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Rapid eye movement sleep behavior disorder (RBD) is a parasomnia characterized by loss of muscle atonia during rapid eye movement sleep, associated with complex motor enactment of dreams. Obstructive sleep apnea (OSA) is a relatively common sleep disorder characterized by repetitive episodes of upper airway obstruction while sleeping, which can result in hypoxemia and sleep fragmentation. Even though the nature of RBD and OSA is different, OSA may sometimes be accompanied by RBD symptoms. Accordingly, it is reasonable to distinguish these 2 sleep disorders in people with dream enactment behaviors. Although RBD and OSA share similar sleep phenomena, their association has yet to be elucidated. Herein we draw attention to various RBD-mimicking conditions, RBD combined with OSA, and the relationship between RBD and OSA. Furthermore, the clinical implications of OSA in neurodegeneration and the optimized management of RBD combined with OSA are also discussed in this review. CITATION: Jung YJ, Oh E. Is REM sleep behavior disorder a friend or foe of obstructive sleep apnea? Clinical and etiological implications for neurodegeneration. J Clin Sleep Med. 2021;17(6):1305–1312.

Heat shock proteins (HSPs) play an essential role as molecular chaperones to prevent abnormal protein aggregation and misfolding. Moreover, they protect dopamine neurons from oxidative stress, inflammation, and apoptosis, all well-known pathomechanisms of Parkinson's disease (PD). Melatonin is a potent antioxidant that has the beneficial ability to prevent neurodegenerative diseases like PD. We aimed to explore the protective properties of melatonin in an in vitro PD model, focusing on its underlying mechanism using HSPs. A 1-methyl-4-phenylpyridimium (MPP+)-induced toxin model was established with retinoic acid (RA)-differentiated SH-SY5Y cells. Cell viability and apoptosis were measured using MTT and DAPI. Intracellular reactive oxygen species (ROS) levels were measured by the cell-permeant fluorescent probe DCFH-DA. The level of malondialdehyde and the activities of superoxide dismutase and glutathione peroxidase were assessed using ELISA kits. Apoptotic markers of Bax, Bcl2, and cleaved caspase-3, as well as HSP70 and heat shock factor-1 (HSF1), were measured by Western blot. The melatonin effect through HSP70 was tested with silencing of HSF1 in the MPP + -treated SH-SY5Y cells. Melatonin can protect against MPP + -induced neuronal toxicity by promoting anti-oxidative and anti-apoptotic properties. SH-SY5Y cells exposed to melatonin with MPP + showed increased expression of HSP70 and HSF1 compared with those exposed to MPP + alone. However, siRNA-mediated downregulation of HSF1 significantly attenuated the protective effects of melatonin in the MPP + -induced in vitro PD model. Our findings revealed the protective roles of melatonin in an in vitro PD model. Melatonin can hinder the toxic effects of MPP + on dopaminergic neuronal cells via upregulation of the HSF1/HSP70 pathway. Further experimental studies would verify the therapeutic relevance of melatonin with HSP70 and HSF1 to prevent and decelerate PD-like neurodegeneration.

Dysphagia associated with Parkinson's disease (PD) affects the mortality and quality of life of patients with PD. Avoiding aspiration and maintaining swallowing ability are among the concerns regarding PD care. Therefore, we developed a swallowing supplement for easier swallowing and tolerability in patients with PD. Thirty patients with PD and 50 healthy controls were enrolled and their swallowing function measured using the videofluoroscopic swallowing study (VFSS) and several dysphagia scales. The Unified Parkinson's Disease Rating Scale motor scores, Hoehn and Yahr stage, and levodopa doses were evaluated in patients with PD. The VFSS and survey were used to assess the viscosity, color, taste, nutrition, safety, and tolerability of the swallowing supplement. The MMSE score, serum albumin, and hemoglobin levels, and oral conditions were worse in the PD group than in the control group. Compared with controls, patients with PD had significantly lower total and sub-item scores of the swallowing quality of life (swal-QoL). Using commercialized yogurt, the pharyngeal delay time (PDT) and the modified penetration aspiration scale were higher in the PD group than in the control group. The swallowing supplement significantly shortened the PDT and pharyngeal transit time (PTT). Moreover, compared with commercialized yogurt, it improved pharyngeal wall coating, PTT, and aspiration in the videofluoroscopic dysphagia subscales. The survey scores were above average to good in the "easy swallowing" and "pharyngeal residual sense" items and tolerable in the remaining 6 preference items. This swallowing supplement could prevent aspiration and dysphagia complications in patients with PD.

