Risk Of Parkinson's Disease Research Articles

Observational and genetic associations between cardiorespiratory fitness and age-related diseases: longitudinal analyses in the UK Biobank study.

Observational studies have indicated that increased cardiorespiratory fitness is associated with a decreased risk of cardiovascular disease (CVD), Alzheimer's disease (AD), and Parkinson's disease (PD). However, the causal mechanisms remain unclear. The objective of this study was to assess the role of fitness in the early detection and reduction of disease risk within the framework of predictive, preventive, and personalized medicine (PPPM/3PM). The associations of fitness with CVD, AD, and PD were explored in a large cohort of up to 502,486 individuals between the ages of 40 and 69years from the UK Biobank. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of CVD, AD, and PD among participants who completed a submaximal fitness test. Causality relationships were assessed via two-sample Mendelian randomization (MR). After a median of 11years of follow-up, each 3.5ml of O2⋅min-1⋅kg-1 increase in total body mass (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviations (SDs)) was associated with decreased risks of CVD (20.0%, 95% CI 17.6-22.3%), AD (31.9%, 95% CI 26.7-33.6%), and PD (21.2%, 95% CI 11.2-31.8%). After adjusting for obesity, the observational associations were attenuated. According to the MR analyses, fitness was associated with PD (OR IVW 0.937, 95% CI 0.897-0.978) and small vessel stroke (OR IVW 0.964, 95% CI 0.933-0.995). Our results indicate that fitness has an effect on age-related diseases. Protective associations of higher fitness levels with the risk of CVD, AD, and PD were validated in this cohort study. These findings might be valuable for predicting, preventing, and reducing disease morbidity and mortality through primary prevention and healthcare in the context of PPPM. The online version contains supplementary material available at 10.1007/s13167-024-00382-4.

Gut-Brain Nexus: Mapping Multi-Modal Links to Neurodegeneration at Biobank Scale.

Alzheimer's disease (AD) and Parkinson's disease (PD) are influenced by genetic and environmental factors. Using data from UK Biobank, SAIL Biobank, and FinnGen, we conducted an unbiased, population-scale study to: 1) Investigate how 155 endocrine, nutritional, metabolic, and digestive system disorders are associated with AD and PD risk prior to their diagnosis, considering known genetic influences; 2) Assess plasma biomarkers' specificity for AD or PD in individuals with these conditions; 3) Develop a multi-modal classification model integrating genetics, proteomics, and clinical data relevant to conditions affecting the gut-brain axis. Our findings show that certain disorders elevate AD and PD risk before AD and PD diagnosis including: insulin and non-insulin dependent diabetes mellitus, noninfective gastro-enteritis and colitis, functional intestinal disorders, and bacterial intestinal infections, among others. Polygenic risk scores revealed lower genetic predisposition to AD and PD in individuals with co-occurring disorders in the study categories, underscoring the importance of regulating the gut-brain axis to potentially prevent or delay the onset of neurodegenerative diseases. The proteomic profile of AD/PD cases was influenced by comorbid endocrine, nutritional, metabolic, and digestive systems conditions. Importantly, we developed multi-modal prediction models integrating clinical, genetic, proteomic and demographic data, the combination of which performs better than any single paradigm approach in disease classification. This work aims to illuminate the intricate interplay between various physiological factors involved in the gut-brain axis and the development of AD and PD, providing a multifactorial systemic understanding that goes beyond traditional approaches. Further, we have developed an interactive resource for the scientific community [https://gut-brain-nexus.streamlit.app/] where researchers can investigate components of the predictive model and can investigate feature effects on a sample level.

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.

Associations of milk, dairy products, calcium and vitamin D intake with risk of developing Parkinson´s disease within the EPIC4ND cohort

Literature indicates a potential association between dairy consumption and risk of Parkinson´s disease (PD), especially among men, yet the results remain inconclusive. We investigated this association in a large prospective European cohort. Dietary and non-dietary data was collected from 183,225 participants of the EPIC-for-Neurodegenerative-Diseases (EPIC4ND) cohort, a sub-cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Crude and multivariable-adjusted Cox proportional hazards models were employed to examine potential associations between baseline dietary intake of dairy, calcium and vitamin D with incident PD risk. No relationship was observed between dairy consumption (HR 1.07, 95% CI 0.82–1.39), individual dairy products (milk: HR 0.95, 95% CI 0.73–1.23; yogurt: HR 1.03, 95% CI 0.82–1.29; cheese: HR 1.13, 95% CI 0.85–1.51), or vitamin D (HR 1.08, 95% CI 0.80–1.45) with PD risk. However, we observed a risk-increasing association with higher calcium intakes (HR 1.33, 95% CI 1.00-1.78, p for trend = 0.031), which was more pronounced in men (HR 1.50, 95% CI 1.00-2.25, p for trend = 0.044) and in ever smokers (HR 1.64, 95% CI 1.06–2.53, p for trend = 0.014). No compelling evidence was found for an association between dairy products or vitamin D intake and PD risk indicating a potentially limited relevance of dairy intake in PD risk than previously described. Our observations of a positive association between dietary calcium intake and PD risk in men and in ever smokers require further validation.

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.

Dissecting Causal Links Between Gut Microbiota, Inflammatory Cytokines, and Parkinson's Disease: A Mendelian Randomization Study.

