Publications by authors named "Manho Kim"

228 Publications

Tolerability of lacosamide rapid dose titration: A randomized, multicenter, prospective, open-label study.

Epilepsy Behav 2021 Feb 17;115:107663. Epub 2020 Dec 17.

Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea. Electronic address:

Objective: Currently recommended dosing of lacosamide often necessitates long titration periods. However, the use of a regimen consisting of initial loading dose of 200 mg followed by a maintenance dose of 200 mg/day in practice suggests tolerability of more rapid titration schedules. We aimed to clarify whether the shortened titration schedule affects tolerability of lacosamide.

Methods: We evaluated the safety of two rapid titration protocols designed to reach the target dose of 400 mg/day within 1 week, and the conventional weekly titration protocol (reaching the target dose of 400 mg/day in three weeks). The ≥50% responder rate and steady-state plasma concentration of lacosamide were also analyzed. Adverse events were assessed at 1 week and 5 weeks after reaching the target dose.

Results: Seventy-five patients with epilepsy were enrolled and evenly distributed to three titration protocols, from which 5 patients were lost to follow-up and excluded from the safety analysis. Discontinuation of lacosamide or dose reductions due to adverse events occurred in 32 patients (46%), of whom a large majority (74%) had experienced adverse events after reaching 400 mg/day, demonstrating apparent dose-dependency. There was no difference in safety outcomes among the three titration groups. Concomitant use of sodium channel blockers significantly increased the risk of adverse events.

Conclusion: Rapid titration protocols for lacosamide were not associated with an increased risk of adverse events compared to the conventional weekly titration protocol. Uptitration of lacosamide at shorter intervals to an effective target dosage may be feasible in appropriate clinical situations.
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http://dx.doi.org/10.1016/j.yebeh.2020.107663DOI Listing
February 2021

Two-weeks repeated-dose oral toxicity study of Pediococcus acidilactici J9 in a mice model.

BMC Microbiol 2020 12 9;20(1):372. Epub 2020 Dec 9.

Department of Neurology, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.

Background: Helicobacter pylori (H. pylori) is an important pathogen that causes chronic gastritis and peptic ulcer, and is related to the development of gastric carcinoma. Several chemicals, including antibiotics, have been used to eradicate H.pylori. However, more studies are yet requred to accomplish a sufficient therapy. Pediococcus acidilactici (P. acidilactici) J9 were studied for inhibition of binding of H.pylori binding to human gastric cell lines. This study was performed in order to investigate the repeated-dose toxicity of P. acidilactici J9 in male and female mice.

Results: C57BL/6 male and female Mus musculus were divided into four groups (n = 10 in each group). P. acidilactici J9 was administered daily by oral injection of vehicle control at dosage levels to a low-dose group (500 mg/kg/day), middle-dose group (1000 mg/kg/day), and high-dose group (2000 mg/kg/day) for 2 weeks. After 14 days of exposure, the blood biochemistry and hematology were investigated, along with a histopathology exam. There were no bacterial-related deaths or abnormal clinical signs in either gender of mouse. The data was observed during the period in terms of body weight, food intake, and water consumption. Also, no alterations in organ weights upon administration of P. acidilactici J9 alone were observed. The adhesion and growth of H. pylori were inhibited by a 24 h treatment of H. pylori and P. acidilactici J9 on adenocarcinoma gastric (AGS) cells, which are gastric cancer cells. Compared to the control group (AGS cell and H. pylori), the number of H. pylori analyzed by FACS significantly (p < 0.01) decreased after incubation of AGS cell with P. acidilactici J9 for 24 h.

Conclusions: These results suggest that the oral application of P. acidilactici J9, up to a dosage level of 2000 mg/kg/day, causes no adverse effects in both male and female mice. P. acidilactici J9 inhibits the adhesion of H.pylori to AGS cancer cells. When used as probiotics, P. acidilactici J9 may help decrease the occurrence of gastritis and reduce the risk of H.pylori infection with promising safety issues.
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http://dx.doi.org/10.1186/s12866-020-02055-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727177PMC
December 2020

Effect of desalted Salicornia europaea L. ethanol extract (PM-EE) on the subjects complaining memory dysfunction without dementia: a 12 week, randomized, double-blind, placebo-controlled clinical trial.

Sci Rep 2020 11 16;10(1):19914. Epub 2020 Nov 16.

Department of Neurology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.

Desalted Salicornia europaea L. (SE) inhibits acetylcholine esterase, attenuates oxidative stress and inflammatory cytokines, and activates neurotrophic pathway. We performed 12-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy of PhytoMeal(a desalted SE)-ethanol extract (PM-EE), in improving the cognitive performance in patients with subjective memory impairment. 63 participants complaining memory dysfunction without dementia (Korean Mini-Mental State Examination [K-MMSE] score ≥ 23) were assigned to PM-EE 600 mg/day or placebo. The cognitive domain of the Alzheimer's disease assessment scale-Korean version (ADAS-K) was set as the primary outcome. After 12 weeks, there was no differences in the changes in the primary outcome or the frequency of adverse events between the groups. In the subgroup analysis for the 30 subjects with mild cognitive impairment (MCI, baseline K-MMSE scores ≤ 28), PM-EE significantly improved the color-reading score of the Korean color-word stroop test (8.2 ± 25.0 vs. - 4.7 ± 13.2, P = 0.018). Our findings suggest that PM-EE is safe but might not be effective in this setting of this study. However, PM-EE may improve the frontal executive function in the patients with MCI. Further large-sized studies with longer follow-up period is warranted (trial registration number KCT0003418).
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http://dx.doi.org/10.1038/s41598-020-76938-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670404PMC
November 2020

Nonrapid eye movement sleep electroencephalographic oscillations in idiopathic rapid eye movement sleep behavior disorder: a study of sleep spindles and slow oscillations.

Sleep 2021 Feb;44(2)

Department of Neurology, Seoul National University Hospital, Seoul, South Korea.

Study Objectives: We investigated electroencephalographic (EEG) slow oscillations (SOs), sleep spindles (SSs), and their temporal coordination during nonrapid eye movement (NREM) sleep in patients with idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD).

Methods: We analyzed 16 patients with video-polysomnography-confirmed iRBD (age, 65.4 ± 6.6 years; male, 87.5%) and 10 controls (age, 62.3 ± 7.5 years; male, 70%). SSs and SOs were automatically detected during stage N2 and N3. We analyzed their characteristics, including density, frequency, duration, and amplitude. We additionally identified SO-locked spindles and examined their phase distribution and phase locking with the corresponding SO. For inter-group comparisons, we used the independent samples t-test or Wilcoxon rank-sum test, as appropriate.

