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

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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.

Parkinsonism in corticobasal syndrome may not be primarily due to presynaptic dopaminergic deficiency

The clinical features of corticobasal degeneration (CBD) are quite asymmetric. The severity of clinical symptoms and dopamine transporter (DAT) bindings were less correlated compared to other parkinsonisms, suggesting that presynaptic nigrostriatal dopaminergic dysfunction may not explain extrapyramidal manifestations in CBD. Therefore we wanted to reexamine asymmetry and severity between DAT imaging and clinical findings. We studied patients meeting the diagnostic criteria for CBD based on clinical features. We collected their clinical information and imaging retrospectively. Seven patients were enrolled and all had asymmetric rigidity, bradykinesia and unilateral limb dystonia. These symptoms did not improve with levodopa. All patients showed symptoms bilaterally in the last visit, but asymmetry of clinical symptoms was remarkable at the time of DAT imaging. The DAT bindings were decreased in six subjects. However, one patient showed normal DAT binding. Four patients had a more evident DAT reduction on the side contralateral to the more clinically affected side, however, two patients had a more prominent reduction on the ipsilateral side. The symptoms that we regard as parkinsonian features in CBD are not only explained by presynaptic dopaminergic dysfunction. Our findings suggest that postsynaptic dopaminergic or nondopaminergic systems may play a major role in parkinsonian symptoms in corticobasal syndrome.

The Prevalence of Essential Tremor in Elderly Koreans

Essential tremor (ET) is one of the most common movement disorders. The prevalence of ET varies substantially among studies. In Korea, there is no well-designed epidemiological study of the prevalence of ET. Thus, we investigated the prevalence of ET in a community in Korea. Standardized interviews and in-person neurological examinations were performed in a random sample of the elderly aged 65 yr or older. Next, movement specialists attempted to diagnose ET clinically. People who showed equivocal parkinsonian features underwent dopamine transporter imaging using [123I]-FP-CIT SPECT, to differentiate ET from parkinsonism. A total of 714 subjects participated in this population-based study. Twenty six of these subjects were diagnosed as having ET. The crude prevalence of ET was 3.64 per 100 persons. Age, gender, or education period were not different between the ET patients and the non-ET subjects. The prevalence of ET was slightly lower than those reported in previous studies. Further studies including more subjects are warranted.

PRRT2 mutation in Korean patients with paroxysmal kinesigenic dyskinesia: A clinico-genetic analysis

Background & Objective: Recently, mutations in PRRT2 have been found to cause paroxysmal kinesigenic dyskinesia (PKD). However, only several reports have described the detailed clinical features of patients with the PRRT2 mutation compared to those without the mutation. Furthermore, 16p11.2 microdeletions including PRRT2 also have been reported in patients with PKD; however, it is unknown to what extent the PRRT2 deletion contributes to the development of PKD. Methods: We performed mutation screening in 29 Korean patients with PKD analyzing the sequence and gene dosage of PRRT2 and their clinical features. Results: Overall, genetic abnormalities in PRRT2 were identified in 7 patients (24%): 3 from the 6 familial cases (50%) and 4 from the 23 sporadic cases (17%). The previously reported c.649dupC and c.649delC were found in 5 and 1 patient, respectively, and a novel mutation c.323_324delCA was found in 1 patient. No patients had deletions involving the PRRT2 gene. Compared with the mutation-negative cases, the age of PKD onset was earlier in the mutation-positive cases. However, there were no differences in the other clinical features. A dystonia-only phenotype was reported only in the mutation-negative cases. Contrary to common belief that patients with PKD have an excellent response to carbamazepine, 3 mutation-positive patients taking carbamazepine reported only a partial response. Conclusions: PRRT2 is a common causative gene for Korean patients with PKD. Our results show that the incomplete response to carbamazepine does not exclude the PRRT2 mutation.