Background The present study was a randomized, double-blind, placebo-controlled, multi-center trial to evaluate the efficacy and safety of prolonged-release melatonin (PRM) in Parkinson's disease (PD) patients with poor sleep quality. Methods PD patients with a global Pittsburgh Sleep Quality Index (PSQI) score > 5 were included. Patients were assessed using the PSQI, a rapid eye movement sleep behavior disorder screening questionnaire, the Epworth Sleepiness Scale, Non-Motor Symptoms Scale (NMSS), Parkinson's Disease Quality of Life-39 (PDQ-39), and Unified Parkinson's Disease Rating Scale (UPDRS)-III at the beginning of the study and after 4 weeks of treatment with 2 mg of PRM. Partial correlation analysis was performed to investigate the relationship between PSQI score and the other scales. Results Thirty-four PD patients with poor sleep quality were enrolled and divided into 2 groups based on medication; PRM (n = 16) and placebo (n = 18). Regarding efficacy, PSQI was significantly improved in the PRM group compared to the control group. Improvement in the NMSS and PDQ-39 summary index were observed in the PRM but not in the placebo group; UPDRS-III score was not significantly changed in either group. PSQI improvement correlated with improvement in NMSS score and PDQ-39 summary index. Regarding safety, all enrolled subjects did not complain of side effects due to PRM. Conclusion PRM is an effective and safe treatment option for subjective sleep quality in PD patients and beneficial effects on sleep quality are associated with improved non-motor symptoms and quality of life in PD patients.

Introduction In the present study, midbrain atrophy and the pons-to-midbrain area ratio (P/M ratio) were investigated as diagnostic markers for presymptomatic progressive supranuclear palsy-Richardson's syndrome (Pre-PSP-RS). Methods The present study included 27 patients with probable PSP-RS who underwent brain MRI at least twice before and after the development of clinical symptoms, age- and sex-matched participants with Parkinson's disease (PD, n = 27), and healthy controls (n = 27). The midbrain area, pons area, and P/M ratio of the Pre-PSP-RS, PD, and control subjects were measured using midsagittal images from brain MRI, and the parameters were compared among the groups. Results The midbrain area decreased and the P/M ratio increased significantly in the Pre-PSP-RS patients compared with both the PD and control subjects (midbrain, Pre-PSP-RS vs. PD = 1.01 cm2 vs. 1.29 cm2, p Conclusion Midbrain atrophy precedes the clinical symptoms of PSP-RS and could be a useful diagnostic imaging biomarker for Pre-PSP-RS. Furthermore, this information could play an important role in the development of future treatment strategies.

Cerebral microbleeds (CMBs) are increasingly recognized neuroimaging findings, occurring with cerebrovascular disease, dementia, and aging. CMBs are associated with subsequent hemorrhagic and ischemic stroke, and also with an increased risk of cognitive deterioration and dementia. They occur in the setting of impaired small vessel integrity due to hypertension or cerebral amyloid angiopathy. This review summarizes the concepts, cause or risk factors, histopathological mechanisms, and clinical consequences of CMBs.