Results: The SOs of iRBD patients had significantly lower amplitude, longer duration (p = 0.005 for both), and shallower slope (p < 0.001) than those of controls. The SS power of iRBD patients was significantly lower than that of controls (p = 0.002), although spindle density did not differ significantly. Furthermore, SO-locked spindles of iRBD patients prematurely occurred during the down-to-up-state transition of SOs, whereas those of controls occurred at the up-state peak of SOs (p = 0.009). The phase of SO-locked spindles showed a positive correlation with delayed recall subscores (p = 0.005) but not with tonic or phasic electromyography activity during REM sleep.

Conclusions: In this study, we found abnormal EEG oscillations during NREM sleep in patients with iRBD. The impaired temporal coupling between SOs and SSs may reflect early neurodegenerative changes in iRBD.
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http://dx.doi.org/10.1093/sleep/zsaa160DOI Listing
February 2021

Echocardiographic index E/e' in association with cerebral white matter hyperintensity progression.

PLoS One 2020 27;15(7):e0236473. Epub 2020 Jul 27.

Department of Neurology, The Armed Forces Capital Hospital, Seongnam-si, Gyeonggi-do, South Korea.

Cerebral white-matter hyperintensities (WMHs) on MRI is associated with reduced compliance of the cerebral arterioles. We hypothesized that an echocardiography index for left ventricular (LV) diastolic function, E/e', might reflect the cerebral arteriolar compliance and evaluated the association between E/e' and long-term progression rate of the cerebral WMH volume. This retrospective study included individuals who were ≥ 50 years of age, with a preserved LV ejection fraction (≥ 50%) and neurological function status (modified Rankin scale score ≤1), and underwent initial and follow-up MRI evaluations within intervals of 34-45 months. Baseline clinical, laboratory, and echocardiography markers such as ejection fraction, LV mass index, and E/e' were obtained. WMH volume progression rate between the baseline and follow-up MRIs was designated as the outcome factor. 392 individuals (57.1% men; mean age: 66.7±8.4 years) were followed-up for 38.2±3.4 months. The mean WMH volume progression rate was 1.35±2.65 mL/year. The log-transformed value of WMH volume progression rate was linearly associated with the log-transformed E/e' (B coefficient = 0.365; 95% confidence interval [CI] 0.180-0.551; P = 0.001), along with the log-transformed values of baseline WMH volume (B = 0.142; 95% CI 0.106-0.179; P<0.001) and glomerular filtration rate (B = -0.182; 95% CI -0.321-0.044; P = 0.010). Additionally, a subgroup with an E/e' ≥15 exhibited a significantly higher WMH progression rate compared to the subgroups with lower E/e' values (P<0.001), especially in the lower quartiles (quartiles 1 and 2) of the baseline WMH volume. We concluded that echocardiographic marker E/e' is associated with the long-term progression rate of cerebral WMHs in population with preserved LV systolic function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236473PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384642PMC
September 2020

Downregulated miR-18b-5p triggers apoptosis by inhibition of calcium signaling and neuronal cell differentiation in transgenic SOD1 (G93A) mice and SOD1 (G17S and G86S) ALS patients.

Transl Neurodegener 2020 07 1;9(1):23. Epub 2020 Jul 1.

Department of Neurology, Seoul National University Hospital 28 yongon-Dong, Chongno-gu, Seoul, 110-744, Republic of Korea.

Background: MicroRNAs (miRNAs) are endogenous non-coding RNAs that regulate gene expression at the post-transcriptional level and are key modulators in neurodegenerative diseases. Overexpressed miRNAs play an important role in ALS; however, the pathogenic mechanisms of deregulated miRNAs are still unclear.

Methods: We aimed to assess the dysfunction of RNAs or miRNAs in fALS (SOD1 mutations). We compared the RNA-seq of subcellular fractions in NSC-34 WT (hSOD1) and MT (hSOD1 (G93A)) cells to find altered RNAs or miRNAs. We identified that Hif1α and Mef2c were upregulated, and Mctp1 and Rarb were downregulated in the cytoplasm of NSC-34 MT cells.

Results: SOD1 mutations decreased the level of miR-18b-5p. Induced Hif1α which is the target for miR-18b increased Mef2c expression as a transcription factor. Mef2c upregulated miR-206 as a transcription factor. Inhibition of Mctp1 and Rarb which are targets of miR-206 induces intracellular Ca levels and reduces cell differentiation, respectively. We confirmed that miR-18b-5p pathway was also observed in G93A Tg, fALS (G86S) patient, and iPSC-derived motor neurons from fALS (G17S) patient.

Conclusions: Our data indicate that SOD1 mutation decreases miR-18b-5p, which sequentially regulates Hif1α, Mef2c, miR-206, Mctp1 and Rarb in fALS-linked SOD1 mutation. These results provide new insights into the downregulation of miR-18b-5p dependent pathogenic mechanisms of ALS.
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http://dx.doi.org/10.1186/s40035-020-00203-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328278PMC
July 2020

Usefulness of saliva for perampanel therapeutic drug monitoring.

Epilepsia 2020 06 7;61(6):1120-1128. Epub 2020 May 7.

Department of Neurology, Seoul National University Hospital, Seoul, South Korea.

Objective: Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) helps optimize drug management for patients with epilepsy. Salivary testing is both noninvasive and easy, and has several other advantages. Due to technical advances, salivary TDM has become feasible for several drugs, including AEDs, and its value has been investigated. Until recently, saliva TDM of perampanel (PER) had not been reported. The purpose of our study was to confirm whether saliva is a biological substitute for plasma in PER TDM.

Methods: Adult patients diagnosed with epilepsy who received PER from August 2018 to March 2019 at Seoul National University Hospital were enrolled. Total and free PER were measured in simultaneously obtained plasma and saliva samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-performance liquid chromatographic (HPLC). We examined the correlations between saliva and plasma PER concentrations and whether the use of concomitant medications classified as cytochrome P450 (CYP)3A4 inducers affected the correlations.

