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Hyperuricemia has been identified as an independent risk factor for coronary artery disease (CAD), with a dose-response association. In this study, we explored the causal association between gout and antigout medication and the risk of incidental CAD. We sampled data from the National Health Insurance Research Database and recruited 37,091 patients as the gout cohort, and 37,091 controls. Our primary endpoint was the diagnosis of CAD during follow-up. The overall study population was followed up until CAD diagnosis, withdrawal from the National Health Insurance program, or the end of the study. Cox proportional hazards regression models were used to examine the effect of gout on the risk of CAD, represented by the HR with the 95% CI. Patients with gout were at greater risk of CAD, compared with those without gout: HR=1.49 after adjusting for potential confounders. Non-steroidal anti-inflammatory drugs and prednisolone use was associated with a reduced risk of CAD: HR=0.63 and 0.50, respectively. Patients with gout, treated with antigout medication, exhibited a reduced risk of CAD compared with non-gout patients. Among patients with gout, those on antigout therapy had 32% lower risk compared with those not on antigout therapy: adjusted HR=0.68, 95% CI 0.63 to 0.73. Gout increases the risk of CAD, and the use of antigout medication reduces CAD risk. These results indicate that gout or hyperuricemia is a modifiable risk factor for CAD.

Background: Freezing of gait (FOG) in Parkinson's disease (PD) is a devastating clinical phenomenon that has a detrimental impact on patients. It tends to be triggered more often during turning (complex) than during forwarding straight (simple) walking. The neural mechanism underlying this phenomenon remains unclear and requires further elucidation.Objective: To investigate the differences in cerebral functional magnetic resonance imaging responses between PD patients with and without FOG during explicitly video-guided motor imagery (MI) of various complex (normal, freezing) and simple (normal, freezing) walking conditions.Methods: We recruited 34 PD patients, namely, 20 with FOG and 14 without FOG, and 15 normal controls. Participants underwent video-guided MI of turning and straight walking, with and without freezing, while their brain blood oxygen level-dependent (BOLD) activities were measured. Gait analysis was performed.Results: While comparing FOG turning with FOG straight walking, freezers showed higher activation of the superior occipital gyrus, left precentral gyrus, and right postcentral gyrus compared with non-freezers. Normal controls also manifest similar findings compared with non-freezers, except no difference was noted in occipital gyrus activity between the two groups. Freezers also displayed a higher effect size in the locomotor regions than non-freezers during imagery of normal turning.Conclusions: Our findings suggest that freezers require a higher drive of cortical and locomotion regions to overcome the overinhibition of the pathways in freezers than in non-freezers. Compared with simple walking, increased dorsal visual pathway and deep locomotion region activities might play pivotal roles in tackling FOG in freezers during complex walking.

Objective: Stroke in young adults is uncommon, and the etiologies and risk factors of stroke in young adults differ from those in older populations. Smoker's paradox is an unexpected favorable outcome, and age difference is used to explain the association between smoking and the favorable functional outcome. This study aimed to investigate the existence of this phenomenon in young stroke patients.Methods: We analyzed a total of 9,087 young stroke cases registered in the nationwide stroke registry system of Taiwan between 2006 and 2016. Smoking criteria included having a current history of smoking more than one cigarette per day for more than 6 months. After matching for sex and age, a Cox model was used to compare mortality and function outcomes between smokers and non-smokers.Results: Compared with the non-smoker group, smoking was associated with older age, higher comorbidities, and higher alcohol consumption. Patients who report smoking with National Institutes of Health Stroke Scale scores of 11–15 had a worse functional outcome (adjusted odds ratio, 0.81; 95% confidence interval, 0.76 – 0.87).Conclusion: Smokers had a higher risk of unfavorable functional outcomes at 3 months after stroke, and therefore, we continue to strongly advocate the importance of smoking cessation.

Objective: Multiple system atrophy (MSA) is a neurodegenerative disorder manifesting as parkinsonism, cerebellar ataxia, and autonomic dysfunction. It is categorized into MSA with predominant parkinsonism (MSA-P) and into MSA with predominant cerebellar ataxia (MSA-C). The pathophysiology of motor control circuitry involvement in MSA subtype is unclear. Bereitschaftspotential (BP) is a feasible clinical tool to measure electroencephalographic activity prior to volitional motions. We recorded BP in patients with MSA-P and MSA-C to investigate their motor cortical preparation and activation for volitional movement.Methods: We included eight patients with MSA-P, eight patients with MSA-C, and eight age-matched healthy controls. BP was recorded during self-paced rapid wrist extension movements. The electroencephalographic epochs were time-locked to the electromyography onset of the voluntary wrist movements. The three groups were compared with respect to the mean amplitudes of early (1,500–500 ms before movement onset) and late (500–0 ms before movement onset) BP.Results: Mean early BP amplitude was non-significantly different between the three groups. Mean late BP amplitude in the two patient groups was significantly reduced in the parietal area contralateral to the movement side compared with that in the healthy control group. In addition, the late BP of the MSA-C group but not the MSA-P group was significantly reduced at the central parietal area compared with that of the healthy control group.Conclusions: Our findings suggest that patients with MSA exhibit motor cortical dysfunction in voluntary movement preparation and activation. The dysfunction can be practicably evaluated using late BP, which represents the cerebello-dentato-thalamo-cortical pathway.

Background Altered γ-aminobutyric acid signaling is believed to disrupt the excitation/inhibition balance in the striatum, which may account for the motor symptoms of Huntington's disease. Na-K-2Cl cotransporter-1 is a key molecule that controls γ-aminobutyric acid-ergic signaling. However, the role of Na-K-2Cl cotransporter-1 and efficacy of γ-aminobutyric acid-ergic transmission remain unknown in Huntington's disease. Methods We determined the levels of Na-K-2Cl cotransporter-1 in brain tissue from Huntington's disease mice and patients by real-time quantitative polymerase chain reaction, western blot, and immunocytochemistry. Gramicidin-perforated patch-clamp recordings were used to measure the Eγ-aminobutyric acid in striatal brain slices. To inhibit Na-K-2Cl cotransporter-1 activity, R6/2 mice were treated with an intraperitoneal injection of bumetanide or adeno-associated virus-mediated delivery of Na-K-2Cl cotransporter-1 short-hairpin RNA into the striatum. Motor behavior assays were employed. Results Expression of Na-K-2Cl cotransporter-1 was elevated in the striatum of R6/2 and Hdh150Q/7Q mouse models. An increase in Na-K-2Cl cotransporter-1 transcripts was also found in the caudate nucleus of Huntington's disease patients. Accordingly, a depolarizing shift of Eγ-aminobutyric acid was detected in the striatum of R6/2 mice. Expression of the mutant huntingtin in astrocytes and neuroinflammation were necessary for enhanced expression of Na-K-2Cl cotransporter-1 in HD mice. Notably, pharmacological or genetic inhibition of Na-K-2Cl cotransporter-1 rescued the motor deficits of R6/2 mice. Conclusions Our findings demonstrate that aberrant γ-aminobutyric acid-ergic signaling and enhanced Na-K-2Cl cotransporter-1 contribute to the pathogenesis of Huntington's disease and identify a new therapeutic target for the potential rescue of motor dysfunction in patients with Huntington's disease. © 2019 International Parkinson and Movement Disorder Society.

Background: This study evaluated short-term (1-month) and long-term (1-year) mortality risks associated with kidney function measured by estimated glomerular filtration rate (eGFR) levels at admission for patients with intracerebral hemorrhage. Methods: From the Taiwan Stroke Registry data, we identified and stratified patients with intracerebral hemorrhage into 5 subgroups by the eGFR levels at admission: ≥ 90, 60-89, 30-59, 15-29, and < 15 mL/min/1.73m2 or on dialysis from April 2006 to December 2016. Risks of 1-month mortality and 1-year mortality rates after intracerebral hemorrhage were investigated by the eGFR levels. Results: Both the 1-month mortality and 1-year mortality rates increased as the eGFR level decreased. The 1-month mortality rate was over 5-fold greater in patients with eGFR < 15 mL/min/1.73m2 or on dialysis than in patients with eGFR levels ≥ 90 mL/min/1.73m2 (8.31 versus 1.50 per 1000 person-days), with an adjusted hazard ratio (HR) of 4.59 [95% confidence interval (CI) = 2.71-7.78]. Similarly, the 1-year mortality rate was 7.5-fold greater in patients with eGFR < 15 mL/min/1.73m2 or on dialysis than in patients with eGFR ≥ 90 mL/min/1.73m2, with an adjusted HR of 4.54 (95% CI 2.95-6.98). Conclusion: The eGFR level can be an indicator of prognosis for patients with intracerebral hemorrhage.

