Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans: A Genome-Wide Association Study.

Importance: Large-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the largest population worldwide (ie, Asian). Objectives: To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts. Design Setting, and Participants: Genome-wide association data generated from PD cases and controls in an Asian population (ie, Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea) were collected from January 1, 2016, to December 31, 2018, as part of an ongoing study. Results were combined with inverse variance meta-analysis, and replication of top loci in European and Japanese samples was performed. Discovery samples of 31 575 individuals passing quality control of 35 994 recruited were used, with a greater than 90% participation rate. A replication cohort of 1 926 361 European-ancestry and 3509 Japanese samples was analyzed. Parkinson disease was diagnosed using UK Parkinson's Disease Society Brain Bank Criteria. Main Outcomes and Measures: Genotypes of common variants, association with disease status, and polygenic risk scores. Results: Of 31 575 samples identified, 6724 PD cases (mean [SD] age, 64.3 [10] years; age at onset, 58.8 [10.6] years; 3472 [53.2%] men) and 24 851 controls (age, 59.4 [11.4] years; 11 030 [45.0%] men) were analyzed in the discovery study. Eleven genome-wide significant loci were identified; 2 of these loci were novel (SV2C and WBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association for SV2C (rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21; P = 1.17 × 10-10 in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (rs9638616; I2=67.1%; P = 3.40 × 10-3 for hetereogeneity). Polygenic risk score models including variants at these 11 loci were associated with a significant improvement in area under the curve over the model based on 78 European loci alone (63.1% vs 60.2%; P = 6.81 × 10-12). Conclusions and Relevance: This study identified 2 apparently novel gene loci and found 9 previously identified European loci to be associated with PD in this large, meta-genome-wide association study in a worldwide population of Asian individuals and reports similarities and differences in genetic risk factors between Asian and European individuals in the risk for PD. These findings may lead to improved stratification of Asian patients and controls based on polygenic risk scores. Our findings have potential academic and clinical importance for risk stratification and precision medicine in Asia.

Evaluating Mild Cognitive Dysfunction in Patients with Parkinson's Disease in Clinical Practice in Taiwan.

Our study aimed to examine the contribution of commonly used tools, including the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), and develop a formula for conversion of these tests in the Chinese population. We also create a predictive model for the detection of Chinese patients' mild cognitive impairment (MCI). We recruited 168 patients with Parkinson's disease (PD) from 12 medical centres or teaching hospitals in Taiwan, and each participant received a comprehensive neuropsychological assessment. Logistic regression analysis was conducted to find predictors of MCI with the help of a generalized additive model. We found that patients with an MMSE > 25 or a MoCA > 21 were less likely to have MCI. The discrimination powers of the two tests used for detecting MCI were 0.902 and 0.868, respectively, as measured by the area under the receiver operating characteristic curve (ROC). The best predictive model suggested that patients with a higher MMSE score, delayed recall scores of the 12-item Word Recall Test ≥ 5.817, and no test decline in the visuospatial index were less likely to have MCI (ROC = 0.982). Our findings have clinical utility in MCI detection in Chinese PD and need a larger sample to confirm.

Variability of presynaptic nigrostriatal dopaminergic function and clinical heterogeneity in a dopa-responsive dystonia family with GCH-1 gene mutation.

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.

Evaluation of the interaction between LRRK2 and PARK16 loci in determining risk of Parkinson's disease: analysis of a large multicenter study.

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted.

PDD-5S: A useful screening tool for Parkinson's disease dementia.

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.

Large-scale assessment of polyglutamine repeat expansions in Parkinson disease.