Results: Thirty patients were enrolled, aged 16 to 60; 10 (33%) were women. Patients received 2 to 12 mg (mean, 6 mg) of PER. The average total and free concentrations of PER were 343.02 (46.6-818.0) and 1.53 (0.51-2.92) ng/mL in plasma and 9.74 (2.21-33.0) and 2.83 (1.01-6.8) ng/mL in saliva, respectively. A linear relationship was observed between the total PER concentrations in saliva and the total and free PER concentrations in plasma (both P < .001; r = .678 and r = .619, respectively). The change in the PER concentration caused by the CYP3A4 inducer did not affect the correlation between saliva and plasma concentrations (all P < .001).

Significance: The PER concentration in saliva was correlated with that in plasma. This correlation was not affected by CYP3A4 inducers. Our results demonstrate for the first time that PER is measurable in saliva and suggest the potential for the clinical application of the saliva PER TDM matrix.
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http://dx.doi.org/10.1111/epi.16513DOI Listing
June 2020

Comorbid Depression Is Associated with a Negative Treatment Response in Idiopathic REM Sleep Behavior Disorder.

J Clin Neurol 2020 Apr;16(2):261-269

Department of Neurology, Seoul National University Hospital, Seoul, Korea.

Background And Purpose: The first-line medications for the symptomatic treatment of rapid eye movement sleep behavior disorder (RBD) are clonazepam and melatonin taken at bedtime. We aimed to identify the association between depression and treatment response in patients with idiopathic RBD (iRBD).

Methods: We reviewed the medical records of 123 consecutive patients (76 males; age, 66.0±7.7 years; and symptom duration, 4.1±4.0 years) with iRBD who were treated with clonazepam and/or melatonin. Clonazepam and melatonin were initially administered at 0.25-0.50 and 2 mg/day, respectively, at bedtime, and the doses were subsequently titrated according to the response of individual patients. Treatment response was defined according to the presence or absence of any improvement in dream-enacting behaviors or unpleasant dreams after treatment.

Results: Forty (32.5%) patients were treated with clonazepam, 56 (45.5%) with melatonin, and 27 (22.0%) with combination therapy. The doses of clonazepam and melatonin at followup were 0.5±0.3 and 2.3±0.7 mg, respectively. Ninety-six (78.0%) patients reported improvement in their RBD symptoms during a mean follow-up period of 17.7 months. After adjusting for potential confounders, depression was significantly associated with a negative treatment response (odds ratio=3.76, 95% confidence interval=1.15-12.32, =0.029).

Conclusions: We found that comorbid depression is significantly associated with a negative response to clonazepam and/or melatonin in patients with iRBD. Further research with larger numbers of patients is needed to verify our observations and to determine the clinical implications of comorbid depression in the pathophysiology of iRBD.
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http://dx.doi.org/10.3988/jcn.2020.16.2.261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174129PMC
April 2020

Altered resting-state thalamo-occipital functional connectivity is associated with cognition in isolated rapid eye movement sleep behavior disorder.

Sleep Med 2020 05 18;69:198-203. Epub 2020 Jan 18.

Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea. Electronic address:

Objective: Isolated rapid eye movement sleep behavior disorder (iRBD) patients are at risk of cognitive impairments, however the underlying mechanism is still unclear. This study aimed to evaluate thalamo-cortical functional connectivity (FC) using resting-state functional magnetic resonance imaging (fMRI) and its correlation with cognitive dysfunction in patients with iRBD.

Methods: A total 37 polysomnographies (PSGs) confirmed iRBD patients and 15 age-sex matched controls underwent resting-state fMRI and comprehensive neuropsychological assessment. Thalamo-cortical FC was evaluated by using seed-to voxel analysis and was compared between the iRBD and controls. Correlation between the average value of significant clusters and cognitive function scores in iRBD were calculated.

Results: Compared to the control subjects, patients with iRBD patients showed cognitive decline in word list recognition (p = 0.016), and constructional recall (p = 0.044). The FC analysis showed increased FC between the left thalamus and occipital regions including the right cuneal cortex, left fusiform gyrus and lingual gyrus (cluster level p < 0.05, corrected for false discovery rate). The averaged thalamo-fusiform FC value positively correlated with word list recognition after adjusting for age and sex (adjusted r = 0.347, p = 0.041).

Conclusion: Thalamic resting state FC is altered in iRBD patients and is associated with the cognitive function. Enhancement of the thalamo-occipital FC may reflect a compensatory mechanism for cognitive impairment in iRBD.
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http://dx.doi.org/10.1016/j.sleep.2020.01.010DOI Listing
May 2020

Efficacy of atomoxetine versus midodrine for neurogenic orthostatic hypotension.

Ann Clin Transl Neurol 2020 01 19;7(1):112-120. Epub 2019 Dec 19.

Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Center for Medical Innovations, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.

Objective: The efficacy and safety of 1-month atomoxetine and midodrine therapies were compared. Three-month atomoxetine and combination therapies were investigated for additional benefits.

Methods: This prospective open-label randomized trial included 50 patients with symptomatic neurogenic orthostatic hypotension (nOH). The patients received either atomoxetine 18 mg daily or midodrine 5 mg twice daily and were evaluated 1 and 3 months later. Those who still met the criteria for nOH at 1 month received both midodrine and atomoxetine for an additional 2 months, and if not, they continued their initial medication. The primary outcome was an improvement in orthostatic blood pressure (BP) drop (maximum BP change from supine to 3 min after standing) at 1 month. The secondary endpoints were symptom scores, percentage of patients with nOH at 1 and 3 months.

Results: Patients with midodrine or atomoxetine treatment showed comparative improvement in the orthostatic BP drop, and overall only 26.2% of the patients had nOH at 1 month, which was similar between the treatment groups. Only atomoxetine resulted in significant symptomatic improvements at 1 month. For those without nOH at 1 month, there was additional symptomatic improvement at 3 months with their initial medication. For those with nOH at 1 month, the combination treatment resulted in no additional improvement. Mild-to-moderate adverse events were reported by 11.6% of the patients.

Interpretation: One-month atomoxetine treatment was effective and safe in nOH patients. Atomoxetine improved orthostatic BP changes as much as midodrine and was better in terms of ameliorating nOH symptoms.
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http://dx.doi.org/10.1002/acn3.50968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952305PMC
January 2020

Periodicity of cerebral flow velocity during sleep and its association with white-matter hyperintensity volume.

Sci Rep 2019 10 29;9(1):15510. Epub 2019 Oct 29.

Department of Neurology, The Armed Forces Capital Hospital, Sungnam, South Korea.