Objective: Stroke in young adults is uncommon, and the etiologies and risk factors of stroke in young adults differ from those in the older populations. Smoker’s paradox is an unexpected favorable outcome, and age difference was used to explain the association between smoking and the favorable functional outcome. This study aimed to investigate the existence of this phenomenon in young stroke patients.Methods: We analyzed a total of 9,460 young stroke cases registered in the nationwide stroke registry system of Taiwan between 2006 and 2016. Smoking criteria included having a past or current history of smoking more than 1 cigarette per day for more than 6 months. After matching for sex and age, a Cox model was used to compare complications, mortality and outcomes between smokers and non-smokers.Results: Smoking was associated with older age, higher comorbidities, and higher alcohol consumption. Smoking patients with NIHSS scores of 11–15 had a worse functional outcome (adjusted OR, 0.81; 95% CI, 0.76–0.87), and smoking cessation would substantially reverse those effects.Conclusion: The smoker’s paradox definitely does not exist, and therefore we continue to strongly advocate the importance of smoking cessation.

Background: In most countries, large cerebral artery occlusion is identified as the leading cause of disability. In 2015, five large-scale clinical trials confirmed the benefit of intra-arterial thrombectomy. However, thrombectomy is a highly technical and facility-dependent procedure. Primary stroke centers need to transfer patients to comprehensive stroke centers to perform thrombectomy. The time-lapse during interhospital transfer would decrease the chance of the patient's proper recovery. Communication barriers also contribute to this delay.Aims: We used a smartphone application to overcome communication barriers between hospitals. We aimed to shorten the door-to-puncture time of interhospital transfer patients.Methods: We began using a smartphone application, “LINE,” to facilitate interhospital communication on May 01, 2018. We carried out retrospective data analyses for all the transfer patients (n = 351), with the primary outcome being the door-to-puncture time in our comprehensive stroke center (China Medical University Hospital). We compared the three periods: May 01 to Dec 31, 2017 (before the use of the smartphone application); May 01 to Dec 31, 2018 (the 1st year of using the smartphone application); and May 01 to Dec 31, 2019 (the 2nd year of using the smartphone application). We also compared the transfer data with non-transfer thrombectomies in the same period.Results: We compared 2017, 2018, and 2019 data. The total number of transfer patients increased over the years: 63, 113, 175, respectively. The mean door-to-puncture time decreased significantly, going from 109, through 102, to 92 min. Meanwhile, the mean door-to-puncture time in non-transfer patients were 140.3, 122.1, and 129.3 min. The main reason of time saving was the change of the way of communication, from point-to-point interhospital communication to hub-to-spoke interhospital communication.Conclusions: We used this smartphone application to enhance interhospital communication, changed from the point-to-point to hub-to-spoke method. It made us overcome the communication barrier and build up interhospital connection, thus shortening the door-to-puncture time. Our experience demonstrated the importance of close communication and teamwork in hyperacute stroke care, especially in interhospital transfer for thrombectomy.

Objective: Review and integrate the neurologic manifestations of the Coronavirus Disease 2019 (COVID-19) pandemic, to aid medical practitioners who are combating the newly derived infectious disease. Methods: We reviewed the clinical research, consisting of mainly case series, on reported neurologic manifestations of COVID-19. We also reviewed basic studies to understand the mechanism of these neurologic symptoms and signs. Results: We included 79 studies for qualitative synthesis and 63 studies for meta-analysis. The reported neurologic manifestations were olfactory/taste disorders (35.6%), myalgia (18.5%), headache (10.7%), acute cerebral vascular disease (8.1%), dizziness (7.9%), altered mental status (7.8%), seizure (1.5%), encephalitis, neuralgia, ataxia, Guillain-Barre syndrome, Miller Fisher syndrome, intracerebral hemorrhage, polyneuritis cranialis, and dystonic posture. Conclusions: Neurologic manifestations in COVID-19 may alert physicians and medical practitioners to rule in high-risk patients. The increasing incidence of olfactory/taste disorders, myalgia, headache, and acute cerebral vascular disease renders a possibility that COVID-19 could attack the nervous system. The cytokine secretion and bloodstream circulation (viremia) are among the most possible routes into the nervous system.

Patients with Parkinson’s disease (PD) suffer from motor and non-motor symptoms; 40% would develop dementia (PD-D). Impaired face and emotion processing in PD has been reported; however, the deficits of face processing in PD-D remain unclear. We investigated three essential aspects of face processing capacity in PD-D, and the associations between cognitive, neuropsychiatric assessments and task performances. Twenty-four PD-D patients (mean age: 74.0 ± 5.55) and eighteen age-matched healthy controls (HC) (mean age: 71.0 ± 6.20) received three computerized tasks, morphing-face discrimination, dynamic facial emotion recognition, and expression imitation. Compared to HC, PD-D patients had lower sensitivity (d’) and greater neural internal noises in discriminating faces; responded slower and had difficulties with negative emotions; imitated some expressions but with lower strength. Correlation analyses revealed that patients with advancing age, slow mentation, and poor cognition (but not motor symptoms) showed stronger deterioration in face perception. Importantly, these correlations were absent in the age-matched HC. The present study is among the first few examined face processing in patients with PD-D, and found consistent deficits correlated with advancing age and slow mentation. We propose that face discrimination task could be included as a potential test for the early detection of dementia in PD.

Background: Prior literatures have shown inflammatory bowel disease (IBD) could increase fibromyalgia (FM) risk. However, studies about gender and age distributions of FM risk among patients with IBD are rare. With large study samples, this study aimed to evaluate the FM risk among IBD patients with different gender and different age. Objective: We aim to estimate the FM risk among male and younger IBD patients with a large patient sample. Study Design: A retrospective cohort study was arranged in this research. Setting: The data used in this research were selected from the Taiwan National Health Insurance Research Database (NHIRD). Methods: From the Taiwan NHIRD, we selected 4,510 patients with IBD and 18,040 randomly gender- and age-matched patients without a history of IBD from the beginning of 2000 to the end of 2005 to analyze the development of FM over a 12-year follow-up period (2000– 2011). The Cox regression model was used to assess the effects of IBD on the risk of FM by adjusting for gender, age, and comorbidities, including hypertension, diabetes, hyperlipidemia, depression, anxiety, and sleep disorder. Results: After adjusting suitable covariates, the IBD patients had a greater FM risk (adjusted hazard ratio [aHR] 1.70, 95% confidence interval [CI] 1.59–1.83) than the controls. Male IBD patients had a higher FM risk than female IBD patients did (aHR 2.00, 95% CI 1.79–2.23 and aHR 1.52, 95% CI 1.38–1.67, respectively). The greatest age-specific FM risk occurred in the youngest IBD subgroup (≤ 39 years old) (aHR 1.92, 95% CI 1.68–2.19). Limitations: The information about personal behaviors was unobtainable in the Taiwan NHIRD. Other risk factors for cardiovascular disease that might augment FM cannot be excluded entirely in this study. Conclusion: IBD is disclosed to be correlated with an enhanced risk to develop FM, particularly in male and younger IBD patients. For preventing FM, it is necessary to pay more attention to the management of the IBD patients. Future researches are needed to further confirm the findings in this study. Key words: Inflammation, inflammatory bowel disease, fibromyalgia, Taiwan National Health Insurance Research Database

BACKGROUND Prior investigations with few cases have disclosed lack of pressure sore (PrS) formation was characteristic in amyotrophic lateral sclerosis (ALS) patients. However, studies with larger samples are lacking to ascertain this concept. OBJECTIVE To investigate whether patients with ALS have higher risk of PrS. METHODS Utilizing a Taiwan National Insurance claims data set with 23 million participants, we extracted 514 patients with ALS and 2056 controls from 1 January 2000 to 31 December 2008. Both groups were followed up until PrS occurrence during study period (2000-2011). The PrS risk was calculated with Cox proportional regression model. RESULTS The patients with ALS had a greater PrS risk (adjusted hazard ratio [aHR] = 8.82, 95% confidence interval [CI] = 4.90-15.9, P

Background and aims Renal dysfunction is a potent risk factor for cardiovascular diseases, including stroke. This study aimed to evaluate the impact of admission estimated glomerular filtration rate (eGFR) levels on short-term (1-month) and long-term (1-year) mortality in patients with acute ischemic stroke. Methods From the Taiwan Stroke Registry data, we classified ischemic stroke patients, identified from April 2006 to December 2015, into 5 groups by eGFR at admission: ≥ 90, 60–89, 30–59, 15–29, and Results Among 52,732 ischemic stroke patients, 1480 died within one month. The 1-month mortality rate was over 5-fold greater in patients with eGFR Conclusions After acute ischemic stroke, patients with reduced eGFR are at elevated risks of short-term and long-term deaths in a graded relationship.

