Erratum: Validation Study of the Official Korean Version of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale.

This corrects the article on p. 633 in vol. 16, PMID: 33029970.

Validation Study of the Official Korean Version of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale.

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.

Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans: A Genome-Wide Association Study.

Importance: Large-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the largest population worldwide (ie, Asian). Objectives: To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts. Design Setting, and Participants: Genome-wide association data generated from PD cases and controls in an Asian population (ie, Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea) were collected from January 1, 2016, to December 31, 2018, as part of an ongoing study. Results were combined with inverse variance meta-analysis, and replication of top loci in European and Japanese samples was performed. Discovery samples of 31 575 individuals passing quality control of 35 994 recruited were used, with a greater than 90% participation rate. A replication cohort of 1 926 361 European-ancestry and 3509 Japanese samples was analyzed. Parkinson disease was diagnosed using UK Parkinson's Disease Society Brain Bank Criteria. Main Outcomes and Measures: Genotypes of common variants, association with disease status, and polygenic risk scores. Results: Of 31 575 samples identified, 6724 PD cases (mean [SD] age, 64.3 [10] years; age at onset, 58.8 [10.6] years; 3472 [53.2%] men) and 24 851 controls (age, 59.4 [11.4] years; 11 030 [45.0%] men) were analyzed in the discovery study. Eleven genome-wide significant loci were identified; 2 of these loci were novel (SV2C and WBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association for SV2C (rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21; P = 1.17 × 10-10 in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (rs9638616; I2=67.1%; P = 3.40 × 10-3 for hetereogeneity). Polygenic risk score models including variants at these 11 loci were associated with a significant improvement in area under the curve over the model based on 78 European loci alone (63.1% vs 60.2%; P = 6.81 × 10-12). Conclusions and Relevance: This study identified 2 apparently novel gene loci and found 9 previously identified European loci to be associated with PD in this large, meta-genome-wide association study in a worldwide population of Asian individuals and reports similarities and differences in genetic risk factors between Asian and European individuals in the risk for PD. These findings may lead to improved stratification of Asian patients and controls based on polygenic risk scores. Our findings have potential academic and clinical importance for risk stratification and precision medicine in Asia.

Comparison of five automated urine sediment analyzers with manual microscopy for accurate identification of urine sediment.

Background While the introduction of automated urine analyzers is expected to reduce the labor involved, turnaround time and potential assay variations, microscopic examination remains the "gold standard" for the analysis of urine sediments. In this study, we evaluated the analytical and diagnostic performance of five recently introduced automated urine sediment analyzers. Methods A total of 1016 samples were examined using five automated urine sediment analyzers and manual microscopy. Concordance of results from each automated analyzer and manual microscopy were evaluated. In addition, image and microscopic review rates of each system were investigated. Results The proportional bias for red blood cells (RBCs), white blood cells (WBCs) and squamous epithelial cells in the automated urine sediment analyzers were within ±20% of values obtained using the manual microscope, except in the cases of RBCs and WBCs analyzed using URiSCAN PlusScope and Iris iQ200SPRINT, respectively. The sensitivities of Roche Cobas® u 701 and Siemens UAS800 for pathologic casts (73.6% and 81.1%, respectively) and crystals (62.2% and 49.5%, respectively) were high, along with high image review rates (24.6% and 25.2%, respectively). The detection rates for crystals, casts and review rates can be changed for the Sysmex UF-5000 platform according to cut-off thresholds. Conclusions Each automated urine sediment analyzer has certain distinct features, in addition to the common advantages of reducing the burden of manual processing. Therefore, laboratory physicians are encouraged to understand these features, and to utilize each system in appropriate ways, considering clinical algorithms and laboratory workflow.

Erratum to: The KMDS-NATION Study: Korean Movement Disorders Society Multicenter Assessment of Non-Motor Symptoms and Quality of Life in Parkinson's Disease NATION Study Group.

