Parkinson's Disease In Taiwan Research Articles

Association of ITPKB, IL1R2 and COQ7 with Parkinson's disease in Taiwan

Genetic and environmental factors play significant roles in the pathogenesis of Parkinson's disease (PD). Recently, 17 novel risk loci of PD were identified in a meta-analysis of genome-wide association study (GWAS) in the European populations. In order to clarify if these risk loci are associated with PD in Taiwanese population, we conducted a case-control study including 14 of the novel risk loci and analyzed the genetic distribution and allele frequency.A total of 2798 subjects were recruited in this study. Genotyping was performed in 672 PD patients and 609 healthy controls by using Mass ARRAY, and data of another 1517 healthy controls from Taiwan Biobank were also examined.Our results show that the dominant models of ITPKB rs4653767 (OR (95% CI) = 0.832 (0.699, 0.990), p = 0.038), IL1R2 rs34043159 (OR (95% CI) = 0.812 (0.665, 0.992), p = 0.041) and COQ7 rs11343 (OR (95% CI) = 0.304 (0.180, 0.512), p < 0.001) were associated with PD. In allelic analysis, the T allele of IL1R2 rs34043159 (OR (95% CI) = 0.873 (0.772, 0.987), p = 0.03) and T allele of COQ7 rs11343 (OR (95% CI) = 0.098 (0.040, 0.238), p < 0.001) showed lower risk of PD. After Bonferroni correction, only dominant model and T allele of COQ7 rs11343 showed significantly reduced the risk of PD.This study suggests that ITPKB, IL1R2 and COQ7 have influence on the risk of PD in Taiwan.

Cost-Effectiveness Analysis of Deep Brain Stimulation for Parkinson Disease in Taiwan

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an effective therapy for Parkinson disease (PD). However, cost-effectiveness analysis is required because most patients are older adults and decision makers must therefore consider whether the long-term effectiveness outweighs the initial cost. A Markov decision model was constructed on the basis of a societal perspective. The Hoehn and Yahr scale and Unified PD Rating Scale motor score were used in the polytomous logistic regression model. Markov Chain Monte Carlo simulation was used to initiate the probabilistic cost-effectiveness analysis. The life-year gained (LYG) in the STN-DBS group and medication group was, respectively, 2.937 and 2.632 years at the 3-year follow-up and 7.417 and 5.971 years at the 10-year follow-up. The quality-adjusted life-year (QALY) gained in the STN-DBS and medication groups was, respectively, 1.739 and 1.220 at the 3-year follow-up and 4.189 and 2.88 at the 10-year follow-up. The incremental cost-effectiveness ratio of STN-DBS compared with medication was $147,065 per LYG and $123,436 per QALY gained at the 3-year follow-up and $36,833 and $69,033 at the 10-year follow-up, respectively. STN-DBS is an optimal strategy when the willingness to pay is $150,000 per LYG and over $90,000 per QALY gained in 3 years and when the willingness to pay is over $38,000 per LYG and over $41,000 per QALY gained in 10 years. This study provided data comparing STN-DBS and medical treatment for PD with respect to LYG and QALY gained. STN-DBS was more cost-effective in terms of LYG and QALY gained according to the current gross domestic product of Taiwan.

Anxiety and Levodopa Equivalent Daily Dose Are Potential Predictors of Sleep Quality in Patients With Parkinson Disease in Taiwan.

Background and Purpose: Non-motor symptoms of Parkinson disease (PD) have a strong negative impact on the health-related quality of life (QoL) of patients with PD. Sleep disturbance is an important non-motor symptom because of its high prevalence. However, previous studies investigating the determinants of sleep quality in patients with PD have revealed inconsistent results. Our study evaluated the correlations between sleep quality in patients with PD and disease-related variables, medications used depression, anxiety, and QoL and identified the determinants of sleep disturbance in people with PD in Taiwan.Methods: A total of 134 patients with PD were recruited from the outpatient clinic. We examined the correlations between the Parkinson disease sleep scale-2 (PDSS-2) scores and different variables, namely the Unified Parkinson Disease Rating Scale, Parkinson disease questionnaire, Beck Depression Inventory, and Beck Anxiety Inventory (BAI). Logistic regression analysis was used to assess the potential predictive variables for sleep quality in patients with PD.Results: Among our participants, 47.8% were classified as poor sleepers (PDSS-2 = 15–60). Correlation analysis demonstrated that poor sleepers exhibited longer disease durations, higher levodopa equivalent daily doses (LEDDs), higher PD severity, more depression and anxiety symptoms, poorer QoL, more frequent unemployed status, higher hypnotics use, higher dependency for activities of daily living, more motor impairments, and more therapy-related complications. Logistic regression revealed that the LEDD was a significant predictive factor of sleep quality.Conclusion: Poor sleepers constituted approximately half of our patients with PD. The participants experienced more favorable sleep if they were currently working. Increased PD duration, severity, depression or anxiety symptoms, and doses of dopaminergic therapy were significantly associated with poor sleep quality. Continued working, attempts to treat comorbid anxiety or depression, and avoidance of overdosage of dopaminergic treatments may improve sleep quality in patients with PD.

