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Objective Safinamide is a selective, reversible monoamine oxidase B inhibitor with demonstrated efficacy and tolerability in placebo-controlled studies and is clinically useful for patients with motor fluctuations. This study evaluated the efficacy and safety of safinamide as a levodopa adjunct therapy in Asian patients with Parkinson’s disease.Methods Data from 173 Asian and 371 Caucasian patients from the international Phase III SETTLE study were included in this post hoc analysis. The safinamide dose was increased from 50 mg/day to 100 mg/day if no tolerability issues occurred at week 2. The primary outcome was the change from baseline to week 24 in daily ON-time without troublesome dyskinesia (i.e., ON-time). Key secondary outcomes included changes in Unified Parkinson’s Disease Rating Scale (UPDRS) scores.Results Safinamide significantly increased daily ON-time relative to placebo in both groups (least-squares mean: 0.83 hours, p = 0.011 [Asians]; 1.05 hours, p < 0.0001 [Caucasians]). Motor function relative to placebo (UPDRS Part III) improved significantly in Asians (-2.65 points, p = 0.012) but not Caucasians (-1.44 points, p = 0.0576). Safinamide did not worsen Dyskinesia Rating Scale scores in either subgroup, regardless of the presence or absence of dyskinesia at baseline. Dyskinesia was largely mild for Asians and moderate for Caucasians. None of the Asian patients experienced adverse events leading to treatment discontinuation.Conclusion Safinamide as a levodopa adjunct is well tolerated and effective in reducing motor fluctuations in both Asian and Caucasian patients. Further studies to investigate the real-world effectiveness and safety of safinamide in Asia are warranted.

Objective: The study was undertaken to identify a monogenic cause of early onset, generalized dystonia. Methods: Methods consisted of genome-wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain magnetic resonance imaging, and protein expression studies in skin fibroblasts from patients. Results: We identified a heterozygous variant, c.388G>A, p.Gly130Arg, in the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) gene, segregating with early onset isolated generalized dystonia in 5 patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded 2 unrelated Caucasian patients with an identical heterozygous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G>C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A>C, p.Asn32Thr. These 3 missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In 3 patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (protein kinase R [PKR]) that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR-mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA (protein interferon-inducible double-stranded RNA-dependent protein kinase activator A), the product of another gene causing monogenic dystonia. Interpretation: We identified EIF2AK2 variants implicated in early onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2α pathway in the pathogenesis of dystonia. ANN NEUROL 2021;89:485–497.

Modern technological applications, including exergames and virtual technology-assisted rehabilitation (VTAR) programmes, are promising for Parkinson's disease (PD) rehabilitation. However, evidence regarding their efficacy for rehabilitation is inconclusive.This network meta-analysis (NMA) investigated the efficacy of exergames and VTAR on gait and balance outcomes and acceptability for patients with PD.ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed, ScienceDirect, Web of Science and ClinicalTrials.gov.Randomised controlled trials (RCTs) investigating changes in gait or balance parameters were included in this study.In the NMA, standardised mean differences with 95% confidence intervals were calculated using a frequentist model. GRADE ratings were used to evaluate the quality of evidence in this study.Twenty-three RCTs with 949 participants were included. Exergames and VTAR were associated with significantly better improvements in balance and gait outcomes than usual treatment and other active control interventions. However, exergames were not associated with changes in depressive symptoms. The evaluation of acceptability results indicated that all exergames and VTAR were adequately tolerated, as indicated by the low drop-out rates.Small sample sizes and heterogeneity were the key limitations of this study.This NMA confirmed that exergames are associated with more favourable gait and balance outcomes in patients with PD compared with usual treatment and other active control interventions. GRADE ratings revealed that most direct, indirect and overall network evidence was of low to medium quality. Larger-scale studies with longer follow-up periods are warranted.

AIM To explore the effect of home-based exercise on motor symptoms (MS), non-motor symptoms (NMS), and health-related quality of life (HRQOL) in Parkinson's disease (PD) patients. METHODS This study was a randomized control trial with a convenience sample of 98 PD patients. Data were collected at baseline and interventions after 4 and 8 weeks. The exercise group was instructed to perform 150 min/week of exercise at home; the control group maintained their regular lifestyle. Questionnaires measured MS, NMS, and HRQOL. We also compare compliance and non-compliance subgroups of the exercise group. The generalized estimating equation (GEE) was used to determine the exercise effect of 120 and 150 min per week after testing for exercise times was at six time points (90-140 min). RESULTS The exercise (n = 49) and control groups (n = 49) were homogeneous except for disease stage at baseline. Significant differences were found for depression, HRQOL, motor ability, activity of daily living, and fatigue (p

