Increased Risk Of Parkinson's Disease Research Articles

Malassezia and Parkinson's Disease.

Parkinson's disease (PD) is a common debilitating neurodegenerative disease caused by a loss of dopamine neurons in the substantia nigra within the central nervous system (CNS). The process leading to this neuronal loss is poorly understood. Seborrheic dermatitis (SD) is a common benign inflammatory condition of the skin which mainly affects lipid-rich regions of the head and trunk. SD is caused by over proliferation of the lipophilic fungus Malassezia. PD and SD are strongly associated. The increased PD risk following an SD diagnosis (OR = 1.69, 95% CI 1.36, 2.1; p < 0.001) reported by Tanner and colleagues remains unexplained. Malassezia were historically considered commensals confined to the skin. However, many recent studies report finding Malassezia in internal organs, including the CNS. This raises the possibility that Malassezia might be directly contributing to PD. Several lines of evidence support this hypothesis. AIDS is causally associated with both parkinsonism and SD, suggesting that weak T cell-mediated control of commensal microbes such as Malassezia might contribute to both. Genetic polymorphisms associated with PD (LRRK2, GBA, PINK1, SPG11, SNCA) increase availability of lipids within human cells, providing a suitable environment for Malassezia. Four LRRK2 polymorphisms which increase PD risk also increase Crohn's disease risk; Crohn's disease is strongly associated with an immune response against fungi, particularly Malassezia. Finally, Malassezia hypha formation and melanin synthesis are stimulated by L-DOPA, which could promote Malassezia invasiveness of dopamine neurons, and contribute to the accumulation of melanin in these neurons. Although Malassezia's presence in the substantia nigra remains to be confirmed, if Malassezia play a role in PD etiology, antifungal drugs should be tested as a possible therapeutic intervention.

Use of β2-adrenoreceptor agonist and antagonist drugs and risk of Parkinson disease.

To verify the previously reported association between long-term use of β2-adrenoreceptor (β2AR) agonist and antagonist with reduced and increased risk of Parkinson disease (PD), respectively. We obtained odds ratios (ORs) associating time of β2AR agonist and antagonist use with PD risk in nationwide Danish health registries. We included 2,790 patients with PD and 11,160 controls. Long-term β2AR agonist use was associated with reduced PD risk (OR 0.57, 95% confidence interval [CI] 0.40-0.82) in this cohort. Unexpectedly, short-term β2AR agonist use was equally associated (OR 0.64, 95% CI 0.42-0.98). Because β2AR agonists are prescribed mostly for chronic obstructive pulmonary disease (COPD), often caused by long-term nicotine abuse, we analyzed other markers of smoking. Diagnosis of COPD (OR 0.51, 95% CI 0.37-0.69) and use of inhaled corticosteroids (OR 0.78, 95% CI 0.59-1.02) or inhaled anticholinergics (OR 0.41, 95% CI 0.25-0.67) were also inversely associated with PD. Increased PD risk was not found for all β2AR antagonists but only for propranolol and metoprolol. Associations were markedly stronger for short-term than long-term use. We confirmed β2AR agonist use to be associated with reduced PD risk and β2AR antagonist use with increased PD risk. However, our data indicate the association of β2AR agonists to be indirectly mediated by smoking, which is repeatedly associated with reduced risk of PD. The association of β2AR antagonists indicates reverse causation, with PD symptoms triggering their prescription rather than β2AR antagonists causing PD. Thus, current epidemiologic data do not support a causal link between β2AR agonists and antagonists and PD risk.

Mitochondria function associated genes contribute to Parkinson\u2019s Disease risk and later age at onset

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson’s disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial function-associated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD.

SNCA but not DNM3 and GAK modifies age at onset of LRRK2-related Parkinson's disease in Chinese population.