Impaired sleep-related activation of the cerebral waste-clearance system might be related with the brain aging process. We hypothesized that cerebral blood-flow pattern changes during sleep might reflect the activation of the cerebral waste-clearance system and investigated its association with the cerebral white-matter hyperintensity (WMH) volume. Fifty healthy volunteers were prospectively recruited. In addition to the baseline transcranial Doppler parameters, the mean flow velocity (MFV) of the middle cerebral artery was monitored during waking and short-term non-REM sleep. Spectral density analysis was performed to analyze the periodic MFV variation patterns. For the aged subgroup (>50 years, n = 25), the WMH volumes in the total, subcortical, and periventricular regions were measured. The MFV periodic pattern during sleep was substantially augmented over that in the waking status. Spectral density analysis of MFV showed a noticeable peak in the very-low-frequency (VLF) band during sleep status (sleep/waking ratio 2.87 ± 2.71, P < 0.001). In linear regression analysis in the aged subgroup, the sleep/waking ratio of the VLF peak was inversely associated with total (P = 0.013) and subcortical (P = 0.020) WMH volumes. Sleep-related amplification of the cerebral flow-velocity periodicity might reflect the activation of cerebral waste clearance system during sleep, and be related to the pathogenesis of cerebral WMH.
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http://dx.doi.org/10.1038/s41598-019-52029-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820785PMC
October 2019

Rapid diagnosis of bacterial meningitis by nanopore 16S amplicon sequencing: A pilot study.

Int J Med Microbiol 2019 Sep 12;309(6):151338. Epub 2019 Aug 12.

Department of Neurology, Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea. Electronic address:

Early administration of antibiotics is crucial in the management of bacterial meningitis. Rapid pathogen identification helps to make a definite diagnosis of bacterial meningitis and enables tailored antibiotic treatment. We investigated if the 16S amplicon sequencing performed by MinION, a nanopore sequencer, was capable of rapid pathogen identification in bacterial meningitis. Six retrospective cases of confirmed bacterial meningitis and two prospective cases were included. The initial cerebrospinal fluid (CSF) samples of these patients were used for the experiments. DNA was extracted from the CSF, and PCR was performed on the 16S ribosomal DNA (16S rDNA). Sequencing libraries were prepared using the PCR products, and MinION sequencing was performed for up to 3 h. The reads were aligned to the bacterial database, and the results were compared to the conventional culture studies. Pathogenic bacteria were successfully detected from the CSF by 16S sequencing in all retrospective cases. 16S amplicon sequencing was more sensitive than conventional diagnostic tests and worked properly even in antibiotics-treated samples. MinION sequencing significantly reduced the turnaround time, and even 10 min of sequencing was sufficient for pathogen detection in certain cases. Protocol adjustment could further increase the sensitivity and reduce the turnaround time for MinION sequencing. Finally, the prospective application of MinION 16S sequencing was successful. Nanopore 16S amplicon sequencing is capable of rapid bacterial identification from the CSF of the bacterial meningitis patients. It may have many advantages over conventional diagnostic tests and should therefore be applied in a larger number of patients in the future.
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http://dx.doi.org/10.1016/j.ijmm.2019.151338DOI Listing
September 2019

Possible epigenetic regulatory effect of dysregulated circular RNAs in Alzheimer's disease model.

Sci Rep 2019 08 16;9(1):11956. Epub 2019 Aug 16.

Department of Neurology, Comprehensive Epilepsy Center, Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.

As circular RNAs (circRNAs) regulates the effect of micro RNAs (miRNAs), circRNA-miRNA-mRNA network might be implicated in various disease pathogenesis. Therefore, we evaluated the dysregulated circRNAs in the Tg2576 mouse Alzheimer's disease (AD) model, their possible regulatory effects on downstream target mRNAs, and their pathomechanistic role during the disease progression. The microarray-based circRNA expression analysis at seven- and twelve-months of ages (7 M and 12 M) returned 101 dysregulated circRNAs at 7 M (55 up-regulated and 46 down-regulated) and twelve dysregulated circRNAs at 12 M (five up-regulated and seven down-regulated). For each dysregulated circRNA, potential target miRNAs and their downstream target mRNAs were searched. Dysregulation of circRNAs was associated with increased frequency of relevant dysregulation of their downstream target mRNAs. Those differentially expressed circRNA-miRNA-mRNA regulatory network included 2,275 networks (876 for up-regulated circRNAs and 1,399 for down-regulated circRNAs) at 7 M and 38 networks (25 for up-regulated circRNAs and 13 for down-regulated circRNAs) at 12 M. Gene ontology (GO) and pathway analyses demonstrated that the dysregulated mRNAs in those networks represent the AD pathomechanism at each disease stage. We concluded that the dysregulated circRNAs might involve in the AD pathogenesis by modulating disease relevant mRNAs via circRNA-miRNA-mRNA regulatory networks.
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http://dx.doi.org/10.1038/s41598-019-48471-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697677PMC
August 2019

Altered Vascular Permeability in Migraine-associated Brain Regions: Evaluation with Dynamic Contrast-enhanced MRI.

Radiology 2019 09 2;292(3):713-720. Epub 2019 Jul 2.

From the Departments of Radiology (Y.S.K., S.H.C., R.E.Y., K.M.K., T.J.Y.), Neurology (M.K., S.T.L., J.M., Y.W.S.), and Neurosurgery (J.M.), Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea; Department of Radiology (Y.S.K., S.H.C., R.E.Y., K.M.K., T.J.Y.), Neuroscience Research Institute (M.K.), and Protein Metabolism Research Center (M.K.), Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Republic of Korea (S.H.C.); and Department of Radiology, Korea University Anam Hospital, Seoul, Republic of Korea (S.H.Y.).