Utilization of Chinese herbal medicine and its association with the risk of fracture in patients with Parkinson's disease in Taiwan

Ethnopharmacological relevanceTraditional Chinese medicine (TCM) has been used for over two thousand years to treat motor impairments corresponding to the clinical manifestations of Parkinson's disease (PD). Aim of the studyThis study aimed to investigate the prescription of Chinese herbal medicine (CHM) for the management of PD and further determine whether CHM can improve motor function and decrease the risk of incident fracture. Materials and methodsPatients older than 40 years newly diagnosed with PD between January 1997 and December 2010 were selected from the National Health Insurance Research Database (NHIRD) and followed up until the end of 2013. We used 1:1 frequency matching by age, sex, index year, and initial diagnostic year to compare the TCM users and non-TCM users. We used a Cox regression model and the Kaplan-Meier method to estimate the risk of developing fracture among the TCM and non-TCM users. ResultsIn total, 7197 patients older than 40 years were newly diagnosed with PD between 1997 and 2010 in Taiwan. Among these patients, 3456 were TCM users, and 3730 were non-TCM users. We compared 2007 PD patients with comparable demographic characteristics and comorbidity profiles between the two cohorts. During the follow-up period, compared with the non-TCM cohort, fewer patients in the TCM cohort had incident fractures (adjusted hazard ratio: 0.5, 95% CI: 0.44–0.56). The cumulative incidence of fracture was lower in the TCM cohort (log-rank test, p < 0.0001). Shi-Chang-Pu (Acorus gramineus Aiton), Yuan-Zhi (Polygala tenuifolia Willd), Bei-Mu (Fritillaria cirrhosa D. Don), Hai-Piao-Xiao (Sepiella maindronide Rochebrune; Sepia esculenta Hoyle), and Tian-Ma (Gastrodia elata Blume) constituted the core Chinese herbal medicine prescriptions used to treat PD patients. ConclusionsThe present study identified the core prescription pattern for the management of PD in Taiwan. Complementary CHM therapy was associated with a reduced risk of fracture in PD patients.

DLG2, but not TMEM229B, GPNMB, and ITGA8 polymorphism, is associated with Parkinson's disease in a Taiwanese population

Transmembrane or membrane-associated protein dysfunction is increasingly recognized as an important mechanism of pathogenesis in Parkinson's disease (PD). Previous genome-wide association studies and their meta-analysis in PD genes have identified several risk foci in transmembrane protein-encoding genes. Herein, we investigated the effect of 4 such PD-associated genetic variants reported in Caucasians, including discs-large membrane-associated guanylate kinase scaffolding protein 2 (DLG2 rs3793947), transmembrane protein 229B (TMEM229B rs1555399), glycoprotein nonmetastatic melanoma protein B (GPNMB rs199347), and integrin subunit alpha 8 (ITGA8 rs7077361). A total of 1185 Taiwanese subjects comprising 592 PD patients and 593 unrelated age-matched controls were genotyped. DLG2 rs3793947 AA genotype showed a significantly lower prevalence in female PD patients compared to the female controls (p = 0.019). The recessive model analysis also demonstrated a reduced PD risk for females in AA genotype (odds ratio = 0.573, 95% confidence interval: 0.379–0.868, p = 0.008). The frequencies of TMEM229B rs1555399 and GPNMB rs199347 genotypes and alleles were similar in PD patients and controls. ITG8 rs7077361 was not polymorphic in all subjects of this study. These data suggested that DLG2, but not TMEM229B, GPNMB, and ITGA8, influenced the risk of PD in Taiwan.

