Risk Of Parkinson's Disease Research Articles

Peripheral immune cell abundance differences link blood mitochondrial DNA copy number and Parkinson's disease.

Mitochondrial dysfunction plays an important role in Parkinson's disease (PD), with mitochondrial DNA copy number (mtDNA-CN) emerging as a potential marker for mitochondrial health. We investigated the links between blood mtDNA-CN and PD severity and risk using the Accelerating Medicines Partnership program for Parkinson's Disease dataset, replicating our results in the UK Biobank. Our findings reveal that reduced blood mtDNA-CN levels are associated with heightened PD risk and increased severity of motor symptoms and olfactory dysfunction. We estimated blood cell composition using complete blood cell profile when available or RNA-sequencing data as a surrogate. After adjusting for blood cell composition, the associations between mtDNA-CN and PD risk and clinical symptoms became non-significant. Bidirectional Mendelian randomization analysis also found no evidence of a direct causal relationship between blood mtDNA-CN and PD susceptibility. Hence peripheral inflammatory immune responses rather than mitochondrial dysfunction underpin these previously identified associations in PD.

Gut Microbial Metabolites and Future Risk of Parkinson's Disease: A Metabolome-Wide Association Study.

Alterations in gut microbiota are observed in Parkinson's disease (PD). Previous studies on microbiota-derived metabolites in PD were small-scale and post-diagnosis, raising concerns about reverse causality. Our goal was to prospectively investigate the association between plasma microbial metabolites and PD risk within a metabolomics framework. A nested case-control study within the prospective EPIC4PD cohort, measured pre-diagnostic plasma microbial metabolites using untargeted metabolomics. Thirteen microbial metabolites were identified nominally associated with PD risk (P-value < 0.05), including amino acids, bile acid, indoles, and hydroxy acid, although none remained significant after multiple testing correction. Three pathways were implicated in PD risk: valine, leucine, and isoleucine degradation, butanoate metabolism, and propanoate metabolism. PD-associated microbial pathways were more pronounced in men, smokers, and overweight/obese individuals. Changes in microbial metabolites may represent a pre-diagnostic feature of PD. We observed biologically plausible associations between microbial pathways and PD, potentially influenced by individual characteristics. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The protective effect of higher serum triacylglycerol (51:4) levels against Parkinson's disease.

Emerging evidence has shown a strong correlation between serum triacylglycerol (TAG) levels, the inflammatory response, and Parkinson's disease (PD) onset. However, the causal relationship between TAG levels and PD has not been well-established. We aimed to investigate the relationship between serum TAG levels and risk of PD and explore the potential mediating role of circulating immune cells and inflammatory proteins. We utilised genotype data from the GeneRISK cohort, and summary data from genome wide association studies investigating PD, circulating immune cells, inflammatory proteins, and plasma lipidomes. Using Mendelian randomization (MR) and multivariate MR (MVMR) analysis, we further adjusted for phosphatidylcholine (17:0_18:1) and triacylglycerol (58:7). Our results suggested a robust causal link between higher serum TAG (51:4) levels and a decreased risk of PD, with one standard deviation genetically instrumented higher serum TAG (51:4) level leading to a 21 percent [95% CI, 0.66 - 0.96] reduction in the risk of PD (p = 0.015). Additionally, the results of the mediation analysis suggested a possible role for mediation through circulating immune cells (including IgD-CD38-B cells and resting CD4 regulatory T cells), but not circulating inflammatory proteins, in the causal relationship between the plasma lipidomes and PD. Our study confirms a causal relationship between higher serum TAG (51:4) levels and a lower risk of PD and clarifies a possible role for mediation through circulating immune cells, but not inflammatory proteins. These findings indicate that serum triacylglycerol (51:4) regulates immunity to effectively lower the risk of PD.

M6A-related genes and their role in Parkinson's disease: Insights from machine learning and consensus clustering.