OBJECTIVES: We aim to clarify the pathogenic role of intermediate size repeat expansions of SCA2, SCA3, SCA6, and SCA17 as risk factors for idiopathic Parkinson disease (PD). METHODS: We invited researchers from the Genetic Epidemiology of Parkinson's Disease Consortium to participate in the study. There were 12,346 cases and 8,164 controls genotyped, for a total of 4 repeats within the SCA2, SCA3, SCA6, and SCA17 genes. Fixed- and random-effects models were used to estimate the summary risk estimates for the genes. We investigated between-study heterogeneity and heterogeneity between different ethnic populations. RESULTS: We did not observe any definite pathogenic repeat expansions for SCA2, SCA3, SCA6, and SCA17 genes in patients with idiopathic PD from Caucasian and Asian populations. Furthermore, overall analysis did not reveal any significant association between intermediate repeats and PD. The effect estimates (odds ratio) ranged from 0.93 to 1.01 in the overall cohort for the SCA2, SCA3, SCA6, and SCA17 loci. CONCLUSIONS: Our study did not support a major role for definite pathogenic repeat expansions in SCA2, SCA3, SCA6, and SCA17 genes for idiopathic PD. Thus, results of this large study do not support diagnostic screening of SCA2, SCA3, SCA6, and SCA17 gene repeats in the common idiopathic form of PD. Likewise, this largest multicentered study performed to date excludes the role of intermediate repeats of these genes as a risk factor for PD.

Prevalence and risk factors of cognitive impairment in Parkinson disease: a population-based case-control study in Taiwan.

The aim of this study was to evaluate the Parkinson disease (PD) prevalence of cognitive impairment in Taiwan.The case-control study consisted of 6177 cognitive impairment patients and 24,708 noncognitive impairment as controls for the period of 2006 to 2010 and both of the groups aged ≥50 years. The multivariable logistic regression analyses were used to estimate the odds ratio (OR) for cognitive impairment, and the 95% confidence intervals (CIs) among patients with PD were compared with those of non-PD patients.PD (adjusted odds ratio [aOR] is 3.07, 95% CI 2.76-3.41) is the one of the most contributed risk factors for cognitive impairment. Besides, we found a remarkable result of the diagnosed cognitive impairment of PD that was found highest in the first 6 months (aOR 11.98, 95% CI 8.51-16.86) and then decrease the incident year by year. The PD prevalence in a patient with cognitive impairment in our data present is 12.1% lower than those with truly dementia published previously and documented by western studies.We found a remarkable result of the diagnosed cognitive impairment of PD that was found highest in the first 6 months and then decrease the incident year by year.

TREM2 R47H variant and risk of essential tremor: a cross-sectional international multicenter study.

INTRODUCTION: Essential tremor (ET) is the most frequent movement disorder in adults. Its pathophysiology is not clearly understood, however there is growing evidence showing common etiologic factors with other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases (AD, PD). Recently, a rare p.R47H substitution (rs75932628) in the TREM2 protein (triggering receptor expressed on myeloid cells 2; OMIM: *605086) has been proposed as a risk factor for AD, PD and amyotrophic lateral sclerosis (ALS). The objective of the study was to determine whether TREM2 p.R47H allele is also a risk factor for developing ET. METHODS: This was a cross-sectional multicenter international study. An initial case-control cohort from Spain (n = 456 ET, n = 2715 controls) was genotyped. In a replication phase, a case-control series (n = 897 ET, n = 1449 controls) from different populations (Italy, Germany, North-America and Taiwan) was studied. Owed to the rarity of the variant, published results on p.R47H allele frequency from 14777 healthy controls from European, North American or Chinese descent were additionally considered. The main outcome measure was p.R47H (rs75932628) allelic frequency. RESULTS: There was a significant association between TREM2 p.R47H variant and ET in the Spanish cohort (odds ratio [OR], 5.97; 95% CI, 1.203-29.626; p = 0.042), but it was not replicated in other populations. CONCLUSIONS: These results argue in favor of population-specific differences in the allelic distribution and suggest that p.R47H (rs75932628) variant may contribute to the susceptibility of ET in Spanish population. However, taking into account the very low frequency of p.R47H, further confirmatory analyses of larger ET series are needed.

Spinocerebellar ataxia 35: novel mutations in TGM6 with clinical and genetic characterization.

