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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; I2 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. © 2009 Elsevier Inc.

This article explores the use of probabilistic classification, namely finite mixture modelling, for identification of complex disease phenotypes, given cross-sectional data. In particular, if focuses on posterior probabilities of subgroup membership, a standard output of finite mixture modelling, and how the quantification of uncertainty in these probabilities can lead to more detailed analyses. Using a Bayesian approach, we describe two practical uses of this uncertainty: (i) as a means of describing a person's membership to a single or multiple latent subgroups and (ii) as a means of describing identified subgroups by patient-centred covariates not included in model estimation. These proposed uses are demonstrated on a case study in Parkinson's disease (PD), where latent subgroups are identified using multiple symptoms from the Unified Parkinson's Disease Rating Scale (UPDRS).

Depression is common in Parkinson's disease (PD) and contributes significantly to a reduced quality of life in PD patients. The determinants of depression in PD are complex and poorly understood. We investigated the factors associated with depression in PD.PD patients were recruited from Neurology clinics. A validated method was used to screen for a lifetime history of depression. 'Depressed' patients were identified by a score of6 in the Geriatric Depression Scale (GDS-15) or by having had prescribed treatment for depression. 'Never depressed' patients were recognised by a score of5 in the GDS-15 with no signs of a history of depression. A newly developed and validated questionnaire was used to collect other information.Depression was identified in 66% of the 639 PD patients who met the inclusion criteria. Depression was associated with an increased severity of illness as evidenced by higher Unified PD Rating Scale scores and a higher Hoehn and Yahr stage. Other clinical factors associated with disease severity were also more frequently observed in depressed patients. Similar to findings in non-PD samples, depressed PD patients were more likely to have a lower education level, a history of smoking and to regularly use non-aspirin based NSAIDs or analgesics. Comorbidities such as anxiety, memory problems, hallucinations, sleep disturbances and postural hypotension were more common in depressed PD patients.To avoid patient exhaustion of over-surveying, some factors within the psychological domain were not examined.Our results provide a focus for future intervention strategies.

SUMMARY There is a pressing need for patient-derived cell models of brain diseases that are relevant and robust enough to produce the large quantities of cells required for molecular and functional analyses. We describe here a new cell model based on patient-derived cells from the human olfactory mucosa, the organ of smell, which regenerates throughout life from neural stem cells. Olfactory mucosa biopsies were obtained from healthy controls and patients with either schizophrenia, a neurodevelopmental psychiatric disorder, or Parkinson’s disease, a neurodegenerative disease. Biopsies were dissociated and grown as neurospheres in defined medium. Neurosphere-derived cell lines were grown in serum-containing medium as adherent monolayers and stored frozen. By comparing 42 patient and control cell lines we demonstrated significant disease-specific alterations in gene expression, protein expression and cell function, including dysregulated neurodevelopmental pathways in schizophrenia and dysregulated mitochondrial function, oxidative stress and xenobiotic metabolism in Parkinson’s disease. The study has identified new candidate genes and cell pathways for future investigation. Fibroblasts from schizophrenia patients did not show these differences. Olfactory neurosphere-derived cells have many advantages over embryonic stem cells and induced pluripotent stem cells as models for brain diseases. They do not require genetic reprogramming and they can be obtained from adults with complex genetic diseases. They will be useful for understanding disease aetiology, for diagnostics and for drug discovery.

Anxiety disorders are common in Parkinson's disease (PD) patients, yet are poorly studied. We examined the prevalence of anxiety disorders in PD, investigated the association between anxiety, and presentation and progression of PD, and studied for the first time the contribution of putative risk factors for anxiety in PD. A case-series of 79 PD patients recruited from neurology out-patient clinics was examined for anxiety disorders using the DSM-IV criteria. The Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr Staging of PD were employed to understand the relationship between anxiety disorders, and the clinical presentation and severity of PD. A validated survey assessed putative risk factors for anxiety in PD. Twenty-five percent of PD patients were diagnosed with anxiety. Panic disorder, generalised anxiety disorder and social phobia were prevalent anxiety disorders. Comorbid depression with anxiety was observed (14%). The severity but not the duration of PD was positively related to anxiety. PD patients with postural instability and gait dysfunction symptom clustering were more likely to experience anxiety than tremor-dominant patients. While levodopa dosage had no relationship to anxiety, experience of dyskinesias or on/off fluctuations increased the risk. Lateralisation of PD had no association with anxiety. Anxiety disorders decreased with age and young onset PD patients were more likely to experience anxiety than the late onset subjects. Anxiety adds to the complexity of PD, lowering patients' quality of life. Future research can be directed to identify reactive and organic nature of anxiety in PD.

Early genome-wide association (GWA) studies on Parkinson's disease (PD) have not been able to yield conclusive, replicable signals of association, perhaps due to limited sample size. We aimed to investigate whether association signals derived from the meta-analysis of the first two GWA investigations might be replicable in different populations. We examined six single-nucleotide polymorphisms (SNPs) (rs1000291, rs1865997, rs2241743, rs2282048, rs2313982, and rs3018626) that had reached nominal significance with at least two of three different strategies proposed in a previous analysis of the original GWA studies. Investigators from the "Genetic Epidemiology of Parkinson's Disease" (GEOPD) consortium were invited to join in this study. Ten teams contributed replication data from 3,458 PD cases and 3,719 controls. The data from the two previously published GWAs (599 PD cases, 592 controls and 443 sibling pairs) were considered as well. All data were synthesized using both fixed and random effects models. The summary allelic odds ratios were ranging from 0.97 to 1.09 by random effects, when all data were included. The summary estimates of the replication data sets (excluding the original GWA data) were very close to 1.00 (range 0.98-1.09) and none of the effects were nominally statistically significant. The replication data sets had significantly different results than the GWA data. Our data do not support evidence that any of these six SNPs reflect susceptibility markers for PD. Much stronger signals of statistical significance in GWA platforms are needed to have substantial chances of replication. Specifically in PD genetics, this would require much larger GWA studies and perhaps novel analytical techniques. (C) 2009 Wiley-Liss, Inc. American Journal of Medical Genetics Part B-Neuropsychiatric Genetics