To explore the effect of home-based exercise on motor symptoms (MS), non-motor symptoms (NMS), and health-related quality of life (HRQOL) in Parkinson's disease (PD) patients.This study was a randomized control trial with a convenience sample of 98 PD patients. Data were collected at baseline and interventions after 4 and 8 weeks. The exercise group was instructed to perform 150 min/week of exercise at home; the control group maintained their regular lifestyle. Questionnaires measured MS, NMS, and HRQOL. We also compare compliance and non-compliance subgroups of the exercise group. The generalized estimating equation (GEE) was used to determine the exercise effect of 120 and 150 min per week after testing for exercise times was at six time points (90-140 min).The exercise (n = 49) and control groups (n = 49) were homogeneous except for disease stage at baseline. Significant differences were found for depression, HRQOL, motor ability, activity of daily living, and fatigue (p .000) between the exercise and control groups, and also between the compliance and non-compliance subgroups (p .05). The GEE revealed that exercising 150 min/week significantly improved HRQOL, depression, motor ability, ADL, fatigue, and sleep quality (p .05), though not anxiety, and exercising 120 min/week was also effective.This home-based exercise was effective in improving MS, NMS, and HRQOL. We recommend PD patients to exercise 30-50 min at least three times a week, or 10-15 min per session daily, to accumulate 120-150 min per week.

Spinocerebellar ataxia type 3 (SCA3) is a fatal neurodegenerative disease for which no identified effective treatment or prevention methods exist. However, low-dose growth hormone (GH) therapy, as a potential off-label use, may deter the progress of SCA3. SCA3 15Q and SCA3 84Q transgenic mice harboring a YAC transgene that expresses the human ATXN3 gene with a pathogenic expanded 15 CAG repeat and 84 CAG repeat motif, respectively, were recruited. SCA3 15Q transgenic mice were considered as the healthy control group, whereas low-dose GH- and PBS-treated SCA3 84Q transgenic mice were considered as the study and sham groups, respectively. The SCA3 84Q transgenic mice were administered intraperitoneal injections of GH or PBS weekly from the postnatal age of 9 months–18 months. After 9 months of GH treatment in the SCA3 84Q transgenic mice, all locomotor functions including rotarod test, behavior box analysis were restored. The GH-treated SCA3 84Q transgenic mice revealed more preserved Purkinje cells/cerebellar cortex and less ataxin-3 aggregation, DNA oxidative, cell apoptosis compared with the PBS-treated SCA3 84Q transgenic mice. GH therapy may be one of the potential off-labeled using in the alleviation of SCA3 progression.

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.

To survey AOAN member countries regarding their organizational structure, postgraduate neurology training program, and resources for neurological care provision.A cross-sectional survey using a 36-item questionnaire was conducted among country representatives to AOAN from August 2015 to August 2016.A total of 18/20 AOAN member countries participated in the survey. All the countries have organized association with regular meetings, election of officers and neurology training program. In 9/18 countries, professionals other than neurologists were eligible for affiliation. In 11/18 countries, prior Internal medicine training (or equivalent postgraduate housemanship) is prerequisite to neurology program. Recertification examination is not a practice, but submission of CME is required in 7/18 countries to maintain membership. 12/18 countries publish peer-reviewed journals with at least 1 issue per year. Subspecialty training is offered in 14/18 countries. The ratio of neurologist to population ranges from 1:14,000 to as low as 1:32 million with 9/18 having1 neurologist per 100,000 population. 6/18 countries have at least 1 specialized center solely for neurological diseases. In government-funded hospitals, the lag time to be seen by a neurologist and/or obtain neuroimaging scan ranges from 1day to 3months. All except one country have several medical- and lay- advocacy or support groups for different neurological conditions.The data generated can be used for benchmarking to improve neurological care, training, collaborative work and research in the field of neurosciences among the AOAN member countries. The paper presented several strategies used by the different organizations to increase their number of neurologists and improve the quality of training. Sharing of best practices, academic networking, exchange programs and use of telemedicine have been suggested.

We investigated the impact of serum cholesterol levels on 30-day mortality after ischemic stroke in dialysis patients.From the Taiwan Stroke Registry data, we identified 46,770 ischemic stroke cases, including 1101 dialysis patients and 45,669 nondialysis patients from 2006 to 2013.Overall, the 30-day mortality was 1.46-fold greater in the dialysis group than in the nondialysis group (1.75 versus 1.20 per 1000 person-days). The mortality rates were 1.64, .62, 2.82, and 2.23 per 1000 person-days in dialysis patients with serum total cholesterol levels of 120 mg/dL, 120-159 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively. Compared to dialysis patients with serum total cholesterol levels of 120-159 mg/dL, the corresponding adjusted hazard ratios of mortality were 4.20 (95% confidence interval [CI] = 1.01-17.4), 8.06 (95% CI = 2.02-32.2), and 6.89 (95% CI = 1.59-29.8) for those with cholesterol levels of 120 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively.Dialysis patients with serum total cholesterol levels of ≥160 mg/dL or 120 mg/dL on admission are at an elevated hazard of 30-day mortality after ischemic stroke.