Parkinson disease (PD) is a chronic neurological disorder primarily characterized by a deficiency of dopamine in the brain. In recent years, numerous studies have highlighted the substantial influence of RNA N6-methyladenosine (m6A) regulators on various biological processes. Nevertheless, the specific contribution of m6A-related genes to the development and progression of PD remains uncertain. In this study, we performed a differential analysis of the GSE8397 dataset in the Gene Expression Omnibus database and selected important m6A-related genes. Candidate m6A-related genes were then screened using a random forest model to predict the risk of PD. A nomogram model was built based on the candidate m6A-related genes. By employing a consensus clustering method, PD was divided into different m6A clusters based on the selected significant m6A-related genes. Finally, we performed immune cell infiltration analysis to explore the immune infiltration between different clusters. We performed a differential analysis of the GSE8397 dataset in the Gene Expression Omnibus database and selected 11 important m6A-related genes. Four candidate m6A-related genes (YTH Domain Containing 2, heterogeneous nuclear ribonucleoprotein C, leucine-rich pentatricopeptide repeat motif containing protein and insulin-like growth factor binding protein-3) were then screened using a random forest model to predict the risk of PD. A nomogram model was built based on the 4 candidate m6A-related genes. The decision curve analysis indicated that patients can benefit from the nomogram model. By employing a consensus clustering method, PD was divided into 2 m6A clusters (cluster A and cluster B) based on the selected significant m6A-related genes. The immune cell infiltration analysis revealed that cluster A and cluster B exhibit distinct immune phenotypes. In conclusion, m6A-related genes play a significant role in the development of PD and our study on m6A clustering may potentially guide personalized treatment strategies for PD in the future.

Identification of Novel Genetic Loci Affecting Age at Onset of Parkinson's Disease: A Genome-wide Association Study.

The age at onset (AAO) of Parkinson's disease (PD) varies widely among individuals and significantly influences disease progression and prognosis. However, few genome-wide association studies (GWASs) have investigated genetic variants determining AAO, particularly in East Asian populations. To identify single-nucleotide polymorphisms (SNPs) affecting AAO of PD in Korean patients. We conducted a GWAS on AAO of PD in 1048 Korean patients using sex-adjusted linear regression models. Additionally, we conducted downstream analyses of our primary GWAS results. rs2134545 demonstrated genome-wide significance (β = -2.459; standard error [SE] = 0.851; P = 1.898 × 10-8) and is an intergenic SNP near the ALCAM gene associated with an average AAO reduction of 3.47 years. Additionally, rs4366309 (LYST; MIR1537) demonstrated suggestive significance (β = 2.949; SE = 1.072; P = 8.68 × 10-8) and was associated with an average delay of 3.05 years. The polygenic risk score based on known PD risk loci also affected the AAO for European and Korean PD risk loci, respectively (β = -0.149; P < 0.001 and β = -0.096; P = 0.002). However, the proportion of variance was small (r2 = 0.022 and 0.009, respectively). We identified a novel SNP associated with the AAO of PD near the ALCAM gene, distinct from previously reported PD risk loci. These findings need further functional validation; however, they suggest unique genetic pathways influencing the AAO of PD and highlight the need for further research in diverse populations. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Chronic Musculoskeletal Pain and Risk of Incident Parkinson's Disease: A 13-Year Longitudinal Study.

Chronic musculoskeletal pain often co-occurs with Parkinson's disease (PD); however, whether individuals with chronic pain have a higher risk of developing PD is unclear. To investigate the associations between chronic pain and incident risk of three neurodegenerative parkinsonism categories including PD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). This study included 355,890 participants (mean [standard deviation] age, 56.51 [8.07] years, 48.40% male) who did not have parkinsonism at baseline from a population-based cohort. Musculoskeletal pain in the hip, neck/shoulder, back, knee, or "all over the body" was assessed. Chronic pain was defined if pain lasted ≥3 months. Participants were categorized into four groups: no chronic pain, having one or two, three or four sites, and pain "all over the body." The diagnosis of PD, MSA, and PSP used self-reports, hospital records, and death registries. Multivariable-adjusted Cox regression was performed for the analyses. Over a median follow-up of 13.0 years, 2044 participants developed PD, 77 participants developed MSA, and 126 participants developed PSP. In multivariable analyses, there was a dose-response relationship between number of chronic pain sites and incident risk of PD (hazard ratio, 1.15; 95% confidence interval, 1.07-1.23). Participants with one or two pain sites and three or four pain sites had an 11% and 49% increased risk of developing PD, respectively. There were no associations between chronic pain and MSA or PSP. Chronic musculoskeletal pain was independently associated with PD, suggesting that chronic pain could be used to identify individuals at risk of developing PD. © 2024 International Parkinson and Movement Disorder Society.

Risk of subsequent Parkinson's disease among patients with bipolar disorder or major depression: A nationwide longitudinal study in Taiwan.