The first Korean case of adult-onset Alexander disease

Alexander disease (AxD) is a progressive neurodegenerative disorder caused by mutations in the gene encoding the glial fibrillary acidic protein (GFAP). Three subtypes of AxD have been identified based on the age of onset: infantile (under age 2), juvenile (age 2 to 12) and adult (over age 12). The adult form is rare and presents with unique clinical features different from those of the infantile forms. Here, we present the first Korean case of adult-onset cerebellar ataxia with typical tadpole-like brainstem atrophy on the magnetic resonance imaging (MRI). Molecular genetic analysis revealed a heterozygous missense mutation (c.1246C>T, p.R416W) in the GFAP gene.

Hypothesis: Somatic Mosaicism and Parkinson Disease

Mutations causing genetic disorders can occur during mitotic cell division after fertilization, which is called somatic mutations. This leads to somatic mosaicism, where two or more genetically distinct cells are present in one individual. Somatic mutations are the most well studied in cancer where it plays an important role and also have been associated with some neurodegenerative disorders. The study of somatic mosaicism in Parkinson disease (PD) is only in its infancy, and a case with somatic mutation has not yet been described. However, we can speculate that a somatic mutation affecting cells in the central nervous system including substantia nigra dopaminergic neurons could lead to the development of PD through the same pathomechanisms of genetic PD even in the absence of a germ-line mutation. Theoretically, a number of genes could be candidates for genetic analysis for the presence of somatic mosaicism. Among them, SNCA and PARK2 could be the best candidates to analyze. Because analyzing brain tissues in living patients is impossible, alternative tissues could be used to indicate the genetic status of the brain. Performance of the technology is another factor to consider when analyzing the tissues.

Musculoskeletal problems need more attention in deep brain stimulation for Parkinson’s disease

Background and Objectives: This study aimed to examine factors of poor outcome by analyzing the outcomes of bilateral subthalamic deep brain stimulation in Parkinson’s disease after 3 years. Methods: We assumed that patients who could not manage independent life in their best stimulationon/medication-on condition after a defi ned period might not have been a good surgical candidate. A poor outcome is defi ned as a failure to maintain functional independence at three years during a stimulation-on/medication-on state. Results: A total of 84 patients underwent bilateral subthalamic deep brain stimulation and all were followed up for 3 years. We excluded one patient who had intracranial hemorrhage. Twenty-one patients of the 83 patients could not keep up independent life even during their best condition for the following reasons: freezing in 15 patients, dementia in 5, depression in 3, musculoskeletal problems in 7, and cancer in one patient. Conclusions: Many patients could not keep up independent life during their best condition as early as three years after deep brain stimulation. Musculoskeletal problems were one major cause of disabilities, as were freezing and dementia. We emphasize that musculoskeletal problems need more attention in the preoperative screening of deep brain stimulation candidates and during the follow up.

Use of the Pill Questionnaire to detect cognitive deficits and assess their impact on daily life in patients with Parkinson’s disease

The Pill Questionnaire (PillQ) has been proposed as a simple way to evaluate cognitive deficits and their impact on the daily lives of those with Parkinson’s disease (PD) by asking patients or caregivers about whether patients can independently manage their pills. We used the PillQ to investigate the association of ability to manage medication with cognition and activities of daily living (ADLs) in patients with PD. Patients were divided into two groups based on PillQ scores. The no-impact group was able to take their antiparkinsonian medication independently, and the impact group exhibited problems describing their treatment or taking their drugs independently. A total of 208 participants (93 men) were included. 111 patients (53.4%) were included in the no-impact group, and 97 (46.6%) were included in the impact group. The impact group showed significantly lower cognitive functioning, difficulties with the performance of ADLs, and severe motor dysfunction. PillQ scores were significantly correlated with Mini-Mental State Examination and the Montreal Cognitive Assessment, and Clinical Dementia Rating scores. Management of medication by PD patients is associated with cognitive function, and the PillQ is an easy and useful test for detecting cognitive impairment and its impact on daily life.

