Parkinson's Disease In Individuals Research Articles

Unraveling the Ties: Type 2 Diabetes and Parkinson's Disease - A Nano-Based Targeted Drug Delivery Approach.

The link between Type 2 Diabetes (T2DM) and Parkinson's Disease (PD) dates back to the early 1960s, and ongoing research is exploring this association. PD is linked to dysregulation of dopaminergic pathways, neuroinflammation, decreased PPAR-γ coactivator 1-α, increased phosphoprotein enriched in diabetes, and accelerated α-Syn amyloid fibril production caused by T2DM. This study aims to comprehensively evaluate the T2DM-PD association and risk factors for PD in T2DM individuals. The study reviews existing literature using reputable sources like Scopus, ScienceDirect, and PubMed, revealing a significant association between T2DM and worsened PD symptoms. Genetic profiles of T2DM-PD individuals show similarities, and potential risk factors include insulin-resistance and dysbiosis of the gut-brain microbiome. Anti-diabetic drugs exhibit neuroprotective effects in PD, and nanoscale delivery systems like exosomes, micelles, and liposomes show promise in enhancing drug efficacy by crossing the Blood-Brain Barrier (BBB). Brain targeting for PD uses exosomes, micelles, liposomes, dendrimers, solid lipid nanoparticles, nano-sized polymers, and niosomes to improve medication and gene therapy efficacy. Surface modification of nanocarriers with bioactive compounds (such as angiopep, lactoferrin, and OX26) enhances α-Syn conjugation and BBB permeability. Natural exosomes, though limited, hold potential for investigating DM-PD pathways in clinical research. The study delves into the underlying mechanisms of T2DM and PD and explores current therapeutic approaches in the field of nano-based targeted drug delivery. Emphasis is placed on resolved and ongoing issues in understanding and managing both conditions.

Detecting Misfolded α-Synuclein in Blood Years before the Diagnosis of Parkinson's Disease.

Identifying individuals with Parkinson's disease (PD) already in the prodromal phase of the disease has become a priority objective for opening a window for early disease-modifying therapies. The aim was to evaluate a blood-based α-synuclein seed amplification assay (α-syn SAA) as a novel biomarker for diagnosing PD in the prodromal phase. In the TREND study (University of Tuebingen) biennial blood samples of n = 1201 individuals with/without increased risk for PD were taken prospectively over 4 to 10 years. We retrospectively analyzed blood samples of 12 participants later diagnosed with PD during the study to detect and amplify pathological α-syn conformers derived from neuronal extracellular vesicles using (1) immunoblot analyses with an antibody against these conformers and (2) an α-syn-SAA. Additionally, blood samples of n = 13 healthy individuals from the TREND cohort and n = 20 individuals with isolated rapid eye movement sleep behavior disorder (iRBD) from the University Hospital Cologne were analyzed. All individuals with PD showed positive immunoblots and a positive α-syn SAA at the time of diagnosis. Moreover, all PD patients showed a positive α-syn SAA 1 to 10 years before clinical diagnosis. In the iRBD cohort, 30% showed a positive α-syn SAA. All healthy controls had a negative SAA. We here demonstrate the possibility to detect and amplify pathological α-syn conformers in peripheral blood up to 10 years before the clinical diagnosis of PD in individuals with and without iRBD. The findings of this study indicate that this blood-based α-syn SAA assay has the potential to serve as a diagnostic biomarker for prodromal PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Association between lipid levels and the risk of Parkinson's disease in individuals with diabetes mellitus: A nationwide population-based cohort study

