Y. Yih

Evaluation of somnolence in Parkinson’s disease: Comparison with age- and sex-matched controls

Abstract—The authors found a significantly higher prevalence of daytime somnolence in 201 patients with PD compared with 214 age- and sex-matched healthy control subjects (Epworth Sleepiness Scale score 5.6 vs 4.6). The prevalence of “sleep attacks” (SA) was about seven times higher in patients with PD than in control subjects (13.9% vs 1.9%;p < 0.0005). Multivariate analysis demonstrated that a higher dose of levodopa and longer duration of disease significantly predicted for SA in patients with PD. Epworth Sleepiness Scale scores of ≥10 had 71.4% sensitivity and 88.4% specificity for SA.

Dose-dependent protective effect of coffee, tea, and smoking in Parkinson's disease: a study in ethnic Chinese

INTRODUCTION Few studies have examined the relationship of coffee and tea in Parkinsons disease (PD). The potential protective effect of coffee intake and risk of PD has not been studied in a Chinese population. There is a high prevalence of caffeine takers among Chinese in our population. OBJECTIVE We undertook a case control study to examine the relationship between coffee and tea drinking, cigarette smoking, and other enviromental factors and risk of PD among ethnic Chinese in our population. METHODS AND RESULTS 300 PD and 500 population controls were initially screened. Two hundred case control pairs matched for age, gender, and race were finally included in the analysis. Univariate analysis revealed significant association of PD with coffee drinking (p<0.0005), tea drinking (p=0.019), alcohol drinking (p=0.001), cigarette smoking (p<0.0005), and exposure to heavy metals (p=0.006). Conditional logistic regression analysis demonstrated that amount of coffee drunk (OR 0.787, 95%CI 0.664-0.932, p=0.006), amount of tea drunk (OR 0.724, 95%CI 0.559-0.937, p=0.014), number of cigarettes smoked (OR 0.384, 95%CI 0.204-0.722, p=0.003), history of heavy metal and toxin exposure (OR 11.837, 95%CI 1.075-130.366, p=0.044), and heart disease (OR 5.518, 95%CI 1.377-22.116, p=0.016) to be significant factors associated with PD. One unit of coffee and tea (3 cups/day for 10 years) would lead to a 22% and 28% risk reduction of PD. One unit of cigarette smoke (3 packs/day for 10 years) reduced the risk of PD by 62%. CONCLUSIONS We demonstrated a dose-dependent protective effect of PD in coffee and tea drinkers and smokers in an ethnic Chinese population. A history of exposure to heavy metals increased the risk of PD, supporting the multifactorial etiologies of the disease.

The G2019S LRRK2 mutation is uncommon in an Asian cohort of Parkinson's disease patients

A common heterozygous leucine-rich repeat kinase 2 (LRRK2) mutation 6055G > A transition (G2019S) accounts for about 3-7% of familial Parkinsons disease (PD) and 1-1.6% sporadic PD in a number of European populations. To determine the prevalence of the G1019S mutation in our Asian population, we conducted genetic analysis of this mutation in 1000 PD and healthy controls. The G2019S mutation was not detected in any of our study subjects. The prevalence of G2019S mutation is rare (< 0.1%) in our population, suggesting that occurrence of this mutation may vary amongst different ethnic races. This has important clinical implication when implementing guidelines for genetic testing.

Alpha-synuclein haplotypes implicated in risk of Parkinson’s disease

The authors examined four- and six-loci haplotype constructs (from five single nucleotide polymorphisms and three microsatellite regions) of the alpha-synuclein gene in patients with Parkinson’s disease (PD) and controls in an ethnic Chinese population. Logistic regression analysis demonstrated an association of NACP-Rep1 (p = 0.002) and L478 (p < 0.0001) with risk of PD after correction for the effects of age, sex, and the other polymorphic loci. Specific four-loci and six-loci haplotypes were significantly associated with an increased or decreased risk of PD.

Fragile X premutation alleles in SCA, ET, and parkinsonism in an Asian cohort

Among 367 subjects, the authors analyzed 167 patients with essential tremor, sporadic progressive cerebellar ataxia, multiple-system atrophy, and atypical parkinsonism and 200 healthy control subjects for FMR1 premutation alleles. None of the subjects carried alleles within the premutation range. These findings suggest that in the absence of other supportive clinical or imaging features, the cost-effectiveness of routine fragile X tremor/ataxia syndrome screening in this Asian cohort with movement disorders was low.

LINGO1 VARIANT INCREASES RISK OF FAMILIAL ESSENTIAL TREMOR

Essential tremor (ET), a neurologic disorder characterized by postural and action tremor, is one of the most common adult-onset motor disorders.1,2 While linkage regions have been identified in Icelandic and North American families, the causative gene remains elusive.1–4 Recently, a sequence variant (rs9652490 G allele) of the LINGO1 gene was found to be associated with ET in the first genome-wide association study in European and American populations.5 Here we determined the linkage disequilibrium (LD) of single nucleotide polymorphisms (SNPs) 100 kb up/downstream of the implicated LINGO1 SNP and analyzed the SNP in a case control study in an Asian population. We included consecutive patients with ET who presented to a tertiary referral center and examined by movement disorders neurologists following a methodology as previously described.6 We followed the diagnostic criteria of classic ET based on the recommendations of the Consensus Statement of the Movement Disorders Society in 1998.7 Patients with at least one affected first-degree relative were classified as familial ET. Controls of similar gender, race, and age as ET patients and physically examined by the authors at the Health Screening Unit of the same hospital were included. Informed consent from all the study subjects was taken and the work received approval from the institutional ethics committee. The LINGO1 SNP (rs9652490) was screened …

Monoamine oxidase B polymorphism, cigarette smoking and risk of Parkinson's disease: a study in an Asian population.