Recently, rs2421947 in DNM3 (dynamin 3) was reported as a genetic modifier of age at onset (AAO) of LRRK2 G2019S-related Parkinson's disease (PD) in a genome-wide association study in Arab-Berber population. Rs356219 in SNCA (α-synuclein) was also reported to regulate the AAO of LRRK2-related PD in European populations, and GAK (Cyclin G-associated kinase) rs1524282 was reported to be associated with an increased PD risk with an interaction with SNCA rs356219. G2019S variant is rare in Asian populations, whereas two other Asian-specific LRRK2 variants, G2385R and R1628P, are more frequent with a twofold increased risk of PD. In this study, we investigated whether rs2421947, rs356219 and rs1524282 modified AAO in LRRK2-related PD patients in Han Chinese population. We screened LRRK2 G2385R and R1628P variants in 732 PD patients and 1992 healthy controls, and genotyped DNM3 rs2421947, SNCA rs356219 and GAK rs1524282 among the LRRK2 carriers. The SNCA rs356219-G allele was found to increase the risk of PD in LRRK2 carriers (OR 1.50, 95%CI 1.08-2.01, P = 0.016), and the AAO of AG + GG genotypes was 4years earlier than AA genotype (P = 0.006). Nonetheless, no similar association was found in DNM3 rs2421947 and GAK rs1524282. Our results show that SNCA but not DNM3 or GAK is associated with AAO of LRRK2-PD patients in Chinese population.

Vitamin D receptor polymorphisms and the susceptibility of Parkinson’s disease

Epidemiological evidence concerning the association between vitamin D receptor (VDR) polymorphisms, including rs2228570, rs731236, rs7975232, rs1544410 and Parkinson’s disease (PD) risk is inconsistent. A meta-analysis was performed to evaluate these associations via searching PubMed and EMBASE databases up to Jan 4, 2019. Odds ratio (OR) with 95% confidence interval (CI) were applied to assess the strength of these associations. 6 studies with 1391 PD cases and 1570 controls for rs2228570, 7 studies with 1881 PD cases and 2135 controls for rs731236, 5 studies with 1298 PD cases and 1536 controls for rs7975232, and 6 studies with 932 PD cases and 1377 controls for rs1544410 were included in this meta-analysis. Significant associations between rs2228570 and PD risk were found in allelic, dominant, and additive models but not in recessive model. Stratified study revealed that rs2228570 was associated with PD susceptibility in Asian population, while no significant association was observed in Caucasian population. Sensitivity analysis showed stable results for rs2228570 and no publication bias existed. Rs731236 was associated with increased PD risk in dominant model, however, this result was unstable. No significant association was found between rs7975232 or rs1544410 and PD.

β2-adrenoreceptor medications and risk of Parkinson disease.

A recent study observed a 2-fold greater risk of Parkinson disease (PD) in relation to the β2-adrenoreceptor antagonist propranolol and a markedly lower risk of PD for the β2-adrenoreceptor agonist salbutamol. We examined whether confounding by clinical indication for these medications, that is, tremor and smoking-related pulmonary conditions, explained these associations. In a large, population-based case-control study of United States Medicare beneficiaries in 2009 with diagnosis codes, procedure codes, and prescription data (48,295 incident PD cases, 52,324 controls), we examined the risk of PD in relation to use of selected β antagonists (propranolol, carvedilol, metoprolol), the β2 agonist salbutamol, and other medications used for the same clinical indications (primidone, inhaled corticosteroids). We adjusted for demographics, smoking, and overall use of medical care. We then examined the effect of also adjusting for clinical indication and applying medication exposure lagging. Propranolol appeared to increase PD risk (odds ratio [OR] = 3.62, 95% confidence interval [CI] = 3.31-3.96). When we adjusted for tremor or abnormal involuntary movement prior to the PD diagnosis/reference date and lagged propranolol exposure, the association was 0.97 (95% CI = 0.80-1.18). Primidone, also used for tremor, was similarly sensitive to this adjustment and lagging. β Antagonists not indicated for tremor appeared to reduce PD risk (carvedilol: OR = 0.77, 95% CI = 0.73-0.81; metoprolol: OR = 0.94, 95% CI = 0.91-0.97) and were insensitive to adjustment for indications and lagging. Neither salbutamol nor inhaled corticosteroids were consistently associated with PD risk. β2-adrenoreceptor agonists and antagonists do not appear to alter PD risk. Ann Neurol 2018;84:691-701.