Background: Clinical and epidemiological studies suggest that two of the most common geriatric diseases, type 2 diabetes and Parkinson’s disease (PD), are linked. These studies notably suggest that treatment of insulin resistance in type 2 diabetes may beneficially modify the pathophysiology of PD and help to maintain motor and nonmotor function. In this meta-analysis, we evaluate the efficacy of new antidiabetic agents in the treatment of PD. Methods: We systematically searched PubMed, Medline, ProQuest, ScienceDirect, ClinicalKey, and Cochrane Library from the date of their inception until 15 March 2020. Multiple efficacy parameters were compared between treatment groups. The results are expressed as mean differences with 95% confidence intervals (CIs) in a random-effects model. Results: A meta-analysis of the data extracted from three randomized control trials revealed that treatment with exenatide yielded significant improvements in scores on the Unified Parkinson’s Disease Rating Scale Part I (UPDRS-I) (−0.438, 95% CI, −0.828 to −0.048, p = 0.028), UPDRS Part IV (UPDRS-IV) (−0.421, 95% CI, −0.811 to −0.032, p = 0.034) and the Mattis Dementia Rating Scale (MDRS) (−0.595, 95% CI, −1.038 to −0.151, p = 0.009). At the 12-month follow-up, the UPDRS Part III (UPDRS-III) scores in the off-medication phase revealed significant improvements in patients using exenatide (−0.729; 95% CI, −1.233 to −0.225, p = 0.005). Treatment with pioglitazone did not yield significant improvements in UPDRS, MDRS, or Parkinson’s Disease Questionnaire scores. Conclusion: This meta-analysis suggests that exenatide use is associated with the alleviation of cognitive, motor and nonmotor symptoms. However, long-term studies with a large sample size of patients with PD of varying severity are required.

Rationale: Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset progressive muscle disorder typically characterized by ptosis, difficulty in swallowing, and proximal limb weakness. Underdiagnosis of OPMD is common in Asian countries and results in delayed diagnoses and fatal events. Patient concerns: Here, we report the case of a 53-year-old female who suffered from progressive dysphagia and experienced several choking events involving solid material. An extensive family history of dysphagia was noted, and 2 family members had died as a result of aspiration. Diagnoses: PABPN1 genotyping and DNA sequence analysis revealed a heterozygous (GCG)10(GCA)3GCG mutation that led to the diagnosis of OPMD. Interventions: Rehabilitation exercises, namely, the Shaker exercise and the Masako maneuver, were suggested. Outcomes: Improved swallowing ability with safe food intake was noted after 2 months of training. Surgical intervention will be considered when progression of the disease is noted. Lessons: Underdiagnosis and a lack of awareness of OPMD may lead to choking, aspiration pneumonia, and death in multiple members of affected families. Currently, there is no definitive treatment for OPMD, but rehabilitation exercises and surgical intervention are helpful in relieving dysphagia.

Background: Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)–defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH). Methods: An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population. Results: A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52–1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor. Conclusions: Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01994720.

Homeobox genes encode transcription factors that regulate embryonic development programs including organogenesis, axis formation and limb development. Previously, we identified and cloned a mouse double homeobox gene, Duxbl, whose homeodomain exhibits the highest identity (67 %) to human DUX4, a candidate gene of facioscapulohumeral muscular dystrophy (FSHD). Duxbl proteins have been shown to be expressed in elongated myocytes and myotubes of trunk and limb muscles during embryogenesis. In this study, we found that Duxbl maintained low expression levels in various adult muscles. Duxbl proteins were induced to express in activated satellite cells and colocalized with MyoG, a myogenic differentiating marker. Furthermore, Duxbl proteins were not detected in quiescent satellite cells but detected in regenerated myocytes and colocalized with MyoD and MyoG following cardiotoxin-induced muscle injury. Ectopic Duxbl overexpressions in C2C12 myoblast cells promoted cell proliferation through mainly enhancing cyclin D1 and hyper-phosphorylated retinoblastoma protein but reducing p21 expression. However, Duxbl overexpression in C2C12 cells inhibited myogenic differentiation by decreasing MyoD downstream gene expressions, including M-cadherin, MyoG, p21 and cyclin D3 but not MyoD itself. Duxbl overexpressions also promoted cell proliferation but blocked MyoD-induced myogenic conversion in multipotent mesenchymal C3H10T1/2 cells. In addition, results of a luciferase reporter assay suggest that Duxbl negatively regulated MyoG promoter activity through the proximal two E boxes. In conclusion, these results indicate that Duxbl may play a crucial role in myogenesis and postnatal muscle regeneration by activating and proliferating satellite and myoblast cells.