Background Recent studies showed the possible association between inflammation-induced blood-brain barrier (BBB) structural changes followed by greater permeability of the BBB and chronic pain. Thus, measurement of BBB breakdown would be a valuable aid in the diagnosis in migraine. Dynamic contrast material-enhanced (DCE) MRI can determine perfusion and permeability properties related to the BBB. Purpose To evaluate the relationship between permeability of the BBB in migraine-associated brain regions by using DCE MRI. Materials and Methods In this prospective study, from September 2016 to December 2017, 56 study participants underwent DCE MRI after gadobutrol administration and were classified into migraine ( = 35) and healthy control ( = 21) groups. Automatic volumetric segmentation was performed on the pre-contrast-enhanced T1-weighted images by using FreeSurfer, and migraine-associated brain region masks were extracted by using the software NordicICE. The corresponding maps for pharmacokinetic parameters (the volume transfer constant) and (the fractional plasma volume) were coregistered with the region-of-interest masks, and their mean values of corresponding total volume of interest were calculated. For comparison analyses, the Mann-Whitney tests were used. Receiver operating characteristic curve analysis and Spearman rank correlation tests were used to identify correlations between clinical characteristics and the aforementioned perfusion parameters. Results Mean age was younger in the migraine group (mean ± standard deviation, 57 years ± 12) than in the healthy control group (mean, 71 years ± 8) ( < .001). In the migraine group, the mean value of in the left amygdala (median, 0.27 mL/100 g) was lower than that in the healthy control group (median, 0.39 mL/100 g) ( = .04). The mean value of in the left amygdala was correlated with the intensity of headache attack in participants with migraine (correlation coefficient, -0.34; = .04). Conclusion Lower fractional plasma volume in the left amygdala was observed in participants with migraine than in healthy participants. © RSNA, 2019 See also the editorial by Carroll and Ginat in this issue.
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http://dx.doi.org/10.1148/radiol.2019182566DOI Listing
September 2019

The Efficacy of Shinbaro for the Preventive Treatment of Migraine: A Pilot Study.

Evid Based Complement Alternat Med 2019 13;2019:2363420. Epub 2019 May 13.

Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea.

Objective: To investigate the therapeutic potential and efficacy of Shinbaro, an herbal medication for inflammatory diseases and bone disorders, as a preventive treatment of migraine.

Methods: In this prospective, interventional, single-arm, pre-post study, 37 migraine patients took 600mg bid of Shinbaro for 12 weeks. At 4-week intervals, the migraine frequency and the rescue medications frequency were measured from each patient's headache diary. The modified Migraine Disability Assessment (MIDAS) questionnaires to assess migraine associated disabilities were also completed at each visit. The serum calcitonin gene-related peptide (CGRP) concentrations before and after 12 weeks of Shinbaro administration were compared.

Results: The monthly migraine frequency was significantly reduced from 20.5 days at baseline to 16.4 days at week 12 ( =0.003), and 22% of the participants showed ≥ 50% reduction. The frequency reduction was observed by week 4 ( =0.035) and continuously occurred through week 8 ( =0.001) and week 12 ( =0.003). The rescue medications frequency also decreased significantly from 17.4 days at baseline to 13.2 days at week 12 ( =0.035). Lastly, the serum CGRP concentration dropped from 434.6 pg/mL at baseline to 371.4 pg/mL at week 12, which was statistically significant ( <0.001).

Conclusions: Shinbaro demonstrated prophylactic effects in migraine patients, significantly reducing their mean migraine frequency, rescue medications frequency, and the serum CGRP concentration after 12 weeks of treatment. This study is registered in Clinical Research Information Service, Seoul National University Hospital Clinical Research Institute (IRB No. 1604-138-758).
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http://dx.doi.org/10.1155/2019/2363420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545806PMC
May 2019

Human leukocyte antigen associations in postural tachycardia syndrome.

Ann Clin Transl Neurol 2019 May 4;6(5):962-967. Epub 2019 Apr 4.

Department of Neurology Laboratory for Neurotherapeutics Biomedical Research Institute Seoul National University Hospital Seoul South Korea.

Associations between human leukocyte antigen (HLA) and postural orthostatic tachycardia syndrome (POTS) have not been investigated. We included patients diagnosed with POTS and showing orthostatic heart rate increases ≥ 50 during orthostatic vital sign measurement or experiencing syncope/near-syncope while standing (prominent POTS;  = 17). DQB1*06:09 was present in seven (41%) patients, a significantly higher percentage than in healthy Koreans (7%; odds ratio [OR] 8.7, 95% confidence interval [CI] 3.1-24.3, corrected  = 3.2 × 10) and epilepsy controls (8%; OR 7.9, 95% CI 2.7-23.5, corrected  = 3.2 × 10). Six (35.3%) carried the A*33:03-B*58:01-C*03:02-DRB1*13:02-DQB1*06:09 haplotype. The results signify an autoimmune etiology in prominent POTS.
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http://dx.doi.org/10.1002/acn3.766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529927PMC
May 2019

Increasing prevalence of antimicrobial resistance in urinary tract infections of neurological patients, Seoul, South Korea, 2007-2016.

Int J Infect Dis 2019 Jul 8;84:109-115. Epub 2019 May 8.

Department of Neurology, Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea. Electronic address:

Objectives: Urinary tract infection (UTI) is a common medical complication experienced by patients with neurologic diseases. In this study, we established the microbial etiologies of UTI, and resistances to antibiotics in UTI as well as determining which appropriate empirical antibiotics should be used to treat UTI in neurological patients.

Designs And Methods: We retrospectively reviewed microbial etiologies and antimicrobial resistance among patients experiencing UTI events in the neurology ward of Seoul National University Hospital from 2007 to 2016.

Results: The total number of UTI events observed was 301, and Klebsiella pneumoniae was the most common pathogen observed in UTIs. But in catheter-associated UTI (CAUTI), Enterococcus species were the most prevalent pathogens. Susceptibility to commonly-prescribed antibiotics decreased over 10 years, indicating increased antibiotic resistance in pathogens associated with UTI. ESBL-producing K. pneumoniae increased significantly, while increases of MDR K. pneumoniae, ESBL-producing E. coli, and VRE were not observed.

Conclusions: The worldwide trend of increasing drug-resistant pathogens should be considered, and further studies on antibiotics resistance in UTI are needed. These data will greatly assist physicians when they select antibiotics to treat UTIs in neurological patients.
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http://dx.doi.org/10.1016/j.ijid.2019.05.002DOI Listing
July 2019

Prolonged-release melatonin in patients with idiopathic REM sleep behavior disorder.

Ann Clin Transl Neurol 2019 Apr 7;6(4):716-722. Epub 2019 Mar 7.

Department of Neurology Seoul National University Hospital Seoul Republic of Korea.

Objective: We investigated the effects of prolonged-release melatonin (PRM) on idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD).