Previous data on the prevalence of olfactory dysfunction in Parkinson's disease (PD) range from 45% to 90%. The present multicenter study aimed to provide data on the prevalence of smell loss in a large sample of PD patients from three independent populations. Olfactory sensitivity was tested in 400 patients from Australia, Germany, and The Netherlands by means of a psychophysical olfactory test, the "Sniffin' Sticks", which is comprised of 3 subtests of olfactory function. Out of the total number of patients 45.0% presented as functionally anosmic, 51.7% were hyposmic, whereas only 3.3% were normosmic. This indicates that 96.7% of PD patients present with significant olfactory loss when compared to young normosmic subjects. This figure falls to 74.5%, however, when adjusted to age-related norms. Thus, olfactory dysfunction should be considered as a reliable marker of the disease.

The study of Parkinson's disease (PD), like other complex neurodegenerative disorders, is limited by access to brain tissue from patients with a confirmed diagnosis. Alternatively the study of peripheral tissues may offer some insight into the molecular basis of disease susceptibility and progression, but this approach still relies on brain tissue to benchmark relevant molecular changes against. Several studies have reported whole-genome expression profiling in post-mortem brain but reported concordance between these analyses is lacking. Here we apply a standardised pathway analysis to seven independent case-control studies, and demonstrate increased concordance between data sets. Moreover data convergence increased when the analysis was limited to the five substantia nigra (SN) data sets; this highlighted the down regulation of dopamine receptor signaling and insulin-like growth factor 1 (IGF1) signaling pathways. We also show that case-control comparisons of affected post mortem brain tissue are more likely to reflect terminal cytoarchitectural differences rather than primary pathogenic mechanisms. The implementation of a correction factor for dopaminergic neuronal loss predictably resulted in the loss of significance of the dopamine signaling pathway while axon guidance pathways increased in significance. Interestingly the IGF1 signaling pathway was also over-represented when data from non-SN areas, unaffected or only terminally affected in PD, were considered. Our findings suggest that there is greater concordance in PD whole-genome expression profiling when standardised pathway membership rather than ranked gene list is used for comparison.

Defining depression in Parkinson's disease (PD) is challenging, given the overlap of symptoms between parkinsonism and depression. We recently reported on the validity of two self‐rated depression rating scales in PD.1 These rating scales are useful to identify current depressive status in PD patients, but by themselves, do not identify a lifetime history of depression. We have recently extended our original work, and here we report and validate a self‐rated method to dichotomise PD patients according to their lifetime history of depression. This method can be used in risk factor studies to obtain two extreme groups of ‘ever’ and ‘never’ depressed; as illustrated in our recent genetic study.2

Recent whole genome association studies provided little evidence that polymorphisms at the familial Parkinsonism loci influence the risk for Parkinson's disease (PD). However, these studies are not designed to detect the types of subtle effects that common variants may impose. Here, we use an alternative targeted candidate gene approach to examine common variation in 11 genes related to familial Parkinsonism. PD cases (n = 331) and unaffected control subjects (n = 296) were recruited from three specialist movement disorder clinics in Brisbane, Australia and the Australian Electoral Roll. Common genetic variables (76 SNPs and 1 STR) were assessed in all subjects and haplotype, genotype, and allele associations explored. Modest associations (uncorrected P < 0.05) were observed for common variants around SNCA, UCHL1, MAPT, and LRRK2 although none were of sufficient magnitude to survive strict statistical corrections for multiple comparisons. No associations were seen for PRKN, PINK1, GBA, ATP13A2, HTRA2, NR4A2, and DJ1. Our findings suggest that common genetic variables of selected PD-related loci contribute modestly to PD risk in Australians.

MtDNA haplogroups J and K have been associated with a decreased risk of developing Parkinson's disease (PD). To confirm this finding, we compared the distribution of mtDNA haplogroups J and K in a large sample of Australian patients with PD (n = 890) to population-based controls (n = 3,491). We assigned subjects to haplogroups J or K using standard PCR/RFLP techniques. Of the 890 subjects with PD, 10.6% were haplogroup J (95% CI 8.6-12.8, n = 94) and 7.1% were haplogroup K (95% CI 5.5-8.9, n = 63). In our controls, 10.2% belonged to haplogroup J (95% CI 9.2-11.2, n = 356), and 7.8% were in haplogroup K (95% CI 6.9-8.7, n = 272). There was no significant difference in the prevalence of mtDNA haplogroup J or K in PD patients compared to population-based controls. Our findings indicate that mtDNA haplogroups J and K are not associated with a lower risk of PD.

Idiopathic Parkinson's disease is a common movement disorder characterized by a loss of dopaminergic neurons in the substantia nigra. Its pathogenesis is postulated to involve complex interactions between genetic susceptibility and environmental exposures. The IGF2-INS-TH gene cluster on the telomeric end of human chromosome 11 is a gene rich region expressing several proteins important for dopamine neuron homeostasis. We used a haplotyping approach to determine whether common genetic variation in the IGF2-INS-TH cluster influences the risk of idiopathic Parkinson's disease in a Caucasian case-control group recruited from Brisbane, Australia. Three tagging polymorphisms, the SNPs, rs680 and rs689 and the microsatellite, HUMTH01, were genotyped in 215 cases and 215 age- and gender-matched controls. Eight common haplotypes accounted for 91% of the genetic variation in our control group and one haplotype, IGF2-INS-TH*6, was significantly under-represented among the cases with idiopathic Parkinson's disease (OR = 0.42, 95% CI = 0.25-0.72, P-value = 0.001). Analysis of the individual polymorphisms showed that the IGF2-rs680 alternate 'A' allele accounted for the majority of the protective effect. Our findings suggest that common genetic variants in the IGF2-INS-TH cluster modify susceptibility to idiopathic Parkinson's disease.