IntroductionMany studies have examined the positive association between diabetes mellitus (DM) and the risk of Parkinson's disease (PD). Dyslipidemia has been reported to be prevalent in patients with diabetes; thus, lipid levels and the drugs for dyslipidemia could influence the development of PD in patients with DM. This study aimed to examine the association between lipid levels and the risk of PD in individuals with DM and evaluate whether the association changes with the use of statins. MethodsThis nationwide population-based retrospective cohort study included individuals with DM according to the International Classification of Diseases between 2009 and 2012. Among the 2,361,633 patients with DM followed up for up to 9 years, 17,046 were newly diagnosed with PD. Patients with DM were categorized into quartile groups of total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels. ResultsThere was an inverse association between lipid levels and PD development in the unadjusted model; however, this relationship became less significant after adjusting the use of statins in triglyceride and total cholesterol. In the analysis stratified by statin use, total cholesterol level was associated with decreased PD risk in non-statin users with DM; however, there was no significant association between total cholesterol level and PD risk in statin users. ConclusionWe found an inverse relationship between lipid levels and PD risk in patients with DM, which was influenced by statin use. Future studies about optimal target lipid levels relevant to PD risk considering statin dose in DM patients are needed.

Bone Mineral Density and the Risk of Parkinson's Disease in Postmenopausal Women.

Whether bone mineral density (BMD) is related to the risk of Parkinson's disease (PD) is unclear. The objective of this study was to examine the association between BMD status and incident PD in postmenopausal women. We retrospectively examined a nationwide cohort of 272,604 women aged 66 years who participated in the 2009-2012 Korean national health screening for transitional ages. BMD was evaluated using dual-energy X-ray absorptiometry of the central bones. The use of antiosteoporosis medications (AOMs) was assessed. We performed multivariable Cox proportional hazards regression to evaluate the association between BMD and PD risk by calculating hazardratios (HRs) and 95% confidence intervals (CIs). During the median follow-up of 7.7 years, 2,884 (1.1%) incident PD cases developed. After adjusting for confounding factors, lower BMD was associated with an increased risk of PD (P for trend <0.001). Individuals with osteoporosis had a 1.40-fold higher HR (1.40, 95% CI: 1.25-1.56) than those with a normal BMD. Sensitivity analyses suggested the associations robust to longer lag periods and further adjustment. These associations were prominent in individuals without AOM use before or after enrollment (P for interaction = 0.031 and 0.014). Increased risks of PD in individuals with osteopenia and osteoporosis who did not use AOMs were attenuated by the medication use during the follow-up period, regardless of previous AOM use. Lower postmenopausal BMD and osteoporosis were associated with an increased risk of PD. In addition, this association could be mitigated using AOMs. Proper management of BMD in postmenopausal women may help prevent PD. © 2023 International Parkinson and Movement Disorder Society.

Molecular mechanisms defining penetrance of LRRK2-associated Parkinson's disease.

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of dominantly inherited Parkinson's disease (PD). LRRK2 mutations, among which p.G2019S is the most frequent, are inherited with reduced penetrance. Interestingly, the disease risk associated with LRRK2 G2019S can vary dramatically depending on the ethnic background of the carrier. While this would suggest a genetic component in the definition of LRRK2-PD penetrance, only few variants have been shown to modify the age at onset of patients harbouring LRRK2 mutations, and the exact cellular pathways controlling the transition from a healthy to a diseased state currently remain elusive. In light of this knowledge gap, recent studies also explored environmental and lifestyle factors as potential modifiers of LRRK2-PD. In this article, we (i) describe the clinical characteristics of LRRK2 mutation carriers, (ii) review known genes linked to LRRK2-PD onset and (iii) summarize the cellular functions of LRRK2 with particular emphasis on potential penetrance-related molecular mechanisms. This section covers LRRK2's involvement in Rab GTPase and immune signalling as well as in the regulation of mitochondrial homeostasis and dynamics. Additionally, we explored the literature with regard to (iv) lifestyle and (v) environmental factors that may influence the penetrance of LRRK2 mutations, with a view towards further exposomics studies. Finally, based on this comprehensive overview, we propose potential future in vivo, in vitro and in silico studies that could provide a better understanding of the processes triggering PD in individuals with LRRK2 mutations.