Pleckstrin 2 (PLEK2), one of the pleckstrin homology domain proteins, have been suggested to modulate actin rearrangement and cell spreading in T lymphocytes. Recently studies also implicated that PLEK2 paly an importance role in human myeloproliferative neoplasms, melanoma, and lung cancers. PLEK2 mRNA genes were related to poor overall survival in lung adenocarcinoma patients. However, the biological functions of PLEK2 in lung cancer is not clear. We detected the expression of PLEK2 in various lung adenocarcinoma cell lines using quantitative RT-PCR methods. Molecular manipulations were performed to investigate the roles of PLEK2 in lung cancer cells. Over-expression of PLEK2 in lung cancer cells exhibited markedly promoting in the proliferation and anchorage independent growth, whereas reduced of PLEK2 was found to suppress lung cancer cell progression. This studies also indicated that PLEK2 may play an important role in the epithelial-mesenchymal transition (EMT) features, including a morphological change, increased invasive and migratory ability, reduction the epithelial marker expression and up-regulated EMT regulators. Our results suggested that PLEK2 expression induce lung cancer cell EMT phenomenon through up-regulation Snail1 expression. These results will provide information and help us to understand the roles of PLEK2 in lung cancer cells. Citation Format: En-Chu Liu, Tsai-Tu Lee, Shey-Lin Wu, Tai-Lin Lee, Meng-Feng Tsai. PLEK2 promotes epithelial mesenchymal transition through increasing Snail1 in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1035.

Far infrared radiation (FIR) is currently investigated as a potential therapeutic strategy in various diseases though the mechanism is unknown. Presently, we tested if FIR mediates beneficial effects in a cell model of the neurodegenerative disease spinocerebellar ataxia type 3 (SCA3). SCA3 is caused by a mutation leading to an abnormal polyglutamine expansion (PolyQ) in ataxin-3 protein. The consequent aggregation of mutant ataxin-3 results in disruption of vital cell functions. In this study, neuroblastoma cells (SK-N-SH) was transduced to express either non-pathogenic ataxin-3-26Q or pathogenic ataxin-3-78Q proteins. The cells expressing ataxin-3-78Q demonstrated decreased viability and increased sensitivity to metabolic stress in the presence rotenone, an inhibitor of mitochondrial respiration. FIR exposure was found to protect against these effects. Moreover, FIR improved mitochondrial respiratory function, which was significantly compromised in ataxin-3-78Q and ataxin-3-26Q expressing cells. This was accompanied by decreased levels of mitochondrial fragmentation in FIR treated cells, as observed by fluorescence microscopy and protein expression analysis. Finally, the expression profile LC3-II, Beclin-1 and p62 suggested that FIR prevent the autophagy inhibiting effects observed in ataxin-3-78Q expressing cells. In summary, our results suggest that FIR have rescuing effects in cells expressing mutated pathogenic ataxin-3, through recovery of mitochondrial function and autophagy.

Background Diabetes is associated with an increased risk of developing dementia. However, data on the patients with newly diagnosed type 2 diabetes are limited. Objective To investigate the relationship between newly diagnosed type 2 diabetes and the risk of developing dementia, ischemic stroke and intracranial hemorrhage after disease diagnosis and the interrelationship between dementia and the stroke events. Method Data were collected from the National Health Insurance Research Database of Taiwan. The study cohort included 3717 patients newly diagnosed with type 2 diabetes and 37,170 age- and sex-matched comparison patients from the same period. All patients were tracked for 7 years following their index visit in 2000–2001. Result After adjusting for potential confounders, dementia risk was approximately 63% higher (hazard ratio [HR], 1.63; 95% CI, 1.33–1.99) among newly diagnosed type 2 diabetic patients than among comparison subjects. Newly diagnosed type 2 diabetes also increased the risk of developing ischemic stroke but not intracranial hemorrhage. About 43.6% of diabetic patients who developed dementia also had ischemic stroke during the follow-up period, higher than the rate 29.6% in the comparison group. Conclusion This study shows that newly diagnosed type 2 diabetes is associated with a 63% higher future risk of dementia during the 7-year follow-up period. The high dementia and ischemic stroke overlap rate in the diabetic study group suggests vascular events play an important role in the pathogenesis of developing dementia.

Granulocyte colony-stimulating factor (G-CSF) may protect ischemic brain injury either in animal or human. No studies have reported that endogenous G-CSF (enG-CSF) level is related to the severity of ischemic stroke. This study was designed to assess the severity of ischemic patients correlated with the alteration of enG-CSF on the 1st day after an ischemic event. Patient's plasma enG-CSF and scoring of National Institute of Health Stroke Scale were measured on the 1st day after ischemic stroke. The acute ischemic stroke could significantly induce enG-GCF secretion as compared with healthy control group (16.77 vs. 22.86 μg/L, p = 0.001). Elevated enG-CSF concentration was positively correlated with the severity of stroke patients on day 1 after the event (p = 0.006; Spearman correlation coefficient = 0.268). The enG-CSF is a good biomarker for prediction of severity of acute ischemic stroke.

