind trial examining the efficacy of escitalopram on emotional and neurological disturbances after acute stroke. Patients with no/minimal disability initially (modified Rankin Scale (mRS) 0-1) were excluded. Of the participants, 301 underwent genetic studies of the STin2 (a variable number tandem repeat (VNTR) in intron 2) (STin2 12/10 and STin2 12/12 genotypes) and 5-HTTLPR (a variable-length repeat in the promoter region) polymorphisms of SERT. We explored whether neurological function (National Institutes of Health Stroke Scale (NIHSS) score and mRS) at 3 months would differ according to SERT polymorphisms within each treatment arm (escitalopram and placebo). RESULTS: Among the escitalopram users (n=159), neurological function in subjects with STin2 12/10 (n=29) improved significantly more than that in STin2 12/12 carriers (n=130) at 3 months. After adjusting for age, initial NIHSS and depression, STin2 12/10 independently predicted a good clinical outcome (mRS 0-1) (OR 2.99, 95% CI 1.04 to 8.58) at 3 months. However, differences between STin2 polymorphisms were not shown in the placebo group (n=142). 5-HTTLPR polymorphisms were not associated with neurological recovery in any treatment group. CONCLUSION: STin2 VNTR polymorphisms may be associated with poststroke neurological recovery after SSRI therapy. Further studies are needed to identify the role of serotonin in neurological recovery after stroke.

Factors predicting remission in thymectomized patients with acetylcholine receptor antibody-positive myasthenia gravis.

INTRODUCTION: Although thymectomy is an important therapeutic option for myasthenia gravis (MG), factors predicting remission after thymectomy are not well known. METHODS: We retrospectively reviewed patients with acetylcholine receptor antibody (AChR-Ab)-positive MG who had undergone thymectomy. Prognostic factors predicting remission were investigated. Changes in AChR-Ab titer before and after thymectomy were also evaluated. RESULTS: Among the 179 patients, 52.5% achieved complete stable or pharmacologic remission. Nonthymomatous pathology and mild preoperative status were favorable predictors of remission. The decrease in AChR-Ab titer after thymectomy was significant in nonthymomatous MG but not in thymomatous MG. DISCUSSION: Nonthymomatous pathology and mild preoperative status are prognostic factors that may predict remission after thymectomy. The decrease in AChR-Ab titer after thymectomy was significant in nonthymomatous MG but not in thymomatous MG, suggesting that the pathogenic role of the thymus differs according to pathology. Muscle Nerve 58:796-800, 2018.

Correlation between the CAG repeat size and electrophysiological findings in patients with spinal and bulbar muscular atrophy.

INTRODUCTION: Spinal and bulbar muscular atrophy (SBMA) is caused by the expansion of a CAG repeat in the androgen receptor gene. The relationship between the CAG repeat size and electrophysiological findings is not completely understood. METHODS: We retrospectively analyzed 62 SBMA patients to assess the correlation between their CAG repeat size and electrophysiological findings. RESULTS: In multiple regression analysis including age at examination and disease duration, we identified a negative correlation between the CAG repeat size and the compound muscle action potential (CMAP) amplitude. No significant correlation was found between the CAG repeat size and sensory nerve action potential (SNAP) amplitude. DISCUSSION: Contrary to previous reports of motor- and sensory-dominant phenotypes correlating with CAG repeat sizes, the CAG repeat size was negatively correlated only with CMAP amplitude, and not with SNAP amplitude. Muscle Nerve 57: 683-686, 2018.

The Impact of Cerebral Atherosclerosis According to Location on Prognosis after Coronary Artery Bypass Grafting.