Obstructive sleep apnea and the risk of Alzheimer's disease and Parkinson disease: A Mendelian randomization study OSA, Alzheimer's disease and Parkinson disease

BackgroundPrevious studies reported that obstructive sleep apnea (OSA) was associated with neurodegenerative diseases. However, whether these associations are causal are still unsettled. In our study, we investigated the causal effects of genetically-predicted OSA on Alzheimer's disease (AD) and Parkinson disease (PD). MethodsWe implemented two-sample Mendelian randomization to judge causation using summary statistics from three independent and large genome-wide association studies on OSA (cases n = 16,761, controls n = 201,194), AD (cases n = 71,880, controls n = 383,378) and PD (cases n = 33,774, controls n = 449,056). Four single nucleotide polymorphisms (SNPs) with genome-wide significance associated with OSA served as instrumental variables. We prioritized the inverse variance weighted method when generating unconfounded estimates. Besides, MR-Egger regression, weighted mode, and weighted median methods were adopted as a supplement to the inverse variance weighted method. ResultsWe found no evidence supporting significant causal relationships between OSA and AD or PD among European population. The risk ratio of AD was 0.99 (95% confidence interval (CI) [0.92,1.08]) and that of PD was 0.82 (95%CI [0.47, 1.40]). Results from alternative approaches were generally consistent with that of the inverse variance weighted method. ConclusionThe present study found no evidence for causal associations between OSA and the risk of AD or PD in individuals of European ancestry.

Association between body weight variability and incidence of Parkinson disease: A nationwide, population-based cohort study.

Although body weight variability has been associated with mortality, cardiovascular disease, and dementia, the relationship between body weight variability and Parkinson disease (PD) has rarely been studied. We aimed to investigate the longitudinal association between body weight variability and PD incidence. A nationwide population-based, cohort study was conducted using the database from the Health Insurance Review and Assessment Service of the whole Korean population. We analyzed 2,815,135 participants (≥40years old, mean age = 51.7 ± 8.6 years, 66.8% men) without a previous PD diagnosis. We determined individual body weight variability from baseline weight and follow-up visits. We used Cox proportional hazards regression models. The highest quartile group was associated with increased PD incidence compared with the lowest quartile group after adjustment for confounding factors (hazard ratio [HR] = 1.18, 95% confidence interval [CI] = 1.08-1.29). In contrast, baseline body mass index, baseline waist circumference, and waist circumference variability were not associated with increased PD incidence. In the body weight loss group, individuals within the quartile of the highest variation in body weight showed a higher HR of PD risk than those within other quartiles (HR = 1.41, 95% CI = 1.18-1.68). Body weight variability, especially weight loss, was associated with higher PD incidence. This finding has important implications for clinicians and supports the need for preventative measures and surveillance for PD in individuals with fluctuating body weight.

Association study of MCCC1/LAMP3 and DGKQ variants with Parkinson's disease in patients of Malay ancestry.

Genome-wide association studies (GWAS) have shown that variants in the 3-methylcrotonyl-CoA carboxylase (MCCC1)/lysosome-associated membrane protein 3 (LAMP3) loci (rs10513789, rs12637471, rs12493050) reduce the risk of Parkinson's disease (PD) in Caucasians, Chinese and Ashkenazi-Jews while the rs11248060 variant in the diacylglycerol kinase theta (DGKQ) gene increases the risk of PD in Caucasian and Han Chinese cohorts. However, their roles in Malays are unknown. Therefore, this study aims to investigate the association of these variants with the risk of PD in individuals of Malay ancestry. A total of 1114 subjects comprising of 536 PD patients and 578 healthy controls of Malay ancestry were recruited and genotyped using Taqman® allelic discrimination assays. The G allele of rs10513789 (OR = 0.83, p = 0.001) and A allele of rs12637471 (OR = 0.79, p = 0.007) in the MCCC1/LAMP3 locus were associated with a protective effect against developing PD in the Malay population. A recessive model of penetrance showed a protective effect of the GG genotype for rs10513789 and the AA genotype for rs12637471. No association with PD was found with the other MCCC1/LAMP3 rs12493050 variant or with the DGKQ (rs11248060) variant. No significant associations were found between the four variants with the age at PD diagnosis. MCCC1/LAMP3 variants rs10513789 and rs12637471 protect against PD in the Malay population.

Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans

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

Effect of LRRK2 G2385R Variant on Subthalamic Deep Brain Stimulation Efficacy in Parkinson's Disease in a Han Chinese Population

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for advanced Parkinson's disease (PD). The G2385R variant of LRRK2 is a risk factor for PD in Han Chinese individuals. We retrospectively compared the clinical outcomes of STN-DBS surgery between PD Han Chinese G2385R variant carriers and non-carriers. Fifty-seven PD patients with bilateral STN-DBS were enrolled, including 8 G2385R+ variant carriers (G2385R+ group) and 49 non-carriers (G2385R– group). Clinical data included Unified Parkinson's Disease Rating Scale (UPDRS) parts I to IV, levodopa equivalent daily dose (LEDD), Mini-Mental State Examination Scale (MMSE) score, and Hamilton Depression Rating Scale (HAMD) score measured prior to DBS and 12 months post-DBS. DBS settings were also recorded. All PD patients benefited from STN-DBS surgery. There were no statistical differences between the two groups in terms of motor function, daily living activities, and LEDD reductions at 12 months post-DBS. The rigidity of the post-surgical G2385R+ group was significantly improved compared with that of the G2385R– group (P = 0.045). Post-surgical voltage in the G2385R+ group was significantly higher than that in the G2385R– group (P = 0.033). STN-DBS outcomes were not influenced by the LRRK2 G2385R variant in Han Chinese patients.

Transcranial brain sonography for Parkinsonian syndromes.

Substantia nigra (SN) hyperechogenicity has been proved to be a characteristic finding for idiopathic Parkinson's disease (PD), occurring in more than 90% of the patients. This echofeature is owed to increased amounts of iron in the SN region and reflects a functional impairment of the nigrostriatal dopaminergic system. In a prospective blinded study in which a group of patients with early mild signs and symptoms of unclear Parkinsonism were followed until a definite clinical diagnosis of PD, the hyperechogenicity of the SN was demonstrated to be highly predictive of a final diagnosis of PD. For the diagnosis of PD in individuals with early motor symptoms, both the sensitivity and positive predictive value of SN hyperechogenicity were higher than 90% and both the specificity and negative predictive value were higher than 80%. For early differential diagnosis between PD and atypical Parkinsonian syndromes, the sensitivity and positive predictive value of SN hyperechogenicity were higher than 90%, and both the specificity and negative predictive value were higher than 80%. The diagnostic specificity is increased if combining the TCS findings of SN, lenticular nucleus and third ventricle. In asymptomatic adult subjects, SN hyperechogenicity, at least unilaterally, indicates a subclinical functional insufficiency of the nigrostriatal dopaminergic system. Recent papers revealed that SN hyperechogenicity might suggest preclinical PD. Reduced echogenicity of midbrain raphe indicates increased risk of depression in PD patients. Caudate nucleus hyperechogenicity has been associated with drug-induced psychosis, and frontal horn dilatation >20 mm with dementia. Transcranial brain sonography can be a valuable tool for managing patients with Parkinsonian signs and symptoms.