Motor and non-motor fluctuations are well known sequelae of dopaminergic therapies for Parkinson's disease (PD), particularly during the advanced stages. However, the prevalence of fluctuations early in the treatment course has been less well recognised and may be missed clinically if not specifically probed. We examined the used of a survey for this purpose. Patients to be surveyed were recruited by neurologists and geriatricians at 20 Australian centres. Patients had a diagnosis of idiopathic PD with a duration of fewer than 5 years and were considered by their treating physician to be non-fluctuating or had no change in their treatment plan in the prior 6 months. Patients, with or without assistance, completed a 19-item wearing-off questionnaire to assess the presence of motor and non-motor fluctuations that indicated early wearing-off. Investigators assessed the usefulness of the questionnaire in detecting fluctuations and guiding PD treatment. Of 105 patients recruited, 92 were eligible for analysis. There were 56 (61%) identified as having fluctuations. Patients with wearing-off were younger (mean 67 vs 72 years), and more likely to have had PD for more than 3 years. About half the patients (49%) were able to complete the questionnaire independently. Clinicians perceived the questionnaire as useful for detecting fluctuations and adjusting treatment. A simple and easily administered wearing-off questionnaire may be useful in the early detection of fluctuations in PD patients and assist in guiding therapy.

Subthalamic nucleus (STN) deep brain stimulation (DBS) has become an established treatment strategy for patients with medically refractory Parkinson’s disease (PD). There are however numerous strategies employed for STN lead placement. Variations include method of STN localisation, use of microelectrode recording, number of microelectrode recording passes and time taken for the procedure. We describe a relatively simple and rapid technique of STN lead placement utilising CT / MRI image fusion, microelectrode recording and test stimulation.

Parkinson’s disease (PD) is a complex neurodegenerative disorder influenced by a combination of genetic and environmental factors. The molecular mechanisms that underlie PD are unknown; however, oxidative stress and impairment of antioxidant defence mechanisms have been implicated as major contributors to disease pathogenesis. Previously, we have reported a PD patient-derived cellular model generated from biopsies of the olfactory mucosa, termed hONS cells, in which the NRF2-mediated antioxidant response pathway genes were among the most differentially-expressed. To date, few studies have examined the role of the NRF2 encoding gene, NFE2L2, and PD. In this study, we comprehensibly assessed whether rare and common NFE2L2 genetic variations modify susceptibility to PD using a large Australian case-control sample (PD=1338, controls=1379). We employed a haplotype-tagging approach that identified an association with the tagging SNP rs2364725 and PD (OR = 0.849 (0.760-0.948), P = 0.004). Further genetic screening in hONS cell lines produced no obvious pathogenic variants in the coding regions of NFE2L2. Finally, we investigated the relationship between xenobiotic exposures and NRF2 function, through gene-environment interactions, between NFE2L2 SNPs and smoking or pesticide exposure. Our results demonstrated a significant interaction between rs2706110 and pesticide exposure (OR = 0.597 (0.393-0.900), P = 0.014). In addition, we were able to identify some age-at-onset modifying SNPs and replicate an ‘early-onset’ haplotype that contains a previously identified ‘functional promoter’ SNP (rs6721961). Our results suggest a role of NFE2L2 genetic variants in modifying PD susceptibility and onset. Our findings also support the utility of testing gene-environment interactions in genetic studies of PD.

Summary Background Parkinson's disease is thought to be secondary to the presence of neurotoxins, and pesticides have been implicated as possible causative agents. Glutathione transferases (GST) metabolise xenobiotics, including pesticides. Therefore, we investigated the role of GST polymorphisms in the pathogenesis of idiopathic Parkinson's disease. Methods We genotyped by PCR polymorphisms in four GST classes (GSTM1, GSTT1, GSTP1, and GSTZ1) in 95 Parkinson's disease patients and 95 controls. We asked all patients for information about pesticide exposure. Findings The distribution of the GSTP1 genotypes differed significantly between patients and controls who had been exposed to pesticides (controls vs patients: AA 14 [54%] of 26 vs seven [18%] of 39; AB 11 [42%] of 26 vs 22 [56%] of 39; BB 1 [4%] of 26 vs six [15%] of 39; AC 0 vs four [10%] of 39, p=0.009). No association was found with any of the other GST polymorphisms. Pesticide exposure and a positive family history were risk factors for Parkinson's disease. Interpretation GSTP1-1, which is expressed in the blood-brain barrier, may influence response to neurotoxins and explain the susceptibility of some people to the parkinsonism-inducing effects of pesticides.

International audience; BACKGROUND: A genome-wide association study identified 13 single-nucleotide polymorphisms (SNPs) significantly associated with Parkinson's disease. Small-scale replication studies were largely non-confirmatory, but a meta-analysis that included data from the original study could not exclude all SNP associations, leaving relevance of several markers uncertain. METHODS: Investigators from three Michael J Fox Foundation for Parkinson's Research-funded genetics consortia-comprising 14 teams-contributed DNA samples from 5526 patients with Parkinson's disease and 6682 controls, which were genotyped for the 13 SNPs. Most (88%) participants were of white, non-Hispanic descent. We assessed log-additive genetic effects using fixed and random effects models stratified by team and ethnic origin, and tested for heterogeneity across strata. A meta-analysis was undertaken that incorporated data from the original genome-wide study as well as subsequent replication studies. FINDINGS: In fixed and random-effects models no associations with any of the 13 SNPs were identified (odds ratios 0.89 to 1.09). Heterogeneity between studies and between ethnic groups was low for all SNPs. Subgroup analyses by age at study entry, ethnic origin, sex, and family history did not show any consistent associations. In our meta-analysis, no SNP showed significant association (summary odds ratios 0.95 to 1.08); there was little heterogeneity except for SNP rs7520966. INTERPRETATION: Our results do not lend support to the finding that the 13 SNPs reported in the original genome-wide association study are genetic susceptibility factors for Parkinson's disease.