No association of DNM3 with age of onset in Asian Parkinson's disease

Genetic variability in DNM3 has been shown to modify age of onset of Parkinson's disease (PD) among LRRK2 Gly2019Ser carriers in North African Arab-Berber populations. In Asian populations, the Gly2019Ser mutation is rare or absent but two other LRRK2 variants, Gly2385Arg and Arg1628PPro, increase PD risk. We aimed to determine whether the DNM3 locus was associated with age of PD onset in both carriers and non-carriers of LRRK2 risk variants in Asians. We analyzed the association of DNM3 rs2421947 genotypes with age of PD onset in 3645 Chinese samples, of which 369 carried at least one of two Asian LRRK2 risk variants. DNM3 rs2421947 genotypes were not associated with age of PD onset in Chinese samples. We observed no heterogeneity in the effect of rs2421947 between the Asian LRRK2 risk variant carriers and non-carriers. DNM3 rs2421947 was not associated with age of PD onset in LRRK2 risk variant carriers and non-carriers in Chinese samples. Further studies in other Asian populations will be of interest.

Occupational stress and risk for Parkinson's disease: A nationwide cohort study.

ABSTRACT Background: Stress has been suggested as a contributing factor in the etiology of Parkinson's Disease (PD), but epidemiological evidence is sparse. Objective: The objective of this study was to explore the association between occupational stress according to the job demands‐control model and the risk for PD. Methods: We conducted a population‐based cohort study with 2,544,748 Swedes born 1920 to 1950 who had an occupation reported in the population and housing censuses in 1980 or, if missing, in 1970. Job demands and control were measured using a job‐exposure matrix. Incident PD cases were identified using Swedish national health registers from 1987 to 2010. Data were analyzed with Cox regression with age as the underlying time scale, adjusting for sex, education, and chronic obstructive pulmonary disease as a proxy for smoking. Results: During a mean follow‐up time of 21.3 years, 21,544 incident PD cases were identified. High demands were associated with increased PD risk among men, most evident in men with high education. High control was associated with increased PD risk among the low educated. This association was more pronounced in women. High‐strain jobs (high demands and low control) was only associated with increased PDrisk among men with high education, whereas active jobs (high demands and high control) were associated with increased PD risk among men with low education. Interpretation: High job demands appear to increase PD risk in men, especially in men with high education, whereas high job control increases PD risk among low educated, more strongly in women. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Nationwide study of Parkinson's disease incidence between 2010 and 2015 among the French agricultural population

Introduction The role of farming and professional pesticide exposure is well established in Parkinson's disease (PD). PD is multifactorial disease, and there are other risk/protective factors that may have an influence on the incidence of the disease in the agricultural population. The impact of professional pesticide exposure on the spatial distribution of the disease is not well known. Our objectives were to estimate PD incidence among the French agricultural population and to compare it to PD incidence in the general population, and to examine its spatial distribution. Methods We used French national drug claims databases to identify PD cases each year between 2010 and 2015 using a validated algorithm. We defined the agricultural population based on affiliation to the “Mutualite sociale agricole” (MSA), the only health insurance for farmers and agricultural workers. We compared PD incidence in MSA farmers, MSA workers, and affiliates to the General scheme (GS, that represents about 91% of the French population) of the social security using Poisson regression adjusted for overdispersion, 5-year groups of age, sex, age × sex, and year, and estimated relative risks (RRs) and 95% confidence intervals (CIs). We also examined multiplicative interactions of agricultural status with age, sex, and year. We estimated PD incidence ratios standardized for age, sex, and year in each French “departement” among MSA farmers and MSA workers and estimated the intraclass correlation coefficient (ICC), a measure of the proportion of the variance in PD incidence that is due to between-departement variation. Results During the study period, between 2253 and 2628 MSA affiliates were annually identified as newly treated for PD; the total number of incident PD cases was of 14,464 (72% farmers, 28% workers). The crude annual incidence ranged from 0.715 to 0.791 per 1,000 person-years. PD incidence was 7% higher in 2010 (P = 0.001) than in the rest of the period but no linear trend was observed between 2011 and 2015 (P for trend = 0.560). The mean age was 75 years (SD = 12) and 7990 (55%) were males. PD incidence was 12% higher among MSA affiliates compared to GS affiliates (RR = 1.12; 95% CI: 1.09–1.15). Among MSA affiliates, farmers had a higher risk of PD than other workers (RR = 1.10; 95% CI: 1.05–1.15). The increased PD risk in farmers depended on age (P for interaction = 0.004), with a stronger association at older ages, but not on sex (P for interaction = 0.085) or calendar year (P for interaction = 0.443). Regarding the spatial distribution of PD incidence, we observed a more pronounced between-departement variation among MSA farmers (ICC = 87%) than among other MSA workers (ICC = 79%). Conclusion Higher PD incidence among French farmers compared to the general population and agricultural workers, as well as the marked spatial variation of PD incidence in this population are consistent with the role of occupational pesticide exposure in PD. These findings warrant the epidemiological surveillance of PD among French farmers.