OBJECTIVE: To elucidate the clinical and cellular characteristics of spinocerebellar ataxia type 35 (SCA35), which is caused by mutations in the TGM6 gene encoding transglutaminase 6 (TG6), in a Taiwanese cohort. METHODS: Mutations in TGM6 were ascertained in 109 unrelated probands of Chinese descent with molecularly unassigned SCA from 512 pedigrees, in whom mutations responsible for 15 other ataxia syndromes had been excluded. The clinical features of all patients with a TGM6 mutation were systematically analyzed. The biological consequences of the newly identified TGM6 mutations were investigated in HEK293 cells transfected with mutant complementary DNA constructs. RESULTS: Two missense mutations (p.R111C and p.D510H) and one 3-base pair deletion (p.E574del) in TGM6 were identified. Among them, p.R111C and p.E574del were novel. The common features of SCA35 include a slowly progressive clinical course, trunk/limb ataxia, and hand tremors. The age at onset varies from adolescence to the fifth decade. Torticollis and intellectual impairment are rare manifestations. Brain MRI reveals diffuse cerebellar atrophy without involvement of the cerebral hemispheres or brainstem. The 3 mutations identified here attenuated the protein stability and catalytic activities of TG6. CONCLUSIONS: SCA35 is an uncommon ataxia syndrome, accounting for 0.6% (3/512) of SCAs among the Han-Chinese descent in Taiwan. This study broadens the mutational spectrum of SCA35 and stresses the importance of TG6 in cerebellar functions.

Comparison of activities of daily living impairments in Parkinson's disease patients as defined by the Pill Questionnaire and assessments by neurologists.

OBJECTIVES: 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). BACKGROUND: 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. METHODS: 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. 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, p<0.001). 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. CONCLUSIONS: A comprehensive interview is essential to determine the presence of ADL impairment in PD patients, especially in patients with early PD.

Reversible oro-lingual dyskinesia related to lithium intoxication.

PURPOSE: To report the first case of Taiwanese with lithium intoxication presenting as oro-lingual dyskinesia. CASE REPORT: A 68-year-old man had bipolar disorder with chronic lithium treatment. He had acute conscious disturbance, atrial flutter, myoclunus of limbs, and oro-lingual dyskinesia. Biochemistry study revealed elevated blood urea nitrogen, creatinine, and lithium level (3.43 Eq/L). The lithium is discontinued and he received conservational treatment. Along with reduction of serum lithium level, his involuntary movement subsided following by clear consciousness. He had no residual neurological deficit in 3 years of follow up. CONCLUSION: Oro-lingual dyskinesia is a rare presentation of lithium intoxication. This case reminds us such diagnostic possibilities especially in elder patients who receive a chronic lithium therapy.

A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants.

BACKGROUND: Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. METHODS AND RESULTS: We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. CONCLUSIONS: Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

Familial paroxysmal nonkinesigenic dyskinesia: clinical and genetic analysis of a Taiwanese family.

Paroxysmal nonkinesigenic dyskinesia (PNKD) is a rare disorder in autosomal dominant inheritance. The clinical features and genetic findings of PNKD, rarely described in the Asians, were mostly delineated from European families. The present study characterized the clinical and genetic findings of a Taiwanese PNKD family. The clinical features of our five patients in successive three generations included onset age less than 10 years, attack duration between 3 min and 4h, and a variety of aura symptoms. The attacks were provoked not by sudden action but by emotional stress, caffeine, fatigue, heavy exercise and sleep deprivation. Sleep could abolish or diminish the attack and the attacks responded well to clonazepam. Sequencing the whole coding region of PNKD/MR-1 gene identified a heterozygous c.20 C>T (p.Ala7Val) mutation which was clearly segregated in the five affected patients. Comparing our patients with previously reported 18 families with PNKD/MR-1 mutations, the majority of the patients exhibited quite similar manifestations in attack patterns and precipitating factors. The recurrent conservative mutations in different ethnicities indicate importance in the pathogenesis of PNKD.

Large-scale replication and heterogeneity in Parkinson disease genetic loci.

OBJECTIVE: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. METHODS: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. RESULTS: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. CONCLUSION: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.