The presence of surfactant proteins (SPs), critical to local barrier and defense functions and usually associated with the lung, was revealed in adult and fetal human skin complementary deoxyribonucleic acid, in skin samples from three adult female donors and also in cultured fibroblasts, keratinocytes, and melanocytes. Using reverse transcription-PCR, SP-A, SP-B, SP-C, and SP-D messenger ribonucleic acid expression was detected to varying extents in the different skin sources. The stronger expression of SP-C in fetal skin, compared to adult skin, suggested that the role of this protein alters with age. Immunohistochemical studies showed variable distribution of SPs in human epidermis and dermis, confirming that these proteins are indeed translated and expressed in skin tissue. In vitro studies showed that the surface tension of SP-deficient artificial sebum is (a) lowered by skin-extracted SP-B and (b) further reduced to a level comparable to normal sebum by the additional presence of skin-extracted SP-A and SP-D, consistent with their surface tension-lowering capabilities in lung. The possible roles of SPs in skin, based on their known functions in the lung are discussed. However, their potential as therapeutic targets or diagnostic markers of skin disease remains to be elucidated.

International audience; CONTEXT: Identification and replication of susceptibility genes for Parkinson disease at the population level have been hampered by small studies with potential biases. Alpha-synuclein (SNCA) has been one of the most promising susceptibility genes, but large-scale studies have been lacking. OBJECTIVE: To determine whether allele-length variability in the dinucleotide repeat sequence (REP1) of the SNCA gene promoter is associated with Parkinson disease susceptibility, whether SNCA promoter haplotypes are associated with Parkinson disease, and whether REP1 variability modifies age at onset. DESIGN, SETTING, AND PARTICIPANTS: We performed a collaborative analysis of individual-level data on SNCA REP1 and flanking markers in patients with Parkinson disease and controls. Study site recruitment, data collection, and analyses were performed between April 5, 2004, and December 31, 2005. Eighteen participating sites of a global genetics consortium provided clinical data. Genotyping was performed for SNCA REP1, -770, and -116 markers at individual sites; however, each site also provided 20 DNA samples for regenotyping centrally. MAIN OUTCOME MEASURES: Measures included estimations of Hardy-Weinberg equilibrium in controls; a test of heterogeneity; analyses for association of single variants or haplotypes; and survival analyses for age at onset. RESULTS: Of the 18 sites, 11 met stringent criteria for concordance with Hardy-Weinberg equilibrium and low genotyping error rate. These 11 sites provided complete data for 2692 cases and 2652 controls. There was no heterogeneity across studies (P>.60). The SNCA REP1 alleles differed in frequency for cases and controls (P

Cigarette smoking is consistently associated with a reduced risk of Parkinson disease (PD), having been reported in prospective studies,1 retrospective case-control studies,2 twin studies,3 and studies of case-sibling pairs.4 Conjecture remains as to whether this association reflects a true biologic neuroprotection from tobacco smoking or whether shared genetic and behavioral factors influence both smoking propensity and PD risk. Although genetic and behavioral factors may have less influence on an individual’s exposure to passive tobacco smoke, there are no previous reports on the effects of passive smoking on the risk for PD. Here we provide evidence that passive exposure to cigarette smoke might also be less common in PD. We recruited 163 patients with PD. Inclusion criteria were community-dwelling patients who had consulted the clinic of one of the authors between October 2003 and October 2004 and received a diagnosis of definite idiopathic PD5; assessed at >27 on the Mini-Mental State Examination (MMSE); capable of completing the risk factor questionnaire; and currently listed in the Australian Commonwealth Electoral Roll …

The ecogenetic theory contends that most cases of Parkinson’s disease (PD) result from the actions of environmental factors in genetically susceptible individuals on a background of normal ageing. This notion is supported by epidemiologic data; family history of PD and exposures to environmental toxins such as pesticides increase risk, while cigarette smoking reduces risk. As a result, polymorphic genes that code for metabolic enzymes have been considered as candidates for conferring differential risk for PD. Given their prominence in xenobiotic metabolism, the cytochrome P450 (CYP) genes have come under great scrutiny. The activity of CYP2D6 is largely determined by genetic variability and common sequence variants exist in human populations that lead to poor metaboliser (PM) phenotypes. These have been extensively studied as genetic risk factors for PD with inconsistent results. However, these studies have disregarded interactive effects (e.g. gene × environment interactions) despite the assertions of the ecogenetic theory. Data from our group and others suggest that the CYP2D6 PM genotype interacts with certain environmental factors such as pesticide exposure and cigarette smoking to confer differential risk for PD. Previous failure to consider such interactions might, in part, explain the inconsistencies observed in the CYP2D6 genetic risk-factor literature. Our data illustrate, using CYP2D6 as an exemplar, that it is crucial to consider both genetic and environmental factors, and their interactions, in any examination of risk factors for PD.