This corrects the article on p. 393 in vol. 12, PMID: 27819413.

Hallmarks of Treatment Aspects: Parkinson's Disease Throughout Centuries Including l-Dopa.

Deficit of striatal dopamine was first discovered in postmortem brain of patients with Parkinson's disease in 1960. This observation was the starting point for dopamine replacement therapy, and successful introduction of high dose l-dopa therapy in the 1969 revolutionized the treatment of Parkinson's disease. Since then, constant attempts have been made to enhance the efficacy of l-dopa and reduce motor complications by providing more continuous dopamine stimulation. This chapter traces the hallmarks of medical treatments for Parkinson's disease throughout centuries including the first description of antiparkinsonian effects of anticholinergics, the birth of apomorphine in the 1900s, then discovery of l-dopa in the 1960s, and development of dopamine agonists since the 1970s.

Correlation of electrode position and clinical outcomes in globus pallidus stimulation for dystonia.

BACKGROUND: The correlation between the electrode location and the clinical outcome for internal globus pallidus (GPi) deep brain stimulation (DBS) has not been fully elucidated. OBJECTIVE: The aim of this study was to determine the discrepancies between the theoretical target planned by magnetic resonance imaging (MRI) and the actual electrode location in postoperative MRI, as well as to find the correlation between the final electrode locations and the clinical outcome after GPi DBS. METHODS: Thirty-six patients who underwent GPi DBS for dystonia were included in this retrospective study. The X coordinate was defined as the lateral distance from the midline, the Y coordinate as the anterior distance from the midcommissural point, and the Z coordinate as the inferior distance from the intercommissural line. RESULTS: All coordinates showed a significant difference between theoretical and actual values for all electrode locations (p < 0.05). In particular, greater differences were exhibited for Y than for the X and Z coordinates. There was no significant difference in the accuracy of the localization of the left-side versus the right-side electrode for any coordinates. The patients whose electrodes were located within or near the posteroventral GPi showed better clinical outcomes. CONCLUSIONS: The actual electrode location was slightly more posterior to the theoretically planned target. Electrodes concentrated near the posteroventral GPi tended to yield favorable outcomes.

Pregnancy and Delivery in a Generalized Dystonia Patient Treated with Internal Globus Pallidal Deep Brain Stimulation: a Case Report.

Internal globus pallidus (GPi) deep brain stimulation (DBS) has been widely accepted as an effective treatment modality of medically refractory dystonia. However, there have been few studies regarding the safety issue of pregnancy and childbirth related with DBS. This report describes a female patient who was pregnant and delivered a baby after GPi DBS surgery. A 33-year-old female patient with acquired generalized dystonia underwent bilateral GPi DBS implantation. She obtained considerable improvement in both movement and disability after DBS implantation. Four years later, she was pregnant and the obstetricians consulted us about the safety of the delivery. At 38-weeks into pregnancy, a scheduled caesarian section was carried out under general anesthesia. After induction using thiopental and succinylcholine, intubation was done quickly, followed by DBS turn off. For hemostasis, only bipolar electrocautery was used. Before awakening from the anesthesia, DBS was turned on as the same parameters previously adjusted. After delivery, she could feed her baby by herself, because the dystonia of left upper extremity and hand was improved. Until now, she has been showing continual improvement and being good at housework, carrying for children, with no trouble in daily life. This observation indicates that the patients who underwent DBS could safely be pregnant and deliver a baby.

Evaluation of the interaction between LRRK2 and PARK16 loci in determining risk of Parkinson's disease: analysis of a large multicenter study.

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted.

The KMDS-NATION Study: Korean Movement Disorders Society Multicenter Assessment of Non-Motor Symptoms and Quality of Life in Parkinson's Disease NATION Study Group.