Exposure to particulate matter (PM) has been considered a potential risk factor for various neurodegenerative diseases, whereas nicotine has protective effects on Parkinson's disease (PD). However, it is still unclear whether or how PM alone and in combination with nicotine affects the pathogenesis of PD. We investigated the potential neurotoxicity of PM and the protective properties of nicotine in an in vitro PD model. A 1-methyl-4-phenylpyridimium (MPP+)-induced neurotoxicity model was established with SH-SY5Y cells. Cell viability and apoptosis were measured using MTT and TUNEL assays, respectively. Intracellular reactive oxygen species (ROS) levels were analyzed using the cell-permeant fluorescent probe DCFH-DA. We investigated mitochondrial apoptotic markers such as Bax, Bcl2, cytochrome C, and cleaved caspase-3 and analyzed their levels by Western blotting. SH-SY5Y cells exposed to PM and MPP+ exhibited significantly increased intracellular ROS and decreased cell viability with those exposed to PM alone. PM strikingly exacerbated MPP+-induced mitochondrial dysfunction, including an increase in the Bax/Bcl2 ratio and the release of cytochrome C and cleaved caspase-3. On the other hand, pretreatment of SH-SY5Y cells with nicotine reduced the MPP+-induced loss of cell viability and levels of intracellular ROS and mitochondrial apoptotic signaling proteins. However, pretreatment with nicotine did not prevent PM-induced toxicity in MPP+-treated SHSY5Y cells. PM and MPP+ synergistically increased ROS levels and mitochondrial apoptosis, which led to SH-SY5Y cell death. The protective effect of nicotine cannot rescue PM-induced synergistic neurotoxicity in the MPP+-induced PD model. Our findings verified the opposing roles of PM and nicotine in a model of PD pathogenesis. A large number of in vivo and in vitro studies would verify the roles of PM and nicotine in the future.

A 73-year-old right-handed man with hypertension, hypercholesterolemia, renal insufficiency, and cyclothymic disorder presented with 1 year of insidious onset tremor in his right hand when carrying his briefcase. Psychotropic drugs included bupropion and lamotrigine. He was neurologically intact except for a very low amplitude bilateral kinetic tremor (L > R) and a much larger amplitude right hand task-specific tremor (video 1) characterized by EMG (figure).

Orthostatic tremor (OT) is not an uncommon symptom in various neurodegenerative diseases. However, the nature and pathophysiology of OT involve a complex network of tremors and dopaminergic pathways. We assessed patients who complained of prominent leg tremors described as “shaky leg.” We analyzed their characteristics and evaluated them with neuroimaging and electrophysiological tools. A total of 23 patients who experienced an uncomfortable symptom of leg tremor were retrospectively enrolled from April 2014 to October 2019. Previous medical history, brain MRI, and surface electromyography (EMG) data were analyzed. The [18F]-FP-CIT brain positron emission tomography (PET) and the Unified Parkinson’s Disease Rating Scale (UPDRS) were assessed for patients who showed parkinsonism. The causes of OT varied: parkinsonism (n = 5), idiopathic causes (n = 4), secondary causes (n = 3, trauma, brain lesion, arteriovenous malformation), drug reactions (n = 3, valproate, perphenazine, haloperidol), other neurological disorders (n = 5, essential tremor, dystonia, restless leg syndrome, REM sleep behavior disorder, dementia), alcohol withdrawal (n = 1), functional movement disorder (n = 1), and an unknown cause (n = 1). The frequency range varied (2.6–15 Hz) and according to the new consensus statement on the classification of OT, 4 patients had primary OT, 2 had “primary OT plus,” 12 had slow OT, and 5 had orthostatic myoclonus. The prognosis associated with the use of medication was generally poor; however, clonazepam and levodopa were the most effective drugs. In conclusion, we found that different types of OT and orthostatic myoclonus were diagnosed by electrophysiological evaluation and neuroimaging tools even if they showed the same symptoms as “shaky leg.” In addition, it is possible to roughly estimate the response to medication according to the type of OT and the cause. To clarify the pathophysiology of OT, a large number of longitudinal cohort studies and detailed neuroimaging and electrophysiological evaluations are needed.