SNCA REP1 and Parkinson’s disease

REP1 is a polymorphic dinucleotide repeat sequence located in the promoter region of the SNCA gene (OMIM 163890). Opinions regarding the interaction between the various REP1 alleles and Parkinson’s disease (PD) or its phenotypes have been inconsistent and have thus far not been comprehensively analyzed. In this study, we searched Medline, Embase and Cochrane databases as well as the Chinese-language Wanfang and CNKI databases using strict inclusion and exclusion criteria and conducted our analysis using Revman 5.3 software. Our search produced 28 articles describing REP1 alleles and their associated PD risks and 8 articles which discussed the relationship between REP1 variation and PD phenotypes. We found that the 265-, 269-, and 271-bp alleles of REP1 (using the nomenclature established by Xia et al.) increased the risk of PD (OR: 1.81, 1.05, 1.17; p: 0.0002, 0.003, 0.002) while the 267-bp allele decreased PD risk (OR: 0.86, p: <0.00001) when taking all populations into account. By ethnicity, we observed an obvious population heterogeneity in the effects of various alleles, where the 269-, 271-, and 273-bp alleles increased PD risk (OR: 1.06, 1.22, 1.89; p: 0.001, 0.003, 0.001) and the 267-bp allele decreased PD risk (OR: 0.85; p: <0.00001) in Caucasian populations, and the 263- and 265-bp alleles increased the risk of PD (OR: 2.22, 2.03; p: 0.03, 0.0002) and the 267- and 273-bp alleles decreased PD risk (OR: 0.90, 0.78; p: 0.02, 0.03) in Asian populations. We also determined that the 267-, 269-, and 271-bp alleles occurred the most frequently, although the frequency distribution varied among different ethnicities. Phenotypic analysis demonstrated that PD patients carrying the 271-bp allele were prone to early onset PD (OR: 1.75, p: 0.02) while the 267-bp had the opposite effect (OR: 0.81; p: 0.01).

MTHFR C677T and A1298C polymorphisms may contribute to the risk of Parkinson's disease: A meta-analysis of 19 studies.

The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been reported to be a candidate gene for susceptibility to Parkinson's disease (PD), but results of different studies are conflicting. Here, we conducted a meta-analysis of published case-control studies to evaluate the association between MTHFR C677T and A1298C gene polymorphisms with the risk of PD. Electronic search through PubMed, EmBase, ScienceDirect and Cochrane Library was conducted to identify all relevant studies. A total of 19 studies with 2746 cases and 8967 controls were included. No significant association between MTHFR C677T polymorphism and PD risk was found in the overall population in all five genetic models. In the subgroup analysis stratified by ethnicity, a significant association between MTHFR C677T and PD risk was observed in the dominant model in Caucasians (OR=1.175, 95%CI: 1.008-1.369, P=0.040), but not in Asians. Significant association was found between MTHFR A1298C polymorphism and PD risk in the overall population in the dominant (OR=1.168, 95%CI: 1.008-1.353, P=0.039) and heterozygous model (OR=1.172, 95%CI: 1.004-1.367, P=0.044). But in the subgroup analysis, no association was found between MTHFR A1298C and PD neither in Caucasians nor in Asians. Our meta-analysis suggests that MTHFR C677T polymorphism may be associated with increased PD risk in Caucasians and MTHFR A1298C polymorphism may also increase susceptibility to PD.

More than constipation - bowel symptoms in Parkinson's disease and their connection to gut microbiota.