BACKGROUND AND PURPOSE: Nonmotor symptoms (NMS) in Parkinson's disease (PD) have multisystem origins with heterogeneous manifestations that develop throughout the course of PD. NMS are increasingly recognized as having a significant impact on the health-related quality of life (HrQoL). We aimed to determine the NMS presentation according to PD status, and the associations of NMS with other clinical variables and the HrQoL of Korean PD patients. METHODS: We surveyed patients in 37 movement-disorders clinics throughout Korea. In total, 323 PD patients were recruited for assessment of disease severity and duration, NMS, HrQoL, and other clinical variables including demographics, cognition, sleep scale, fatigability, and symptoms. RESULTS: In total, 98.1% of enrolled PD subjects suffered from various kinds of NMS. The prevalence of NMS and scores in each NMS domain were significantly higher in the PD group, and the NMS worsened as the disease progressed. Among clinical variables, disease duration and depressive mood showed significant correlations with all NMS domains (p<0.001). NMS status impacted HrQoL in PD (rS=0.329, p<0.01), and the association patterns differed with the disease stage. CONCLUSIONS: The results of our survey suggest that NMS in PD are not simply isolated symptoms of degenerative disease, but rather exert significant influences throughout the disease course. A novel clinical approach focused on NMS to develop tailored management strategies is warranted to improve the HrQoL in PD patients.

Weight Change Is a Characteristic Non-Motor Symptom in Drug-Naïve Parkinson's Disease Patients with Non-Tremor Dominant Subtype: A Nation-Wide Observational Study.

Despite the clinical impact of non-motor symptoms (NMS) in Parkinson's disease (PD), the characteristic NMS in relation to the motor subtypes of PD is not well elucidated. In this study, we enrolled drug-naïve PD patients and compared NMS between PD subtypes. We enrolled 136 drug-naïve, early PD patients and 50 normal controls. All the enrolled PD patients were divided into tremor dominant (TD) and non-tremor dominant (NTD) subtypes. The Non-Motor Symptom Scale and scales for each NMS were completed. We compared NMS and the relationship of NMS with quality of life between normal controls and PD patients, and between the PD subtypes. Comparing with normal controls, PD patients complained of more NMS, especially mood/cognitive symptoms, gastrointestinal symptoms, unexplained pain, weight change, and change in taste or smell. Between the PD subtypes, the NTD subtype showed higher total NMS scale score and sub-score about weight change. Weight change was the characteristic NMS related to NTD subtype even after controlled other variables with logistic regression analysis. Even from the early stage, PD patients suffer from various NMS regardless of dopaminergic medication. Among the various NMS, weight change is the characteristic NMS associated with NTD subtype in PD patients.

DCTN1 p.K56R in progressive supranuclear palsy.

INTRODUCTION: Mutations in dynactin DCTN1 (p150(glued)) have previously been linked to familial motor neuron disease or Perry syndrome (PS) consisting of depression, parkinsonism and hypoventilation. METHODS: We sequenced DCTN1 in 636 Caucasian patients with parkinsonism (Parkinson's disease and Parkinson-plus syndromes) and 508 healthy controls. Variants (MAF < 0.01) were subsequently genotyped in Caucasian (1360 cases and 1009 controls) and Asian cohorts (1046 cases and 830 controls), and the functional implications of pathogenic variants were assessed. RESULTS: We identified 17 rare variants leading to non-synonymous amino-acid substitutions. Four of the variants were only observed in control subjects, four in both cases and controls and the remaining nine in cases only. One of the variants, DCTN1 p.K56R, was present in two patients with progressive supranuclear palsy (PSP) with a shared minimal 2.2 Mb haplotype. Both subjects have parkinsonism as the most prominent symptom with abnormal ocular movements, moderate cognitive impairment and little to no l-dopa response. Neither subject presents with depression, central hypoventilation or weight loss. For one of the subjects MRI shows symmetrical atrophy of temporal and frontoparietal lobes. In HEK293 cells mutant p150(glued) (p.K56R) shows less affinity for microtubules than wild-type, with a more diffuse cytoplasmic distribution. CONCLUSIONS: We have identified DCTN1 p.K56R in patients with PSP. This variant is immediately adjacent to the N-terminal p150(glued) 'CAP-Gly' domain, affects a highly conserved amino acid and alters the protein's affinity to microtubules and its cytoplasmic distribution.