Parkinson's disease (PD) is a common age-related neurodegenerative disorder thought to result from the integrated effects of genetic background and exposure to neuronal toxins. Certain individual nuclear-encoded mitochondrial complex I gene polymorphisms were found to be associated with∼2-fold risk variation in an Australian case-control sample. We further characterized this sample of306cases and321controls to determine the mutual information contained in the22SNPs and, additionally, level of pesticide exposure: five distinct risk sets were identified using grade-of-membership analysis. Of these, one was robust to pesticide exposure (I), three were vulnerable (II, III, IV), and another (V) denoted low risk for unexposed persons. Risk for individual subjects varied>16-fold according to level of membership in the vulnerable groups. We conclude that inherited variation in mitochondrial complex I genes and pesticide exposure together modulate risk for PD.

The study of family history in Parkinson's disease (PD) has resulted in considerable debate over the role of genetic factors in the development of PD. Despite this, family history is consistently identified as an independent risk factor for PD. A multifactorial disease process in which genetic, environmental and lifestyle factors culminate in overall risk seems most likely. This article reviews existing studies of familial aggregation in PD. Recent insights into rare genetic causes of PD have affirmed the importance of ongoing family history research. Future efforts should emphasise well-designed family studies with extensive, non-exclusive phenotyping and ideally long-term follow-up.

Two brothers presented in their mid-forties with movement disorders including atypical parkinsonism, choreiform movements, stereotypies, ataxia and dysarthria. Both brothers showed putaminal lucencies on imaging and, in the proband, a deficiency of the pyruvate dehydrogenase complex (PDHC) was found on skin fibroblast assay.

Within the glutathione transferase (GST) superfamily, the Omega class contains two expressed genes ( hGSTO1 and hGSTO2 ) and one pseudogene ( hGSTO3p ).1 The hGSTO1 and hGSTO2 genes lie 7.5 kb apart on chromosome 10q24.3,1 between the markers D10S603 and D10S597. This region overlaps the D10S1239-D10S1237 interval implicated in age at onset (AAO) of Alzheimer disease (AD) and Parkinson disease (PD).2 We previously identified three polymorphisms in hGSTO genes: hGSTO1*A140D, hGSTO1*E155del, and hGSTO2*N142D.1 Omega class GSTs regenerate ascorbate,3 an important antioxidant in the brain. Additionally, GSTO1-1 may activate interleukin-1β4 and contribute to inflammation, which is implicated in AD and PD pathogenesis. We investigated the relationship between known GST Omega polymorphisms and PD. After this study was initiated, others confirmed a link between GSTO and PD.5 ### Cases. PD patients were recruited from hospitals, private neurologic clinics, and PD support groups throughout Queensland, Australia. Subjects were examined by a neurologist with special interest in movement disorders. All cases were diagnosed with …

The reported inverse association between the S18Y variant of the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene and Parkinson's disease (PD) has strong biological plausibility. If confirmed, genetic association of this variant with PD may support molecular targeting of the UCHL1 gene and its product as a therapeutic strategy for PD. In this light, we performed a collaborative pooled analysis of individual-level data from all 11 published studies of the UCHL1 S18Y gene variant and PD. There were 1,970 cases and 2,224 unrelated controls. We found a statistically significant inverse association of S18Y with PD. Carriers of the variant allele (Y/Y plus Y/S vs S/S) had an odds ratio (OR) of 0.84 (95% confidence interval [CI], 0.73-0.95) and homozygotes for the variant allele (Y/Y vs S/S plus Y/S) had an OR of 0.71 (95% CI, 0.57-0.88). There was a linear trend in the log OR consistent with a gene dose effect (p = 0.01). The inverse association was most apparent for young cases compared with young controls. There was no evidence for publication bias and the associations remained significant after excluding the first published, hypothesis-generating study. These findings confirm that UCHL1 is a susceptibility gene for PD and a potential target for disease-modifying therapies.

Current opinion contends that complex interactions between genetic and environmental factors play a role in the etiology of Parkinson’s disease (PD). Cigarette smoking is thought to reduce risk of PD, and emerging evidence suggests that genetic factors may modulate smoking’s effect. We used a case-only design, an approach not previously used to study gene–environment interactions in PD, specifically to study interactions between glutathione-S-transferase (GST) gene polymorphisms and smoking in relation to PD. Four-hundred PD cases (age at onset: 60.0 ± 10.7 years) were genotyped for common polymorphisms in GSTM1, P1, T1 and Z1 using well-established methods. Smoking exposure data were collected in face-to-face interviews. The independence of the studied GST genotypes and smoking exposure was confirmed by studying 402 healthy, aged individuals. No differences were observed in the distributions of GSTM1, T1 or Z1 polymorphisms between ever-smoked and never-smoked PD cases using logistic regression (all P > 0.43). However, GSTP1 *C haplotypes were over-represented among PD cases who ever smoked (odds ratio for interaction (ORi) = 2.00 (95% CI: 1.11–3.60, P = 0.03)). Analysis revealed that ORi between smoking and the GSTP1-114Val carrier status increased with increasing smoking dose (P = 0.02 for trend). These data suggest that one or more GSTP1 polymorphisms may interact with cigarette smoking to influence the risk for PD.

A primary haplotype (H1) of the microtubule-associated protein Tau (MAPT) gene is associated with Parkinson's disease (PD). However, the mechanism for disease susceptibility remains unknown. We examined the promoter region of MAPT and identified single nucleotide polymorphisms and insertions of 1 to 11 nucleotides. These polymorphisms corresponded to the previously characterized haplotypes, H1 and H2, as well as a novel variant of the H1 haplotype, H1'. As observed in other studies, we demonstrated a significant association with the H1/H1 promoter genotype and PD in a cohort of 206 idiopathic late-onset cases. This is in contrast with a panel of 13 early-onset PD patients, for whom we did not detect any mutations in MAPT. By examining single nucleotide polymorphisms in adjacent genes, we showed that linkage disequilibrium does not extend beyond the MAPT haplotype to neighboring genes. To define the mechanism of disease susceptibility, we examined the transcriptional activity of the promoter haplotypes using a luciferase reporter assay. We demonstrated in two human cell lines, SK-N-MC and 293, that the H1 haplotype was more efficient at driving gene expression than the H2 haplotype. Our data suggest that an increase in expression of the MAPT gene is a susceptibility factor in idiopathic PD.