Methods: In this 4-week, randomized, double-blind, placebo-controlled pilot study, 30 participants with polysomnography-confirmed iRBD were assigned to receive PRM 2 mg per day, PRM 6 mg per day, or placebo. Medication was administered orally 30 min before bedtime. Primary outcomes included scores from the Clinical Global Impression-Improvement (CGI-I) and the Korean version of the RBD questionnaire-Hong Kong (RBDQ-KR). The secondary outcomes included RBDQ-KR factor 1 and factor 2 subscores, the Pittsburgh Sleep Quality Index score, the Epworth Sleepiness Scale score, the Short Form Health Survey version 2 score, and the frequency of dream-enacting behaviors assessed using a sleep diary.

Results: After 4 weeks, there were no differences in the proportions of patients with a CGI-I score of much improved or very much improved among the study groups. In addition, RBDQ-KR scores and secondary outcomes were not improved in all groups at 4 weeks, and there were no differences between the groups.

Conclusion: Our findings suggest that PRM may not be effective in treating RBD-related symptoms within the dose range used in this study. Further studies using doses higher than 6 mg per day are warranted.
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http://dx.doi.org/10.1002/acn3.753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469244PMC
April 2019

iNKT Cell Activation Exacerbates the Development of Huntington's Disease in R6/2 Transgenic Mice.

Mediators Inflamm 2019 15;2019:3540974. Epub 2019 Jan 15.

Department of Integrative Bioscience and Biotechnology, Institute of Anticancer Medicine Development, Sejong University, Seoul 05006, Republic of Korea.

Huntington's disease (HD) is an inherited neurodegenerative disorder which is caused by a mutation of the huntingtin (HTT) gene. Although the pathogenesis of HD has been associated with inflammatory responses, if and how the immune system contributes to the onset of HD is largely unknown. Invariant natural killer T (iNKT) cells are a group of innate-like regulatory T lymphocytes that can rapidly produce various cytokines such as IFN and IL4 upon stimulation with the glycolipid -galactosylceramide (-GalCer). By employing both R6/2 Tg mice (murine HD model) and J18 KO mice (deficient in iNKT cells), we investigated whether alterations of iNKT cells affect the development of HD in R6/2 Tg mice. We found that J18 KO R6/2 Tg mice showed disease progression comparable to R6/2 Tg mice, indicating that the absence of iNKT cells did not have any significant effects on HD development. However, repeated activation of iNKT cells with -GalCer facilitated HD progression in R6/2 Tg mice, and this was associated with increased infiltration of iNKT cells in the brain. Taken together, our results demonstrate that repeated -GalCer treatment of R6/2 Tg mice accelerates HD progression, suggesting that immune activation can affect the severity of HD pathogenesis.
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http://dx.doi.org/10.1155/2019/3540974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350536PMC
August 2019

Pneumonia in hospitalized neurologic patients: trends in pathogen distribution and antibiotic susceptibility.

Antimicrob Resist Infect Control 2019 1;8:25. Epub 2019 Feb 1.

1Department of Neurology, Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744 South Korea.

Background: Bed-ridden state, dysphagia, altered mental state, or respiratory muscle weakness are common in neurologic patients and increase the risk of pneumonia. The major causes of pneumonia in neurologic patients may differ from those in the general population, resulting in a different pathogen distribution. We investigated the trends of pathogen distribution in culture-positive pneumonia in hospitalized neurologic patients and the related antibiotic resistance in those with hospital-acquired pneumonia (HAP).

Methods: A retrospective study was performed at Seoul National University Hospital, South Korea. Patients admitted to the Department of Neurology with a positive respiratory specimen culture between 2007 and 2016 were included. Pneumonia events in patients were screened by chronologically associating the date of respiratory specimen acquisition for culture studies and the date of antibiotics administration. Subgroup analyses regarding multidrug resistance in HAP were performed in different pneumonia categories, by presence of ≥1 risk factor and by time period (first half vs. second half of study period). Microbial resistance profiles of isolates from patients with pneumonia were analyzed.

Results: We identified 351 pneumonia cases in 227 patients involving 36 different pathogens. 232 cases were HAP, of which 70 cases were intensive care unit (ICU)-HAP. The leading pathogens were , , , , and which were isolated in 133 (37.9%), 72 (20.5%), 55 (15.7%), 44 (12.5%), 33 (9.4%), and 27 (7.7%) cases, respectively. Cases with HAP showed a higher proportion of and a lower proportion of (both,  < 0.05) than those with non-HAP. ICU-HAP isolates showed a higher multidrug resistance (MDR) rate than non-ICU-HAP isolates ( < 0.005) in those with ≥1 MDR risk factor. Non-susceptibility to imipenem ( < 0.0005), piperacillin-tazobactam ( < 0.001), cefepime ( < 0.005), and trimethoprim-sulfamethoxazole ( < 0.05) in Gram-negative pathogens increased over time in both ICU and non-ICU settings.

Conclusions: , , , , and were the leading isolates in culture-positive pneumonia in hospitalized neurologic patients. Antimicrobial resistance of Gram-negative pathogens in neurologic patients with culture-positive HAP has recently increased.
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http://dx.doi.org/10.1186/s13756-019-0475-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359823PMC
March 2020

Development of the clinical assessment scale in autoimmune encephalitis.

Ann Neurol 2019 03 10;85(3):352-358. Epub 2019 Feb 10.

Department of Neurology, Seoul National University Hospital, Seoul, South Korea.

Objective: There is no scale for rating the severity of autoimmune encephalitis (AE). In this study, we aimed to develop a novel scale for rating severity in patients with diverse AE syndromes and to verify the reliability and validity of the developed scale.

Methods: The key items were generated by a panel of experts and selected according to content validity ratios. The developed scale was initially applied to 50 patients with AE (development cohort) to evaluate its acceptability, reproducibility, internal consistency, and construct validity. Then, the scale was applied to another independent cohort (validation cohort, n = 38).

Results: A new scale consisting of 9 items (seizure, memory dysfunction, psychiatric symptoms, consciousness, language problems, dyskinesia/dystonia, gait instability and ataxia, brainstem dysfunction, and weakness) was developed. Each item was assigned a value of up to 3 points. The total score could therefore range from 0 to 27. We named the scale the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). The new scale showed excellent interobserver (intraclass correlation coefficient [ICC] = 0.97) and intraobserver (ICC = 0.96) reliability for total scores, was highly correlated with modified Rankin scale (r = 0.86, p < 0.001), and had acceptable internal consistency (Cronbach α = 0.88). Additionally, in the validation cohort, the scale showed high interobserver reliability (ICC = 0.99) and internal consistency (Cronbach α = 0.92).

