Evidence of Inflammation in Parkinson’s Disease and Its Contribution to Synucleinopathy

Accumulation of alpha-synuclein (αSyn) protein in neurons is a renowned pathological hallmark of Parkinson’s disease (PD). In addition, accumulating evidence indicates that activated inflammatory responses are involved in the pathogenesis of PD. Thus, achieving a better understanding of the interaction between inflammation and synucleinopathy in relation to the PD process will facilitate the development of promising disease-modifying therapies. In this review, the evidence of inflammation in PD is discussed, and human, animal, and laboratory studies relevant to the relationship between inflammation and αSyn are explored as well as new therapeutic targets associated with this relationship.

The Protein-Protein Interaction Network of Hereditary Parkinsonism Genes Is a Hierarchical Scale-Free Network

Purpose@#Hereditary parkinsonism genes consist of causative genes of familial Parkinson’s disease (PD) with a locus symbol prefix (PARK genes) and hereditary atypical parkinsonian disorders that present atypical features and limited responsiveness to levodopa (non-PARK genes). Although studies have shown that hereditary parkinsonism genes are related to idiopathic PD at the phenotypic, gene expression, and genomic levels, no study has systematically investigated connectivity among the proteins encoded by these genes at the protein-protein interaction (PPI) level. @*Materials and Methods@#Topological measurements and physical interaction enrichment were performed to assess PPI networks constructed using some or all the proteins encoded by hereditary parkinsonism genes (n=96), which were curated using the Online Mendelian Inheritance in Man database and literature. @*Results@#Non-PARK and PARK genes were involved in common functional modules related to autophagy, mitochondrial or lysosomal organization, catecholamine metabolic process, chemical synapse transmission, response to oxidative stress, neuronal apoptosis, regulation of cellular protein catabolic process, and vesicle-mediated transport in synapse. The hereditary parkinsonism proteins formed a single large network comprising 51 nodes, 83 edges, and three PPI pairs. The probability of degree distribution followed a power-law scaling behavior, with a degree exponent of 1.24 and a correlation coefficient of 0.92. LRRK2 was identified as a hub gene with the highest degree of betweenness centrality; its physical interaction enrichment score was 1.28, which was highly significant. @*Conclusion@#Both PARK and non-PARK genes show high connectivity at the PPI and biological functional levels.

Accuracy of Machine Learning Using the Montreal Cognitive Assessment for the Diagnosis of Cognitive Impairment in Parkinson’s Disease

Objective@#The Montreal Cognitive Assessment (MoCA) is recommended for assessing general cognition in Parkinson’s disease (PD). Several cutoffs of MoCA scores for diagnosing PD with cognitive impairment (PD-CI) have been proposed, with varying sensitivity and specificity. This study investigated the utility of machine learning algorithms using MoCA cognitive domain scores for improving diagnostic performance for PD-CI. @*Methods@#In total, 2,069 MoCA results were obtained from 397 patients with PD enrolled in the Parkinson’s Progression Markers Initiative database with a diagnosis of cognitive status based on comprehensive neuropsychological assessments. Using the same number of MoCA results randomly sampled from patients with PD with normal cognition or PD-CI, discriminant validity was compared between machine learning (logistic regression, support vector machine, or random forest) with domain scores and a cutoff method. @*Results@#Based on cognitive status classification using a dataset that permitted sampling of MoCA results from the same individual (n = 221 per group), no difference was observed in accuracy between the cutoff value method (0.74 ± 0.03) and machine learning (0.78 ± 0.03). Using a more stringent dataset that excluded MoCA results (n = 101 per group) from the same patients, the accuracy of the cutoff method (0.66 ± 0.05), but not that of machine learning (0.74 ± 0.07), was significantly reduced. Inclusion of cognitive complaints as an additional variable improved the accuracy of classification using the machine learning method (0.87–0.89). @*Conclusion@#Machine learning analysis using MoCA domain scores is a valid method for screening cognitive impairment in PD.

Early Impairment of Chopsticks Skills in Parkinsonism Suggests Progressive Supranuclear Palsy