Background and Relevance: Intracranial atherosclerosis is responsible for 70,000 ischemic strokes each year in the USA. Noninvasive testingsuch as transcranial Doppler ultrasound (TCD) and magnetic resonance angiography (MRA) to identify intracranial atherosclerosis is in widespread use, but has not been rigorously validated against the gold standard, catheter angiography. The recently NIH-funded Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial will compare warfarin with aspirin for stroke prevention in patients with intracranial atherosclerosis. WASID requires performance of angiography along with TCD and MRA, providing an opportunity to critically evaluate these noninvasive tests. Main Objective: The purpose of the Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) study is to develop the noninvasive diagnosis of intracranial atherosclerosis. The primary aim of SONIA is to define velocity values on TCD and anatomic abnormalities on MRA that identify severe (50–99%) intracranial stenosis of large, proximal arteries seen on catheter angiography. SONIA will define the criteria, or ‘cutpoints’, for an abnormal TCD or MRA and show that they perform with a reliable positive predictive value (PPV). Study Design: SONIA will be conducted in collaboration with WASID. Study-wide cutpoints defining positive TCD and MRA have been developed and reviewed by the site investigators of WASID. Hard copy angiography, TCD and MRA generated in WASID will be centrally read in SONIA. TCD and MRA cutpoints seek to achieve a target PPV of 80% for the identification of severe intracranial stenosis on angiography. Conclusions: Central readings will be used to validate the cutpoints and to develop measures of negative predictive value, and inter- and intra-observer variability. Sensitivity and specificity will be determined after adjustment for verification bias and employed in receiver-operator characteristic analyses. SONIA will use these techniques to develop TCD and MRA cutpoints that minimize the clinical consequences of test errors occurring in the noninvasive evaluation of patients with suspected intracranial atherosclerosis.

This review paper compares the differences in prevalence, and environmental and genetic risk factors for Parkinson’s disease between Chinese and Caucasian subjects. Comparison of age-specific prevalence between Chinese people and Caucasians suggests that the prevalence is lower in the Chinese (at least in the past), although the prevalence rate in China appears to be rising. Distinctions in environmental risk factors and genetic factors are discussed. The difference in prevalence may be due to distinctions in environmental and genetic risk factors as well as the complex interaction between these environmental and genetic factors, although discrepancies in methodology for prevalence surveys can also be an explanation.

Genetic factors play an important role in the aetiology of Parkinson's disease (PD). We have screened nuclear genes encoding subunits of mitochondrial complex I for associations between single nucleotide polymorphisms (SNPs) and PD. Abnormal functioning of complex I is well documented in human PD. Moreover, toxicological inhibition of complex I can lead to parkinsonism in animals. Thus, commonly occurring variants in these genes could potentially influence complex I function and the risk of developing PD. A sub-set of 70 potential SNPs in 31 nuclear complex I genes were selected and association analysis was performed on 306 PD patients plus 321 unaffected control subjects. Genotyping was performed using the DASH method. There was no evidence that the examined SNPs were significant genetic risk factors for PD, although this initial screen could not exclude the possibility that other disease-influencing variations exist within these genes.

The interaction between genetic and environmental factors for PD was examined in a Chinese population. It was found that although the intron 2 MAOB (GT)(n) repeat polymorphism was not associated with PID in the population, a relationship might have been masked by the protective effect of tea drinking. In individuals who did not drink tea (

Iron homeostasis is altered in Parkinson's disease (PD). The HFE protein is an important regulator of cellular iron homeostasis and variations within this gene can result in iron overload and the disorder known as hereditary haemochromatosis. We studied the Cys282Tyr single nucleotide polymorphism as a genetic risk factor for PD in two distinct and separately collected cohorts of Australian PD patients and controls. In the combined cohort comprising 438 PD patients and 485 control subjects, we revealed an odds ratio for possession of the 282Tyr allele of 0.61 (95% confidence interval, CI=0.42-0.90, P=0.011) from univariate chi-squared and 0.59 (95% CI=0.39-0.90, P=0.014) after logistic regression analyses (correcting for potential confounding factors). These results suggest that possession of the 282Tyr allele may offer some protection against the development of PD.

Apart from very few families who have a direct cause from genetic mutation, causes of most Parkinson's disease (PD) remain unclear. Many allelic association studies on polymorphism of different candidate genes have been studied. Although these association studies do not imply a causal relationship, it does warrant further studies to elucidate the pathophysiologic significance. CYP1A1 polymorphisms have been reported to be associated with PD in a Japanese population sample. Since CYP1A1 transforms aromatic hydrocarbons into products that may be neurotoxic and perhaps lead to PD, we therefore undertook a study to look at the possible association of CYP1A1 polymorphism and PD in a Chinese population. Contrary to the Japanese result, we did not find any statistically significant difference between the PD group and the control group in our study with a bigger sample size.

This study determined the frequencies of a G-to-A transition (S/N167) polymorphism in exon 4 of the parkin gene in Australian Parkinson's disease patients and control subjects. The genotype of each subject was determined using the polymerase chain reaction and restriction-fragment-length-polymorphism analysis. Overall, the A allele was significantly less common in the Parkinson's disease group (1.7%) compared with the control group (3.8%, OR = 0.43, 95% CI = 0.19-1.00, P l 0.05), although the frequency in the young onset Parkinson's disease group (6.6%) was not significantly different to controls. The A allele is less common in Australian Caucasian subjects compared to Japanese Parkinson's disease patients and appears to be under-represented in older-onset Parkinson's disease. l(c)g 2001 Elsevier Science Ltd. All rights reserved.