Cognitive decline is observed in aging and neurodegenerative diseases, including Alzheimer&rsquo, s disease (AD) and dementia. Intracellular energy produced via mitochondrial respiration is used in the regulation of synaptic plasticity and structure, including dendritic spine length and density, as well as for the release of neurotrophic factors involved in learning and memory. To date, a few synthetic agents for improving mitochondrial function have been developed for overcoming cognitive impairment. However, no natural compounds that modulate synaptic plasticity by directly targeting mitochondria have been developed. Here, we demonstrate that a mixture of Schisandra chinensis extract (SCE) and ascorbic acid (AA) improved cognitive function and induced synaptic plasticity-regulating proteins by enhancing mitochondrial respiration. Treatment of embryonic mouse hippocampal mHippoE-14 cells with a 4:1 mixture of SCE and AA increased basal oxygen consumption rate. We found that mice injected with the SCE-AA mixture showed enhanced learning and memory and recognition ability. We further observed that injection of the SCE-AA mixture in mice significantly increased expression of postsynaptic density protein 95 (PSD95), an increase that was correlated with enhanced brain-derived neurotrophic factor (BDNF) expression. These results demonstrate that a mixture of SCE and AA improves mitochondrial function and memory, suggesting that this natural compound mixture could be used to alleviate AD and aging-associated memory decline.

The purpose of our study was to investigate the association between olfactory function in Parkinson's disease (PD) and serum vitamin D status. Thirty-nine patients with de novo PD were enrolled in this study. Olfactory function was assessed by an odor identification test, as a part of the KVSS (Korean version of sniffin' sticks) II test. All patients were also assessed with the NMSS (Non-Motor Symptoms Scale for PD) to check the subjective change in ability to smell. Vitamin D status was determined by measuring the level of serum 25-hydroxyvitamin D3 (25-OHD3). Multiple linear regression tests and correlation analysis were applied to verify the association between serum 25-OHD3 level and patients' subjective and objective olfactory dysfunction. The serum 25-OHD3 level was independently associated with odor identification score in patients with PD (β = 0.38, p 0.01). Another statistically significant variable was clinical subtype of PD (Intermediate subtype: β = -0.33, p 0.05; Akinetic rigid type: β = -0.55, p 0.01). The serum 25-OHD3 level was also negatively correlated with the score for item number 28 in NMSS (Spearman's rho = -0.32, p 0.05). Our results showed that vitamin D status might be an independent factor for olfactory dysfunction in PD. Although the underlying mechanism has not been clearly identified, we postulate that vitamin D plays a role in the pathogenesis of olfactory dysfunction in PD. Further investigation to elucidate the precise relationship of vitamin D to PD is essential.

Objective Postural instability and gait disturbance are the cardinal symptoms associated with falling among patients with Parkinson's disease (PD). The Tinetti mobility test (TMT) is a well-established measurement tool used to predict falls among elderly people. However, the TMT has not been established or widely used among PD patients in Korea. The purpose of this study was to evaluate the reliability and validity of the Korean version of the TMT for PD patients. Methods Twenty-four patients diagnosed with PD were enrolled in this study. For the interrater reliability test, thirteen clinicians scored the TMT after watching a video clip. We also used the test-retest method to determine intrarater reliability. For concurrent validation, the unified Parkinson's disease rating scale, Hoehn and Yahr staging, Berg Balance Scale, Timed-Up and Go test, 10-m walk test, and gait analysis by three-dimensional motion capture were also used. We analyzed receiver operating characteristic curve to predict falling. Results The interrater reliability and intrarater reliability of the Korean Tinetti balance scale were 0.97 and 0.98, respectively. The interrater reliability and intra-rater reliability of the Korean Tinetti gait scale were 0.94 and 0.96, respectively. The Korean TMT scores were significantly correlated with the other clinical scales and three-dimensional motion capture. The cutoff values for predicting falling were 14 points (balance subscale) and 10 points (gait subscale). Conclusion We found that the Korean version of the TMT showed excellent validity and reliability for gait and balance and had high sensitivity and specificity for predicting falls among patients with PD.