Background Carbamazepine, an anticonvulsant and a mood-stabilizing drug, is the main cause of the Stevens–Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), in Southeast Asian countries. Carbamazepine-induced SJS–TEN is strongly associated with the HLA-B*1502 allele. We sought to prevent carbamazepine-induced SJS–TEN by using HLA-B*1502 screening to prospectively identify subjects at genetic risk for the condition. Methods From 23 hospitals in Taiwan, we recruited 4877 candidate subjects who had not taken carbamazepine. We genotyped DNA purified from the subjects' peripheral blood to determine whether they carried the HLA-B*1502 allele. Those testing positive for HLA-B*1502 (7.7% of the total) were advised not to take carbamazepine and were given an alternative medication or advised to continue taking their prestudy medication; those testing negative (92.3%) were advised to take carbamazepine. We interviewed the subjects by telephone once a week for 2 months to monitor them ...

Donepezil has been approved for the treatment for mild-to-moderate Alzheimer's disease (AD), but the therapeutic response rate varies from 20 to 60%. A higher oral dosage was suggested to have a better therapeutic response in reported results, but the plasma concentration of donepezil was not examined with respect to the therapeutic outcomes in those studies. Therefore, we analyzed the therapeutic responses, measured by neuropsychological assessments, among 70 newly diagnosed AD patients taking donepezil (5 mg daily) in relation to their plasma concentration of donepezil, apolipoprotein E genotype, and demographic characteristics. Our results have showed 60% of recruited AD patients improved in cognition, measured by Mini-Mental Status Examination (MMSE), and 57.1% in global status, by Clinical Dementia Rating Scale (CDR) sum of boxes (CDR-SB). In cognition, compared to the improving group, the clinically worsening group had a significantly higher donepezil concentration [p = 0.022, odds ratio (OR) = 1.024, 95% CI = 1.003-1.045] and higher initial MMSE score (p = 0.007, OR = 1.330, 95% CI = 1.080-1.639). In global status, initially higher CDR-SB (p = 0.028, OR = 2.318, 95% CI = 1.096-4.903) and initially higher MMSE (p = 0.036, OR = 1.201, 95% CI = 1.012-1.425), not donepezil concentration (p = 0.883), were significantly associated with clinical worsening. Our results have indicated that the dosage of donepezil should be reconsidered for AD patients, especially those clinically worsening in cognition.

BACKGROUND: The aim of this work was to determine the effects of oral administration of dioscorea on the morphometric and mechanical properties of the femur in ovariectomised (OVX) rats. Female Wistar rats that had undergone surgery for ovariectomy were used as a model of menopause and osteoporosis. Four weeks after surgery the animals were given oral dioscorea (0, 250, 750 or 1500 mg kg−1 day−1) for 27 days, then the porosity, mineral fraction, stiffness and toughness of the femur and the ultimate force needed to break the femur were measured. RESULTS: Ovariectomy resulted in an increase in the total volume, dry weight and porosity but a decrease in the mineral fraction of femora. Subsequent chronic administration of dioscorea reversed the effect on porosity and increased the ultimate force of the femur in OVX rats but did not affect the bone properties of sham-operated rats. CONCLUSION: These results suggest that chronic administration of dioscorea may enhance bone strength and provide insight into the role of dioscorea in bone remodeling and osteoporosis during the menopause. However, the benefit is not clear for the reproductive female. Copyright © 2008 Society of Chemical Industry

The effect of honokiol, an active component of Magnolia officinalis, on glutamate release from isolated nerve terminals (synaptosomes) was examined. Honokiol potently inhibited 4-aminopyridine (4-AP)-evoked glutamate release in a concentration-dependent manner, and this effect resulted from a reduction of vesicular exocytosis and not from an inhibition of Ca2+-independent efflux via glutamate transporter. The inhibitory action of honokiol was not due to decreasing synaptosomal excitability or directly interfering with the release process at some point subsequent to Ca2+ influx, because honokiol did not alter the 4-AP-evoked depolarization of the synaptosomal plasma membrane potential or Ca2+ ionophore ionomycin-induced glutamate release. Rather, examination of the effect of honokiol on cytosolic [Ca2+] revealed that the diminution of glutamate release could be attributed to a reduction in voltage-dependent Ca2+ influx. Consistent with this, the honokiol-mediated inhibition of 4-AP-evoked glutamate release was completely prevented in synaptosomes pretreated with a wide-spectrum blocker of N-, P-, and Q-type Ca2+ channels, ω-conotoxin MVIIC. In addition, honokiol modulation of 4-AP-evoked glutamate release appeared to involve a protein kinase C (PKC) signaling cascade, in so far as pretreatment of synaptosomes with the PKC inhibitors Ro318220 or GF109203X all effectively occluded the inhibitory effect of honokiol. Furthermore, honokiol attenuated 4-AP-induced phosphorylation of PKC. Together, these results suggest that honokiol effects a decrease in PKC activation, which subsequently attenuates the Ca2+ entry through voltage-dependent N- and P/Q-type Ca2+ channels to cause a decrease in evoked glutamate exocytosis. These actions of honokiol may contribute to its neuroprotective effect in excitotoxic injury. Synapse 62:890–901, 2008. © 2008 Wiley-Liss, Inc.