Glutathione transferase genes ( GST ) are candidate genes for Parkinson's disease because they are involved with the metabolism of pesticides, dopamine, and glutathione. Recent reports have suggested an association between Parkinson's disease and polymorphisms of GSTP1 1 or GSTM1 and GSTT1 .2 Recently we discovered a new polymorphic site in the zeta class G→T ( GSTZ1 ) gene.3 This consists of a C6T transition at nucleotide 245 in exon 5 that results in an amino acid change at position 82 from methionine to threonine. The T substitution occurs in 14% of white people. We have previously reported two other polymorphic sites at nucleotides 94 and 124 in exon 3.4 There are now thought to be four alleles of GSTZ1: Z1*A (A94A124C245), Z1*B (A94G124C245), Z1*C (G94G124C245,) and Z1*D (G94G …

Parkinson's disease (PD) has been associated with exposure to pesticides and oxidative injury. The involvement of paraoxonase in both pesticide metabolism and lipid peroxidation suggests that it may play a role in the pathogenesis of PD. We examined the frequency of polymorphic alleles of the PON1 and PON2 genes in a sample of caucasian subjects with PD. The frequency distribution of these genotypes did not differ significantly between patients and controls, including those who had reported exposure to pesticides.

To study the Ala53Thr and Ala30Pro mutations of the alpha-synuclein gene in a large number of Chinese patients with Parkinson disease (PD) as well as controls.We recruited 183 Chinese patients with sporadic PD, 17 with younger-onset PD (onset age50 years), and 7 with PD and a positive family history as well as 227 unaffected Chinese control subjects from the outpatient departments of 2 major hospitals in Hong Kong. All subjects were assessed for the the diagnosis of PD by a consultant neurologist or geriatrician. Subjects were interviewed with a standard questionnaire that also questioned for family history. Venous blood samples were obtained from the subjects and genomic DNA was extracted and studied for the presence of Ala53Thr mutation in exon 4 and Ala30Pro mutation in exon 3 of the alpha-synuclein gene using a polymerase chain reaction restriction fragment length polymorphism method.None of the Chinese PD patients or controls had either the Ala53Thr (exon 4) or Ala30Pro (exon 3) mutation of the alpha-synuclein gene.We failed to discover Ala53Thr or Ala30Pro mutations in a large number of Chinese patients with PD and control subjects, adding to the emerging consensus that variations in the alpha-synuclein gene are associated with PD in few families worldwide.

Monoamine oxidase B (MAOB) metabolises dopamine and activates neurotoxins known to induce parkinsonism in humans and primates. Therefore the MAOB gene (MAOB; Xp15.21–4) is a candidate gene for Parkinson’s disease (PD). Longer length dinucleotide repeat sequences in a highly polymorphic GT repeat region of intron 2 of this gene showed an association with PD in an Australian cohort. We repeated this allele-association study in a population of 176 Chinese PD patients ¶(90 men, 86 women) and 203 age-matched controls (99 men, 104 women). Genomic DNA was extracted from venous blood and the polymerase chain reaction was used to amplify the appropriate regions of the MAOB gene. The length of each (GT) repeat sequence was determined by 5% polyacrylamide denaturing gel electrophoresis. There was no significant difference in allele frequencies of the (GT) repeat allelic variation between patients and controls (χ2 = 2.48; df = 5, P < 0.75). Therefore the longer length GT repeat alleles are not associated with PD in this Chinese population. Possible reasons for the discrepancy between Chinese and Australian populations include a different interaction between this genetic factor and environmental factors in the two populations and the possibility that the long length GT repeat alleles may represent a marker mutation, genetically linked to another susceptibility allele in whites but not in Chinese. Methodological differences in the ascertainment of cases and controls in this cohort could also explain the observed differences. Further study is required to determine whether the longer length GT repeat alleles are true susceptibility alleles in PD.

The deletion allele (D allele) polymorphism in the angiotensin converting enzyme (ACE) gene is associated with increased levels of the neuropeptide substance P in the basal ganglia and substantia nigra. A reduction of substance P levels in the brain occurs in Parkinson’s disease (PD) and has been implicated in the pathogenesis of the disease. We investigated the hypothesis that the D allele may be protective towards PD by examining the frequency of the ACE (I/D) polymorphism in 178 PD cases (male:female ratio = 1.4) and 192 controls (male:female ratio = 1.5). ACE (I/D) genotype was determined using polymerase chain reaction and 3% agarose gel electrophoresis. Unadjusted chi-square analysis revealed no significant difference between genotype frequencies (χ2 = 3.30, p > 0.10) or allele frequencies (χ2 = 2.52, p > 0.10) between patient and control groups, although PD patients were less likely to be homozygous (OR = 0.80, 95% CI = 0.49–1.29) or heterozygous (OR = 0.80, 95% CI = 0.59–1.06) for the D allele. A stepwise logistic regression analysis of the ACE deletion and risk factor data confirmed that there was no significant association between the ACE deletion (D allele) polymorphism and PD (OR = 0.62, 95% CI = 0.35–1.10, p = 0.10). This study does not support the hypothesis that the D allele of the ACE gene confers a protective effect with respect to PD.