Generalized chorea in the syndrome of acute bilateral basal ganglia lesions in patients with diabetic uremia.

The syndrome of acute bilateral basal ganglia (BG) lesions in patients with diabetic uremia normally affects Asian patients and usually presents with parkinsonian symptoms. We report two patients with this syndrome suffering from acute generalized choreic movements. The brain MRI of both patients revealed a cytotoxic-type of edema in the bilateral BG during the acute phase of the syndrome. After supportive treatment, they completely recovered from generalized chorea and the period of hyperkinesia corresponded to the acute exacerbation of the metabolic disturbance. Follow-up brain MRI revealed complete resolution of the abnormal signal. Thus, generalized chorea may be the initial presenting symptom of the syndrome and bilateral BG lesions probably originate from cytotoxic-type edema.

Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan.

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 for symptoms. We used the estimated historical incidence of SJS-TEN as a control. RESULTS: Mild, transient rash developed in 4.3% of subjects; more widespread rash developed in 0.1% of subjects, who were hospitalized. SJS-TEN did not develop in any of the HLA-B*1502-negative subjects receiving carbamazepine. In contrast, the estimated historical incidence of carbamazepine-induced SJS-TEN (0.23%) would translate into approximately 10 cases among study subjects (P<0.001). CONCLUSIONS: The identification of subjects carrying the HLA-B*1502 allele and the avoidance of carbamazepine therapy in these subjects was strongly associated with a decrease in the incidence of carbamazepine-induced SJS-TEN. (Funded by the National Science Council of Taiwan and the Taiwan Drug Relief Foundation.).

A large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson's disease.

High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson's disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinson's disease (GEO-PD) consortium. GEO-PD sites provided clinical and genetic data including affection status, gender, ethnicity, age at study, age at examination (all subjects); age at onset and family history of PD (patients). Genotyping was performed for the five most informative SNPs spanning the Omi/HtrA2 gene in approximately 2-3 kb intervals (rs10779958, rs2231250, rs72470544, rs1183739, rs2241028). Fixed as well as random effect models were used to provide summary risk estimates of Omi/HtrA2 variants. The 20 GEO-PD sites provided data for 6378 cases and 8880 controls. No overall significant associations for the five Omi/HtrA2 SNPs and PD were observed using either fixed effect or random effect models. The summary odds ratios ranged between 0.98 and 1.08 and the estimates of between-study heterogeneity were not large (non-significant Q statistics for all 5 SNPs; I(2) estimates 0-28%). Trends for association were seen for participants of Scandinavian descent for rs2241028 (OR 1.41, p=0.04) and for rs1183739 for age at examination (cut-off 65 years; OR 1.17, p=0.02), but these would not be significant after adjusting for multiple comparisons and their Bayes factors were only modest. This largest association study performed to define the role of any gene in the pathogenesis of Parkinson's disease revealed no overall strong association of Omi/HtrA2 variants with PD in populations worldwide.

High frequency of multiexonic deletion of the GCH1 gene in a Taiwanese cohort of dopa-response dystonia.

Large deletions in the GCH1 gene have been reported in a minority of cases of dopa-responsive dystonia (DRD). In this study, we performed an extensive clinical and genetic investigation of 22 affected members in eight families. Sequence analysis revealed five different mutations in five families (n = 10); Ser81Pro (novel), Ser76X, Gly203Arg, 249del A, and IVS5 + 3insT. Applying multiple ligation-dependent probe amplification analysis, we detected a large heterozygous deletion of exons 1-3 in the remaining three families (n = 12), which was verified by quantitative real-time PCR analysis. Therefore, the large deletion accounted for 37.5% of the total families and 55% of our DRD population. The deletion appeared to have high penetrance and was associated with multifocal dystonia and adult onset in males. Adult-onset patients were commonly presenting with resting tremor, rigidity, and bradykinesia, indistinguishable from those in Parkinson's disease. In conclusion, a high frequency of multiexonic deletion of GCH1 was identified in the Taiwanese DRD population. By dosage analysis, we were able to detect a mutation in all patients. Our study demonstrates that dosage analysis is necessary for molecular diagnostics in DRD patients of Han Chinese ethnicity.