This study aimed to clarify the effects of inescapable and escapable stressors on behavior and interleukin-2 (IL-2) levels in the brain. Inescapable trials, consisting of pairings of conditioned and unconditioned stimuli, were used to induce fear-conditioned stress, whereas trials of escapable pairings of conditioned and unconditioned stimuli in an active avoidance test were used as acute and conditioned stressors. IL-2 levels in the brain were analyzed by enzyme-linked immunoadsorbent assays. Inescapable and escapable stressors had different effects on behavior in the modified active avoidance test and on IL-2 levels in brain areas that are known to be involved in emotional processes. These data provide insight into the pathophysiological role of IL-2 in stress-related disorders.

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.

Background Serum fibroblast growth factor 21 (FGF21) was proven to be a useful biomarker for the presence of mitochondrial neuromuscular disease. Methods In the present study, we used the difference in the serum FGF21 level to differentiate between ataxia patients with hereditary spinocerebellar atrophy (SCA-ataxia) and those with mitochondrial syndrome (Mito-ataxia). Patients with SCA-ataxia (SCA2, SCA3) and Mito-ataxia (MELAS, MERRF, LHON, maternal inherited hearing impairment mtDNA A1555G mutation) were recruited in this study. All SCA-ataxia patients revealed a consistent pattern of cerebellar atrophy. On the contrary, some of the Mito-ataxia patients exhibited a vascular lesion with cerebellar infarction. Results Extremely higher levels of serum FGF21 were found in the Mito-ataxia patients with MERRF and MELAS diseases, but not in patients with SCA-ataxia or LHON/mtDNA A1555G mutation. The positive trend between the mtDNA heteroplasmy and serum FGF21 was indicated in either MERRF (P = 0.003, r = 0.923) or MELAS (P = 0.070, r = 0.566) patients. Conclusion Serum FGF21 can be applied as the first molecular screening among patients suspected to be victims of hereditary ataxia with neuromuscular degeneration prior to mass genetic screening.

Background Discharge disposition planning is vital for poststroke patients. We investigated clinical factors associated with discharging patients to nursing homes, using the Taiwan Stroke Registry data collected from 39 major hospitals. Methods We randomly assigned 21,575 stroke inpatients registered from 2006 to 2008 into derivation and validation groups at a 3-to-1 ratio. We used the derivation group to develop a prediction model by measuring cumulative risk scores associated with potential predictors: age, sex, hypertension, diabetes mellitus, heart diseases, stroke history, snoring, main caregivers, stroke types, and National Institutes of Health Stroke Scale (NIHSS). Probability of nursing home care and odds ratio (OR) of nursing home care relative to home care by cumulative risk scores were measured for the prediction. The area under the receiver operating characteristic curve (AUROC) was used to assess the model discrimination against the validation group. Results Except for hypertension, all remaining potential predictors were significant independent predictors associated with stroke patient disposition to nursing home care after discharge from hospitals. The risk sharply increased with age and NIHSS. Patients with a cumulative risk score of 15 or more had an OR of 86.4 for the nursing home disposition. The AUROC plots showed similar areas under curves for the derivation group (.86, 95% confidence interval [CI], .85-.87) and for the validation group (.84, 95% CI, .83-.86). Conclusions The cumulative risk score is an easy-to-estimate tool for preparing stroke patients and their family for disposition on discharge.

To compare the clinical judgment of experienced neurologists after interviewing Parkinson's disease (PD) patients and their caregivers with the use of the Pill Questionnaire to determine the presence of impairments on activities of daily living (ADL).ADL impairment is a criterion for the diagnosis of dementia associated with PD. The Pill Questionnaire has been recommended as a screening tool to assess ADL impairment in PD patients, but its usefulness and validity have not been fully investigated.We recruited idiopathic PD patients from 12 hospitals in Taiwan, and the patients underwent clinical assessments, a neuropsychological test battery and the Unified Parkinson Disease Rating Scale evaluation. The Pill Questionnaire was administered by study assistants. Patient and caregiver interviews were performed by experienced neurologists who were blinded to the Pill Questionnaire results.In total, 284 PD patients (mean age 71.8±9 years, mean education 8.7±5.3 years, mean disease duration 5.4±5.3 years) were recruited. 63 patients showed ADL impairment by the Pill Questionnaire, and 108 patients showed ADL impairment by neurologists' clinical interviews. κ Statistics showed moderate agreement between the two methods (κ=0.521, p0.001). Of the 108 patients who were diagnosed with ADL impairment by neurologists, only 56 patients (51.9%) showed impairment according to the Pill Questionnaire. Most of the missed patients had milder cognitive impairment and lower motor disability.A comprehensive interview is essential to determine the presence of ADL impairment in PD patients, especially in patients with early PD.