Bipolar disorder (BD) and major depression have been associated with an increased risk of developing Parkinson's disease (PD); however, few studies have directly compared the risk of PD development between patients with BD and major depression while considering relevant risk factors and psychotropic medications. Using the Taiwan National Health Insurance Research Database, 21,186 patients with BD, 21,188 patients with major depression, and 42,374 controls were enrolled between 2001 and 2009, and followed until the end of 2011. Individuals who developed PD during the follow-up period were identified. Cox regression models were used to analyze the hazard ratio (HR) of developing PD, adjusting for demographic factors, comorbidities, and psychotropic medication usage. Both patients with BD [HR 8.63, 95% confidence interval (CI) 6.35-11.72] and those with major depression (HR 5.68, 95% CI 4.15-7.78) had an elevated risk of subsequent PD compared to the controls. Patients with BD were associated with a 51% increased risk of subsequent PD compared with patients with major depression. Long-term treatment with antiepileptic mood stabilizers was associated with increased PD risk among patients with late-onset BD and high Charlson comorbidity index scores. Lithium was not associated with an increased PD risk. The study highlights an elevated PD risk in patients with BD and major depression compared to the controls, with BD patients at highest risk. Further research is needed to elucidate the complex interplay between psychotropic medications and neurodegenerative processes in BD, aiming to optimize therapeutic strategies and improve patient outcomes.

Comparing machine learning and deep learning models to predict cognition progression in Parkinson's disease.

Cognitive decline in Parkinson's disease (PD) varies widely. While models to predict cognitive progression exist, comparing traditional probabilistic models to deep learning methods remains understudied. This study compares sequential modeling techniques to identify cognitive progression in individuals with and without PD. Using data from the Parkinson's Progression Marker Initiative, shallow Markov, deep recurrent (long short-term memory [LSTM]), and nonrecurrent (temporal fusion transformer [TFT]) models were compared to predict cognitive status over time. Cognitive status was categorized into normal cognition (NC), mild cognitive impairment (MCI), and dementia. Predictions were made annually for up to 3 years using clinical data, including demographics, cognitive assessments, PD severity, and medical history. Each approach was evaluated using inverse probability weighted (IPW-) F1 scores. An ensemble method combined outputs from the Markov, LSTM, and TFT models. The dataset included 917 individuals (53% PD; 30% at risk for PD; 17% Healthy Controls). The TFT model outperformed others across all annual periods (IPW-F1 = 0.468) compared to the Markov (IPW-F1 = 0.349) and LSTM (IPW-F1 = 0.414) models, with improved performance using an ensemble approach (IPW-F1 = 0.502). For MCI and dementia predictions, which were rarer occurrences compared to NC status (ratios: 50:8:1), the TFT model consistently outperformed competing models, achieving IPW-F1 scores of 0.496 and 0.533 for MCI and dementia, respectively. In conclusion, sequential deep learning models like TFT, which mitigate long-term memory loss and can interpret complex, high-dimensional data, perform best overall in predicting clinically important cognitive transitions. These methods should be further explored for predicting degenerative conditions.

The Impact of Anti-inflammatory Therapy on Parkinson's Disease Incidence: A Retrospective Cohort Study

BackgroundPrevious research suggests shared pathophysiology between Parkinson's Disease (PD) and autoimmune disorders, with inflammation reduction as a potential PD intervention. The impact of anti-tumor necrosis factor (anti-TNF) and anti-interleukin (IL)-17 drugs on PD development has yielded conflicting results. ObjectivesThe study investigated the association between PD incidence and immunosuppressive anti-inflammatory drugs in patients with autoimmune diseases (rheumatoid arthritis, ulcerative colitis, Crohn’s disease, ankylosing spondylitis, psoriasis/psoriatic arthritis). MethodsA retrospective study was conducted using data from 2014-2022 from the US Komodo Health claims database. Two cohorts of patients diagnosed with autoimmune diseases were designed: 1) exposed to biologic disease-modifying antirheumatic drugs (bDMARDS e.g., anti-TNF/anti-IL-17 drugs) and 2) absent such exposure. Person-time incidence rates of PD per 100 person-years (PY) and incidence rate ratios (IRRs) were calculated and covariate adjusted via Poisson regressions. ResultsAmong 2,105,677 identified patients with autoimmune disease, 114,082 were treated with anti-TNF/anti-IL-17 and 1,991,595 were not. Unadjusted analyses indicated lower PD incidence in those treated with bDMARDscompared to the not treated (0.661 vs 0.949 per 100-PY; IRR 0.696 [95% CI: 0.669-0.724]). Multivariate Poisson models comparing cohorts exposed to bDMARDs vs those lacking exposure resulted in significantly lower risk of PD (adjusted IRR 0.77 [95% CI 0.74-0.80], p-value <.0001). For patients exposed to anti-TNF or anti-IL-17 therapies, the IRRs were 0.77 (95% CI 0.74-0.81) and 0.64 (95% CI 0.52-0.80), respectively (p-values<0.001). ConclusionsThe results suggest that reduced systemic inflammation via anti-TNF or anti-IL-17 treatment may decrease PD risk in patients with autoimmune diseases.