Tremor frequency characteristics in Parkinson's disease under resting-state and stress-state conditions.

Tremor characteristics-amplitude and frequency components-are primary quantitative clinical factors for diagnosis and monitoring of tremors. Few studies have investigated how different patient's conditions affect tremor frequency characteristics in Parkinson's disease (PD). Here, we analyzed tremor characteristics under resting-state and stress-state conditions. Tremor was recorded using an accelerometer on the finger, under resting-state and stress-state (calculation task) conditions, during rest tremor and postural tremor. The changes of peak power, peak frequency, mean frequency, and distribution of power spectral density (PSD) of tremor were evaluated across conditions. Patients whose tremors were considered more than "mild" were selected, for both rest (n=67) and postural (n=25) tremor. Stress resulted in both greater peak powers and higher peak frequencies for rest tremor (p<0.001), but not for postural tremor. Notably, peak frequencies were concentrated around 5 Hz under stress-state condition. The distributions of PSD of tremor were symmetrical, regardless of conditions. Tremor is more evident and typical tremor characteristics, namely a lower frequency as amplitude increases, are different in stressful condition. Patient's conditions directly affect neural oscillations related to tremor frequencies. Therefore, tremor characteristics in PD should be systematically standardized across patient's conditions such as attention and stress levels.

Clinical Heterogeneity of Atypical Pantothenate Kinase-Associated Neurodegeneration in Koreans.

OBJECTIVE: Neurodegeneration with brain iron accumulation (NBIA) represents a group of inherited movement disorders characterized by iron accumulation in the basal ganglia. Recent advances have included the identification of new causative genes and highlighted the wide phenotypic variation between and within the specific NBIA subtypes. This study aimed to investigate the current status of NBIA in Korea. METHODS: We collected genetically confirmed NBIA patients from twelve nationwide referral hospitals and from a review of the literature. We conducted a study to describe the phenotypic and genotypic characteristics of Korean adults with atypical pantothenate kinase-associated neurodegeneration (PKAN). RESULTS: Four subtypes of NBIA including PKAN (n = 30), PLA2G6-related neurodegeneration (n = 2), beta-propeller protein-associated neurodegeneration (n = 1), and aceruloplasminemia (n = 1) have been identified in the Korean population. The clinical features of fifteen adults with atypical PKAN included early focal limb dystonia, parkinsonism-predominant feature, oromandibular dystonia, and isolated freezing of gait (FOG). Patients with a higher age of onset tended to present with parkinsonism and FOG. The p.R440P and p.D378G mutations are two major mutations that represent approximately 50% of the mutated alleles. Although there were no specific genotype-phenotype correlations, most patients carrying the p.D378G mutation had a late-onset, atypical form of PKAN. CONCLUSIONS: We found considerable phenotypic heterogeneity in Korean adults with atypical PKAN. The age of onset may influence the presentation of extrapyramidal symptoms.

Long-Term Clinical Outcome of Internal Globus Pallidus Deep Brain Stimulation for Dystonia.