Background Colonic diverticular disease is a chronic gastrointestinal disorder. Previous studies have suggested that chronic gastrointestinal tract is involved in the pathophysiology of Parkinson's disease. Object This study investigated the potential link between colonic diverticular disease and risk of Parkinson's disease. Methods Data in this nationwide population-based cohort study were obtained from the National Health Insurance Research Database. Patients with colonic diverticular disease were identified from among 23.22 million insured Taiwanese residents who had been diagnosed between 2000 and 2005 and were aged ≥20 years ( n = 23367). The comparison cohort included patients without colonic diverticular disease, matched by sex, age, and all comorbidities with the colonic diverticular disease patients cohort ( n = 23367). Using univariable and multivariable Cox proportional hazard regression models, we estimated the adjusted hazard ratio (aHR) for PD with a 95% confidence interval (CI) after adjusting for age, sex, and all of comorbidities. Results The risk of Parkinson's disease was higher in the CDD cohort than in the comparison cohort (HR = 1.27, 95%CI = 1.10–1.47). Compared with patients aged ≥65 years without CDD, the CDD patients in the equal age group had a 1.25-fold increased risk of PD (95% CI = 1.07–1.46). Conclusion Colonic diverticular disease may be associated with an increased risk of Parkinson's disease. Thus, the risk of this neurodegenerative disease should be considered in patients with colonic diverticular disease.

Background: Disruptions in gamma-aminobutyric (GABA) acid signaling are believed to be involved in Huntington's disease pathogenesis, but the regulation of GABAergic signaling remains elusive. Here we evaluated GABAergic signaling by examining the function of GABAergic drugs in Huntington's disease and the expression of GABAergic molecules using mouse models and human brain tissues from Huntington's disease. Methods: We treated wild-type and R6/2 mice (a transgenic Huntington's disease mouse model) acutely with vehicle, diazepam, or gaboxadol (drugs that selectively target synaptic or extrasynaptic GABAA receptors) and monitored their locomotor activity. The expression levels of GABAA receptors and a major neuron-specific chloride extruder (potassium-chloride cotransporter-2) were analyzed by real-time quantitative polymerase chain reaction, Western blot, and immunocytochemistry. Results: The R6/2 mice were less sensitive to the sedative effects of both drugs, suggesting reduced function of GABAA receptors. Consistently, the expression levels of α1/α2 and δ subunits were lower in the cortex and striatum of R6/2 mice. Similar results were also found in 2 other mouse models of Huntington's disease and in Huntington's disease patients. Moreover, the interaction and expression levels of potassium-chloride cotransporter-2 and its activator (brain-type creatine kinase) were decreased in Huntington's disease neurons. These findings collectively suggest impaired chloride homeostasis, which further dampens GABAA receptor-mediated inhibitory signaling in Huntington's disease brains. Conclusions: The dysregulated GABAergic responses and altered expression levels of GABAA receptors and potassium-chloride cotransporter-2 in Huntington's disease mice appear to be authentic and may contribute to the clinical manifestations of Huntington's disease patients. © 2017 International Parkinson and Movement Disorder Society

Chronic inflammation, which changes the neurotransmitter metabolism and kindles neuroendocrine system dysfunction in the central nervous system, might cause fibromyalgia (FM) formation. In FM patients without traditional FM risk factors, such as hypertension, hyperlipidemia, diabetes, sleep disorder, depression, and anxiety, the chronic inflammatory process is a possible risk factor for FM. Thus, we investigated whether chronic osteomyelitis (COM), a disease characterized by chronic inflammation, increases FM risk. Including data for 1 million enrollees, the Longitudinal Health Insurance Database was used, and 1,244 COM patients without FM history and 4,976 randomly selected sex- and age-matched control subjects without COM or FM history were extracted. The development of FM over a 13-year follow-up period from 1999 to 2011 was evaluated, and FM risk was estimated using the Cox proportional regression model. The aforementioned FM risk factors were more common in COM patients, who had a significantly greater FM risk than did the control subjects. Compared with those who had no associated risk factors, patients with COM had a greater FM risk than did the control subjects (adjusted hazard ratio [aHR] = 1.32, 95% confidence interval [CI], .99–1.75). Younger people had an even greater risk (age younger than 35 years: aHR = 1.58, 95% CI, 1.03–2.44; age 60 years or older: aHR = 1.03, 95% CI, .78–1.36). To our knowledge, this is the first study to link COM to an enhanced risk of FM development. The results imply that COM is a predictor of FM, suggesting that close follow-up for patients with COM is required to prevent FM, especially in younger populations. Perspective COM is associated with the augmented risk of developing FM, and rigorous treatments for COM patients might decrease the future risk of FM formation, especially in those with relatively younger ages.

Introduction: Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant, cerebellar degeneration predominant disease caused by excessive CAG repeats. We examined event-related dysynchronization/synchronization (ERD/ERS) in patients with SCA3. Methods: We assessed ERD/ERS of self-paced voluntary hand movements in 15 patients with genetically proven SCA3 in comparison with healthy controls. Results: In ERS, a significant interaction effect between group, frequency, and period (F = 1.591; p = 0.005; ρI = 0.86) was observed. The post-hoc two-tailed independent t-test showed significant differences in high beta and low beta ERS. By contrast, in ERD, no apparent differences were observed in the pattern of patients with SCA3 in comparison with healthy controls (F = 1.01; p = 0.442). Conclusion: The study revealed a decreased ERS in patients with SCA3, especially at the frequency of 20–30 Hz. This study elucidates the significant role of cerebellum in motor control.

The time to initiate intravenous thrombolysis for acute ischemic stroke is generally limited to within 4.5 hours after the onset of symptoms. Some trials have suggested that the treatment window may be extended in patients who are shown to have ischemic but not yet infarcted brain tissue on imaging.We conducted a multicenter, randomized, placebo-controlled trial involving patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging. The patients were randomly assigned to receive intravenous alteplase or placebo between 4.5 and 9.0 hours after the onset of stroke or on awakening with stroke (if within 9 hours from the midpoint of sleep). The primary outcome was a score of 0 or 1 on the modified Rankin scale, on which scores range from 0 (no symptoms) to 6 (death), at 90 days. The risk ratio for the primary outcome was adjusted for age and clinical severity at baseline.After 225 of the planned 310 patients had been enrolled, the trial was terminated because of a loss of equipoise after the publication of positive results from a previous trial. A total of 113 patients were randomly assigned to the alteplase group and 112 to the placebo group. The primary outcome occurred in 40 patients (35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo group (adjusted risk ratio, 1.44; 95% confidence interval [CI], 1.01 to 2.06; P = 0.04). Symptomatic intracerebral hemorrhage occurred in 7 patients (6.2%) in the alteplase group and in 1 patient (0.9%) in the placebo group (adjusted risk ratio, 7.22; 95% CI, 0.97 to 53.5; P = 0.05). A secondary ordinal analysis of the distribution of scores on the modified Rankin scale did not show a significant between-group difference in functional improvement at 90 days.Among the patients in this trial who had ischemic stroke and salvageable brain tissue, the use of alteplase between 4.5 and 9.0 hours after stroke onset or at the time the patient awoke with stroke symptoms resulted in a higher percentage of patients with no or minor neurologic deficits than the use of placebo. There were more cases of symptomatic cerebral hemorrhage in the alteplase group than in the placebo group. (Funded by the Australian National Health and Medical Research Council and others; EXTEND ClinicalTrials.gov numbers, NCT00887328 and NCT01580839.).