Background@#and PurposeChopsticks are a primary eating utensil in East Asia, but systematic assessments of chopsticks skills in parkinsonian disorders is lacking. We aimed to identify any differences in chopsticks skills in the early stages of Parkinson's disease (PD) and atypical parkinsonism (AP), including progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal syndrome (CBS). @*Methods@#We consecutively recruited 111 patients with PD and 74 with AP (40 with PSP, 30 with MSA, and 4 with CBS) who were in a drug-naïve state. The motor and cognitive functions of the patients were evaluated using a standardized protocol. Everyday chopsticks skills were evaluated using a chopsticks questionnaire developed in-house. The chopsticks skills test (CST) involved counting the number of pills that the subject was able to carry using chopsticks between two dishes separated by 20 cm within 20 seconds. @*Results@#Patient responses to the questionnaire indicating poor chopsticks skills (“I cannot pick up some of the food items” or “I cannot use chopsticks anymore”) were present in 23.0% of AP patients and 30% of PSP patients, compared to only 5.6% of PD patients [odd ratio (OR)=5.07 and OR=7.29, p≤0.001 in both]. The performance in the CST was worse in PSP than in PD (p<0.001). The CST results were correlated with hand motor skills including in the coinrotation test, timed figure-tapping test, and motor Unified Parkinson's Disease Rating Scale scores in all of the patient groups (p<0.001). In PSP, a decline in visuospatial function and frontal executive function was associated with a poor performance in the CST in addition to poor motor performance (p<0.05). @*Conclusions@#Impairments in chopsticks skills were more common in PSP than in PD during the early stages of parkinsonism. This suggests that early functional impairment of chopsticks skills can be used as a warning sign for PSP.

An Autopsy Proven Case of CSF1R-mutant Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) with Premature Ovarian Failure

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a progressive degenerative white matter disorder caused by mutations in the tyrosine kinase domain of the CSF1R gene. ALSP is often misdiagnosed as other diseases due to its rarity and various clinical presentations such as Parkinsonism, pyramidal signs, cognitive impairment and/or psychiatric symptoms. We describe an autopsy case of ALSP with a CSF1R mutation. A 61-year-old woman presented insidious-onset gait difficulty for 12 years since her age of 49, and premature ovarian failure since her age of 35. At initial hospital visit, brain magnetic resonance imaging revealed hydrocephalus. Initially, Parkinson's syndrome was diagnosed, and she was prescribed L-dopa/carbidopa because of spasticity and rigidity of extremities, which had worsened. Subsequently, severe neuropsychiatric symptoms and cognitive impairment developed and radiologically, features of leukoencephalopathy or leukodystrophy were detected. She showed a down-hill course and died, 12 years after initial diagnosis. At autopsy, the brain showed severe symmetric atrophy of bilateral white matter, paper-thin corpus callosum, thin internal capsule, and marked hydrocephalus. Microscopically, diffuse loss of white matter, relatively preserved subcortical U-fibers, and many eosinophilic bulbous neuroaxonal spheroids were noted, but there was no calcification. Pigmented glia with brown cytoplasmic pigmentation were readily found in the white matter, which were positive for Periodic acid-Schiff, p62, and CD163 stains, but almost negative for CD68. Whole-exome and Sanger sequencing revealed a CSF1R mutation (c.2539G>A, p.Glu847Lys) which was reported in prior one ALSP case. This example demonstrates that ALSP could be associated with premature ovarian failure.

Novel Ferritin Light Chain Gene Mutation in a Korean Patient with Neuroferritinopathy

No abstract available.

Trends in the Prevalence of Drug-Induced Parkinsonism in Korea

PURPOSE: Discontinuation of offending drugs can prevent drug-induced parkinsonism (DIP) before it occurs and reverse or cure it afterwards. The aim of this study was to investigate the prevalence of DIP and the utilization of offending drugs through an analysis of representative nationwide claims data. MATERIALS AND METHODS: We selected DIP patients of ages ranging from 40 to 100 years old with the G21.1 code from the Korean National Service Health Insurance Claims database from 2009 to 2015. The annual standardized prevalence of DIP was explored from 2009 to 2015. Trends were estimated using the compound annual growth rate (CAGR) and the Cochran-Armitage test for DIP over the course of 6 years. Additionally, the utilization of offending drugs was analyzed. RESULTS: The annual prevalence of DIP was 4.09 per 100000 people in 2009 and 7.02 in 2015 (CAGR: 9.42%, p<0.001). Levosulpiride use before and after DIP diagnosis showed a clear trend for decreasing utilization (CAGR: −5.4%, −4.3% respectively), whereas the CAGR for itopride and metoclopramide increased by 12.7% and 6.4%, respectively. In 2015, approximately 46.6% (858/1840 persons) of DIP patients were prescribed offending drugs after DIP diagnosis. The most commonly prescribed causative drug after DIP diagnosis was levosulpiride. CONCLUSION: The prevalence of DIP has increased. To prevent or decrease DIP, we suggest that physicians reduce prescriptions of benzamide derivatives that have been most commonly used, and that attempts be made to find other alternative drugs. Additionally, the need for continuing education about offending drugs should be emphasized.

A Novel Heterozygous ANO3 Mutation with Basal Ganglia Dysfunction in a Patient with Adult-Onset Isolated Segmental Dystonia

No abstract available.

Erratum to: Ataxia with Oculomotor Apraxia Type 1 without Oculomotor Apraxia: A Case Report

Unfortunately, the original version of this article contained an error in the nomenclature of a variant which was shown in an electropherogram in the Figure 1.