Purpose To report a case of embolic cilioretinal artery occlusion caused by carotid artery dissection. Design Interventional case report. Methods A 38-year-old woman presented with acute visual loss in her right eye. Funduscopy showed a cilioretinal artery occlusion, which was confirmed by a fluorescein angiography. An embolus was found in the distal segment of the vessel. Results Color Doppler images of right internal carotid artery (ICA) disclosed a pseudolumen, suggesting a diagnosis of carotid dissection. Retrobulbar color Doppler image showed relative low flow velocity in the ophthalmic artery without flow reversal. Magnetic resonance angiography and cerebral angiogram showed total occlusion of the right ICA. Follow-up visual field examination revealed an inferior central defect fed by the cilioretinal artery. Conclusion The pathogenesis of retinal artery occlusion caused by carotid dissection may be embolic or hemodynamic. In our case, a permanent visual defect was related to embolic occlusion of the cilioretinal artery.

Although restoration of mitochondrial function in mitochondrial diseases through peptide-mediated allogeneic mitochondrial delivery (PMD) has been demonstrated in vitro, the in vivo therapeutic efficacy of PMD in Parkinson's disease (PD) has yet to be determined. In this study, we compared the functionality of mitochondrial transfer with or without Pep-1 conjugation in neurotoxin (6-hydroxydopamine, 6-OHDA)-induced PC12 cells and PD rat models. We injected mitochondria into the medial forebrain bundle (MFB) of the PD rats after subjecting the nigrostriatal pathway to a unilateral 6-OHDA lesion for 21 days, and we verified the effectiveness of the mitochondrial graft in enhancing mitochondrial function in the soma of the substantia nigra (SN) neuron through mitochondrial transport dynamics in the nigrostriatal circuit. The result demonstrated that only PMD with allogeneic and xenogeneic sources significantly sustained mitochondrial function to resist the neurotoxin-induced oxidative stress and apoptotic death in the rat PC12 cells. The remaining cells exhibited a greater capability of neurite outgrowth. Furthermore, allogeneic and xenogeneic transplantation of peptide-labeled mitochondria after 3 months improved the locomotive activity in the PD rats. This increase was accompanied by a marked decrease in dopaminergic neuron loss in the substantia nigra pars compacta (SNc) and consistent enhancement of tyrosine hydroxylase-positive immunoreaction of dopaminergic neurons in the SNc and striatum. We also observed that in the SN dopaminergic neuron in the treated PD rats, mitochondrial complex I protein and mitochondrial dynamics were restored, thus ameliorating the oxidative DNA damage. Moreover, we determined signal translocation of graft allogeneic mitochondria from the MFB to the calbindin-positive SN neuron, which demonstrated the regulatory role of mitochondrial transport in alleviating 6-OHDA-induced degeneration of dopaminergic neurons.

Background Patients with Parkinson’s disease (PD) are subject to posture instability and falling. However, PD was not included as one of the risk factors in commonly used fracture risk calculation tools and the fracture rate in patients with PD was rarely reported. The aim of this study was to evaluate the risk of hip fracture in patients with PD. Methods Data were collected from the National Health Insurance Research Database of Taiwan. The study group included 394 patients with PD diagnosed in 1999–2000. The comparison cohort was comprised of 3940 age- and sex-matched patients from the same enrollment period. All patients were tracked from their index visits for eight years. Results Hip fracture developed in 10.4% of patients with PD and 4.1% of patients in the comparison cohort during the follow-up period. Log-rank test analysis showed a significantly higher rate of hip fracture in PD. The Cox proportional regression model showed an adjusted hazard ratio of 2.71 (95% confidence interval = 1.92–3.83, P Conclusion The hip fracture rate was as high as 10.4% in PD patients during 8 years follow-up period. While assessing the risk of hip fracture, PD should be taken into consideration. For those very high risk patients (elderly women with PD, osteoporosis, diabetes and diabetic neuropathy), many efforts should be made to prevent fracture.

Agrin isoforms with different bioactivities are synthesized by the nerve and the muscle. Neural agrin containing an 8-amino acid insert (z8) introduced by alternative splicing is the active form that induces synaptic differentiation at the neuromuscular junction. In addition to alternative splicing, extracellular calcium is also required for the activity of neural agrin. To understand better how the activity of agrin is regulated by alternative splicing, we have applied alanine substitution mutagenesis to the z8 insert and the calcium binding site in the minimally functional AgG3z8 fragment. Single alanine substitutions in the 4th through the 7th amino acid of the z8 splice insert significantly reduced the function of agrin, in terms of acetylcholine receptor clustering activity and the affinity for binding to the muscle surface. Mutation of the asparagine at the 4th position drastically reduces bioactivity such that it is equivalent to that of muscle form AgG3z0. These reduced activity mutants also show reduced magnitudes of the calcium-induced CD spectrum change from that observed in AgG3z8 fragments, indicating that cross-talk between calcium and the z8 insert is critical for the normal activity of agrin. However, removal of Ca(2+) binding via mutation of both aspartic acids in the calcium binding site did not totally eliminate the activity of AgG3z8. These results suggest a model wherein the z8 insert is a Ca(2+)-responsive allosteric element that is essential in forming an active conformation in neuronal agrin.