Interpretation: CASE is a novel clinical scale for AE with a high level of clinimetric properties. It would be suitable for application in clinical practice and might help overcome the limitations of current outcome scales for AE. ANN NEUROL 2019;85:352-358.
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http://dx.doi.org/10.1002/ana.25421DOI Listing
March 2019

Possible epigenetic regulatory effect of dysregulated circular RNAs in epilepsy.

PLoS One 2018 28;13(12):e0209829. Epub 2018 Dec 28.

Department of Neurology, Comprehensive Epilepsy Center, Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.

Circular RNAs (circRNAs) involve in the epigenetic regulation and its major mechanism is the sequestration of the target micro RNAs (miRNAs). We hypothesized that circRNAs might be related with the pathophysiology of chronic epilepsy and evaluated the altered circRNA expressions and their possible regulatory effects on their target miRNAs and mRNAs in a mouse epilepsy model. The circRNA expression profile in the hippocampus of the pilocarpine mice was analyzed and compared with control. The correlation between the expression of miRNA binding sites (miRNA response elements, MRE) in the dysregulated circRNAs and the expression of their target miRNAs was evaluated. As miRNAs also inhibit their target mRNAs, circRNA-miRNA-mRNA regulatory network, comprised of dysregulated RNAs that targets one another were searched. For the identified networks, bioinformatics analyses were performed. As the result, Forty-three circRNAs were dysregulated in the hippocampus (up-regulated, 26; down-regulated, 17). The change in the expression of MRE in those circRNAs negatively correlated with the change in the relevant target miRNA expression (r = -0.461, P<0.001), supporting that circRNAs inhibit their target miRNA. 333 dysregulated circRNA-miRNA-mRNA networks were identified. Gene ontology and pathway analyses demonstrated that the up-regulated mRNAs in those networks were closely related to the major processes in epilepsy. Among them, STRING analysis identified 37 key mRNAs with abundant (≥4) interactions with other dysregulated target mRNAs. The dysregulation of the circRNAs which had multiple interactions with key mRNAs were validated by PCR. We concluded that dysregulated circRNAs might have a pathophysiologic role in chronic epilepsy by regulating multiple disease relevant mRNAs via circRNA-miRNA-mRNA interactions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209829PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310357PMC
June 2019

Repeated immune activation with low-dose lipopolysaccharide attenuates the severity of Huntington's disease in R6/2 transgenic mice.

Anim Cells Syst (Seoul) 2018 20;22(4):219-226. Epub 2018 Jun 20.

Department of Integrative Bioscience and Biotechnology, Institute of Anticancer Medicine Development, Sejong University, Seoul, Korea.

Huntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the huntingtin gene. Previously, therapeutic approaches using anti-inflammatory agents were reportedly not effective for preventing HD progression. Since whether immune responses contribute to the onset of HD is not entirely understood, we herein investigated the role of immune activation in HD using the R6/2 transgenic (Tg) HD model mouse. IL12 production and the expression of costimulatory molecules (e.g. CD86 and CD40) on innate immune cells (DCs and macrophages) were diminished in the disease stage of R6/2 Tg mice. Moreover, the number of adaptive T cells (CD4 and CD8 T cells) and the frequency of effector memory phenotype CD4 T cells were decreased in these mice. These results suggest that the severity of HD is closely related to an impaired immune system and might be reversed by activation of the immune system. Since lipopolysaccharide (LPS), a potent TLR4 agonist, activates immune cells, we evaluated the effect of immune activation on the pathogenesis of HD using LPS. The repeated immune activation with low-dose LPS significantly recovered the impaired immune status back to normal levels and attenuated both severe weight loss and the increased clasping phenotype found in the disease stage of R6/2 Tg mice, consequently resulting in prolonged survival. Taken together, these results strongly indicate that immune activation has beneficial influences on alleviating HD pathology and could provide new therapeutic strategies for HD.
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http://dx.doi.org/10.1080/19768354.2018.1473291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138304PMC
June 2018

Abnormal activation of motor cortical network during phasic REM sleep in idiopathic REM sleep behavior disorder.

Sleep 2019 02;42(2)

Department of Neurology, Seoul National University Hospital, Seoul, South Korea.

Study Objectives: We investigated electroencephalography (EEG) power spectral density and functional connectivity during phasic and tonic rapid eye movement (REM) sleep, and examined any differences between patients with idiopathic REM sleep behavior disorder (iRBD) and controls.

Methods: EEG data from 13 people with iRBD (mean age, 66.3 years; men, 84.6%) and 10 controls (mean age, 62.3 years; men, 70%) were analyzed. We selected thirty 3 s miniepochs of both tonic and phasic REM sleep. We estimated relative power for six frequency bands. For functional connectivity analysis, we calculated weighted phase lag index (wPLI) and conducted pairwise comparisons between the two groups.

Results: EEG power spectral analysis revealed significant interactions between the REM sleep state (phasic vs. tonic) and group at sigma (p = 0.009) and beta (p = 0.002) bands. Sigma- and beta-power decrease during phasic REM sleep was more pronounced and extensive in people with iRBD than in controls. Regarding functional connectivity, there were significant interactions between the REM sleep state and group at alpha (p = 0.029), sigma (p = 0.047), beta (p = 0.015), and gamma (p = 0.046) bands. The average wPLI was significantly higher during phasic REM sleep than during tonic REM sleep, which was observed in people with iRBD but not in controls. The altered functional connections mainly involved the frontal and parietal regions at beta and gamma bands.

Conclusions: Our findings provide neurophysiological evidence for pathological motor cortex activation during phasic REM sleep which may be associated with generation of dream-enacting behaviors in iRBD.
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http://dx.doi.org/10.1093/sleep/zsy227DOI Listing
February 2019

Maternal immune activation alters brain microRNA expression in mouse offspring.

Ann Clin Transl Neurol 2018 Oct 19;5(10):1264-1276. Epub 2018 Sep 19.

Laboratory for Neurotherapeutics Department of Neurology Comprehensive Epilepsy Center Biomedical Research Institute Seoul National University Hospital Seoul South Korea.

Objective: Maternal immune activation (MIA) is associated with an increased risk of autism spectrum disorder (ASD) in offspring. Herein, we investigate the altered expression of microRNAs (miRNA), and that of their target genes, in the brains of MIA mouse offspring.