BACKGROUND: In the previous prospective observational study, we found that cerebral atherosclerosis is an independent predictor of acute stroke after coronary artery bypass grafting (CABG). However, it is unknown whether intracranial cerebral atherosclerosis (ICAS) is important as much as extracranial cerebral atherosclerosis (ECAS) in estimating the risk of post-CABG adverse events. Extending the previous study, we aimed to investigate the immediate and long-term prognostic value of the location of cerebral atherosclerosis in CABG patients. METHODS: This follow-up study of previously reported prospective cohort included 1,367 consecutive patients who received CABG between 2004 and 2007. All patients underwent preoperative magnetic resonance angiography (MRA) to assess intracranial and ECAS, both defined by significant steno-occlusion (≥50%). Participants were classified into 4 groups according to the location of cerebral atherosclerosis: no cerebral atherosclerosis, ECAS only, ICAS only, and ECAS + ICAS. Post-CABG stroke within 14 days (immediate outcome) and mortality (long-term outcome) following CABG were compared between the groups. Survival data for all participants through June 2016 were obtained from the Korean National Registry of Vital Statistics. The Cox proportional hazards model was used to estimate the hazard ratio (HR) of post-CABG stroke and mortality; patients lacking cerebral atherosclerosis were defined as the reference group. RESULTS: The median follow-up duration after CABG was 9.2 years (interquartile range 8.4-10.2 years). Of the participants, 278 (20.3%) patients had ICAS only, while 269 (19.7%) and 347 (25.4%) showed ECAS only and ECAS + ICAS, respectively, in their preoperative MRA. Having ICAS only (HR 5.07; 95% CI 1.37-18.75; p = 0.015) and having ECAS + ICAS (HR 8.43; 95% CI, 2.48-28.61; p = 0.001) independently predicted the immediate stroke, whereas being with ECAS only did not (HR 1.71; 95% CI 0.35-8.50; p = 0.509). Conversely, ICAS-only status was not independently associated with long-term mortality (HR 1.22; 95% CI 0.90-1.65; p = 0.207), whereas ECAS-only status (HR 1.42; 95% CI 1.05-1.90; p = 0.021) and ECAS + ICAS status (HR 1.58; 95% CI 1.20-2.07; p = 0.001) showed independent associations. CONCLUSIONS: Over 10 years of follow-up, cerebral atherosclerosis significantly associated with the development of adverse outcomes after CABG. The prognostic value of ICAS might be different from that of ECAS; immediate post-CABG stroke was more closely associated with ICAS, whereas there was a closer association between long-term post-CABG mortality and ECAS.

Prospective Study Comparing Two Second-Look Ultrasound Techniques: Handheld Ultrasound and an Automated Breast Volume Scanner.

OBJECTIVES: The aim of this study was to compare the diagnostic performance of handheld ultrasound (US) and an automated breast volume scanner (ABVS) as second-look US techniques subsequent to preoperative breast magnetic resonance imaging (MRI). METHODS: We prospectively enrolled patients with breast cancer who underwent handheld US and ABVS examinations as second-look US modalities for additional suspicious lesions found via preoperative breast MRI. We reviewed each second-look US modality independently and evaluated the detection rate of each modality. We then analyzed the correlation between the detection rate and the MRI factors (size, distance, and enhancement type). RESULTS: From March to September 2014, both types of second-look US examinations were performed on 40 patients with breast cancer who had 76 additional suspicious lesions detected via preoperative breast MRI. The detection rate of the ABVS was higher than that of handheld US for the second-look examination (94.7% versus 86.8%; P< .05). Among the 76 total lesions, 7 were only identified by the ABVS, 1 was only found by handheld US, and 3 were not detected by either the ABVS or handheld US. When we analyzed the correlation between the detection rate and MRI factors, the only meaningful factor was the enhancement type. The ability to detect a nonmass lesion was lower than the ability to detect a mass-type lesion (P < 0.05) for both the ABVS and handheld US. CONCLUSIONS: For a second-look US examination subsequent to preoperative breast MRI in patients with breast cancer, the ABVS is a more efficient modality than handheld US for preoperative evaluations. However, both techniques have limitations in detecting nonmass lesions.