The association between gut microbiota (GM) and Parkinson's disease (PD) has been well established, but whether there is a causal relationship between the two and whether inflammatory cytokines (ICs) act as mediators remain unclear. We utilized the summary databases of large-scale genome-wide association studies (GWAS) conducting Mendelian randomization (MR) analyses to investigate the causal relationships between GM, ICs, and PD. The inverse-variance weighted (IVW) method was primarily used to identify GM and ICs associated with PD and to examine the mediating role of ICs, supplemented by MR Egger and weighted median. Through MR analysis, we identified three positive causal relationships and six negative causal relationships between GM and PD. Additionally, there were three positive associations and five negative associations between ICs and PD. However, after adjusting for FDR, none of these associations were significant. In reverse MR analysis, we also found causal relationships between PD and various GM and ICs. Further, two-step MR analysis indicated that the negative impact of phylum Actinobacteria on PD may be mediated through Fms-related tyrosine kinase 3 ligand levels. This study strengthens the link between GM and the risk of PD, while also revealing the potential mediating role of ICs in the causal relationships between these factors.

No causal relationship between ankylosing spondylitis and Parkinson's disease: Insights from Mendelian randomization studies

BackgroundRetrospective cohort and cross-sectional studies have indicated an association between ankylosing spondylitis (AS) and Parkinson's disease (PD). However, owing the multitude of limitations, a consistent conclusion has not been determined. Furthermore, whether a causal relationship exists between these two diseases remains unclear. MethodsWe conducted a two-way Mendelian randomization (MR) analysis using genome-wide association study data. For patients with PD, we utilised data from the ieu-b-7 database, whereas for patients with AS, we employed the three databases with the largest sample sizes for a combined analysis. These databases included ebi-a-GCST005529, finn-b-M13 ANKYLOSPON, and finn-b-M13 ANKYLOSPON STRICT. Our primary method of analysis was inverse variance weighting (IVW), supplemented by four other effective methods, to comprehensively infer a potential causal relationship between AS and PD. Additionally, we conduct various sensitivity analyses to assess the robustness of our estimates. ResultsBased on our IVW MR analysis, no significant causal relationship between AS and PD was observed (odds ratio [OR] = 1.01, 95 % confidence interval [CI] = 0.99–1.03, P = 0.26). Additionally, our reverse MR analysis found no evidence supporting a significant causal relationship between PD and AS (OR = 0.93, 95 % CI = 0.85–1.01, P = 0.068). These results were substantiated by comprehensive sensitivity analyses that indicated minimal bias in the causal estimates. ConclusionIn contrast to numerous existing clinical studies, this study failed to provide evidence supporting a significant impact of AS on PD risk, or vice versa. Further investigations regarding the potential causal mechanisms linking AS and PD are warranted.

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.

6-O-alkyl 4-methylumbelliferyl-β-D-glucosides as selective substrates for GBA1 in the discovery of glycosylated sterols

Gaucher disease (GD) is a lysosomal storage disorder (LSD) resulting from inherited glucocerebrosidase (GBA1) deficiency. GD diagnosis relies on GBA1 activity assays, typically employing 4-methylumbelliferyl-β-D-glucopyranoside (4MU-β-Glc) as fluorogenic substrate. However, these assays suffer from background 4MU release by the non-lysosomal GBA2 and cytosolic GBA3 enzymes. Here we developed GBA1-selective fluorogenic substrates by synthesizing a series of 6-O-acyl-4MU-β-Glc substrates with diverse fatty acid tails. Because of the chemical and enzymatic instability of the ester bonds, analogs of 6-O-palmitoyl-4MU-β-Glc (3) with different chemical linkages were synthesized. 6-O-alkyl-4MU-β-Glc 9, featuring an ether linkage, emerged as the most optimal GBA1 substrate, exhibiting both a low Km and compared to substrate 3 a high Vmax. Importantly, substrate 9 is not hydrolyzed by GBA2 and GBA3 and therefore acts as a superior substrate for GD diagnosis. Plants contain glycosyl phytosterols (campesterol, β-sitosterol, and sigmasterol) that may also be acylated at C-6. LC-MS/MS analysis revealed that 6-O-acylated and regular glycosylcholesterol (HexChol) tend to be increased in spleens of patients with GD. Moreover, significant increases in 6-O-acyl-glycosyl-phytosterols were detected in GD spleens. Our findings suggest uptake of (6-O-acyl)-glycosyl-phytosterols from plant food and subsequent lysosomal processing by GBA1, and comprise the first example of accumulation of an exogenous class of glycolipids in GD. Excessive exposure of rodents to glycosylated phytosterols has been reported to induce manifestations of Parkinson’s disease (PD). Further investigation is warranted to determine whether (6-O-acyl)-glycosyl-phytosterols could contribute to the enigmatic link between inherited defects in GBA1 and the risk for PD.

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.

Risk of Parkinson’s disease in spinal cord injury: a nationwide cohort study in South Korea

Despite the association between spinal cord injury (SCI) and various neurological diseases, the risk of Parkinson’s disease (PD) in SCI is not elucidated yet. Especially, the role of SCI severity and injury level in the risk of PD development is not investigated. Based on the nation-wide cohort data the Korean National Health Insurance Service between 2010 and 2018, we investigated the incidence of PD in 7,182 patients with SCI compared with 24,844 age- and sex-matched controls. Adjusted hazard ratio and 95% confidence interval (CI) were calculated using Cox proportional hazards regression. We compared the risk of PD based on the degree of disability (without disability, mild, severe) and SCI level (cervical, thoracic, and lumbar). During the mean follow-up duration of 4.31 years, patients with SCI had a higher risk of PD compared with matched controls. The PD risk was greater among patients with SCI with disability than in those without disability, especially those with mild disability. Additionally, cervical-level injury was associated with the highest risk in patients with SCI without disability, while thoracic-level injury was associated with the highest risk in those with disability. Our study found patients with SCI have increased risk of PD, particularly those with disability and thoracic-level injuries.