Glioblastoma (GBM) is the most commonly occurring tumor in the cerebral hemispheres. Currently, temozolomide (TMZ), an alkylating agent that induces DNA strand breaks, is considered the frontline chemotherapeutic agent for GBM. Despite its frontline status, GBM patients commonly exhibit resistance to TMZ treatment. We have recently established and characterized TMZ-resistant human glioma cells. The aim of this study is to investigate whether curcumin modulates cell apoptosis through the alternation of the connexin 43 (Cx43) protein level in TMZ-resistant GBM. Overexpression of Cx43, but not ATP-binding cassette transporters (ABC transporters), was observed (approximately 2.2-fold) in TMZ-resistant GBM cells compared to the Cx43 levels in parental GBM cells. Furthermore, at a concentration of 10[Formula: see text][Formula: see text]M, curcumin significantly reduced Cx43 protein expression by about 40%. In addition, curcumin did not affect the expression of other connexins like Cx26 or epithelial-to-mesenchymal transition (EMT) proteins such as [Formula: see text]-catenin or [Formula: see text]E-catenin. Curcumin treatment led to an increase in TMZ-induced cell apoptosis from 4% to 8%. Importantly, it did not affect the mRNA expression level of Cx43. Concomitant treatment with the translation inhibitor cycloheximide (CHX) exerted additional effects on Cx43 degradation. Treatment with the autophagy inhibitor 3-MA (methyladenine) did not affect the curcumin-induced Cx43 degradation. Interestingly, treatment with the proteasome inhibitor MG132 (carbobenzoxy-Leu-Leu-leucinal) significantly negated the curcumin-induced Cx43 degradation, which suggests that curcumin-induced Cx43 degradation occurs through the ubiquitin-proteasome pathway.

BackgroundDystonia is a neurological syndrome typically resulting in abnormal postures.ObjectivesWe tested the role of physical injury as potential risk factor for development of dystonia using The National Health Insurance Research Database of Taiwan.MethodsWe identified 65704 people who were coded in the database as having had peripheral traumatic injuries (ICD-9-CM 807-848 and 860-959) in the year 2000. Patients with traumatic brain or spine injuries were excluded from analysis. We matched them using purposive sampling with 65704 people in the database who had not suffered peripheral trauma. We looked then at the incidence of dystonia occurring at least 1 year from the date of the peripheral trauma until 2011. Psychiatric symptoms (depression and anxiety) and sleeps difficulties have been investigated as potential covariates.ResultsWe found 189 patients with dystonia (0.28%) in the trauma group, and 52 patients with dystonia (0.08%) in the non-trauma group. Trauma was independently associated with dystonia (adjusted HR = 3.12, 95% CI = 2.30-4.24). The incidence density of dystonia in the trauma group was 2.27 per 10000 person-years, while it was 0.71 per 10000 person-years in the non-trauma group Beyond the peripheral trauma, other variables associated to the incidence of dystonia included female sex, aged 40 years and above, depression and sleep disorders.ConclusionThese data from a large population dataset support traumatic injury as a risk factor for the development of dystonia.

Aim: LG72 can increase mitochondrial ROSs and oxidative stress has been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS). The serum level of LG72 or LG72-related molecules might therefore be associated with ALS. Here, we aim to determine the serum autoantibody against LG72 has potential as a biomarker for the diagnosis of ALS. Materials: Seventy-eighty patients with ALS, 45 patients with AD, 43 patients with PD and 88 healthy adults were enrolled. Results: The concentration of serum autoantibody against LG72 was more than fourfold lower in ALS than other control groups (p < 0.001). The AUC was 0.9627 when the cut-off value for autoantibody concentration was 0.167 μg/ml. Conclusion: This finding suggests that the autoantibody against LG72 might serve as a surrogate biomarker for ALS.

Robot-assisted gait training (RAGT) systems offer the advantages of standard rehabilitation and provide precise and quantifiable control of therapy. We examined the clinical outcome of RAGT and analyzed the correlations between gait analysis data and event-related desynchronization (ERD) and event-related synchronization (ERS) in patients with chronic stroke. We applied the Berg balance scale (BBS) and analyzed gait parameters and the ERD and ERS of self-paced voluntary leg movements performed by patients with chronic stroke before and after undergoing RAGT. A significant change was observed in BBS (p = 0.011). We also showed preliminary outcomes of changes in gait cycle duration (p = 0.015) and in ipsilesional ERS in the low-beta (p = 0.033) and high-beta (p = 0.034) frequency bands before and after RAGT. In addition, correlations were observed between BBS and ipsilesional ERS in the alpha and low-beta bands (r = &minus, 0.52, p = 0.039, r = &minus, 0.52, p = 0.040). The study demonstrated that RAGT can improve balance and provided an idea of the possible role of brain oscillation and clinical outcomes in affecting stroke rehabilitation.

Objectives According to the data of Organisation for Economic Cooperation and Development, almost all the countries got increased medical expenditures in these years. Among the diseases, migraine is a condition that affects predominantly young and middle-aged people. It results in great economic losses. So we perform this research to investigate the acupuncture effect of reducing medical expenditure and medical resources use. Perspective Acupuncture is a non-pharmacologic treatment and it became popular in recent years. In Taiwan, about 13% migraine patients visited acupuncture doctor. We hypothesized that the acupuncture had the additional effect than the medical treatment. Setting We analysed the economic cost and medical visits in the real word. Methods We used national cohort data from Taiwan, retrospectively gathered between 2000 and 2010. We selected newly diagnosed migraine patients who were diagnosed by registered neurologists formally licensed by the Taiwan Neurological Society. We divided these patients into two groups: with and without acupuncture treatment. The main outcome was medical expenditures and visits within 1 year after acupuncture. Results In migraine patients who received acupuncture treatment, medical expenditures on emergency care and hospitalization were significantly lower than the group without acupuncture treatment. Conclusion According to our real-world data, acupuncture can reduce the medical expenditure in migraine patients within 1 year after diagnosis. For the health policy maker, it is cost effective to encourage combining acupuncture and western medicine to treat migraine patients. For the doctors in routine clinical practice, who may consider to consult acupuncture doctors to deal with the migraine patients together.

OBJECTIVE: Previous electrophysiological and psychophysical tests have suggested that somatosensory integration is abnormal in dystonia. Here, we hypothesised that this abnormality could relate to a more general deficit in pre-attentive error/deviant detection in patients with dystonia. We therefore tested patients with dystonia and healthy subjects using a mismatch negativity paradigm (MMN), where evoked potentials generated in response to a standard repeated stimulus are subtracted from the responses to a rare "odd ball" stimulus. METHODS: We assessed MMN for somatosensory and auditory stimuli in patients with cervical dystonia and healthy age matched controls. RESULTS: We found a significant group ∗ oddball type interaction effect (F (1, 34) = 4.5, p = 0.04, ρI = 0.63). A follow up independent t-test for sMMN data, showed a smaller sMMN amplitude in dystonic patients compared to controls (mean difference control-dystonia: -1.0 µV ± 0.3, p

A 23-year-old man presented to our clinic with acute left-sided numbness for one week. He had been given a diagnosis of lymphoma as a child and had been in remission for more than 10 years. The neurologic examination showed decreased sensation to pinprick over the left side of the patient’s face