Presynaptic Dopaminergic Degeneration in a Patient with Beta-Propeller Protein-Associated Neurodegeneration Documented by Dopamine Transporter Positron Emission Tomography Images: A Case Report

No abstract available.

Patients and Their Caregivers' Burdens for Parkinson's Disease in Korea

OBJECTIVE: Many patients with Parkinson’s disease (PD) suffer from motor and non-motor symptoms. According to these variable symptoms of PD, patients or caregivers have a poorer quality of life than patients with other neurodegenerative diseases. Since the difficulties are varied for all patients, prioritizing their difficulties differs among all cases. The goal of this study was to investigate the burdens of PD among the caregivers as well as patients and to identify areas requiring aid from the government. METHODS: We surveyed the awareness and perceptions of PD in patients and caregivers of PD by a face-to-face questionnaire. The questionnaire was divided into three sections: symptoms of PD (part A), desire for policies (part B), and difficulties faced by their caregivers (part C). Part A comprised 8 questions, Part B had 2 questions, and Part C had 3 questions. RESULTS: In total, 853 subjects (702 patients and 151 caregivers) were enrolled in this study. The major difficulties experienced by PD patients were physical (67%), psychiatric (60%) and socio-economic (52%). Assessing the physical difficulties, more than half the patients experienced severe difficulties (29% very severe, 39% severe). Psychiatric difficulties were assessed as severe (35%) and very severe (21%) among the patients. Severe difficulties were also experienced socio-economically, at 52% in patients and 49% in caregivers, especially among patients in their fifties (58%) and those with their spouse (65%) as caregivers. The topmost need was the introduction of new technology for treatment of PD (62%), followed by relief of costs for treatment (38%) and a family support system (31%). The majority (91%) of the patients were diagnosed with PD within two years after onset of symptoms. CONCLUSION: We know that the difficulties of PD and the needs for government assistance are different between patients and caregivers. These results emphasize that perceiving the difficulties and needs of patients and caregivers early can help to prevent and ameliorate the burden of disease.

Validation of the Korean Version of the Scale for Outcomes in Parkinson's Disease-Autonomic

OBJECTIVE: Autonomic symptoms are commonly observed in patients with Parkinson's disease (PD) and often limit the activities of daily living. The Scale for Outcomes in Parkinson's disease-Autonomic (SCOPA-AUT) was developed to evaluate and quantify autonomic symptoms in PD. The goal of this study was to translate the original SCOPA-AUT, which was written in English, into Korean and to evaluate its reliability and validity for Korean PD patients. METHODS: For the translation, the following processes were performed: forward translation, backward translation, expert review, pretest of the pre-final version and development of the final Korean version of SCOPA-AUT (K-SCOPA-AUT). In total, 127 patients with PD from 31 movement disorder clinics of university-affiliated hospitals in Korea were enrolled in this study. All patients were assessed using the K-SCOPA-AUT and other motor, non-motor, and quality of life scores. Test-retest reliability for the K-SCOPA-AUT was assessed over a time interval of 10−14 days. RESULTS: The internal consistency and reliability of the K-SCOPA-AUT was 0.727 as measured by the mean Cronbach's α-coefficient. The test-retest correlation reliability was 0.859 by the Guttman split-half coefficient. The total K-SCOPA-AUT score showed a positive correlation with other non-motor symptoms [the Korean version of non-motor symptom scale (K-NMSS)], activities of daily living (Unified Parkinson's Disease Rating Scale part II) and quality of life [the Korean version of Parkinson's Disease Quality of Life 39 (K-PDQ39)]. CONCLUSION: The K-SCOPA-AUT had good reliability and validity for the assessment of autonomic dysfunction in Korean PD patients. Autonomic symptom severities were associated with many other motor and non-motor impairments and influenced quality of life.

Ataxia with Oculomotor Apraxia Type 1 without Oculomotor Apraxia: A Case Report

No abstract available.

Missions of Journal of Movement Disorders

No abstract available.

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.