Associations of Matrix Metalloproteinase-9 and Tissue Inhibitory Factor-1 Polymorphisms With Parkinson Disease in Taiwan

Matrix metalloproteinases (MMPs) function in the degradation of extracellular matrix and are considered to play a role in the pathogenesis of neurodegenerative diseases including Parkinson disease (PD). MMPs activities are modulated by tissue inhibitors of metalloproteinases (TIMPs). This study examined whether the genetic polymorphisms of MMP-3, gelatinase (MMP-2 and MMP-9), TIMP-2, and TIMP-1 were associated with PD in Taiwan.A total of 359 PD patients and 332 controls were enrolled. The candidate genetic variants included MMP-2 rs2285053 (−735 C > T), MMP-3 rs3025058 (−1171 5A > 6A), MMP-9 rs3918241 (−1831 T > A), rs17576 (G > A, R279Q), and rs3787268 (G > A, intron), TIMP-1 rs4898 (T > C, F124F), and TIMP-2 rs7503607 (−269 G > T). Associations were tested by logistic regression, adjusted with gender and age at onset.Minor allele frequency of TIMP-1 rs4898 (36.0%) was significantly lower in the male PD patients than in the male controls (51.2%) (χ2 test, P = 0.004). When adjusted with gender and age at onset, MMP-9 rs17576 AA genotype was associated with PD susceptibility in a recessive fashion (odds ratios [OR] = 2.28, 95% confidence intervals [95% CI] = 1.12–4.62, P = 0.02). In males, TIMP-1 rs4898 C allele was associated with a protective effect on PD (OR = 0.75, 95% CI = 0.60–0.94, P = 0.014). We did not find association between the examined genetic variants of MMP-2, MMP-3, and TIMP-2 and PD susceptibility.This is the first study that demonstrated a protective effect of TIMP-1 rs4898 C allele on male PD and a modest association of MMP-9 rs17576 AA genotype with PD susceptibility in the Taiwan population. Further replication is needed for confirmation.

Association of GCH1 and MIR4697, but not SIPA1L2 and VPS13C polymorphisms, with Parkinson's disease in Taiwan

Recently, a large-scale meta-analysis of genome-wide association study (GWAS) data identified several new risk loci that can modulate the risk of Parkinson's disease (PD). These associations have yet to be examined in PD patients in Chinese or Asian population. Because ethnic-specific effect is an important concern for GWAS analysis, we genotyped single-nucleotide polymorphisms in the new genetic loci, GCH1 (rs11158026), SIPA1L2 (rs10797576), VPS13C (rs2414739), and MIR4697 (rs329648), to investigate their associations with risk of PD in Taiwan. Another single-nucleotide polymorphism GCH1 rs7155501, previously identified by GWAS listed at the top 20 genes in PDGene database was also included. A total of 1151 study subjects comprising 598 patients with PD and 553 unrelated healthy controls were recruited. The frequency of minor allele (C allele) of GCH1 rs11158026 was found to be significantly higher in PD cases than in controls (p = 0.003). The CC genotype of rs11158026 increased PD risk compared to TT genotype (odds ratio [OR] = 1.29, 95% confidence interval [CI] = 1.09, 1.53, p = 0.004). Under additive model, the GCH1 rs11158026 increased the risk of developing PD (OR = 1.30, 95% CI = 1.10, 1.54, p = 0.002). In recessive model, the genotype TT of MIR4697 rs329648 marginally decreased the PD risk (OR = 0.62, 95% CI = 0.43, 0.90, p = 0.01). The PD patients demonstrated similar genotypic and allelic frequencies in GCH1 rs7155501, SIPA1L2 rs10797576, and VPS13C rs2414739 with the controls. These findings suggest that the GCH1 and MIR4697 but not SIPA1L2 and VPS13C are genetic loci influencing risk of PD in Taiwan.

STK39, But Not BST1, HLA-DQB1, and SPPL2B Polymorphism, Is Associated With Han-Chinese Parkinson's Disease in Taiwan.