Background: Inflammation may trigger migraine development through neurovascular reactions in the brain. Most of the migraine patients, particularly the younger ones, do not have any risk factors for this disease. Hence, we assessed whether chronic osteomyelitis (COM), a chronic inflammatory disease, increases the risk of migraine. Objective: We aim to evaluate the risk of migraine among female and middle-age COM patients with a large patient sample. Study Design: A retrospective cohort study was conducted in this study. Setting: The data used in this study were extracted from the Taiwan National Health Insurance (NHI) Research Database. Methods: A study group with 2,012 COM patients and 8,048 randomly chosen gender- and age-matched controls were chosen from the Taiwan NHI Research Database (NHIRD) from the start of 2000 to the end of 2009. The risk of migraine was estimated with Cox proportional regression model. Both COM and control groups were followed-up until the occurrence of migraine during the study period (2000–2011). Prevalent covariates, such as age, gender, hypertension, diabetes, hyperlipidemia, stroke, coronary artery disease, depression, anxiety, sleep disorder, bipolar disorder, and epilepsy, were included for further evaluation. The hazard ratio (HR) of migraine was measured with Cox proportional hazard regression model. The primary outcome was the overall migraine risk among COM patients, and the secondary outcome was the migraine risk among COM patients lacking the comorbidities. Additional outcomes included migraine risk among COM patients in different age and gender subgroups. Results: The overall migraine risk was increased in COM patients (adjusted hazard ratio [aHR] 1.74, 95% confidence interval [CI] 1.14–2.65). Even without any prevalent comorbidities, COM patients still exhibited an increased risk of migraine (aHR 2.05, 95% CI 1.06–3.97) than the controls did. Moreover, this risk was relatively higher in COM patients aged < 40 and 45–54 years (aHR 2.07, 95% CI 0.97–4.46 and aHR 2.11, 95% CI 0.97–4.57, respectively) than in their counterparts. Female COM patients had a relatively higher migraine risk (aHR 1.85, 95% CI 1.05–3.24) than male patients did (aHR 1.68, 95% CI 0.89–3.16). Limitations: The messages about personal behaviors were unavailable in the Taiwan NHIRD. Other neurovascular risk factors that might increase migraine cannot be excluded completely in this research. Conclusion: An association between COM and increased risk of migraine was shown in this study. The results suggest that COM is a significant migraine predictor, and thus imply the necessity for rigorous migraine prevention in COM patients, especially female and younger ones. Key words: Inflammation, migraine, chronic osteomyelitis, Taiwan National Health Insurance Research Database

Objectives Parkinson's disease (PD) is a neurodegenerative disease. A decreased risk of cancer, except for melanoma, has been observed in patients with PD. The aim of this study was to evaluate the association between brain tumor and PD in a Taiwanese population. Materials and methods We used data from the National Health Insurance program of Taiwan. The PD cohort contained 2998 patients, and each patient was frequency-matched, based on age and sex, with 4 people without PD, who were randomly selected from the general population. Cox's proportional hazard regression analysis was conducted to estimate the effects of PD on the risk of brain tumor. Results The risk of developing brain tumor was significantly higher in patients with PD than in those without PD (adjusted hazard ratio = 2.11; 95% confidence interval (CI) = 1.24–3.59), and benign brain tumor exhibited a particularly elevated risk of 2.16-fold (95% CI = 1.26–3.68). The hazard ratio (HR) for developing a benign brain tumor was higher in female patients with PD than in female patients without PD, with the risk being 2.65-fold (95% CI = 1.30–5.43). An analysis of the two age groups, 50–64 years and ≥65 years, showed that the HR of only the 50–64-year group was significantly higher between the PD and non-PD groups (HR = 2.77, 95% CI = 1.07–7.14). Conclusion The present study showed that Taiwanese patients with PD are at a higher risk of developing brain tumor than the general population. The exact underlying etiologies require further investigation.

We studied the presynaptic nigrostriatal dopaminergic function using single photon emission computed tomography (SPECT) imaging of a 99mTc-TRODAT-1 (TRODAT) scan in a dopa-responsive dystonia (DRD) family with the guanosine triphosphate cyclohydrolase 1 (GCH-1) gene mutation. Clinically, there was presentation of intrafamilial variability in the DRD family. The index patient was a 10-year-old girl with classic DRD and normal presynaptic nigrostriatal dopaminergic function. However, her grandmother, a 79-year-old woman, presented with slowly progressive Parkinson’s disease (PD) without dystonic symptoms and excellent response to dopaminergic therapy for 21 years. Her brain TRODAT SPECT imaging revealed a markedly and asymmetrically reduced uptake of dopamine transporter at the bilateral striatum. Her father, a 54-year-old man, was an asymptomatic gene carrier and his brain TRODAT SPECT imaging revealed asymmetrically reduced nigrostriatal dopaminergic transmission in the bilateral striatum. We conclude variability of presynaptic nigrostriatal dopaminergic function in patients with DRD is related to their clinical heterogeneity. Significantly, impairment of presynaptic dopamine function actually occurs in the asymptomatic gene carrier.

Background Functional perturbation of the cerebellum-motor cortex (M1) interactions may underlie pathophysiology of movement disorders such as Parkinson’s disease (PD) and spinocerebellar ataxia type 3 (SCA3). Recently M1 motor excitability can be bidirectionally modulated in young subjects by corticocortical paired associative stimulation (PAS) on cerebellum and contralateral M1 with transcranial magnetic stimulation (TMS), probably through the cerebello-dentato-thalamo-cortical (CDTC) circuit. In this study, we investigated the cerebellum to M1 associative plasticity in healthy elderly, PD and SCA3. Methods Ten right-handed PD patients, nine gene-confirmed SCA3 patients and ten age-matched healthy controls (HC) were studied. One hundred and twenty pairs of TMS of the left M1 preceded by right lateral cerebellum (CB) TMS at an interstimulus interval of 2 ms (CB-M1 PAS2ms) and 6 ms (CB-M1 PAS6ms) were respectively applied with at least one week interval. M1 excitability was assessed by motor-evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and cerebellar inhibition (CBI) at the first dorsal interosseous muscle of the right hand before and after the CB-M1 PAS. Results The M1 excitability represented by MEP amplitude was significantly facilitated and suppressed in the HC group by CB-M1 PAS2ms and CB-M1 PAS6ms, respectively. The bidirectional modulation on MEP amplitude was absent in the PD and SCA3 groups. SICI and the baseline CBI were significantly reduced in the SCA3 group compared to those of the HC group irrespective of the CB-M1 PAS protocols. There was a significant reduction of CBI immediately and 60 minutes after the CB-M1 PAS protocols in the HC group but not in the patient groups. No significant change of ICF was found. Conclusions Corticocortical CB-M1 PAS can induce bidirectional motor cortical plasticity in M1 for healthy aged subjects. The modulation may be independent of the inhibitory neurocircuits such as SICI and CBI and the facilitatory mechanism like ICF. Both patients with PD and SCA3 showed impairment of such plasticity, suggesting significant functional perturbation of the CDTC circuit.

Background and aims This cohort study assessed the association between inflammatory bowel disease (IBD) and the risk of future ischemic stroke. Methods The IBD cohort comprised adult patients (≥ 20 years old) who had received either ambulatory or inpatient care between 1998 and 2011 and IBD-free controls were randomly selected from the general population and frequency matched according to age, sex, and index year (included 18,392 patients with IBD and 73,568 control patients). Both cohorts with ischemic stroke before the index date and the ischemic stroke cases diagnosed within one year after the index date were excluded. We observed the study patients until the incidence of ischemic stroke, death, withdrawal from the insurance program, or they were lost to follow-up, or the end of 2011. Results The risk of ischemic stroke was 1.12-fold (95% CI, 1.02–1.23) higher among the IBD cohort than among the non-IBD cohort. Compared to the subjects without IBD, the adjusted HR of ischemic stroke was 1.15 (95% CI 1.04–1.28) in the Crohn's disease (CD) patients and 1.01 (95% CI 0.84–1.21) in the ulcerative colitis (UC) group. The risk of developing ischemic stroke significantly increased with the increased frequency of IBD exacerbation and hospitalization. Furthermore, the adjusted HR among the CD patients increased in conjunction with the number of medical visits, from 1.07 to 6.36 and the adjusted HR among the UC patients also increased in conjunction with the number of medical visits, from 1.11 to 2.10. Conclusions IBD exhibited an increased risk of developing ischemic stroke.