RETRACTED: Silymarin prevents apoptosis through inhibiting the Bax/caspase-3 expression and suppresses toll like receptor-4 pathway in the SNc of 6-OHDA intoxicated rats

Several lines of evidence show that apoptosis, oxidative stress and neuroinflammation are associated with the development of Parkinson's disease (PD). In the present study, we investigated the effect of pre-treatment with silymarin (SM) on oxidative stress, apoptosis and toll-like receptor 4 (TLR4) expression in substantia nigra pars copmacta (SNc) of 6-hydroxydopamine (6-OHDA)-lesioned rats. Animals were pretreated with 100, 200 or 300 mg/kg of SM daily for 5 days and at 6th day 6-OHDA (8 μg/2 μl) was infused unilaterally into the central region of the SNc. 6-OHDA decreased the total glutathione and antioxidant enzymes activity in the SNc. Interestingly, we found that 6-OHDA caused to TLR4 up regulation. The SNc levels of glutathione, superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase were significantly higher in the SM pretreated rats. SM strongly decreased 6-OHDA-induced elevation of SNc apoptosis, caspase-3 and Bax/Bcl-2 ratio. Furthermore, SM markedly (p < 0.001) prevented from SNc over expression of TLR4 caused by 6-OHDA. A significantly high positive correlation was seen between TLR4 activity with caspase-3 protein levels (r = 0.896, P < 0.01), Bax protein levels (r = 0.96, P < 0.01). Pre-treatment of 6-OHDA-lesioned rats with SM reduces SNc neuronal apoptosis possibly through inhibition of TLR4 over expression. Further clinical study should be carried out to prove potential application of SM for protection against PD in susceptible individuals.

Cerebrospinal fluid biomarkers of central dopamine deficiency predict Parkinson's disease

BackgroundConsistent with nigrostriatal dopamine depletion, low cerebrospinal fluid (CSF) concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, characterize Parkinson's disease (PD) even in recently diagnosed patients. Whether low CSF levels of DOPAC or DOPA, the precursor of dopamine, identify pre-clinical PD in at-risk healthy individuals has been unknown. MethodsParticipants in the intramural NINDS PDRisk study entered information about family history of PD, olfactory dysfunction, dream enactment behavior, and orthostatic hypotension at a protocol-specific website. After at least 3 risk factors were confirmed by on-site screening, 26 subjects had CSF sampled for levels of catechols and were followed for at least 3 years. ResultsOf 26 PDRisk subjects, 4 were diagnosed with PD (Pre-Clinical PD group); 22 risk-matched (mean 3.2 risk factors) subjects remained disease-free after a median of 3.7 years (No-PD group). The Pre-Clinical PD group had lower initial DOPA and DOPAC levels than did the No-PD group (p = 0.0302, p = 0.0190). All 3 subjects with both low DOPA (<2.63 pmol/mL) and low DOPAC (<1.22 pmol/mL) levels, based on optimum cut-off points using the minimum distance method, developed PD, whereas none of 14 subjects with both normal DOPA and DOPAC levels did so (75% sensitivity at 100% specificity, p = 0.0015 by 2-tailed Fisher's exact test). ConclusionsIn people with multiple PD risk factors, those with low CSF DOPA and low CSF DOPAC levels develop clinical disease during follow-up. We suggest that neurochemical biomarkers of central dopamine deficiency identify the disease in a pre-clinical phase.

Parkinson's disease prevalence in Fabry disease: A survey study

Recent research has suggested a possible link between Parkinson's disease (PD) and Fabry disease. To test this relationship, we administered a self-report and family history questionnaire to determine the prevalence of PD in Fabry disease patients and family members with likely pathogenic alpha-galactosidase A (GLA) mutations. A total of 90 Fabry patients (77 from the online survey and 13 from the Icahn School of Medicine at Mount Sinai (ISMMS)) were included in the analysis. Two of the Fabry disease patients who completed the online survey were diagnosed with PD (2/90, 2.2%). Among probands older than 60, 8.3% (2/24) were diagnosed with PD. Using Kaplan Meier survival analysis, the age-specific risk of PD by age 70 was 11.1%. Family history was available on 72 Fabry families from the online study and 9 Fabry families from ISMMS. Among these 81 families, 6 (7.4%) had one first degree relative who fit the criteria for a conservative diagnosis of PD. The results of this study suggest that there may be an increased risk of developing PD in individuals with GLA mutations, but these findings should be interpreted with caution given the limitations of the study design.