The use of aspirin as an anti-platelet drug is limited by its propensity to induce gastric injury and by its adverse effect on vascular prostacyclin formation. Two phenolic non-steroidal anti-inflammatory drugs (salicylic acid and diflunisal) were modified by esterification with a series of O-acyl moieties. The short-term ulcerogenic in vitro and in vivo anti-platelet properties, pharmacodynamic profiles, and extent of hepatic extraction of these phenolic esters were compared with aspirin (acetylsalicylic acid). The more lipophilic esters (longer carbon chain length in O-acyl group) show significantly less gastrotoxicity in stressed rats than does aspirin after a single oral dose. The in vitro and in vivo anti-platelet studies show that these phenolic esters inhibited (1) arachidonate-triggered human platelet aggregation and (2) thrombin-stimulated rat serum thromboxane A2 production by platelets in the clotting process almost as effectively as aspirin. The hepatic extractions of these O-acyl derivatives are significantly higher than those of aspirin. The pharmacodynamic studies show that these O-acyl derivatives of salicylic acid and diflunisal probably bind to, or combine with, the same site on the platelet cyclooxygenase as aspirin. Replacing the O-acetyl group with longer chain O-acyl moiety in this series of phenolic esters markedly reduced the potential of these agents to induce short-term gastric injury but did not lessen their activity as inhibitors of platelet aggregation. These non-acetyl salicylates may therefore represent a novel class of anti-platelet drugs with less ulcerogenic potential.

In this work the in-situ perfused rat liver has been used to examine the effect of changing the protein content of the perfusate on the hepatic extraction of O-acyl esters of salicylic acid. The hepatic availability (F) of these solutes was studied at a flow-rate of 30 mL min−1 with perfusate albumin concentrations of 0, 2, and 4% w/v. The hepatic availability of the esters was shown to decrease with increasing carbon-chain length in the O-acyl group; for all the esters the hepatic availability increased with increasing albumin concentration in the perfusate. The dispersion-model-derived efficiency number (RN) of the esters was shown to increase with increasing lipophilicity and decrease with increasing albumin concentration in the perfusate. The unbound fraction (fu) of the esters decreased with lipophilicity. RN/fu for acetylsalicylic acid remained relatively constant as the albumin concentration was increased. However, RN/fu for n-pentanoyl-and n-hexanoylsalicylic acids increased significantly as albumin concentration increased from 0% to 4%. Thus, for the more lipophilic solutes (n-pentanoyl- and n-hexanoylsalicylic acids) the presence of albumin apparently facilitates the uptake of unbound solute relative to acetylsalicylic acid.

The outflow-concentration-time profiles for lignocaine (lidocaine) and its metabolites have been measured after bolus impulse administration of [14C]lignocaine into the perfused rat liver. Livers from female Sprague-Dawley rats were perfused in a once-through fashion with red-blood-cell-free Krebs-Henseleit buffer containing 0 or 2% bovine serum albumin. Perfusate flow rates of 20 and 30 mL min− were used and both normal and retrograde flow directions were employed. Significant amounts of metabolite were detected in the effluent perfusate soon after lignocaine injection. The early appearance of metabolite contributed to bimodal outflow profiles observed for total 14C radioactivity. The lignocaine outflow profiles were well characterized by the two-compartment dispersion model, with efflux rate «influx rate. The profiles for lignocaine metabolites were also characterized in terms of a simplified two-compartment dispersion model. Lignocaine was found to be extensively metabolized under the experimental conditions with the hepatic availability ranging between 0.09 and 0.18. Generally lignocaine and metabolite availability showed no significant change with alterations in perfusate flow rate from 20 to 30 mL min− or protein content from 0 to 2%. A significant increase in lignocaine availability occurred when 1200 μm unlabelled lignocaine was added to the perfusate. Solute mean transit times generally decreased with increasing flow rate and with increasing perfusate protein content. The results confirm that lignocaine pharmacokinetics in the liver closely follow the predictions of the well-stirred model. The increase in lignocaine availability when 1200 μm unlabelled lignocaine was added to the perfusate is consistent with saturation of the hydroxylation metabolic pathways of lignocaine metabolism.

OBJECTIVE: In Parkinson's disease (PD), commonly reported risk factors for malnutrition in other populations commonly occur. Few studies have explored which of these factors are of particular importance in malnutrition in PD. The aim was to identify the determinants of nutritional status in people with Parkinson's disease (PWP). METHODS: Community-dwelling PWP (>18 years) were recruited (n = 125; 73M/52F; Mdn 70 years). Self-report assessments included Beck's Depression Inventory (BDI), Spielberger Trait Anxiety Inventory (STAI), Scales for Outcomes in Parkinson's disease-Autonomic (SCOPA-AUT), Modified Constipation Assessment Scale (MCAS) and Freezing of Gait Questionnaire (FOG-Q). Information about age, PD duration, medications, co-morbid conditions and living situation was obtained. Addenbrooke's Cognitive Examination (ACE-R), Unified Parkinson's Disease Rating Scale (UPDRS) II and UPDRS III were performed. Nutritional status was assessed using the Subjective Global Assessment (SGA) as part of the scored Patient-Generated Subjective Global Assessment (PG-SGA). RESULTS: Nineteen (15%) were malnourished (SGA-B). Median PG-SGA score was 3. More of the malnourished were elderly (84% vs. 71%) and had more severe disease (H&Y: 21% vs. 5%). UPDRS II and UPDRS III scores and levodopa equivalent daily dose (LEDD)/body weight (mg/kg) were significantly higher in the malnourished (Mdn 18 vs. 15; 20 vs. 15; 10.1 vs. 7.6 respectively). Regression analyses revealed older age at diagnosis, higher LEDD/body weight (mg/kg), greater UPDRS III score, lower STAI score and higher BDI score as significant predictors of malnutrition (SGA-B). Living alone and higher BDI and UPDRS III scores were significant predictors of a higher log-adjusted PG-SGA score. CONCLUSIONS: In this sample of PWP, the rate of malnutrition was higher than that previously reported in the general community. Nutrition screening should occur regularly in those with more severe disease and depression. Community support should be provided to PWP living alone. Dopaminergic medication should be reviewed with body weight changes.