Aim We have previously found that sarcosine, a glycine transporter I inhibitor, can improve the psychiatric symptoms of schizophrenia. In this study, we aimed to investigate whether the agent can also ameliorate neuropsychiatric symptoms of Parkinson's disease (PD) patients with dementia. Methods An 8-week, double-blind, placebo-controlled trial was conducted in patients who had PD with dementia (PD-D). Neuropsychiatric manifestations were measured before and at week 2 (V1), week 4 (V2) and week 8 (V3) after treatment. Linear regression with the generalized estimating equations was applied for data analysis. Results Fifteen patients were randomized into a sarcosine group; the other 15 into a placebo group. The generalized estimating equations model revealed significant differences in Hamilton Depression Rating Scale score (P = 0.049) at V1 and Neuropsychiatry Inventory (P = 0.039) at V2 between the treatment and placebo groups. By excluding the advanced patients from analysis, there were significant differences in Unified Parkinson's Disease Rating Scale V2 (P = 0.004) and V3 (P = 0.040), Hamilton Depression Rating Scale V1 (P = 0.014) and V2 (P = 0.047), Neuropsychiatry Inventory V1 (P = 0.002) and V2 (P

Introduction Stiff person syndrome (SPS) is a rare disease entity and the pivotal clinical features contain progressive course of fluctuating stiffness of the low back and lower limbs. Progressive encephalomyelitis with rigidity and myoclonus (PERM) is one of the unique variants of stiff person syndrome, and it was characterized with rigidity, stimulus-sensitive spasms, myoclonus, autonomic disturbance, and brainstem signs. These features resemble those of hyperekplexia. The accurate diagnosis of SPS is difficult but is crucial for the in time intervention with immunotherapy for life saving. In addition to the detection of responsible antibody, clinical electrophysiological manifestation, spasmodic reflex myoclonus, would be of great help in establishing the diagnosis. Methods Multichannel surface electromyogram (sEMG) and accelerometer recordings were conducted over the lumbar paraspinalis, rectus abdominalis, quadriceps, and hamstring muscles. Stimulus sensitive phenomenon was illustrated with accelerometer tapped over the pinprick. The signals were processed and digitized with CED power1401 with Spike2. The band pass for sEMG was set from 80 Hz to 1000 Hz. Results The results demonstrated that episodes of spontaneous onset of spasm of the low trunk and legs lasted about seconds to minutes. Stimuli with nose tip tapping, would elicit vigorous jerks with dissemination of long lasting muscle spasm of the neck, paraspinal muscle, rectus abdominalis muscle, to quadriceps and hamstring muscles in a descending spreading pattern. The unique electrophysiological manifestations illustrate the characteristic feature of spasmodic reflex myoclonus. The surface EMG recording also showed the phenomena of habituation, in which a trend of amplitude decrescendo from the first toward the third EMG responses were observed during consecutive auditory stimulus. The serum levels of anti-glutamic acid decarboxylase 65 antibodies was 164 IU. Conclusion The unique EMG pattern can help identify SPS. The clinical features of spasmodic reflex myoclonus are similar to hyperekplexia. However, there are some differences between the two phenomena. Unlike hyperekplexia, the spasmodic reflex myoclonus can be habituated after repetitive stimulation in the SPS patient. Furthermore, the initial myoclonic bursts of spasmodic reflex myoclonus were not present in hyperekplexia and the EMG burst duration was much shorter of the hyperekplexia as compared with that of spasmodic reflex myoclonus. These neurophysiological features discern spasmodic reflex myoclonus from hyperekplexia and are helpful in making diagnosis of SPS.

Aim The aim of this study was to investigate the possible association between benzodiazepine (BZD) use and risk of incident stroke by utilizing data from 2000 to 2003 from the National Health Insurance system of Taiwan. Methods Study subjects consisted of 38 671 patients with new BZD use and 38 663 people without BZD use who were frequency-matched for age, sex and baseline comorbidity with BZD users. All subjects had no history of stroke. Each study patient's case was followed until a new diagnosis of stroke was made or until the patient was censored by loss to follow up, death, or termination of insurance. The study lasted until the end of 2009. A Cox proportional hazards regression model was used to estimate the incidences and hazard ratios (HR) of stroke. Results The HR of hemorrhagic stroke was significantly lower in the BZD group when compared with the non-BZD group. For patients aged 20–39 years, the HR of ischemic stroke was significantly higher in the BZD group when compared with the non-BZD group. Compared to the non-BZD group, patients with a lower annual dosage (

In a previous multinational, randomized, double-blind, double-dummy study, levodopa–carbidopa intestinal gel (LCIG) was tolerable and significantly improved ‘off’ time in advanced Parkinson’s disease (PD) patients. However, efficacy and safety in the Asian population has not yet been demonstrated. In this open-label study, efficacy and safety of LCIG were assessed in Japanese, Korean, and Taiwanese advanced PD patients with motor complications not adequately controlled by available PD medication. The patients were treated with LCIG monotherapy for 12 weeks. The primary end point was the mean change from baseline to week 12 in ‘off’ time, as reported in the PD Symptom Diary, normalized to a 16 h waking day and analyzed by a mixed-model repeated-measures analysis. Adverse events (AEs) were recorded. Thirty-one patients were enrolled (23 Japanese, 4 Taiwanese, 4 Korean) and 28 (90%) completed the study. For those who completed the study, the mean (s.d.) total daily levodopa dose from LCIG was 1,206.3 (493.6) mg/day at final visit (n=28); last observation carried forward (n=30) was 1,227.6 (482.8) mg/day. There was a significant mean change (s.d.) of −4.6 (3.0) hours of ‘off’ time from baseline (mean (s.d.)=7.4 (2.3)) to week 12 (n=29), P

Parkinson’s disease (PD) and essential tremor (ET) are characterized with motor dysfunctions. Motor circuit dysfunctions can be complementarily investigated by paired associative stimulation (PAS)-induced long-term potentiation (LTP)-like plasticity and diffusion tensor imaging (DTI) of the corticospinal tract (CST). Three groups of twelve subjects with moderate severity PD, ET with intention tremor and healthy controls (HC) were studied. The primary motor cortex (M1) excitability, measured by motor evoked potential (MEP) amplitude and by short-interval and long-interval intracortical inhibition (SICI and LICI) was compared between the three groups before and after PAS. The DTI measures of fractional anisotropy (FA) and mean diffusivity (MD) were acquired. PAS effects and DTI data were simultaneously examined between groups. PAS increased MEP amplitude in HC but not in PD and ET. SICI and LICI were significantly reduced after PAS irrespective of groups. No significant differences of the mean FA and MD were found between groups. There was no significant correlation between the PAS effects and the DTI measures. Findings suggest that both PD and ET with intention tremor have impairment of the associative LTP-like corticospinal excitability change in M1. The microstructure of the CST is not relevant to the deficiency of M1 associative plasticity in PD and ET.

Because of dopaminergic neurodegeneration, patients with Parkinson’s disease (PD) show impairment in the recognition of negative facial expressions. In the present study, we aimed to determine whether PD patients with more advanced motor problems would show a much greater deficit in recognition of emotional facial expressions than a control group and whether impairment of emotion recognition would extend to positive emotions. Twenty-nine PD patients and 29 age-matched healthy controls were recruited. Participants were asked to discriminate emotions in Experiment 1 and identify gender in Experiment 2. In Experiment 1, PD patients demonstrated a recognition deficit for negative (sadness and anger) and positive faces. Further analysis showed that only PD patients with high motor dysfunction performed poorly in recognition of happy faces. In Experiment 2, PD patients showed an intact ability for gender identification, and the results eliminated possible abilities in the functions measured in Experiment 2 as alternative explanations for the results of Experiment 1. We concluded that patients’ ability to recognize emotions deteriorated as the disease progressed. Recognition of negative emotions was impaired first, and then the impairment extended to positive emotions.

The sub-thalamic nucleus (STN) is relevant to the preparation of movement ignition but its role in movement termination is uncertain. Fourteen patients with Parkinson's disease (PD) received local field potentials (LFPs) recording at the left STN on the fourth day after deep brain stimulation surgery. They performed phasic and tonic movements of the right wrist extensor. Movement onset (Mon) and movement offset (Moff) of the electromyographic activities were used as triggers to determine an eight-second LFPs epoch for time-frequency analysis. Movement-related power changes were assessed by repeated measures analysis of variance with within-subject factors of Event (Mon and Moff), Period (ten time periods for phasic movement and six time periods for tonic movement), and Frequency (alpha, low-beta, and high-beta). There was significant triple interaction in both the phasic and tonic movements. By post-hoc analysis, high-beta event-related de-synchronization (ERD) appeared earlier (3 s prior to Mon) than those of low-beta and alpha for the Mon phasic movement. There was no alpha ERD for the Mon tonic movement. Alpha, low-beta, and high-beta ERD all appeared about 1 s prior to the Moff tonic movement. The current findings suggest that STN participates in the preparation of volitional movement termination but via a different mechanism from that in movement initiation. Unlike asynchronous ERD frequency bands present in movement initiation, a simultaneous ERD across wide frequency bands in STN may play a pivotal role in terminating volitional movement.