The derangement of tyrosine hydroxylase (TH) activity reduces dopamine synthesis and is implicated in the pathogenesis of Parkinson's disease. However, the extracellular modulator and intracellular regulatory mechanisms of TH have yet to be identified. Recently, high-mobility group box 1 (HMGB1) was reported to be actively secreted from glial cells and is regarded as a mediator of dopaminergic neuronal loss. However, the mechanism for how HMGB1 affects TH expression, particularly through the receptor for advanced glycation endproducts (RAGE), has not yet been investigated. We found that recombinant HMGB1 (rHMGB1) upregulates TH mRNA expression via simultaneous activation of JNK phosphorylation, and this induction of TH expression is blocked by inhibitors of RAGE and JNK. To investigate how TH expression levels change through the HMGB1-RAGE axis as a result of MPP+ toxicity, we co-treated SN4741 dopaminergic cells with MPP+ and rHMGB1. rHMGB1 blocked the reduction of TH mRNA following MPP+ treatment without altering cell survival rates. Our results suggest that HMGB1 upregulates TH expression to maintain dopaminergic neuronal function via activating RAGE, which is dependent on JNK phosphorylation.

Objective Our study aimed to determine whether the short latency afferent inhibition (SAI) response could be associated with the severity of olfactory dysfunction in PD patients. Methods A total of 71 PD patients and 20 controls were enrolled. All PD patients were classified into 3 groups by the severity of the olfactory deficit. Single-pulse transmagnetic stimulation (TMS) parameters and SAI were assessed. Results The integrated SAI in the PD with anosmia and PD with hyposomia groups was significantly less inhibited than that in the PD with normosmia and control groups [64.79 {Interquartile range (IQR): 59.96, 71.33}, 84.79 {IQR: 75.03, 90.63} versus 36.72 {IQR: 32.28, 48.33}, 42.15 {IQR: 34.60, 44.96}, respectively]. In PD subjects, the severity of olfactory dysfunction also showed a significant negative correlation with the SAI response ( r =−0.829, p Conclusions Considering that the SAI response partly reflects central cholinergic dysfunction and that our study shows a relationship between the SAI response and the severity of olfactory dysfunction in PD, our findings indicate that cholinergic dysfunction could possibly contribute to the pathogenesis of olfactory dysfunction in early PD. Significance SAI could be a useful marker to detect severe olfactory dysfunction in PD.

Movement defects in obesity are associated with peripheral muscle defects, arthritis, and dysfunction of motor control by the brain. Although movement functionality is negatively correlated with obesity, the brain regions and downstream signaling pathways associated with movement defects in obesity are unclear. A dopaminergic neuronal pathway from the substantia nigra (SN) to the striatum is responsible for regulating grip strength and motor initiation through tyrosine hydroxylase (TH) activity-dependent dopamine release. We found that mice fed a high-fat diet exhibited decreased movement in open-field tests and an increase in missteps in a vertical grid test compared with normally fed mice. This motor abnormality was associated with a significant reduction of TH in the SN and striatum. We further found that phosphorylation of c-Jun N-terminal kinase (JNK), which modulates TH expression in the SN and striatum, was decreased under excess-energy conditions. Our findings suggest that high calorie intake impairs motor function through JNK-dependent dysregulation of TH in the SN and striatum.

Background and purpose With the rapid increase in the number of elderly people in Korea, multiple socio-economic problems have emerged. In 2015, 6.4 million people accounting for about 13% of the total population in Korea were aged 65 years and over. As the elderly population continues to grow, the elderly who live alone are also increasing. They have potential risks in medical and neuropsychological aspects. The purpose of this study was to investigate the association between cognition and socio-environmental status in the elderly who live alone. Methods This study was conducted on 512 people who live alone (equivalent to 1% of the total elderly people) in Daejeon Metropolitan City between April and November 2015. Structured questionnaires were used to investigate the general characteristics, socio-economic status, physical status, and mood for participants. Simple tests using Mini-Mental Status Examination-Demetia Screening, Geriatric Depression Scale and Korean-instrumental activities of daily living were also performed. Results Among the 512 participants, 109 participants (21.3%) had cognitive impairment, and 128 participants (25.0%) had depression. The number of daily meals, frequency of meeting with family, and depression were independent risk factors for cognitive impairment. Factors including the duration of living alone, cognitive impairment, poor self-perceived health status, frequency of meeting with family and duration of education were considered an independent risk factor for depression. Conclusions This study showed that the elderly who live alone are susceptible to cognitive impairment and depression, and factors including the number of daily meals, social contact, and self-perceived health status may affect cognition and depressive mood. Thus, physicians need to pay attention to management of major factors that may cause cognition impairment and depression in the elderly who live alone; in addition, they require ongoing community interest and support.