Cigarette smoking is associated with reduced monoamine oxidase B (MAO B) activity. Polymorphisms of the MAO B gene may modify the relationship between smoking and Parkinsons Disease (PD). We examined the association of MAO B intron 13 G/A polymorphism and risk of PD, and the modulation of the polymorphism on smoking and PD in an Asian study population in Singapore. Two hundred and thirty PD patients (mean age 66.0 ± 9.4 years, 63% men) and 241 age, gender, and race matched controls (mean age 64 ± 9.2 years, 58.9% males) were studied. The frequency of G and A alleles in PD and controls was; 66/315 (21.0%) vs. 73/340 (21.5%) and 249/315 (79.0%) vs. 267/340 (78.5%). For women, the genotype frequency in PD and controls was; GG: 7/85 (8.2%) vs. 8/99 (8.1%); GA: 25/85 (29.4%) vs. 27/99 (27.3%); AA: 53/85 (62.4%) vs. 64/99 (64.6%). For men, allele frequency in PD and controls was; A: 118/145 (81.4%) vs. 112/142 (78.9%) and G: 27/145 (18.6%) vs. 30/142 (21.1%). The allele and genotype frequencies were not significantly different between young and late onset PD. The frequency of “ever” smokers in PD and controls was 31/230 (13.5%) vs. 52/241 (21.6%), P = 0.02. A stepwise logistic regression analysis did not reveal any interaction of smoking and the G allele and risk of PD. The MAO B G/A genotype frequency in our Asian population was quite different from Caucasians suggesting that ethnicity specific effects need to be considered in evaluating gene‐environmental interaction.

DRD3 variant and risk of essential tremor

Linkage analysis studies in Icelandic and North American families have identified three genetic loci where the causative essential tremor (ET) gene could be located: chromosome 3q13 (ETM1), 2p22-p25 (ETM2), and 6p23.1–3 The A265G variant in the HS1-BP3 gene has been shown to associate with familial ET.4 ETM2 has previously been linked to ET in our population.5 Though the HS1-BP3 variant was not found in our patients with ET,4 the possible association with other variants of HS1-BP3 or other genes has not been excluded. The dopamine D3 receptor ( DRD3 ) gene is located near the ETM1 locus. Recently, a functional DRD3 variant (Ser9Gly) was found to be associated with risk and age at onset of ET in American and French populations.6 The Gly-9 (G) allele cosegregated with ET in 23 families and Gly-9 homozygotes appeared to have more severe ET symptoms.6 Furthermore, in vitro studies showed that dopamine-mediated cAMP response was increased and mitogen-associated protein kinase (MAPK) was prolonged with the G allele.6 The biologic plausibility of the DRD3 Ser9Gly variant, the concordance of the clinical …

Mitochondrial complex I polymorphism and cigarette smoking in Parkinson’s disease

In recent years, genetic association studies have been the focus of research and debate.1 The presence of mitochondrial complex I (NADH-ubiquinone oxidoreductase) deficiency in PD and the demonstration that rotenone, a complex I inhibitor, selectively kills dopaminergic neurones suggest that variation in the genes encoding mitochondrial complex I may be associated with risk of PD.2 Whereas in vitro experiments implicate a major role for mitochondrial DNA mutations of complex I in PD, clinical studies suggest that such mutations probably are not significant in most patients with PD.3 A polymorphism in mitochondrial nuclear genome (C to T in exon 2 of NDUFV2 ) increases susceptibility to PD in a Japanese population.2 As this polymorphism results in a Ala29Val substitution leading to a structural change in the protein,2 the findings in that study could be of significance. Cigarette smoking is associated with decreased complex I activity4 and is inversely related to risk of PD.5 To test our hypothesis that there may a link between genetic variation of mitochondrial complex 1 and cigarette smoking, we examined the association of NDUFV2 polymorphism and risk of PD and the interaction of this polymorphism and cigarette smoking. Genomic DNA was extracted from 224 patients with PD seen at our Movement Disorder Clinic and from 223 controls similar in age, sex, and …

LRRK2 variant associated with Alzheimer's disease

Overlapping neurodegenerative pathologies (including Alzheimers disease, AD) have been described in Parkinsons disease (PD) patients with leucine-rich repeat kinase-2 (LRRK2) mutations. We analyzed a LRRK2 PD (R1628P) risk variant in a group of 885 subjects comprising of AD and controls. The frequency of the R1628P allele was higher in AD compared to controls (3.5% vs. 1.6%, OR 2.3, 95 CI 1.2-4.4, p=0.018). In vitro, the mean percentage of apoptosis and cell death observed for the R1628P transfected human cell lines was higher compared to wild type 21.8 ± 1.9, vs. 17.1 ± 1.3, p<0.05, 30.2 ± 2.2 vs. 25.7 ± 1.3, p<0.05). The LRRK2 R1628P variant increases the risk of AD in our population and our in vitro findings suggest that it is a functional variant and predisposes to apoptosis.