GBA1 T369M and Parkinson's disease - Further evidence of a lack of association in the Swedish population

Variants in GBA1 are important genetic risk factors in Parkinson's disease (PD). GBA1 T369M has been linked to an ∼80 % increased PD risk but the reports are conflicting and the relevance of GBA1 variants in different populations varies. A lack of association between T369M and PD in the Swedish population was recently reported but needs further validation. We therefore investigated T369M in 1,808 PD patients and 2,183 controls and our results support that T369M is not a risk factor for PD in the Swedish population.

Correlations Between Dietary Magnesium Consumption and Magnesium Depletion Score in Relation to Parkinson's Disease: A Population-Based Study.

The purpose of the study was to examine whether magnesium (Mg) depletion score (MDS) and dietary Mg intake are associated in adults with the risk of developing Parkinson's disease (PD). In this study, we analyzed data from the National Health and Nutrition Examination Survey (NHANES), which included 20,010 adults aged over 40 years old. To evaluate the linear association between PD and dietary intake of Mg or MDS, we conducted weighted logistic regression for univariate analysis and multivariate linear regression models. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models. A restricted cubic spline (RCS) was drawn to visualize the nonlinear relationship between MDS/dietary Mg intake and PD. In addition, we examined the variations in the relationship between MDS and PD across different confounding factors of the association using subgroup analysis. There were 240 PD cases (1.2%), and 19770 non-PD were included in the study. We found that a higher MDS was associated with an increased risk of PD after adjusting for covariates (OR per 1-unit increase, 1.47; 95% CI, 1.16-1.86). There is insufficient evidence to support a significant statistical association between Mg intake and the risk of PD. According to nonlinear regression, high MDS was associated with higher odds of PD and lower odds of PD above 250 mg/day intake of Mg. It has been shown that Mg bioavailability may be negatively associated with PD as measured by MDS. MDS is a potential method for screening the population with PD. Maintaining adequate Mg status may be important for PD prevention.

Behavioral disorders in Parkinson disease: current view.

Patients with Parkinson disease (PD) frequently experience several behavioral symptoms, such as anxiety, apathy, irritability, agitation, impulsive control and obsessive-compulsive or REM sleep behavior disorders, which can cause severe psychosocial problems and impair quality of life. Occurring in 30-70% of PD patients, these symptoms can manifest at early stages of the disease, sometimes even before the appearance of classic motor symptoms, while others can develop later. Behavioral changes in PD show distinct patterns of brain atrophy, dopaminergic and serotonergic deterioration, altered neuronal connectivity in frontostriatal, corticolimbic, default mode and other networks due to a cascade linking molecular pathologies and deficits in multiple behavior domains. The changes suggest a multi-system neurodegenerative process in the context of a specific α-synucleinopathy inducing a variety of biochemical and functional changes, the neurobiological basis and clinical relevance of which await further elucidation. This paper is intended to review the recent literature with focus on the main behavioral disturbances in PD patients, their epidemiology, clinical features, risk factors, animal models, neuroimaging findings, pathophysiological backgrounds, and treatment options of these deleterious lesions.

SGLT2 Inhibitor Use and Risk of Dementia and Parkinson Disease Among Patients With Type 2 Diabetes.