Safety/Tolerability and efficacy of rivastigmine in taiwanese patients with Alzheimer's disease: a prospective post-marketing surveillance study.

BACKGROUND AND OBJECTIVES: Rivastigmine is approved for the symptomatic treatment of mild to moderate dementia in patients with Alzheimer's disease. The drug was launched in Taiwan in 2000. The primary objective of this post-marketing surveillance (PMS) study was to describe the safety/tolerability of treatment with rivastigmine capsules in patients with Alzheimer's disease. The secondary objectives of this study were to define the optimal titration pattern, maintenance dose, efficacy and patient satisfaction with treatment with rivastigmine capsules. METHODS: This was a prospective, non-interventional post-marketing observational study in patients who met the criteria for mild or moderate Alzheimer's disease. The primary outcome measure for this trial was the incidence of emerging adverse events. Dosages related to titration patterns and maintenance doses were summarized. Efficacy evaluations conducted using the Mini-Mental State Examination, Clinical Dementia Rating and modified Instrumental Activities of Daily Living scales were also primary outcome measures, and results are shown descriptively. The patients' therapeutic responses to rivastigmine and satisfaction with rivastigmine were secondary outcome measures. Therapeutic response and treatment satisfaction were summarized descriptively. RESULTS: A total of 264 patients were enrolled into the study. The mean duration of exposure to rivastigmine during the study was 151.1 days. Patients were taking rivastigmine 1.5-6 mg twice daily and the most frequent maintenance dose level was 4.5 mg twice daily. Among patients treated with rivastigmine, all primary and secondary outcome measures showed improvement or stabilization of cognition and global functioning. Of the 253 safety analysis patients, 155 patients (61.3%) reported at least one adverse event. The most frequent adverse events by system organ class were psychiatric disorders (9.1%) and gastrointestinal disorders (8.3%). The most common adverse events observed were dizziness (5.5%), insomnia (5.1%), anorexia (4.0%) and gastrointestinal symptoms such as constipation (4.0%), vomiting (4.0%) and nausea (3.6%). These symptoms were mild in severity. A total of 12 patients (4.7%) reported 16 serious adverse events, including two deaths, three fractures, three behavioural and psychological symptoms of dementia, one syncope with head trauma, one peptic ulcer, and six other hospitalizations. None were reported to be related to rivastigmine. CONCLUSIONS: Based on the results of this study, rivastigmine administered usually at a dose of 3-6 mg twice daily was found to be well tolerated. Although the rate of adverse events was high, the majority of these symptoms were mild in severity and short in duration. This study also demonstrated the efficacy of rivastigmine in at least stabilizing the symptoms of Alzheimer's disease.

5,10-methylenetetrahydrofolate reductase C677T gene polymorphism can influence age at onset of Parkinson's disease.

A case-control study was designed to investigate a possible genetic susceptibility of the MTHFR C677T polymorphism and assess whether the genetic polymorphism could be a predictor of levodopa-induced adverse effects in patients with Parkinson's disease (PD) of Chinese descent living in Taiwan. There were 94 sporadic PD patients with levodopa therapy at least for five years and 146 control subjects, matched by sex and gender, in this study. Results revealed that there were no differences of the allelic and genotypic frequencies of the MTHFR C677T polymorphism between PD patients and the controls. Analysis of age at onset stratified by MTHFR C677T polymorphism showed a trend of early age at onset in the PD patients carrying with T allele. The genetic influence was particularly significant in late-onset PD (onset age at or older than 60 years) with an early age at onset for 3.4 years. However, the MTHFR C677T polymorphism was not associated with the risk to develop dyskinesia, motor fluctuation and psychosis induced by levodopa in PD patients. In conclusion, results of the study revealed that the MTHFR C677T polymorphism could significantly influence age at onset of PD in Chinese population, but neither as a genetic susceptibility nor as a predictor of levodopa-induced adverse effects in PD.