Neuroinflammation is emerging as an important pathway involved in Parkinson's disease (PD) pathogenesis. Herein, we investigated the effect of 4 top PD-associated genetic variants in Caucasians listed on the top risk loci identified by meta-analysis of genome wide-association studies in PDGene database (http://www.pdgene.org/top_results), including serine threonine kinase 39 (STK39) rs1955337, bone marrow stromal cell antigen 1 (BST1) rs11724635, major histocompatibility complex, class II, DQ beta 1 (HLA-DQB1) rs9275326, and signal peptide peptidase-like 2B (SPPL2B) rs62120679, by genotyping 596 Han-Chinese patients with PD and 597 age-matched control subjects. Compared with subjects with STK39 rs1955337 GG genotype, those with TT genotype had a 1.64-fold increased risk of PD (95% confidence interval: 1.13–2.39, P = 0.010). The recessive model also demonstrated an increased PD risk in TT genotype (odds ratio: 1.59, 95% confidence interval: 1.12–2.27) compared with the other genotypes (GT + GG). PD patients demonstrate a similar genotypic and allelic frequency in BST1 rs11724635, HLA-DQB1 rs9275326, and SPPL2B rs62120679 compared with controls. These findings suggested that the STK39 rs1955337 TT genotype is a risk factor for Han-Chinese patients with PD in Taiwan. The ethnic discrepancies of the other 3 genetic variants may indicate a distinct genetic background of neuroinflammation between PD patients in Han-Chinese and Caucasians.

Time trends in the prevalence and incidence of Parkinson's disease in Taiwan: A nationwide, population-based study.

Identifying trends in the prevalence and incidence of Parkinson's disease (PD) may yield information that supports public health goals. Our aim was to evaluate time-trend changes in the prevalence and incidence of PD in Taiwan between 2004 and 2011. This retrospective, nationwide, longitudinal study used the Taiwan National Health Insurance Research Database to identify patients with PD from 2004 to 2011 based on having ICD-9-CM diagnostic codes, which were assigned by neurologists, and being prescribed PD medication. Annual incidence and prevalence were calculated, and time-trend analyses were estimated assuming a Poisson distribution. Over the study period, 19,302 patients in 2004 and 41,606 patients in 2011 fulfilling the study criteria for PD were included in the analysis. The average age-standardized prevalence of PD per 100,000 of population was 84.8 in 2004 and 147.7 in 2011, with a 7.9% yearly increase. Increasing prevalence trends of PD were statistically significant (p<0.001) in all age groups, with the steepest rate among those aged≥80 years. In contrast, the average age-standardized incidence of PD decreased steadily from 35.3 per 100,000 in 2005 to 28.8 per 100,000 in 2011. The incidence rate was higher in men than in women, and increased with age. We identified an increasing trend in the annual prevalence rates of PD from 2004 to 2011; however, the substantial decline in the incidence of PD suggests that some major environmental risk factors for PD were removed from this population during this time period.

LRRK2 R1628P variant is a risk factor of Parkinson's disease among Han‐Chinese from mainland China

Mutations in LRRK2, the gene that encodes leucine-rich repeat kinase 2 (LRRK2), are associated with autosomal dominant and sporadic forms of Parkinson's disease (PD) and are the most common genetic causes of PD. Recently, a R1628P variant has been reported as a risk factor for PD in Taiwan and Singapore. To determine the association of this variant and PD in the Han-Chinese population from mainland China, we analyzed its frequency in a cohort of 600 patients and 459 unrelated healthy controls. Forty (6.7%) patients were heterozygous and 3 (0.5%) homozygous for the R1628P variant, which was significantly more frequent than in the controls [2.4% heterozygous and 0.0% homozygous, Odds ratio = 3.14, 95%CI: 1.60-6.17, P < 0.01]. Considering the age at onset, this difference was found only in late-onset PD (older than 50) [Odds ratio = 3.76, 95% CI: 1.90-7.45, P < 0.01]. Our data confirms that the LRRK2 R1628P variant is associated with an increased risk to develop late onset PD in the ethnic Han-Chinese population.

Novel ATP13A2 variant associated with Parkinson disease in Taiwan and Singapore

To assess the association of ATP13A2 gene mutation among patients with early onset Parkinson disease (EOPD, onset < 50 years) in ethnic Chinese population. Among 771 subjects, we studied 182 patients with EOPD and familial PD and 589 matched controls from two cohorts of Han Chinese in Taiwan and Singapore. The entire ATP13A2 coding region and intron-exon boundaries were sequenced in 71 probands and 70 controls in Taiwanese/ethnic Chinese. An additional 111 index patients with PD in Singapore and 589 controls were later screened to validate possible mutations that were found in the first set of study subjects. We identified one novel missense variant, AL746Thr, in a single heterozygous state in three patients (two were from Taiwan and one was from Singapore) (1.7% in EOPD). The variant was not observed in 589 ethnicity matched controls. The frequency of this variant was significantly higher in PD cases than controls (p = 0.01, relative risk 4.3, 95% CI 1.9-4.3). The clinical phenotype and (18)F-dopa PET image of ATP13A2 Ala78Thr carriers are similar to that seen in idiopathic PD. The variant is located between the highly conserved phosphorylation region and the fifth transmembrane domain of the ATP13A2 protein. A rare variant of the ATP13A2 was associated with an increased risk of Parkinson disease among ethnic Chinese in Asia. Further studies are needed to clarify the functional role of this genetic risk factor.