The majority of Parkinson's disease (PD) patients suffer from gastrointestinal symptoms of which constipation is considered the most prominent. Recently, in addition to constipation, a diagnosis of irritable bowel syndrome (IBS) was also found to be associated with increased PD risk. Gut microbiota alterations have been reported in IBS and recently also in PD. IBS-like bowel symptoms in PD and their possible connection to other non-motor symptoms and faecal microbiota were assessed. This case-control study compared 74 PD patients with 75 controls without any signs of parkinsonism or potential premotor symptoms. IBS-like symptoms were assessed using the Rome III questionnaire. The non-motor symptoms were assessed using the Non-Motor Symptoms Questionnaire and Non-Motor Symptom Scale. Faecal microbiota were assessed by pyrosequencing of the V1-V3 regions of the bacterial 16S ribosomal RNA gene. Symptoms that were IBS-like were significantly more prevalent in PD patients than in controls (24.3% vs. 5.3%; P=0.001). Criteria for functional constipation were met by 12.2% of PD patients and 6.7% of controls (P=0.072).PD patients with IBS-like symptoms had more non-motor symptoms and a lower faecal abundance of Prevotella bacteria than those without IBS-like symptoms. Our results indicate that PD patients may suffer from colonic dysfunction beyond pure constipation. Therefore, a more comprehensive assessment of bowel symptoms could provide valuable information. The lower abundance of Prevotella bacteria in PD patients with IBS-like symptoms suggests that the microbiota-gut-brain axis may be implicated in the gastrointestinal dysfunction of PD patients.

Glucocerebrosidase Mutations in Parkinson Disease.

Following the discovery of a higher than expected incidence of Parkinson Disease (PD) in Gaucher disease, a lysosomal storage disorder, mutations in the glucocerebrocidase (GBA) gene, which encodes a lysosomal enzyme involved in sphingolipid degradation were explored in the context of idiopathic PD. GBA mutations are now known to be the single largest risk factor for development of idiopathic PD. Clinically, on imaging and pharmacologically, GBA PD is almost identical to idiopathic PD, other than certain features that can be identified in the specialist research setting but not in routine clinical practice. In patients with a known GBA mutation, it is possible to monitor for prodromal signs of PD. The clinical similarity with idiopathic PD and the chance to identify PD at a pre-clinical stage provides a unique opportunity to research therapeutic options for early PD, before major irreversible neurodegeneration occurs. However, to date, the molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are not fully elucidated. Experimental models to define the molecular mechanisms and test therapeutic options include cell culture, transgenic mice and other in vivo models amenable to genetic manipulation, such as drosophilia. Some key pathological pathways of interest in the context of GBA mutations include alpha synuclein aggregation, lysosomal-autophagy axis changes and endoplasmic reticulum stress. Therapeutic agents that exploit these pathways are being developed and include the small molecule chaperone Ambroxol. This review aims to summarise the main features of GBA-PD and provide insights into the pathological relevance of GBA mutations on molecular pathways and the therapeutic implications for PD resulting from investigation of the role of GBA in PD.

Occupational pesticide use and Parkinson's disease in the Parkinson Environment Gene (PEG) study

ObjectiveTo study the influence of occupational pesticide use on Parkinson's disease (PD) in a population with information on various occupational, residential, and household sources of pesticide exposure. MethodsIn a population-based case control study in Central California, we used structured interviews to collect occupational history details including pesticide use in jobs, duration of use, product names, and personal protective equipment use from 360 PD cases and 827 controls. We linked reported products to California's pesticide product label database and identified pesticide active ingredients and occupational use by chemical class including fungicides, insecticides, and herbicides. Employing unconditional logistic regression, we estimated odds ratios and 95% confidence intervals for PD and occupational pesticide use. ResultsEver occupational use of carbamates increased risk of PD by 455%, while organophosphorus (OP) and organochlorine (OC) pesticide use doubled risk. PD risk increased 110–211% with ever occupational use of fungicides, herbicides, and insecticides. Using any pesticide occupationally for >10years doubled the risk of PD compared with no occupational pesticide use. Surprisingly, we estimated higher risks among those reporting use of personal protective equipment (PPE). ConclusionsOur findings provide additional evidence that occupational pesticide exposures increase PD risk. This was the case even after controlling for other sources of pesticide exposure. Specifically, risk increased with occupational use of carbamates, OPs, and OCs, as well as of fungicides, herbicides, or insecticides. Interestingly, some types of PPE use may not provide adequate protection during pesticide applications.