Prevalence and Characteristics of Nonmotor Symptoms in Korean Parkinson's Disease Patients and Its Relationship With Experience of Alternative Therapies

BACKGROUND: The aim of this study was to determine the prevalence and characteristics of nonmotor symptoms (NMS)and alternative therapies (ATs) in Korean PD and to elucidate its association. METHODS: Demographic, social, and motor (Hoehn and Yahr stage; HY stage, motor section of Unified Parkinson Disease Rating Scale; mUPDRS) and NMS questionnaire were recorded in all PD patients (N=50) without significant cognitive impairment. RESULTS: Mean age and HY stage were 70.1 years and 2.3. Mean total numbers of positive NMS (tNMS) per patient was 12.9 and all patients had at least five NMS (range, 5-25). The most common items were nocturia (82%), constipation (70%) and memory disturbance (66%). Urinary (68%) domain was the most frequently involved. The tNMS was higher in female and in the group with higher mUPDRS score. Sleep and depression/anxiety domains were more involved in women. 63% of patients had experienced ATs and among them 29% of patients used ATs simultaneously. Health related food (32%), herbal medicine (32%), ginseng (32%) and acupuncture (23%) were the most commonly used. There was no association between ATs usage and demographic, social, motor and nonmotor characteristics. Among the ATs users, 20% of patients reported the effectiveness of ATs but the mean ATs costs was 12.4 fold higher than the medical costs. CONCLUSIONS: We suggest that mean tNMS is higher in Korean PD patients comparing with other previous studies. Women might be more vulnerable to NMS than men expecially in sleep and depression/anxiety. We couldn't found the associated between usage of ATs and clinical variables including NMS.

Striatal Dopaminergic Functioning in Patients with Sporadic and Hereditary Spastic Paraplegias with Parkinsonism

Sporadic spastic paraplegia (SSP) and hereditary spastic paraplegia (HSP) belong to a clinical and genetically heterogeneous group of disorders characterized by progressive spasticity and weakness in the lower extremities. The symptoms are associated with pyramidal tract dysfunction and degeneration of the corticospinal tracts. Parkinsonism is uncommon in SSP/HSP patients. However, both disorders are associated with damage to the nigrostriatal dopaminergic system. In the present study, the clinical features of patients with SSP/HSP were investigated, and nigrostriatal dopaminergic binding potential was assessed using dopamine transporter (DAT) single-photon emission computer tomography (SPECT). Nine patients with spastic paraplegia participated in the present study. The subjects underwent DAT SPECT using the agent [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato (3-)-N2,N20,S2,S20]oxo-[IR-(exo-exo)])-[99mTc]technetium ([99mTc]TRODAT-1). The [99mTc]TRODAT-1 SPECT images of five patients appeared normal, whereas the images of four patients revealed reduced striatal ligand uptake. Among the four patients with reduced uptake, two had parkinsonism, and one exhibited periodic limb movements and restless leg syndrome. Our DAT SPECT imaging study shows that reduced DAT density may be observed in patients with parkinsonism. The results of the present study offer an explanation for the spectrum of spastic paraplegia symptoms and the progression of the disorder.

Meningitis by Toxocara canis after Ingestion of Raw Ostrich Liver

Recently reports on toxocariasis are increasing by serodiagnosis in Korea. A previously healthy 17-yr-old boy complained of headache, fever, dyspnea, and anorexia. He showed symptoms and signs of eosinophilic meningitis with involvement of the lungs and liver. Specific IgG antibody to Toxocara canis larval antigen was positive in serum and cerebrospinal fluid by ELISA. He took raw ostrich liver with his parents 4 weeks before the symptom onset. His parents were seropositive for T. canis antigen but had no symptoms or signs suggesting toxocariasis. This is the first report of toxocariasis in a family due to ingestion of raw ostrich liver in Korea.

Serum progranulin level in a subject carrying ‘predicted’ pathogenic PGRN mutation p.R564C

Although most of the known pathogenic mutations in the progranulin gene (PGRN) are null mutations leading to a reduction in the serum PGRN protein levels, missense mutations also have been identifi ed in patients with frontotemporal lobar degeneration and in patients with Alzheimer disease. Among these, p.R564C mutation was identifi ed in a late-onset AD patient with a reduced serum PGRN level. However, recently, we found the p.R564C mutation in a healthy control subject raising doubts whether this is a pathogenic mutation. In this report, we measured the serum PGRN levels in 20 subjects without the p.R564C mutation and in one subject with the p.R564C mutation, to determine whether the p.R564C mutation is associated with reduced serum PGRN levels. We found that the serum PGRN level in the subject with the p.R564C mutation was not reduced compared to the subjects without the p.R564C mutation. Our result reiterates that p.R564C may not be a pathogenic mutation.