Variant A320V in vacuolar protein sorting 35 (VPS35) in Taiwanese Parkinson’s disease is associated with endosomal alterations and trafficking defects

Background: Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene have recently been reported as a new cause of late-onset, autosomal dominant familial Parkinson's disease (PD). AspD620Asn (D620N), has been identified to cause PD in multiple individuals and families worldwide. VPS35 encoded a core component of the retromer complex, however, the exact molecular mechanism by which VPS35 mutations induce progressive neurodegeneration in PD are not fully elucidated.

Conversion to Parkinson Disease in the PARS Hyposmic and Dopamine Transporter–Deficit Prodromal Cohort

Detecting individuals at risk for Parkinson disease (PD) during the prodromal phase could clarify disease mechanisms and allow for treatment earlier in the disease process to possibly slow or prevent the onset of motor PD. To determine if the combination of smell identification testing followed by dopamine transporter (DAT) imaging can accurately and efficiently identify individuals from the general population at risk for conversion to a clinical diagnosis of PD. Participants were identified from the community by olfactory testing assessed longitudinally with DAT imaging 2 and 4 years after baseline and by annual clinical follow-up to determine whether they had clinical evidence to establish a PD diagnosis. Participants were contacted by mail and completed olfactory testing at home. Longitudinal follow-up of clinical measures and DAT imaging occurred at specialty centers. There were 203 hyposmic and 100 normosmic participants. A total of 185 hyposmic and 95 normosmic individuals had at least 1 follow-up visit, and 152 hyposmic participants (82.2%) were either observed for 4 years or converted to PD during follow-up. Percentage of individuals with hyposmia and a DAT deficit that converted to PD and the change in PD clinical scale scores (Unified Parkinson's Disease Rating Scale) and DAT imaging during 4-year follow-up. Of 280 total participants, 140 (50.0%) were male, and the mean (SD) age of the cohort was 63 (8.7) years. Among 21 participants with hyposmia and a DAT deficit (65% or less of age-expected lowest putamen binding ratio) at baseline, 14 (67%) converted to PD at 4 years compared with 2 of 22 participants (9%) with a DAT in an indeterminate range (greater than 65%-80%) and 3 of 109 participants (2.8%) with no DAT deficit (greater than 80%) at baseline. Individuals with a baseline DAT deficit experienced a 4-year decline in DAT binding of 20.23% (SD, 15.04%) compared with 3.68% (SD, 18.36%) and 5.45% (SD, 13.58%) for participants with an indeterminate and no DAT deficit, respectively (P = .002). The relative risk of conversion to a diagnosis of PD in hyposmic individuals with a DAT deficit was 17.47 (95% CI, 7.02-43.45) compared with individuals with either indeterminate or no DAT deficit. The combination of hyposmia and DAT deficit was highly predictive of conversion to PD within 4 years of clinical follow-up. Individuals with hyposmia and a DAT deficit had a 5% reduction in DAT binding annually, similar to early PD. These results provide a framework for planning disease prevention studies in PD.

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.

DNA variants in CACNA1C modify Parkinson disease risk only when vitamin D level is deficient