Variants in SNCA Gene Are Associated with Parkinson's Disease Risk and Cognitive Symptoms in a Brazilian Sample.

Genetic susceptibility contributes to the etiology of sporadic Parkinson’s Disease (PD) and worldwide studies have found positive associations of polymorphisms in the alpha-synuclein gene (SNCA) with the risk for PD. However, little is known about the influence of variants of SNCA in individual traits or phenotypical aspects of PD. Further, there is a lack of studies with Latin-American samples. We evaluated the association between SNCA single nucleotide polymorphisms (single nucleotide polymorphisms, SNPs – rs2583988, rs356219, rs2736990, and rs11931074) and PD risk in a Brazilians sample. In addition, we investigated their potential interactions with environmental factors and specific clinical outcomes (motor and cognitive impairments, depression, and anxiety). A total of 105 PD patients and 101 controls participated in the study. Single locus analysis showed that the risk allele of all SNPs were more frequent in PD patients (p < 0.05), and the associations of SNPs rs2583988, rs356219, and rs2736990 with increased PD risk were confirmed. Further, the G-rs356219 and C-rs2736990 alleles were associated with early onset PD. T-rs2583988, G-rs356219 and C-2736990 alleles were significantly more frequent in PD patients with cognitive impairments than controls in this condition. In addition, in a logistic regression model, we found an association of cognitive impairment with PD, and the practice of cognitive activity and smoking habits had a protective effect. This study shows for the first time an association of SNCA polymorphism and PD in a South-American sample. In addition, we found an interaction between SNP rs356219 and a specific clinical outcome, i.e., the increased risk for cognitive impairment in PD patients.

Editor's Highlight: Base Excision Repair Variants and Pesticide Exposure Increase Parkinson's Disease Risk.

Exposure to certain pesticides induces oxidative stress and increases Parkinson's disease (PD) risk. Mitochondrial DNA (mtDNA) damage is found in dopaminergic neurons in idiopathic PD and following pesticide exposure in experimental models thereof. Base excision repair (BER) is the major pathway responsible for repairing oxidative DNA damage in cells. Whether single nucleotide polymorphisms (SNPs) in BER genes alone or in combination with pesticide exposure influence PD risk is unknown. We investigated the contributions of functional SNPs in 2 BER genes (APEX1 and OGG1) and mitochondrial dysfunction- or oxidative stress-related pesticide exposure, including paraquat, to PD risk. We also studied the effect of paraquat on levels of mtDNA damage and mitochondrial bioenergetics. 619 PD patients and 854 population-based controls were analyzed for the 2 SNPs, APEX1 rs1130409 and OGG1 rs1052133. Ambient pesticide exposures were assessed with a geographic information system. Individually, or in combination, the BER SNPs did not influence PD risk. Mitochondrial-inhibiting (OR = 1.79, 95% CI [1.32, 2.42]), oxidative stress-inducing pesticides (OR = 1.61, 95% CI [1.22, 2.11]), and paraquat (OR = 1.54, 95% CI [1.23, 1.93]) were associated with PD. Statistical interactions were detected, including for a genetic risk score based on rs1130409 and rs1052133 and oxidative stress inducing pesticides, where highly exposed carriers of both risk genotypes were at the highest risk of PD (OR = 2.21, 95% CI [1.25, 3.86]); similar interactions were estimated for mitochondrial-inhibiting pesticides and paraquat alone. Additionally, paraquat exposure was found to impair mitochondrial respiration and increase mtDNA damage in in vivo and in vitro systems. Our findings provide insight into possible mechanisms involved in increased PD risk due to pesticide exposure in the context of BER genotype variants.

Association of IGF1 gene polymorphism with Parkinson's disease in a Han Chinese population.