Background: Little is known about the relationship between polypharmacy and Parkinson's disease (PD). In the present study, we tested the hypothesis that polypharmacy increases the risk of PD in older people in Taiwan. Methods: From a randomly sampled cohort of one million health insurance enrollees, we identified 2827 new cases of PD over the period 2000–2008 aged ≥65 years and selected 11 308 age-matched controls without PD. Medication history and baseline comorbidities were compared between the two groups. We defined ‘polypharmacy’ as an average daily use of five or more prescribed drugs. Results: Compared with patients using between none and one drug, the odds ratios (ORs) for PD increased to 1.53, 2.08, 2.64, and 2.95 for patients using two to four, five to seven, eight to nine, and ≥10 drugs, respectively. The other conditions associated with PD were dementia (OR 3.43), stroke (OR 2.30), depression (OR 2.15), and alcoholism (OR 2.11). Hyperlipidemia (OR 0.90) was inversely associated with PD. Conclusions: Polypharmacy was shown to increase the risk of PD in older people in Taiwan, with risk increasing with the number of medications taken daily. Dementia, stroke, depression, and alcoholism were also associated with an increased risk of PD, whereas there was an inverse correlation between PD and hyperlipidemia.

Background: Carpal tunnel syndrome (CTS), with unclear etiology, is the most common entrapment neuropathy. Its occurrence is related to lots of medical and non-medical conditions with uncertain causality. With a large population, we characterized selected demographical and clinical factors to add more information on CTS-correlated factors and new insight into future CTS prevention. Methods: A national insurance claim dataset of one million enrollees in Taiwan was used to identify 15 802 patients with CTS and 31 604 randomly selected controls, during a period of 7 years starting 1 January 2000. Statistical association with CTS was determined for five sociodemographic and nine medical factors. Results: Patients were predominantly women (65.6% vs. 47.7% in the control group) and older (40 and above, 62.6% vs. 36.2%). Rheumatoid arthritis was found to be the most significant comorbidity associated with CTS, followed by gout, hypertension, diabetes, obesity, uremia, and acromegaly. For younger group age ≤39, the association of these comorbidities was stronger, and hypothyroidism and vitamin B6 deficiency were additional comorbidities. Aging appears to reduce the relative impact of the diseases commonly associated with CTS as the possible risk factors. Conclusions: Identification of the CTS correlates in younger group would be of greater value in timely detection and treatment for these diseases. Correcting these disorders may aid in removing possible causes of CTS. This is the first report on the effect of aging on probable CTS risk factors. How factors associated with aging contribute to the development of CTS remains to be determined.

We report a case of polycythemia vera with chorea in which the brain metabolism and dopamine system were investigated using 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) and (99m)Tc-labeled tropane dopamine transporter ((99m)Tc-TRODAT-1) single photon emission computed tomography (SPECT). Along with normalization of the hematocrit and clinical symptoms after consecutive phlebotomies, the FDG PET scan and (99m)Tc-TRODAT-1 SPECT images returned towards normal. It is hypothesized that the development of polycythemia chorea is associated with a reversible alteration in the corticobasal ganglia metabolism and disturbed dopaminergic function.

Short-term exposure to a high concentration (TWA > 100 ppm) of toluene can cause hepatotocixity and neurotoxicity in humans. Data on the effects of exposure to low levels of toluene, however, are controversial. In addition, few studies on the effects of toluene exposure on the autonomic nervous system have been conducted. Urine samples from 34 male factory workers in Taiwan who were exposed to low levels of toluene either intermittently (n = 13) or continuously (n = 21) were taken on a Monday morning after a 2-day hiatus and at the end of the workweek on Friday evening. Urinary hippuric acid levels were measured using high-performance liquid chromatography (HPLC). A complete blood work-up was also performed for each subject. The prevalence and severity of neurotoxic symptoms were investigated by a self-reported questionnaire, a neuropsychiatric battery, and sympathetic and peripheral nerve function tests. The mean value of urinary hippuric acid corrected for creatinine (Cr) was 0.34 ± 0.18 g/g Cr on Monday morning and 0.43 ± 0.26 g/g Cr on Friday evening. The difference in the mean value of urinary hippuric acid between the two periods (p < 0.01) and the odds ratio of impairment of sympathetic (OR = 4.13, p = 0.11) and peripheral nerves (OR = 6.94, p = 0.074) were higher in workers continuously exposed to toluene. In addition, workers who were continuously exposed to toluene had a lower mean platelet count (216 ± 41 × 106 /µL) than workers who were intermittently exposed (252 ± 40 × 106/µL), (p = 0.018). Furthermore, there was a positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 0.35-0.66, p < 0.05) in all workers. These data suggest that continuous exposure to low levels of toluene may be associated with sympathetic and peripheral nerve dysfunction and sub-clinical hematological damage. Further research needs to be carried out regarding how chronic exposure to low-levels of toluene affects workers.

Objective Essential tremor (ET) is an involuntary postural oscillation. It is unclear to which extent motor cortical activity in preparation of volitional movement is abnormal in ET. We measured the Bereitschaftspotential (BP) to address this question. Methods Given the known influence of the cerebello-dentato-thalamo-cortical projection in the generation of the BP, patients were divided into two groups, defined by purely postural tremor (ET PT ) or additional presence of intention tremor (ET IT ) and compared to healthy controls. BP was recorded during self-paced rapid wrist extension movements. Results The late BP (500–0 ms before movement onset) was increased over the mid-frontal area in ET PT , whereas it was reduced over the mid-parietal area in ET IT when compared to healthy controls. In addition, the late BP was reduced over a widespread centro-parietal area in ET IT compared to ET PT . Conclusions Findings suggest that presence vs. absence of cerebellar signs (intention tremor) in ET results in differential affection of volitional preparatory motor cortical activity. The BP increase in ET PT may indicate compensatory activity, whereas the widespread centro-parietal BP reduction in ET IT suggests dysfunction of the cerebello-dentato-thalamo-cortical projection. Significance Reduction of the late BP amplitude may serve as a surrogate marker for dysfunction of the cerebello-dentato-thalamo-cortical projection in ET.

Objectives: Levodopa-carbidopa intestinal gel (LCIG) was developed to reduce motor complications in Parkinson’s disease (PD) caused by pulsatile levodopa plasma concentrations following oral levodopa administration. Dyskinesia and ‘wearing off’ symptoms can vary between Asian and Caucasian patients with PD, thus highlighting the importance of assessing the effectiveness of LCIG in an Asian population. Efficacy and safety of LCIG were previously assessed in a 12-week open-label study; we report the efficacy and safety of at least 52 weeks of LCIG treatment in Japanese, Taiwanese, and Korean patients with advanced PD in the ongoing extension study. Methods: In this interim analysis of a phase III, open-label, multicenter extension study in Japan, South Korea, and Taiwan [ClinicalTrials.gov identifier: NCT02082249/JapiCTI-142482], the mean change from baseline to final visit in ‘off’ time, as reported in the PD symptom diary, was normalized to a 16-h waking day. Changes in Parkinson’s Disease Questionnaire-39 (PDQ-39) summary index and domains scores were also analyzed. Adverse events (AEs) were recorded. Results: Of the 28 patients enrolled (21 Japanese, 3 Taiwanese, 4 Korean), 27 completed at least 52 total weeks of treatment, and 25 patients were continuing in the study at data cutoff. The mean [standard deviation (SD)] ‘off’ time was significantly reduced by 4.6 (3.1) h/day ( p < 0.001, n = 28). Patients experienced significant improvements in quality of life, as recorded by the mean change from baseline in PDQ-39 summary index ( p < 0.001). All patients had at least one AE; three patients (11%) discontinued due to an AE. There were two deaths (sepsis and drowning), both of which the investigator considered unrelated to LCIG treatment. Conclusions: These data suggest that LCIG treatment is efficacious, safe, and well tolerated in Japanese, Taiwanese, and Korean patients with advanced PD, thus confirming the consistency of LCIG treatment in patients with advanced PD.