No correlation between COMT genotype and entacapone benefi ts in Parkinson’s disease

Catechol-O-methyltransferase (COMT) inhibitors are used to increase the bioavailability of therapeutic L-dopa. We examined the effi cacy of entacapone in Parkinson’s disease patients who had daily “off” duration of ≤2 hours, and carried different COMT polymorphisms. A total of 168 PD patients were recruited from 19 centers. Subjects were administered with 100–200 mg of entacapone in combination with each dose of L-dopa for 2 months. The clinical effi cacy was evaluated based on the activities of daily living (ADL), score on the Unifi ed Parkinson’s Disease Rating Scale (UPDRS), Hoehn and Yahr (H&Y) stage, and Clinical Global Impression (CGI). COMT polymorphisms were genotyped. 3-O-methyldopa (3-OMD) levels were measured before and after the administration of entacapone. Entacapone administration produced signifi cant improvements in the total daily “on” duration, ADL, UPDRS score, and H&Y stage. Nineteen patients (11.3%) had the low-activity COMT genotype, 68 patients (40.5%) had the intermediate-activity COMT genotype, and 81patients (48.2%) had the high-activity COMT genotype. The effi cacy, and adverse effects of entacapone therapy did not differ between the three groups. There was a signifi cant reduction in 3-OMD, but this did not differ among the three genotypes. Entacapone provided an increased “on” duration and improved motor function in all COMT genotypes.

Episodic astasia-abasia associated with hyper perfusion in the subthalamic region and dorsal brainstem

Astasia-abasia refers to the inability to stand or walk despite possessing good motor strength and conserved voluntary coordination. Although it is usually regarded as a psychogenic disorder, organic causes have been reported. Herein we describe a patient who presented with alcohol-induced episodic astasia-abasia. Interestingly, SPECT performed during an episode showed hyperperfusion in the dorsal brainstem and subthalamic region. These areas roughly coincide with the mesencephalic locomotor region and subthalamic locomotor region, respectively, and it is conceivable that abnormal neural activity in these areas is related to the symptoms in our patient.

Daily dose of dopaminergic medications in Parkinson disease: Clinical correlates and a posteriori equation

Objectives: To survey daily doses of dopaminergic medications and to draw a posteriori equation of the dose in relation to the various clinical variables in Korean patients with Parkinson disease. Methods: A multi-center cross-sectional survey was conducted over a defi ned period. Information on patient demographics and clinical features including age at Parkinson disease onset, disease duration, treatment duration and Hoehn and Yahr stage, and daily doses of anti-parkinsonian drugs was obtained from the patients’ medical records. Results: A total of 1,762 patients with Parkinson disease were recruited from 6 referral centers. The mean L-dopa equivalent daily dose (LEDD) in the whole population was 608.9 mg/day, which tended to increase linearly depending on the duration of disease and Hoehn and Yahr stage. LEDD was also signifi cantly affected by age and gender. We performed multiple linear regression analyses and devised a posteriori equation of LEDD with clinical variables. Conclusions: This survey provides systematic data for mean LEDD in Korean Parkinson disease patients. In spite of profound individual variations in LEDD, our linear regression model provides an insight about the relationship between daily doses of dopaminergic medications and various clinical features of Parkinson disease.

Alfa-Synuclein polymorphism and Parkinson’s disease in a tau homogeneous population

Background & Objective: The MAPT H1 haplotype and SNCA single nucleotide polymorphism (SNP) rs356219 have been reported to have a synergistic effect on the risk of Parkinson’s disease (PD). Because the H1/H1 genotype has been reported to predominate in Korean population, we investigated the polymorphism of rs356219 in 878 PD patients and 559 controls. Methods: The SNCA SNP rs356219 was analyzed in 878 PD patients and in 559 healthy Korean subjects. Results: The G allele of SNCA SNP rs356219 was found to contribute to PD susceptibility with odds ratios (ORs) similar to those reported previously. However, the ORs were not as large as that of the SNCA rs356219 plus MAPT H1/H1 combination reported in the literature, which cast doubt on the existence of a synergistic effect between the two genotypes in our population. Conclusions: This study supports that the G allele of the SNCA SNP rs356219 contributes to PD susceptibility as reported previously, but it does not support the presence of a synergistic interaction between SNCA and MAPT.