BACKGROUND: GPi (Internal globus pallidus) DBS (deep brain stimulation) is recognized as a safe, reliable, reversible and adjustable treatment in patients with medically refractory dystonia. OBJECTIVES: This report describes the long-term clinical outcome of 36 patients implanted with GPi DBS at the Neurosurgery Department of Seoul National University Hospital. METHODS: Nine patients with a known genetic cause, 12 patients with acquired dystonia, and 15 patients with isolated dystonia without a known genetic cause were included. When categorized by phenomenology, 29 patients had generalized, 5 patients had segmental, and 2 patients had multifocal dystonia. Patients were assessed preoperatively and at defined follow-up examinations postoperatively, using the Burke-Fahn-Marsden dystonia rating scale (BFMDRS) for movement and functional disability assessment. The mean follow-up duration was 47 months (range, 12-84). RESULTS: The mean movement scores significantly decreased from 44.88 points preoperatively to 26.45 points at 60-month follow up (N = 19, P = 0.006). The mean disability score was also decreased over time, from 11.54 points preoperatively to 8.26 points at 60-month follow up, despite no statistical significance (N = 19, P = 0.073). When analyzed the movement and disability improvement rates at 12-month follow up point, no significant difference was noted according to etiology, disease duration, age at surgery, age of onset, and phenomenology. However, the patients with DYT-1 dystonia and isolated dystonia without a known genetic cause showed marked improvement. CONCLUSIONS: GPi DBS is a safe and efficient therapeutic method for treatment of dystonia patients to improve both movement and disability. However, this study has some limitations caused by the retrospective design with small sample size in a single-center.

Perverted Head-Shaking and Positional Downbeat Nystagmus in Essential Tremor.

Even though the pathophysiology is not completely understood, cerebellar dysfunction has been invoked in essential tremor (ET). We evaluated cerebellar dysfunction in ET with the presence of perverted head-shaking (pHSN) and positional downbeat nystagmus (pDBN) which are known to reflect cerebellar dysfunction. First, we reviewed the videooculography (VOG) of 185 patients with ET from March 2007 to April 2010. Seventeen of 28 patients with pHSN and pDBN were followed up for at least a 1.8-year interval from baseline to determine the clinical course. And then, we recruited 52 consecutive patients with ET and compared their ocular motor findings with 51 normal controls using VOG. Among the 185 patients with ET, 28 (15.1 %) showed pHSN (n = 23, 12.4 %) or pDBN (n = 8, 4.3 %). Seventeen of them who were followed up did not develop Parkinsonism or other neurologic deficits during the observation period. The subsequent case-control study showed a higher prevalence of pHSN or pDBN (11/52, 21.2 %, pHSN in nine and pDBN in five) in patients with ET than in the normal controls (2/51, 3.9 %, pHSN only, P = 0.015). The tremor rating scale or involved body sites did not differ between the patients with and without pHSN/pDBN. pHSN and pDBN were more common in patients with ET than in the normal controls. This result supports that cerebellar dysfunction is associated with ET.

Large-scale assessment of polyglutamine repeat expansions in Parkinson disease.

OBJECTIVES: We aim to clarify the pathogenic role of intermediate size repeat expansions of SCA2, SCA3, SCA6, and SCA17 as risk factors for idiopathic Parkinson disease (PD). METHODS: We invited researchers from the Genetic Epidemiology of Parkinson's Disease Consortium to participate in the study. There were 12,346 cases and 8,164 controls genotyped, for a total of 4 repeats within the SCA2, SCA3, SCA6, and SCA17 genes. Fixed- and random-effects models were used to estimate the summary risk estimates for the genes. We investigated between-study heterogeneity and heterogeneity between different ethnic populations. RESULTS: We did not observe any definite pathogenic repeat expansions for SCA2, SCA3, SCA6, and SCA17 genes in patients with idiopathic PD from Caucasian and Asian populations. Furthermore, overall analysis did not reveal any significant association between intermediate repeats and PD. The effect estimates (odds ratio) ranged from 0.93 to 1.01 in the overall cohort for the SCA2, SCA3, SCA6, and SCA17 loci. CONCLUSIONS: Our study did not support a major role for definite pathogenic repeat expansions in SCA2, SCA3, SCA6, and SCA17 genes for idiopathic PD. Thus, results of this large study do not support diagnostic screening of SCA2, SCA3, SCA6, and SCA17 gene repeats in the common idiopathic form of PD. Likewise, this largest multicentered study performed to date excludes the role of intermediate repeats of these genes as a risk factor for PD.