Objective:To evaluate the association between the genetic variants in CACNA1C, which encodes the α1 subunit of the L-type voltage-sensitive calcium channel (LVSCC) and Parkinson disease (PD) while accounting for interactions with vitamin D concentration.Methods:Two independent case-control data sets (478 cases and 431 controls; 482 cases and 412 controls) were used. Joint effects of single nucleotide polymorphisms (SNPs) and SNP-vitamin D interaction were analyzed by comparing models containing vitamin D deficiency, SNP genotypes, SNP-vitamin D interaction, and covariates to a restricted model with only vitamin D deficiency and covariates. Meta-analysis was used to combine the joint effects in the 2 data sets. Analysis was stratified by vitamin D deficiency to demonstrate the pattern of SNP-vitamin D interaction.Results:Vitamin D deficiency was associated with PD in both data sets (odds ratio [OR] = 1.9–2.7, p ≤ 0.009). SNP rs34621387 demonstrated a significant joint effect (meta-analysis, p = 7.5 × 10−5; Bonferroni corrected, p = 0.02). The G allele at rs34621387 is associated with PD in vitamin D-deficient individuals in both data sets (OR = 2.0–2.1, confidence interval = 1.3–3.5, p = 0.002) but is not associated with PD in vitamin D–nondeficient individuals (p > 0.8 in both data sets).Conclusions:Previous studies suggest that vitamin D deficiency is associated with PD and sustained opening of LVSCC contributes to the selective vulnerability of dopaminergic neurons in PD. Our data demonstrate that the association between genetic variations in CACNA1C and PD depends on vitamin D deficiency, providing one potential mechanism underlying the association between vitamin D deficiency and PD.

Association analysis of the GRN rs5848 and MAPT rs242557 polymorphisms in Parkinson's disease and multiple system atrophy: a large-scale population-based study and meta-analysis

Background: Previous studies have found an association between the granulin gene rs5848 and microtubule-associated protein tau gene (MAPT) rs242557 polymorphisms and susceptibility to Parkinson's disease (PD). However, the results of association studies between the two polymorphisms and PD have been inconsistent. Given the overlap in clinical and pathological characteristics of PD and multiple system atrophy (MSA), we examined the associations of these two polymorphisms with PD and MSA in a subset of the Chinese population. Methods: In total, 1270 PD patients, 360 MSA patients and 830 healthy controls (HCs) were included in the study. All subjects were genotyped for the two polymorphisms using Sequenom iPLEX Assay technology. After combining our results with the available published data, a meta-analysis was conducted to investigate the association between MAPT rs242557 and the risk of PD. Results: The minor allele “T” of GRN rs5848 decreased the risk for PD (p = 0.0309, odds radio [OR], 0.86; 95% CI, 0.76–0.99). No differences in the genotype distributions and minor allele frequency (MAF) of MAPT rs242557 were observed between the PD and the HCs in our Chinese population. Our meta-analysis revealed an association between MAPT rs242557 and PD in Caucasian and Asian population in a recessive model (p = 0.049 and p = 0.046, respectively). However, no significant differences in the genotype distributions and MAFs of the two polymorphisms were found between the MSA patients and HCs. Conclusion: Our results indicate that GRN rs5458 may decrease the risk of PD in Chinese individuals, and the MAPT rs242557 is marginally associated with PD.

MAPT IVS1+124 C>G modifies risk of LRRK2 G2385R for Parkinson's disease in Chinese individuals

Variants of the MAPT gene have been suggested to be associated with Parkinson's disease (PD) and to modify the risk for leucine-rich repeat kinase 2 (LRRK2) Parkinsonism. However, this has not been confirmed in Asians with ethnicity-specific variants of MAPT and LRRK2. In this study, Asian-specific LRRK2 p.G2385R variant and IVS1+124 C>G, a functional single-nucleotide polymorphism located in the MAPT promoter region, were genotyped in 561 Chinese PD patients and 556 control subjects. Allelic and genotypic frequencies of the 2 variants were compared between cases and control subjects independently and in combination. As a result, the LRRK2 p.G2385R variant alone was associated with an increased risk for PD (Odds ratio, 1.86; 95% confidence intervals, 1.08–3.19; p = 0.014), whereas MAPT IVS1+124 C>G was not (p = 0.34). However, the coexistence of MAPT IVS1+124C>G significantly enhanced the LRRK2 G2385R-conferred risk for PD (Odds ratio, 2.30; 95% confidence intervals, 1.14–4.54; p = 0.012). These results provide further evidence supporting the interaction between MAPT and LRRK2 genes, which increases the susceptibility to PD in Chinese individuals.