The G2019S LRRK2 Mutation is Rare in Korean Patients with Parkinson's Disease and Multiple System Atrophy

BACKGROUND AND PURPOSE: The LRRK2 (PARK8; OMIM607060) substitution was recently identified as a causative mutation for Parkinson's disease (PD). The pathologic heterogeneity of LRRK2-positive patients suggests that mutation of the LRRK2 gene is associated with the pathogenesis of PD and Parkinson-plus disorders, such as multiple system atrophy (MSA). We previously reported that the G2019S LRRK2 mutation-which is the most common LRRK2 mutation-was not found in a sample of 453 Korean PD patients. In the present study, we extended the screening for the G2019S mutation to a larger group of PD and MSA patients. METHODS: We performed a genetic analysis of the G2019S mutation in 877 patients with PD and 199 patients with MSA using a standard PCR and restriction digestion method. RESULTS: None of the subjects carried the G2019S mutation. CONCLUSIONS: The results of the present study support that the G2019S mutation is extremely rare in PD and is unlikely to be associated with MSA in the Korean population.

Nicotine Prevents MPTP-induced Dopaminergic Neurodegeneration

Epidemiological studies of Parkinson disease (PD) have found an inverse correlation between cigarette smoking and the risk of developing PD, which suggests that nicotine has a protective effect. Results from animal models of PD are conflicting, raising questions about a protective potential of nicotine. In this study, mice were pretreated with low-dose nicotine before MPTP administration, and examined to determine a neuroprotective potential of nicotine. The schedule of nicotine administration was selected to simulate the future human trials using this putative neuroprotective agent. Male C57Bl/6 mice were pretreated with nicotine for 5 days (0.2 mg/kg/d, i.p.). After the 5-day-pretreatment with nicotine only, nicotine and MPTP (30 mg/kg/d, i.p.) were co-administered for 1 to 5 consecutive days. The total dose of nicotine, 0.2 mg/kg/d for 6 to 10 days, is the lowest one ever studied. Tyrosine hydroxylase (TH) immunohistochemical staining of the nigral sections was performed. Over the experimental period, there was a significant reduction in the TH-positive cells. In the nicotine-MPTP group, the degree of TH neuron depletion was reduced at days 4 and 5 of co-administration. These findings suggest that the nicotinic neurotransmission on the dopaminergic neurons are promising targets for neuroprotective therapy of PD.

Association Between Parkinsonism and Participation in Agriculture in Korea

Background and purpose: Environmental factors might influence the pathogenesis of Parkinson's disease (PD) or multiple-system atrophy (MSA), and previous examinations of pesticide exposure, well-water drinking, and farming have produced inconclusive results. Because agriculture has been of considerable importance to Korean society, and hence the risk of exposure to pesticides was high in Korea, this study investigated whether such exposure is associated with elevated risks of developing PD and MSA. Methods: Two hundred and thirty-five PD patients, 133 MSA patients, and 77 normal control subjects were examined. Data concerning environmental factors were collected by face-to-face interviews using a structured questionnaire. Odds ratios (ORs) were calculated by binary logistic regression. Results: ORs for environmental risk factors for developing PD were 1.06 [95% confidence interval (CI) = 1.02-1.10] for age and 2.37 (95% CI = 1.32-4.27) for rural well-water drinking for >10 years. Smoking >10 pack-years (OR = 0.31; 95% CI = 0.11-0.64) was a preventable factor for developing PD in this study. However, no significant risk factors were identified for MSA. Conclusions: These results suggest that exposure to certain environmental risk factors plays a role in the development of PD. However, the development of MSA appears to be independent of environmental risk factors in Korean patients.