We aimed to compare the relationship of mean arterial pressure (MAP) and intracranial pressure (ICP) to predict the neurological prognosis in cardiac arrest (CA) survivors. We retrospectively examined out-of-hospital CA patients treated with targeted temperature management. ICP was measured using cerebrospinal fluid (CSF) pressure, whereas MAP was measured as blood pressure monitored through the radial or femoral artery during CSF pressure measurement. Primary outcome was 6-month neurological outcome. Of 92 enrolled patients, the favorable outcome group comprised 31 (34%) patients. The median and interquartile range of MAP were significantly higher and ICP was significantly lower in patients with favorable neurological outcomes than in those with unfavorable neurological outcomes (94.3 mmHg [80.0-105.3] vs. 82.0 mmHg [65.3-96.3]

Aim Cerebrospinal fluid (CSF) neuron-specific enolase (NSE) levels increase ahead of serum NSE levels in patients with severe brain injury. We examined the prognostic performance between CSF NSE and serum NSE levels in out-of-cardiac arrest (OHCA) survivors who had undergone target temperature management (TTM). Methods This single-centre prospective observational study included OHCA patients who had undergone TTM. NSE levels were assessed in blood and CSF samples obtained immediately (Day 0), and at 24 h (Day 1), 48 h (Day 2), and 72 h (Day 3) after return of spontaneous circulation (ROSC). The primary outcome was the 6-month neurological outcome. Results We enrolled 34 patients (males, 24; 70.6%), and 16 (47.1%) had a poor neurologic outcome. CSF NSE and serum NSE values were significantly higher in the poor outcome group compared to the good outcome group at each time point, except for serum Day 0. CSF NSE and serum NSE had an area under curve (AUC) of 0.819–0.972 and 0.648–0.920, respectively. CSF NSE prognostic performances were significantly higher than serum NSE levels at Day 1 and showed excellent AUC values (0.969; 95% confidence interval [CI] 0.844–0.999) and high sensitivity (93.8%; 95% CI 69.8–99.8) at 100% specificity. Conclusion We found CSF NSE values were highly predictive and sensitive markers of 6-month poor neurological outcome in OHCA survivors treated with TTM at Day 1 after ROSC. Therefore, CSF NSE levels at day 1 after ROSC can be a useful early prognosticator in OHCA survivors.

Recently, the effect of genetic variants in the Vitamin D receptor (VDR) gene on Parkinson's disease (PD) has gained interest. However, the precise relationship between VDR polymorphisms and PD remains unclear. In Korea, one study reported an association between VDR gene polymorphisms and PD. However, this study was conducted with a small sample size, and only the Bsml locus was evaluated. Therefore, further investigations about the relationship between VDR polymorphisms and PD are necessary in a Korean population. A total of 300 subjects were included in this study. One hundred and forty-six PD patients were diagnosed according to the United Kingdom Parkinson's Disease Society Brain Bank (UKPDBB) criteria with abnormal dopamine transporter imaging, and 154 healthy control subjects were also enrolled. We used a TaqMan genotyping assay to identify four SNPs of the VDR gene, including BsmI, FokI, ApaI, and TaqI (rs731236, rs2228570, rs7976091, and rs731236). A significant association was not noted between the risk of PD and genetic polymorphisms in the four loci in a Korean population. However, when the genetic variants of the VDR gene were analyzed after adjusting for the serum 25-OH vitamin D3 level, the TaqI and BsmI minor allele increased the risk of PD. Our data suggest no correlation between PD and the VDR polymorphisms, including BsmI, FokI, ApaI, and TaqI, in a Korean population; however, the results should be interpreted carefully because gene-environment interactions may exist. Further investigations of the VDR and its relationship with PD are required to identify the role of vitamin D in the pathogenesis of PD.