HSPA5 promoter polymorphisms and risk of Parkinson's disease in Taiwan

Endoplasmic reticulum (ER) stress induced by misfolded proteins has been implicated in Parkinson's disease (PD) pathogenesis. A malfunction of unfolded protein response (UPR) to ER stress can result in PD as well as other neurodegenerative diseases. Heat shock 70 kDa protein 5 (HSPA5) is one of the UPR chaperones reactive to ER stress to block the apoptotic process. HSPA5 promoter polymorphisms -415 G/A (rs391957), -370 C/T (rs17840761) and -180 del/G (rs3216733) and their derived haplotypes may affect promoter activity of the gene. This study examines whether these HSPA5 promoter polymorphisms are associated with the risk of Taiwanese PD and the age of disease onset using a case-control study. Polymorphisms -415 G/A and -180 del/G were completely linked in our population (D'=1.00, Delta(2)=1.00). The genotype or allele frequency distribution of each HSPA5 polymorphism was not significantly different between the controls (n=341) and the PD patients (n=393). Neither the linked -415 G/A and -180 del/G nor -370 C/T polymorphism influences PD onset age. Our data suggest that the HSPA5 -415 G/A, -370 C/T, and -180 del/G polymorphisms are unlikely to play a major role in risk of developing PD in Taiwan.

LRRK2 Gly2385Arg variant is a risk factor of Parkinson’s disease among Han‐Chinese from mainland China

Mutations in the gene encoding Leucine-rich repeat kinase 2 (LRRK2) have been recently linked with autosomal-dominant parkinsonism, and polymorphisms have been commonly associated with sporadic Parkinson's disease (PD). A p.2385G>R variant has been reported as a risk factor for PD in Taiwan, Singapore and Japan. Herein, we have assessed the frequency of this polymorphism among the ethnic Han-Chinese population in a case-control study. A total of 600 patients with PD and 334 unrelated healthy controls were genotyped using PCR-restriction fragment length polymorphism analysis. Hardy-Weinberg equilibrium of each group was calculated, and differences in genotype frequencies between groups were assessed by the Chi-square test. In the PD cohort, 70 patients (11.7%) were heterozygous and 1 (0.2%) was homozygous for the p.2385G>R variant. This was significantly more frequent than in the controls [3.3%, Odds ratio = 3.9, 95% confidence interval (CI) = 2.1-7.5, P < 0.01]. Clinically, the age of PD onset of the p.2385G>R carriers was lower than the non-carriers (P = 0.01). Our study indicates that this LRRK2 p.2385G>R substitution contributes to the development of PD in ethnic Han-Chinese population, which may play important implications for future study on molecular genetics and pathogenesis of PD.

Environmental risk factors and Parkinson's disease: a case-control study in Taiwan.

To explore environmental risk factors for Parkinson's disease (PD) in Taiwan, we investigated 120 patients with PD and 240 hospital control subjects matched with patients on age (+/-2 years) and sex. Based on a structured open-ended questionnaire, we carried out standardized interviews to obtain history of exposure to environmental factors, including place of residence, source of drinking water, and environmental and occupational exposures to various agricultural chemicals. In the univariate analysis, the history of living in a rural environment, farming, use of herbicides/pesticides, and use of paraquat were associated with an increased PD risk in a dose-response relationship. After adjustment for multiple risk factors through conditional logistic regression, the biological gradient between PD and previous uses of herbicides/pesticides and paraquat remained significant. The PD risk was greater among subjects who had used paraquat and other herbicides/pesticides than those who had used herbicides/pesticides other than paraquat. There were no significant differences in occupational exposures to chemicals, heavy metals, and minerals between PD patients and matched control subjects. The duration of drinking well water and alcohol consumption was not significantly associated with PD. There was an inverse relationship between cigarette smoking and PD. Environmental factors, especially exposures to paraquat and herbicides/pesticides, may play important roles in the development of PD in Taiwan.