Intra-venous thrombolysis (IVT) with recombinant tissue plasminogen activator (r-tPA) is the standard treatment of acute ischemic stroke in Taiwan. However, there are many limitations to this treatment, such as the three-hour therapeutic time window and an age limit of 18 to 80 years.We reported a 15-year-old boy with vertebrobasilar artery total occlusion that presented with a sudden onset of consciousness disturbance. The accompanying findings were clonic-jerky movements of the 4 limbs and startled gazing for 10 minutes. Consciousness soon returned, but left hemiplegia and bilateral total ophthalmoplegia were noted. Brain computed tomography (CT) angiography revealed basilar artery total occlusion. Emergency intra-arterial thrombolysis (IAT) with urokinase was performed 5.3 hours after the onset. The course was smooth and the patient recovered well. He was free of symptoms at clinical follow up 30 months after the IAT.To the best of our knowledge, this is the youngest reported patient with complete basilar artery occlusion to have received IAT and achieve a complete recovery in Taiwan. Our experience might suggest that IAT is an alternative treatment for patients having acute ischemic strokes but exceeding the three-hour time window for IVT with r-tPA, even in adolescence.

Oculopharyngeal muscular dystrophy (OPMD) is a rare inherited muscular disorder, clinically characterized by late-onset, slowly progressive bilateral ptosis, dysphagia, and proximal limb weakness. A short polyalanine expansion in the polyadenylate binding-protein nuclear 1 (PABPN1) gene is a commonly reported mutation.We studied a large family with 12 affected members who inherited a dominant trait. Drooping of eye lids and dysphagia were characteristic phenotypes starting in the sixth decade. We collected blood samples from all available familial members and 30 control subjects. They were analyzed using modified polymerase chain reaction (PCR) amplification and direct sequence analysis.The abnormally extended three GCG resulting in heterozygous (GCG)9 of PABPN1 gene was identified in four affected and two asymptomatic carriers, but not in the 30 control individuals. The expansion of the PABPN1 polyalanine tract which resulted from 10 to 13 alanines was further confirmed by subcloning into TOPO cloning vectors.The phenotypic characteristics and genetic information confirmed our diagnosis of OPMD. We suggest that genetic intervention should be undertaken to understand the genetic epidemiology and provide counseling for carriers of OPMD in Taiwan.

We identified and cloned a mouse double homeobox gene (Duxbl), which encodes two homeodomains. Duxbl gene, a tandem triplicate produces two major transcripts, Duxbl and Duxbl-s. The amino acid sequences of Duxbl homeodomains are most similar to those of human DUX4 protein, associated with facioscapulohumeral muscular dystrophy. In adult tissues, Duxbl is predominantly expressed in female reproductive organs and eyes, and slightly expressed in brain and testes. During gonad development, Duxbl is expressed from embryonic to adult stages and specifically expressed in oocytes and spermatogonia. During embryonic development, Duxbl is transcribed in limbs and tail. However, Duxbl proteins were only detected in trunk and limb muscles and in elongated myocytes and myotubes. In C2C12 muscle cell line, Duxbl expression pattern is similar to differentiated marker gene, Myogenin, increased in expression from 2 days onward in differentiating medium. We suggest that Duxbl proteins play regulatory roles during myogenesis and reproductive developments. Developmental Dynamics 239:927–940, 2010. © 2010 Wiley-Liss, Inc.

Hyperactivation of N-methyl-d-aspartate receptors (NMDARs) leads to neuronal excitotoxicity and is suggested to play a role in many brain disorders, including Alzheimer's disease and schizophrenia. However, the association between polymorphisms in the genes that code for NMDAR subunits, N-methyl-d-aspartate 1 and 2B (GRIN1 and GRIN2B) and Parkinson's disease (PD) remains unclear. In a hospital-based case-control study of PD, DNA samples were collected from 101 PD patients and 205 healthy controls. Genotyping assays were used to screen for polymorphisms in the GRIN1 (rs2301364 T>C, rs28489906 T>C, and rs4880213 T>C) and GRIN2B (C366G, C2664T, and rs1805476 T>G) genes, and logistic regression analysis was then used to assess the association between these single nucleotide polymorphisms (SNPs) and PD susceptibility. None of the 6 SNPs were significantly associated with PD risk on their own. However, in conjunction with putative low-risk genotypes for the GRIN1 gene, the GRIN2BC366G variant was significantly associated with reduced PD risk compared with the homozygous genotype 366CC (OR=0.38, 95%CI=0.17-0.93, P=0.033). A synergistic effect on risk reduction was observed in subjects who carried multiple polymorphisms of GRIN1 and the GRIN2BC366G polymorphism (OR=0.78, 95%CI=0.59-1.02, P(trend)=0.073). Our results suggest that polymorphisms in the GRIN1 and GRIN2B genes may serve as potential biomarkers for a reduced risk of PD among the Chinese population in Taiwan.