Background and purpose The Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is widely used for estimating the symptoms of Parkinson's disease. Translation and validation of the MDS-UPDRS is necessary for non-English speaking countries and regions. The aim of this study was to validate the Korean version of the MDS-UPDRS. Methods Altogether, 362 patients in 19 centers were recruited for this study. We translated the MDS-UPDRS to Korean using the translation-back translation method and cognitive pretesting. We performed both confirmatory and exploratory factor analyses to validate the scale. We calculated the comparative fit index (CFI) for confirmatory factor analysis, and used unweighted least squares for exploratory factor analysis. Results The CFI was higher than 0.90 for all parts of the scale. Exploratory factor analysis also showed that the Korean MDS-UPDRS has the same number of factors in each part as the English version. Conclusions The Korean MDS-UPDRS has the same overall structure as the English MDS-UPDRS. Our translated scale can be designated as the official Korean MDS-UPDRS.

The identification of large numbers of genetic mutations in immature myeloid cells has made it difficult to identify specific targets for acute myeloid leukemia (AML) therapy. Although current pharmacological targets for controlling cancer are focused on identifying genetic mutations, it is hard to develop the specific drugs to achieve complete remission due to complex and variable genetic mutations. To overcome the failure of the genetic mutation theory, the present study targeted mitochondrial metabolism as a strategy for inducing anti‑leukemic activity, based on evidence that AML cells have an abnormally high amount of mitochondria and that somatic mutations can alter metabolic flux in cancer. It was found that L‑deprenyl, which is clinically available for the treatment of Parkinson's disease, exerts anti‑mitochondria activity in KG‑1α cells, as assessed by detection of oxygen consumption rate (OCR) and extracellular acidification (ECAR) using XF analyzer, respectively. Using a luciferase assay for detecting adenosine triphosphate (ATP) content, it was found that suppression of mitochondrial activity led to ATP depletion and was associated with potent cytotoxic activity. L‑deprenyl is known to target monoamine oxidase‑B (MAO‑B) on the outer membrane of mitochondria, therefore, the activity of MAO‑A and ‑B was measured based on the fluorometric detection of H2O2 produced by the enzyme reaction. Notably, MAO‑A and -B activity was low in AML cells and the present findings suggested that the anticancer effect of L‑deprenyl was independent of MAO‑B. Change of mitochondrial respiration‑ and glycolysis‑related gene expression levels were measured by reverse transcription‑quantitative polymerase chain reaction. Consistent with the aforementioned results, treatment with L‑deprenyl reduced the mRNA level of mitochondrial respiration‑ and glycolysis‑related genes. Collectively, the present results identify L‑deprenyl as a novel candidate for the treatment of AML through inhibition of mitochondrial respiration.

Early-onset Parkinson's disease (EOPD) can be linked to different genetic backgrounds depending on the disease characteristics. In Korean patients with EOPD, however, only 5 PARK genes have been tested. We recruited 70 patients with EOPD from 4 hospitals in Korea, and 12 PARK genes were screened via multigene panel sequencing. Large insertions or deletions were confirmed by multiplex ligation-dependent probe amplification. We found 20 rare variants (2 in SNCA, 2 in PRKN, 6 in LRRK2, 3 in PINK1, 1 in DJ1, 4 in FBX07, 1 in HTRA2, and 1 in EIG4G1) in 20 subjects regardless of heterogeneity. Two pathogenic variants (SNCA in 2 subjects and DJ1 in one) were from 3 subjects, and 7 likely pathogenic variants (SNCA, LRRK2, FBXO7, and 2 in PINK1 and PRKN) from 7. Akinetic-rigid subtype and dystonia were more common in patients with EOPD with rare variants than in those without rare variants. Multigene panel tests can be effective at identifying genetic variants in patients with EOPD. In addition, we suggest there are different genetic backgrounds in patients with EOPD.