Cognitive Dysfunction in Drug-induced Parkinsonism Caused by Prokinetics and Antiemetics

The use of prokinetics/antiemetics is one of the leading causes of drug-induced parkinsonism (DIP) observed in neurology clinics. Cognitive dysfunction in DIP has recently been recognized, but pathologies related with cognitive dysfunction is unknown. Among our retrospective cohort of 385 consecutive parkinsonian patients enrolled in our parkinsonism registry, 14 patients were identified who satisfied our inclusion criteria: parkinsonism caused by prokinetics/antiemetics, existing T1-weighted 3D volumetric MR images, and normal [18F]-N-3-fluoropropyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane PET scan images. For the comparison of volumetric MR data, 30 age- and sex-matched healthy individuals were included in this study. Among 14 patients with DIP, 4 patients were diagnosed with dementia, and all other patients had mild cognitive impairment (MCI). Comparisons of MR volumetric data between DIP patients with MCI and controls show that cortical gray matter volumes are reduced bilaterally in DIP (P=0.041) without changes in either total white matter volume or total intracranial volume. Among subcortical structures, the volume of the right hippocampus is reduced in DIP patients compared with controls (P=0.011, uncorrected). In DIP, cortical thickness is reduced in the bilateral lingual (P=0.002), right fusiform (P=0.032) and part of the left lateral occipital gyri (P=0.007). Our results suggests that cognitive dysfunction in DIP caused by prokinetics/antiemetics is common. Structural changes in the brain by 3D MRI may be associated with cognitive decline in DIP.

Erratum: Analysis of Dosage Mutation in PARK2 among Korean Patients with Early-Onset or Familial Parkinson's Disease

Authors would like to change annotation of variants in Table 1 and its legend according to HGVS nomenclature recommendation.

Utility of the Midbrain Tegmentum Diameter in the Differential Diagnosis of Progressive Supranuclear Palsy from Idiopathic Parkinson's Disease

BACKGROUND AND PURPOSE: Various magnetic resonance (MR) measurements have been proposed to aid in differentiating between progressive supranuclear palsy (PSP) and idiopathic Parkinson's disease (IPD); however, these methods have not been compared directly. The aim of this study was to determine which measurement method exhibits the highest power to differentiate between PSP and IPD. METHODS: Brain MR images from 82 IPD and 29 PSP patients were analyzed retrospectively. T1-weighted 3D volumetric axial images, or sagittal images reconstructed from those axial images were examined. MR measurements included the length from the interpeduncular fossa to the center of the cerebral aqueduct at the mid-mammillary-body level, adjusted according to the anterior commissure-posterior commissure length (MB(Tegm)), the ratio of the midbrain area to the pons area (M/P ratio) as measured by both Oba's method (Oba M/P) and Cosottini's method (Cosottini M/P), and a modified MR parkinsonism index (mMRPI). RESULTS: Receiver operating characteristic (ROC) analysis indicated that the areas under the ROC curves (AUCs) exceeded 0.70, with a high intrarater reliability for all MR measurement methods. ROC analyses of four MR measurements yielded AUCs of 0.69-0.76. At the cutoff value with the highest Youden index, mMRPI had the highest sensitivity, while Oba M/P offered the highest specificity. A comparison of the ROC analyses revealed that MB(Tegm) was superior to mMRPI in differentiating PSP from IPD (p=0.049). There was no difference in discriminating power among Oba M/P, Cosottini M/P, and MB(Tegm). CONCLUSIONS: Simple measurements of MB(Tegm) on axial MR images at the mid-mammillary-body level are comparable to measurements of the M/P ratio with regard to their ability to discriminate PSP from IPD.

Reduction of Continuous Theta Burst Stimulation-Induced Motor Plasticity in Healthy Elderly With COMT Val158Met Polymorphism

OBJECTIVE: To delineate whether cortical plasticity induced by continuous theta burst stimulation (cTBS) differed according to catechol-O-methyltransferase (COMT) gene polymorphism in healthy older adults. METHODS: Eighteen healthy older volunteers (mean age 73.78+/-5.04; 12 females and 6 males) were recruited. Volunteers randomly assigned in either a sham-first or real cTBS first group participated in two separate TMS visits with at least a 2-day wash-out period. Genotyping was carried out at baseline by a separate researcher who was blinded. cTBS was delivered in a hot spot over M1 at an active motor threshold of 80%. Motor evoked potentials (MEPs) were obtained at 120% of the resting motor threshold before and after sham/cTBS. RESULTS: The relative MEP to baseline was significantly decreased 0 and 10 minutes post-stimulation and increased 40 minutes post-stimulation, as compared with the sham condition. Immediately after cTBS, the Val/Val group had a significantly reduced relative MEP value, as compared with the MET carrier group. CONCLUSION: In healthy older persons, cTBS-induced motor plasticity was reduced in the COMT Val/Val group as compared with the 158Met carrier group.

Myotonic Potentials in the Myopathy Induced by HMG-CoA Reductase Inhibitor

HMG-CoA reductase inhibitor is widely used for the treatment of dyslipidemia, and for the prevention of stroke and cardiovascular disease. However, it is necessary to consider the adverse effects associated with this drug. Myopathy is a well-known side effect of statin therapy, but myotonic potentials in cases with statin myopathy have thus far been reported only rarely. We report four cases of myopathy with myotonic potentials on electromyography after multidrug administration. All of the patients recovered shortly after statin withdrawal.