Methods: To generate MIA model mice, pregnant mice were injected with polyriboinosinic:polyribocytidylic acid on embryonic day 12.5. We performed miRNA microarray and mRNA sequencing in order to determine the differential expression of miRNA and mRNA between MIA mice and controls, at 3 weeks of age. We further identified predicted target genes of dysregulated miRNAs, and miRNA-target interactions, based on the inverse correlation of their expression levels.

Results: Mice prenatally subjected to MIA exhibited behavioral abnormalities typical of ASD, such as a lack of preference for social novelty and reduced prepulse inhibition. We found 29 differentially expressed miRNAs (8 upregulated and 21 downregulated) and 758 differentially expressed mRNAs (542 upregulated and 216 downregulated) in MIA offspring compared to controls. Based on expression levels of the predicted target genes, 18 downregulated miRNAs (340 target genes) and three upregulated miRNAs (60 target genes) were found to be significantly enriched among the differentially expressed genes. miRNA and target gene interactions were most significant between mmu-miR-466i-3p and (ATP-dependent DNA helicase homolog), and between mmu-miR-877-3p and (aquaporin 6).

Interpretation: Our results provide novel information regarding miRNA expression changes and their putative targets in the early postnatal period of brain development. Further studies will be needed to evaluate potential pathogenic roles of the dysregulated miRNAs.
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http://dx.doi.org/10.1002/acn3.652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186947PMC
October 2018

ginseng as an adjuvant treatment for Alzheimer's disease.

J Ginseng Res 2018 Oct 12;42(4):401-411. Epub 2018 Jan 12.

Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea.

Longevity in medicine can be defined as a long life without mental or physical deficits. This can be prevented by Alzheimer's disease (AD). Current conventional AD treatments only alleviate the symptoms without reversing AD progression. Recent studies demonstrated that ginseng extract improves AD symptoms in patients with AD, and the two main components of ginseng might contribute to AD amelioration. Ginsenosides show various AD-related neuroprotective effects. Gintonin is a newly identified ginseng constituent that contains lysophosphatidic acids and attenuates AD-related brain neuropathies. Ginsenosides decrease amyloid β-protein (Aβ) formation by inhibiting β- and γ-secretase activity or by activating the nonamyloidogenic pathway, inhibit acetylcholinesterase activity and Aβ-induced neurotoxicity, and decrease Aβ-induced production of reactive oxygen species and neuroinflammatory reactions. Oral administration of ginsenosides increases the expression levels of enzymes involved in acetylcholine synthesis in the brain and alleviates Aβ-induced cholinergic deficits in AD models. Similarly, gintonin inhibits Aβ-induced neurotoxicity and activates the nonamyloidogenic pathway to reduce Aβ formation and to increase acetylcholine and choline acetyltransferase expression in the brain through lysophosphatidic acid receptors. Oral administration of gintonin attenuates brain amyloid plaque deposits, boosting hippocampal cholinergic systems and neurogenesis, thereby ameliorating learning and memory impairments. It also improves cognitive functions in patients with AD. Ginsenosides and gintonin attenuate AD-related neuropathology through multiple routes. This review focuses research demonstrating that ginseng constituents could be a candidate as an adjuvant for AD treatment. However, clinical investigations including efficacy and tolerability analyses may be necessary for the clinical acceptance of ginseng components in combination with conventional AD drugs.
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http://dx.doi.org/10.1016/j.jgr.2017.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190533PMC
October 2018

Increased adverse events associated with antiepileptic drugs in anti-leucine-rich glioma-inactivated protein 1 encephalitis.

Epilepsia 2018 10 29;59 Suppl 2:108-112. Epub 2018 Aug 29.

Department of Neurology, Comprehensive Epilepsy Center, Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, South Korea.

Anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis is a rare autoimmune condition presenting mainly as altered mental state, cognitive dysfunction, and seizure. Antiepileptic drugs (AEDs) are usually initiated to control seizures despite their limited efficacy; however, accumulating clinical experience suggests a high incidence of adverse reactions to AEDs in anti-LGI1 encephalitis. We reviewed the medical records of patients who were diagnosed with anti-LGI1 encephalitis to analyze the adverse effects of AEDs in these patients. Among the 20 patients who were treated with AEDs, 10 (50%) changed their AEDs due to adverse cutaneous drug reaction. Eight of them presented with maculopapular eruption, one with drug rash with eosinophilia and systemic symptoms syndrome, and one with eczema. Causative agents mostly consisted of aromatic AEDs. Oxcarbazepine was discontinued in two additional patients due to hyponatremia. Six patients (30%) discontinued their dose of levetiracetam because of psychiatric manifestations including irritability/aggressive behavior (four patients), insomnia (one patient), and depressive mood (one patient). Clinicians should consider adverse cutaneous drug reaction, psychiatric adverse events, and hyponatremia when selecting AEDs for the treatment of anti-LGI1 encephalitis.
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http://dx.doi.org/10.1111/epi.14490DOI Listing
October 2018

Delayed orthostatic hypotension: Severity of clinical symptoms and response to medical treatment.

Auton Neurosci 2018 Sep 28;213:81-85. Epub 2018 Jun 28.

Department of Neurology, Laboratory for Neurotherapeutics, Comprehensive Epilepsy Center, Center for Medical Innovations, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea; Program in Neuroscience, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address:

Introduction: Severity of orthostatic intolerance and the benefit of medical treatment in patients with delayed OH have not been elucidated. This study aimed to compare the symptom severity between classic and delayed OH and evaluate the efficacy of midodrine or pyridostigmine in patients with delayed OH.

Methods: This was an adjunctive study of previously reported randomized, open-label clinical trials evaluating the efficacy and safety of midodrine or pyridostigmine for classic OH. Seventeen patients with delayed OH were enrolled and also received midodrine (2.5 mg twice a day) or pyridostigmine (30 mg twice a day) alone or combined. Result of initial orthostatic vital sign and questionnaires were compared between the patients with delayed OH and previously reported 87 patients with classic OH. Delayed OH patients were followed up at 1 and 3 months post-treatment and the vital sign measurements and questionnaires were repeated during the follow-up period.

Results: Questionnaire scores regarding OH-related symptoms, depression and health-related quality of life (HRQOL) were comparable between the classic and delayed OH patients at baseline. OH-related symptoms and depression were significantly improved after 3 months of medical treatment.

Conclusion: Patients with delayed OH exhibited orthostatic intolerance similar to that of classic OH. This study shows that these patients may benefit from medical treatment with either midodrine or pyridostigmine.
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http://dx.doi.org/10.1016/j.autneu.2018.06.005DOI Listing
September 2018