Accumulating evidence suggests that insulin-like growth factor 1 (IGF1) plays an important role in Parkinson's disease (PD) pathogenesis. However, it is not clear whether IGF1 polymorphism contributes to PD risk. We performed a case-control study in a Han Chinese population that included 512 sporadic PD cases and 535 matched controls. All participants were genotyped for rs972936 using the Sequenom MassARRAY iPLEX platform. Serum IGF1 levels of 61 de novo, drug-naïve PD patients and 55 age- and sex-matched controls were also measured using an enzyme-linked immunosorbent assay. Genotype frequency of rs972936-CC was significantly associated with an increased PD risk (p=0.009), especially in males (p=0.024) and late-onset patients (p=0.013). Serum IGF1 levels were significantly increased in de novo, drug-naïve PD patients compared to controls (p=0.036), although they were not correlated with motor dysfunction in PD patients (p=0.220). The present study shows that rs972936 polymorphism may increase susceptibility to PD, especially in males and late-onset patients. Furthermore, high serum IGF1 levels may be a potential diagnostic biomarker for PD in the Han Chinese population, although they do not correlate with a more severe motor dysfunction.

Advance research on association between environmental compound and parkinson's disease

Parkinson's disease(PD)was the second most common neurodegenerative disorder after Alzheimer's disease. Incidence of PD was ascending year by year. The etiology of PD is poorly understood, involving aging, genetic and environmental factors. Recently, environmental compound had attracted more and more research interest. Studies and extrapolation from epidemiology, animal experiments and cell culture suggested that environmental compound had involved in the molecular mechanisms including mitochondrial dysfunction, oxidative stress, microglia activation, abnormal aggregation of α-synuclein and autophagy damage ,which seemed to increase PD risk.

Gene-environment interactions linking air pollution and inflammation in Parkinson's disease

Both air pollution exposure and systemic inflammation have been linked to Parkinson's disease (PD). In the PASIDA study, 408 incident cases of PD diagnosed in 2006–2009 and their 495 population controls were interviewed and provided DNA samples. Markers of long term traffic related air pollution measures were derived from geographic information systems (GIS)-based modeling. Furthermore, we genotyped functional polymorphisms in genes encoding proinflammatory cytokines, namely rs1800629 in TNFα (tumor necrosis factor alpha) and rs16944 in IL1B (interleukin-1β). In logistic regression models, long-term exposure to NO2 increased PD risk overall (odds ratio (OR)=1.06 per 2.94μg/m3 increase, 95% CI=1.00–1.13). The OR for PD in individuals with high NO2 exposure (≧75th percentile) and the AA genotype of IL1B rs16944 was 3.10 (95% CI=1.14–8.38) compared with individuals with lower NO2 exposure (<75th percentile) and the GG genotype. The interaction term was nominally significant on the multiplicative scale (p=0.01). We did not find significant gene-environment interactions with TNF rs1800629. Our finds may provide suggestive evidence that a combination of traffic-related air pollution and genetic variation in the proinflammatory cytokine gene IL1B contribute to risk of developing PD. However, as statistical evidence was only modest in this large sample we cannot rule out that these results represent a chance finding, and additional replication efforts are warranted.

Appendectomy and risk of Parkinson's disease: A nationwide cohort study with more than 10 years of follow-up.

The appendix may be a key site for the initiation of Parkinson's disease (PD) pathology. We examined the hypothesis that appendectomy is associated with lower PD risk. We used Danish medical and administrative registries to construct a cohort of all patients in Denmark with an operation code of appendectomy during 1980-2010 (n = 265,758) and a matched general population comparison cohort (n = 1,328,790). Using Cox regression, we computed hazard ratios and corresponding 95% confidence intervals for PD, adjusting for potential confounders and stratifying on age at appendectomy (≤45 years / > 45 years), sex, and follow-up time. During follow-up ( > 10 years), PD incidence was 0.19 and 0.15 per 1,000 person-years at risk in the appendectomy cohort and in the general population comparison cohort, respectively, yielding a slightly increased risk of PD (adjusted hazard ratio = 1.14; 95% confidence interval 1.03-1.27). Findings were consistent after more than 20 years of follow-up and when stratified on age of appendectomy and sex. Appendectomy was associated with a small increase in PD risk 10 or more years after surgery. © 2016 International Parkinson and Movement Disorder Society.