Despite the mechanistic potential of sodium-glucose cotransporter 2 inhibitor (SGLT2i) to improve neurologic outcomes, the efficacy of SGLT2i in neurodegenerative disorders among patients with type 2 diabetes is not well established. This population-based cohort study aimed to investigate the association of SGLT2i use with risks of incident dementia and Parkinson disease (PD) in patients with type 2 diabetes. This was a retrospective examination of data from a cohort of 1,348,362 participants with type 2 diabetes (≥40 years), who started antidiabetic drugs from 2014 to 2019, evaluated using the Korean National Health Insurance Service Database. Propensity score matching (1:1; SGLT2i to other oral antidiabetic drugs [OADs]) produced a cohort of 358,862 participants. Primary outcomes were the individual incidence of Alzheimer disease (AD), vascular dementia (VaD), and PD. Secondary outcomes were all-cause dementia (AD, VaD, and other dementia) and a composite of all-cause dementia and PD. Cox proportional hazards models were used to investigate the association between SGLT2i use and the risks of dementia and PD. From the 358,862 participants analyzed (mean [SD] age, 57.8 [9.6] years; 58.0% male), 6,837 incident dementia or PD events occurred. Regarding the individual endpoints, SGLT2i use was associated with reduced risks of AD (adjusted hazard ratio [aHR] 0.81, 95% CI 0.76-0.87), VaD (aHR 0.69, 95% CI 0.60-0.78), and PD (aHR 0.80, 95% CI 0.69-0.91) with a 6-month drug use lag period. In addition, use of SGLT2i was associated with a 21% lower risk of all-cause dementia (aHR 0.79, 95% CI 0.69-0.90) and a 22% lower risk of all-cause dementia and PD than use of other OADs (aHR 0.78, 95% CI 0.73-0.83). The association between the use of SGLT2i and the lowered risk of these neurodegenerative disorders was not affected by sex, Charlson Comorbidity Index, diabetic complications, comorbidities, and medications. Sensitivity analysis further adjusting for bioclinical variables from health screening tests, including blood pressure, glucose, lipid profiles, and kidney function, yielded generally consistent results. In this nationwide population-based study, SGLT2i use significantly reduced the risks of neurodegenerative disorders in patients with type 2 diabetes independent of various factors including comorbidities and bioclinical parameters. This study provides Class II evidence that SGLT2 antidiabetic drugs decrease the risk of dementia and PD in people with diabetes.

The association between brominated flame retardants exposure with Parkinson's disease in US adults: a cross-sectional study of the National Health and Nutrition Examination Survey 2009-2016.

Increasing evidence suggests that environmental factors play a crucial role in the pathogenesis of Parkinson's disease (PD). Humans are simultaneously exposed to multiple brominated flame retardants (BFRs) in the environment. However, the relationship between BFRs and PD remains unclear. This study was designed to investigate the overall association between BFRs and PD in a nationally representative US population and to further identify significant chemicals. This study used data from 7,161 NHANES participants from 2009 through 2016. The serum BFRs registry included PBDE-28, PBDE-47, PBDE-85, PBDE-99, PBDE-100, PBDE-153, PBDE-154, PBDE-183, PBDE-209, and PBB-153. A survey-weighted generalized logistic regression model with restricted cubic splines (RCS) was used to evaluate the association between single BFRs exposure and periodontitis. Meanwhile, weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) were used to evaluate the overall association of mixed frankincense powder with periodontitis and to identify significant chemicals. Sensitivity analysis was performed to evaluate the robustness of the results. Among the 7,161 participants, 65 had PD. PD patients were older (mean age 57.79 vs. 46.57 years) and had a higher proportion of females (70.86%) compared to non-PD participants. Serum levels of PBB-153 were significantly higher in those with PD. Logistic regression analyses revealed a non-linear, inverted U-shaped relationship between serum PBB-153 and PD risk. The risk of PD increased with higher PBB-153 levels up to the 3rd quartile (Q3), beyond which the risk declined (Q3 vs. Q1: OR = 4.98, 95% CI = 1.79-13.86; Q4 vs. Q1: OR = 3.23, 95% CI = 1.03-10.08). PBB-153 (43.40%), PBDE-153 (24.75%), and PBDE-85 (19.51%) contributed most to the weighted quantile sum index associated with PD risk. Bayesian kernel machine regression confirmed the inverted U-shaped dose-response pattern for PBB-153 and the overall BFR mixture. Restricted cubic spline analyses corroborated the non-linear relationship between PBB-153 and PD, which was more pronounced among women and those aged 37-58 years. Sensitivity analyses substantiated these findings. This nationally representative cross-sectional study revealed a novel non-linear, inverted U-shaped relationship between serum levels of the brominated flame retardant PBB-153 and Parkinson's disease risk in U.S. adults. The risk increased with higher PBB-153 exposure up to a point, beyond which it declined. This complex dose-response pattern highlights the importance of considering potential hormetic mechanisms and effect modifiers when evaluating environmental exposures and neurodegenerative diseases. Further research is warranted to elucidate the underlying biological pathways and inform risk mitigation strategies.