Cognitive functions of 24 patients with early onset parkinsonism (age of onset before 40 years) and 24 controls were investigated by a battery of neuropsychological tests. Patients were shown to be impaired in performance IQ (PIQ), conceptual ability and regulation behavior, memory, visuospatial perception, and manual dexterity. Patients were also shown to have a higher Zung Depression score. However, analysis of the testing scores appeared to indicate that only a small portion of poor performance on neuropsychological tests are depression related. The results demonstrated that patients with early onset parkinsonism, in whom the factor of aging is not as important, still show cognitive dysfunction and suggested that Parkinson's disease itself can cause cognitive impairment.

Botulism is a rare but serious paralytic disease caused by botulinum toxin. We report an outbreak of type B botulism in Taiwan in 2006. There were five cases involved in this outbreak. They present ileus and acute cranial nerve dysfunction including dysphagia and blurred vision. One of them had severe neurologic impairment and required mechanical ventilatory support. No patient received antitoxin administration because of delayed diagnosis. The food specimen revealed positive botulism toxin B. There were no fatalities. Consumption of fermented food was significantly associated with this outbreak. We also reviewed the characteristics of cases with botulism in Taiwan since 1985.

Objective Movement-related cortical potentials (MRCP; nomenclature of MRCP components according to Shibasaki and Hallett (Shibasaki H, Hallett M. What is the Bereitschaftspotential? Clin Neurophysiol 2006;117:2341–56) were studied in patients with Machado–Joseph disease (MJD) to elucidate the pathophysiology of voluntary movement. Methods We studied nine genetically proven MJD patients and eight age-matched healthy subjects. Multi-channel electroencephalogram (EEG) recordings were obtained during self-paced fast extensions of the wrist. EEG epochs were time-locked to electromyography (EMG) onset or offset of the voluntary EMG burst and averaged. Results In the MJD patients, the early Bereitschaftspotential (early BP, −1500 to −500 ms) was not affected but the late BP was reduced over the central midline area and contralaterally to the movement side. The amplitude of the fpMP, a post-movement MRCP component, was also reduced. In addition, the offset cortical potential in the first 500 ms after EMG offset (Moff + 500) was attenuated bilaterally over a wide cortical area. Conclusions Findings suggest that cortical activations associated with the initiation and termination of a voluntary movement are impaired in MJD patients. Significance Abnormalities of pre- and post-movement MRCP components provide researchers with pathophysiological insight into voluntary motor dysfunction in MJD.

Study objective Recently, the pathogenesis of Parkinson disease (PD) has been focused on microglial activation, especially the subsequent increase of cytokines. A body of clinical evidence suggests that sleep is altered in patients with PD; however, there is a lack of understanding of the basic cellular mechanism. This study was designed to elucidate the influence of brain interleukin (IL)-1beta on sleep changes, in addition to the dopaminergic and gamma-aminobutyric acid (GABA)-ergic systems, in an animal PD model. Design We employed a long-term subcutaneous infusion of rotenone, a mitochondrial complex-I inhibitor, to induce a parkinsonism-like model in rats. Behavioral tests and tyrosine hydroxylase immunocytochemistry were used for confirmation of PD in this animal model. Pharmacologic agonist and antagonists were administered centrally to test the involvement of dopamine, GABA, and IL-1 in rotenone-induced sleep alteration. Protein expression of cytokines, ie, IL-1beta and tumor necrosis factor alpha (TNF-alpha), in 5 distinct brain regions was also determined by Western blot and enzyme-linked immunosorbent assay (ELISA). Setting Sleep-recording equipment in the National Taiwan University and China Medical University. PARTICIPANT AND INTERVENTIONS: Male Sprague-Dawley rats were implanted with electroencephalogram electrodes, a thermistor, and an intracerebroventricular guide cannula. Chronic infusion of rotenone was given by an Alzet minipump implanted subcutaneously on the back of each rat. Measurement and results We found that locomotion activity was reduced, slow-wave sleep (SWS) was increased during the dark (active) phase and decreased during the light (rest) period, and rapid eye movement sleep (REM) was enhanced in the dark period after rotenone treatment. This rotenone PD animal model successfully causes loss of tyrosine hydroxylase-immunopositive neurons in the substantia nigra; induces the events of sleep disturbance, such as excessive daytime sleepiness and insomnia during the nighttime, that are seen in patients with PD; and suppresses locomotion. Our results that intracerebroventricular administration of dopamine and blockade of GABA in the brain have less significant effect on rotenone-induced sleep alteration suggest that the sleep disturbance is not primarily mediated by the disruption of dopaminergic and GABAergic systems in the current PD rat model. The expression of TNF-alpha was not altered by rotenone. However, the results of enhanced expression of IL-1beta in the hypothalamus after rotenone and that of the blockade of sleep alteration, but not the locomotion activity, by intracerebroventricular administration of an IL-1 receptor antagonist implies that increased IL-1beta in the hypothalamus mediates sleep alteration, but not the locomotion, in rats with rotenone-induced parkinsonism. Conclusion These observations suggest that rotenone-induced sleep-wake alteration is dominated by central increase of somnogenic IL-1.

Background Dopa-responsive dystonia (DRD) is a clinical syndrome characterized by early onset dystonia and a dramatic response to relatively low doses of levodopa. The autosomal dominant DRD is caused by mutations in the gene coding GTP cyclohydrolase 1 (GCH1), the enzyme that catalyzes the first step in the biosynthesis of tetrahydrobiopterin. We herein report a novel gene mutation causally links to DRD. Subject and Methods A 23-year-old woman, presented with a history of gait abnormality and leg dystonia at age 15. Her symptoms were worsened especially in recent 2 years prior to visiting neurological clinic. In view of typical diurnal variation of dystonia, a therapeutic trial with levodopa was given and there was a dramatic response. Hence, a diagnosis of DRD was tentatively made. In addition, her father has leg dystonia since his 14 years old with leg tremor. Her 2 uncles and probably her 2 grandaunts also have limbs tremor. Genetic analysis by using PCR-direct sequencing revealed a novel point mutation (c.263G>T: p. Arg88Leu) in GCH1, including her father and asymptomatic eldest sister. Conclusion We here report a Taiwanese family afflicted with DRD due to a novel missense mutation of the GCH1. The clinical features are considerably variable within the family. The findings extend the genotypic and clinical spectrum of DRD.

Introduction Parkinson's disease dementia (PDD) contributes to poor quality of life and increases the mortality risk. Early detection and diagnosis of PDD are essential for clinical care. Methods We recruited patients with idiopathic Parkinson's disease (PD), who underwent clinical assessments and neuropsychological tests, at 12 teaching hospitals in Taiwan. Probable PDD was diagnosed according to the Movement Disorder Society Task Force clinical criteria. Using binary logistic regression, we selected significant items from an original 30-item informant questionnaire. We utilized these items, along with a simple cognitive test, to discriminate between PDD and nondemented PD (PD-ND). Results Among the 265 PD patients (156 men, 109 women, mean age 71.9 ± 9.1 years), 102 and 163 patients were diagnosed with probable PDD and PD-ND, respectively. The mean education of participants was 8.8 ± 5.3 years, and the mean disease duration was 5.5 ± 5.4 years. When the patients fulfilled either of the following criteria: (1) a score ≥ 3 for the five endorsed screening questions, (2) a score of 1–2 for the five above screening questions combined with a score ≤ 10 items for category verbal fluency, the sensitivity and specificity of the PDD screening tool were 80.4% and 80.4%, respectively. The area under the receiver operating characteristic curve (AUC) was 0.804. We tested this screening tool in another 137 unrelated PD patients and the sensitivity, specificity, and AUC were 77.4%, 96.4%, and 0.869, respectively. Conclusion The “PDD-5S” is a brief and useful screening tool for PDD.