High-mobility group box 1 (HMGB1) is actively secreted from inflammatory cells and acts via a non-cell-autonomous mechanism to play an important role in mediating cell proliferation and migration. The HMGB1-RAGE (receptor for advanced glycation end products) axis upregulates tyrosine hydroxylase (TH) expression in response to extracellular insults in dopaminergic neurons in vitro, but little is known about HMGB1 in modulation of dopaminergic neurons in vivo. Here, using immunohistochemistry, we show that HMGB1 and RAGE expression are higher in the nigral area of MPTP (methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated mice, a toxin-induced Parkinsonian mouse model, compared with saline-treated controls. HMGB1 was predominantly localized to astrocytes and may affect neighboring dopaminergic neurons in the MPTP mouse model, owing to co-localization of RAGE in these TH-positive cells. In addition, MPTP induced a decrease in TH expression, an effect that was potentiated by inhibition of c-Jun N-terminal kinase (JNK) or RAGE. Moreover, stereotaxic injection of recombinant HMGB1 attenuated the MPTP-induced reduction of TH in a Parkinsonian mouse model. Collectively, our results suggest that an increase of HMGB1, released from astrocytes, upregulates TH expression in an acute MPTP-induced Parkinsonian mouse model, thereby maintaining dopaminergic neuronal functions.

Background: To investigate the effect of high frequency repetitive transcranial magnetic stimulation (rTMS) on motor symptoms especially freezing of gait (FoG), and nonmotor symptoms in Parkinson disease (PD). Methods: In this randomized, double-blind, sham-controlled study, fifteen PD patients were enrolled. For 10 days, 5 Hz, both motor cortices and dorsolateral prefrontal cortex (DLPFC) were stimulated. The motor symptoms and FoG were evaluated by the Unified Parkinson’s Disease Rating Scale (UPDRS) part III, FoG questionnaire (FoG-Q), variable parameters of FoG, and kinematic gait analysis. Nonmotor symptoms were evaluated by the Korean version of non-Motor Symptoms Scale (K-NMSS), 39-item Parkinson disease questionnaire (K-PDQ39), Mini-Mental Status examination (K-MMSE), Montreal Cognitive Assessment (K-MoCA), and Frontal assessment battery (FAB). Results: Finally, 12 patients (real:8, sham:4) data were analyzed. FoG-Q and UPDRS part III were improved (p=0.002, 0.022) and variable parameters of FoG was improved after 10 days stimulation in real treatment group. In addition, their effects maintained until 6 weeks from the baseline. In nonmotor symptoms, K-NMSS and K-PDQ 39 were improved until 6 weeks in real treatment group (p=0.002, 0.002), however no changes were shown in cognitive function test. Conclusions: The high frequency rTMS was effective for FoG, in addition to motor and a few nonmotor symptoms in PD. J Korean Neurol Assoc 33(4):297-305, 2015

We aimed to compare Dysport (abobotulinumtoxinA, Ipsen Biopharm, Slough, UK) and Botox (onabotulinumtoxinA, Allergan, Irvine, CA, USA) at a 2.5:1 ratio in the treatment of cervical dystonia (CD). A Dysport/Botox ratio of lower than 3:1 was suggested as a more appropriate conversion ratio, considering its higher efficacy and more frequent incidence of adverse effects not only in the treatment of CD but also in other focal movement disorders. A randomized, double-blind, multicenter, non-inferiority, two-period crossover study was done in CD, with a duration of at least 18 months. Patients were randomly assigned to treatment for the first period with Dysport or Botox, and they were followed up for 16 weeks after the injection. After a 4-week washout period, they were switched to the other formulation and then followed up for 16 weeks. The primary outcome was the changes in the Tsui scale between the baseline value and that at 1 month after each injection. A total of 103 patients were enrolled, and 94 completed the study. Mean changes in the Tsui scale between baseline and 4 weeks after each injection tended to favor Botox; however, this was not statistically significant (4.0 ± 3.9 points for the Dysport treatment vs. 4.8 ± 4.1 points for Botox; 95% confidence interval, −0.1-1.7; P = 0.091). The mean change of the Toronto western spasmodic torticollis rating scale score, the proportion of improvement in clinical global impression and patient global impression, and the incidences of adverse events were not significantly different between the two treatments. With regard to safety and efficacy, Dysport was not inferior to Botox in patients with CD at a conversion factor of 2.5:1. [http//clinicaltrial.gov: {"type":"clinical-trial","attrs":{"text":"NCT00950664","term_id":"NCT00950664"}}NCT00950664] © The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.