Grip strength, genetic predisposition, and Incident Parkinson's disease: a prospective cohort study in the UK Biobank.

To examine the association and modifiable risk factors between grip strength (GS) and Parkinson's disease (PD) incidence considering genetic factors, a total of 411,648 individuals without PD at baseline from the UK Biobank were included. GS was measured by a hydraulic dynamometer. The polygenic risk score assessed the genetic predisposition. Multivariable Cox regression models were performed. During a median follow-up of 12.3 years, 2409 individuals developed PD. Compared with those with high GS, low-GS individuals had a 58.5% increased risk of PD (42.7%-76.1%), and 16.3% of this excess risk could be explained by adjusted risk factors. Low GS and high genetic predisposition contribute to the highest PD risk in an additive interaction. We observed that low GS was associated with higher PD incidence, particularly among individuals with high genetic predisposition. In addition to enhancing GS, interventions targeting risk factors (e.g., unhealthy lifestyles) might also reduce the excess risk.

The Black and African American Connections to Parkinson’s Disease (BLAAC PD) study protocol

Determining the genetic contributions to Parkinson’s disease (PD) across diverse ancestries is a high priority as this work can guide therapeutic development in a global setting. The genetics of PD spans the etiological risk spectrum, from rare, highly deleterious variants linked to monogenic forms with Mendelian patterns of inheritance, to common variation involved in sporadic disease. A major limitation in PD genomics research is lack of racial and ethnic diversity. Enrollment disparities have detrimental consequences on the generalizability of results and exacerbate existing inequities in care. The Black and African American Connections to Parkinson’s Disease (BLAAC PD) study is part of the Global Parkinson’s Genetics Program, supported by the Aligning Science Across Parkinson’s initiative. The goal of the study is to investigate the genetic architecture underlying PD risk and progression in the Black and/or African American populations. This cross-sectional multicenter study in the United States has a recruitment target of up to 2,000 individuals with PD and up to 2,000 controls, all of Black and/or African American ancestry. The study design incorporates several strategies to reduce barriers to research participation. The multifaceted recruitment strategy aims to involve individuals with and without PD in various settings, emphasizing community outreach and engagement. The BLAAC PD study is an important first step toward informing understanding of the genetics of PD in a more diverse population.

The role of genetically predicted serum iron levels on neurodegenerative and cardiovascular traits.

Iron is an essential mineral that supports numerous biological functions. Studies have reported associations between iron dysregulation and certain cardiovascular and neurodegenerative diseases, but the direction of influence is not clear. Our goal was to use computational approaches to better understand the role of genetically predicted iron levels on disease risk. We meta-analyzed genome-wide association study summary statistics for serum iron levels from two cohorts and two previous meta-analyses. We then obtained summary statistics from 11 neurodegenerative, cerebrovascular, cardiovascular or lipid traits to assess global and regional genetic correlation between iron levels and these traits. We used two-sample Mendelian randomization (MR) to estimate causal effects. Sex-stratified analyses were also carried out to identify effects potentially differing by sex. Overall, we identified three significant global correlations between iron levels and (i) coronary heart disease, (ii) triglycerides, and (iii) high-density lipoprotein (HDL) cholesterol levels. A total of 194 genomic regions had significant (after correction for multiple testing) local correlations between iron levels and the 11 tested traits. MR analysis revealed two potential causal relationships, between genetically predicted iron levels and (i) total cholesterol or (ii) non-HDL cholesterol. Sex-stratified analyses suggested a potential protective effect of iron levels on Parkinson's disease risk in females, but not in males. Our results will contribute to a better understanding of the genetic basis underlying iron in cardiovascular and neurological health in aging, and to the eventual identification of new preventive interventions or therapeutic avenues for diseases which affect women and men worldwide.

Prospective Study of Lung Function with Prodromal, Clinical Parkinson's Disease, and Mortality.

The association of lung function with the risk of developing prodromal and clinical-diagnosed Parkinson's disease (PD) and with the risk of mortality among individuals with PD remains unknown. To prospectively examine the associations of lung function with the risk of prodromal, clinical-diagnosed PD, and PD-related mortality in participants of the UK Biobank. Included were 452,518 participants free of PD at baseline. Baseline lung function, including forced expiratory volume in 1-s (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF), and FEV1/FVC ratio, was assessed. Eight prodromal features were measured using self-reported diagnoses, hospital admission, and primary care data. Incident PD cases were identified using linkages with hospital admission, death register, and self-report. Vital status and date of death were provided by the UK National Health Service (NHS) and the NHS Central Register. We used Cox proportional hazard models to evaluate these associations. Poor lung function was associated with higher risk of PD in a dose-response relationship: the adjusted hazard ratio comparing the lowest vs. the highest lung function quintile was 1.18 (95% CI, 1.02- 1.37) for FEV1, 1.14 (95% CI, 0.99- 1.29) for FVC, and 1.23 (95% CI, 1.08- 1.41) for PEF (p-trend <0.05 for all). Similar results were obtained for risk of prodromal PD and mortality among individuals with PD. The current study showed that individuals with poor lung function had a high future risk of prodromal and clinical PD and a higher rate of PD-related mortality.

Infections in the Etiology of Parkinson's Disease and Synucleinopathies: A Renewed Perspective, Mechanistic Insights, and Therapeutic Implications.

Increasing evidence suggests a potential role for infectious pathogens in the etiology of synucleinopathies, a group of age-related neurodegenerative disorders including Parkinson's disease (PD), multiple system atrophy and dementia with Lewy bodies. In this review, we discuss the link between infections and synucleinopathies from a historical perspective, present emerging evidence that supports this link, and address current research challenges with a focus on neuroinflammation. Infectious pathogens can elicit a neuroinflammatory response and modulate genetic risk in PD and related synucleinopathies. The mechanisms of how infections might be linked with synucleinopathies as well as the overlap between the immune cellular pathways affected by virulent pathogens and disease-related genetic risk factors are discussed. Here, an important role for α-synuclein in the immune response against infections is emerging. Critical methodological and knowledge gaps are addressed, and we provide new future perspectives on how to address these gaps. Understanding how infections and neuroinflammation influence synucleinopathies will be essential for the development of early diagnostic tools and novel therapies.

Investigating the Genetic Association of 40 Biochemical Indicators with Parkinson's Disease.

The mechanisms of Parkinson's disease (PD) are not fully understood, which hinders the development of effective therapies. Research indicates that lower levels of biochemical indicators like bilirubin, vitamin D, and cholesterol may elevate the risk of PD. However, clinical studies on abnormal levels of biochemical indicators in PD patients' circulation are inconsistent, leading to ongoing debate about their association with PD. Here, we investigate the genetic correlation between 40 biochemical indicators and PD using a bidirectional two-sample Mendelian randomization (MR) approach to uncover potential causal relationships. Data from genome-wide association studies (GWAS) were utilized, with genetic variations from specific lineages serving as instrumental variables (IVs). The methodology followed the STROBE-MR checklist and adhered to the three principal assumptions of MR. Statistical analyses employed methods including inverse variance weighting (IVW), MR-Egger, weighted median, and weighted mode. Biochemical indicators including albumin, C-reactive protein (CRP), and sex hormone-binding globulin (SHBG) showed significant associations with PD risk. Elevated levels of albumin (OR = 1.246, 95% CI 1.006-1.542, P = 0.043) and SHBG (OR = 1.239, 95% CI 1.065-1.439, P = 0.005) were linked to higher PD risk. Conversely, increased CRP levels (OR = 0.663, 95% CI 0.517-0.851; P = 0.001) could potentially lower PD risk. The robustness of the results was confirmed through various MR analysis techniques, including assessments of directional pleiotropy and heterogeneity using MR-Egger intercept and MR-PRESSO methods. This study systematically reveals, for the first time at the genetic level, the relationship between 40 biochemical indicators and PD risk. Our research verifies the role of inflammation in PD and provides new genetic evidence, further advancing the understanding of PD pathogenesis. The study shows a positive correlation between albumin and SHBG with PD risk and a negative correlation between CRP and PD risk. This study identifies for the first time that SHBG may be involved in the onset of PD and potentially worsen disease progression.