Risk Of PD Research Articles

Fourteen-year follow-up results of imatinib therapy in patients with unresectable and metastatic gastrointestinal stromal tumors.

Imatinib therapy is the gold standard for the treatment of unresectable and metastatic gastrointestinal stromal tumors (GISTs). However, few studies have reported the long-term outcomes of the treatment. Seventy patients who underwent imatinib therapy for unresectable and metastatic GISTs were enrolled between 2001 and 2009, and follow-up data were collected until October 2023. One hundred and sixty-eight months had passed since the final enrollment. The outcome measures were patient survival and the status of GIST and imatinib therapy. The cumulative incidence of disease progression (PD) and the chronological changes in PD hazard rate (HR) were also analyzed. The 5-, 10-, 15-, and 20-year overall survival rates were 64.3%, 30.0%, 16.8%, and 12.2%, respectively. Sixty of the 70 enrolled patients died before the data cutoff date: 47 (78.3%) patients died of GIST progression while the remaining 13 (21.7%) died of diseases other than GISTs. The cumulative incidence of PD logarithmically increased, and PD continued even after 10years of treatment. PD HR decreased over time to reach the lowest value at 9.6years after the initiation of treatment (HR 0.00027; 95% CI 0.00007-0.00174) and after that formed a small peak at 13years (HR 0.00144; 95% CI 0.00043-0.00436). Imatinib therapy showed high clinical efficacy in terms of long-term survival in GIST patients. However, patients undergoing imatinib therapy were at continuous risk of PD even after the 10-year treatment. Long-term treatment and follow-up beyond 10years are necessary for unresectable and metastatic GIST patients.

Effects of educational attainment on comorbidity of pain and depression in Chinese older adults

Pain and depression comorbidity (PD) among older adults in China is common and significantly affects their physical and mental health. The psychosocial factors may affect people's feelings, understanding and expression of pain and depression, leading to inaccurate assessment of this condition. Educational attainment is thought to be associated with either pain or depression. However, we do not yet know the relationship between educational attainment and PD. Using data from the 2018 China Health and Retirement Longitudinal Study in 2018, we analyzed various variables in 7742 individuals aged 60 years and older. Our results indicate significant differences between the PD and non-PD populations in terms of social, lifestyle, and behavioral factors. We observed a significant decrease in the incidence of PD among older adults with higher levels of education (p < 0.001). This association appears to be partially mediated by cognitive ability, suggesting that educational attainment may mitigate the risk of PD through cognitive enhancement. In addition, our analysis shows that the effect of educational attainment on PD is moderated by additional psychosocial factors, including living environment and alcohol consumption patterns. Older adults with higher levels of education tend to live in urban areas and have better control over alcohol consumption, which may contribute to a lower incidence of PD. Therefore, interventions aimed at enhancing cognitive abilities, improving living environments, and promoting healthier lifestyles and habits among older adults could potentially reduce their burden of PD.

Reducing Parkinson's Disease Incidence in Patients with Insomnia through Acupuncture: A Cohort Study

BackgroundParkinson's disease (PD) is a prevalent neurodegenerative condition characterized primarily by motor symptoms, often accompanied by non-motor manifestations such as insomnia. Acupuncture, an increasingly popular alternative therapy, has shown promise in the prevention and alleviation of PD motor symptoms. In Taiwan, acupuncture is considered a viable treatment for insomnia in various health conditions. However, the specific impact of acupuncture on the risk of developing PD in insomnia patients remains uncertain. MethodsIn this retrospective study, we identified and matched 152,585 newly diagnosed insomnia patients from Taiwan's National Health Insurance Research Database (NHIRD) from 2000 to 2010. Using a 1:1 propensity score matching method, we ensured the comparability of two groups: patients who received acupuncture treatment and those who did not. It resulted in a final cohort of 20,112 patients in both the acupuncture and non-acupuncture groups. ResultsOur analysis revealed that insomnia patients who underwent acupuncture treatment exhibited a significantly reduced risk of developing PD. The adjusted hazard ratio (aHR) was 0.44 (95% confidence interval = 0.39–0.50) compared to those who did not receive acupuncture. Furthermore, the cumulative incidence of PD in the acupuncture group was significantly lower, as evidenced by the log-rank test (p < 0.001). ConclusionIn conclusion, our study provides evidence suggesting that acupuncture treatment is associated with a decreased risk of PD in patients with insomnia. However, further research is warranted to strengthen the evidence supporting these findings.

Association between kidney function and Parkinson’s disease risk: a prospective study from the UK Biobank

BackgroundParkinson’s disease (PD) is a neurodegenerative influenced by various clinical factors. The potential relationship between renal function and the risk of PD remains poorly understood. This study aims to explore the association between kidney function and the risk of developing PD.MethodsA population-based cohort study was conducted using data from 400,571 UK Biobank participants. Renal function was assessed using the estimated glomerular filtration rate (eGFR), calculated from serum creatinine and cystatin C levels. The association between eGFR levels and PD risk was evaluated using univariate and multivariate Cox regression analyses, Restricted Cubic Spline (RCS) analysis, and Kaplan-Meier analysis. Additionally, a clinical prediction model was developed and its diagnostic accuracy was evaluated using ROC analysis. A heatmap was also constructed to examine the relationship between clinical factors and gray matter volume in various brain regions.ResultsOver a median observation period of 13.8 years, 2740 PD events were recorded. Cox regression and Kaplan-Meier analyses revealed a significant association between decreased eGFR and increased PD risk, particularly in participants with eGFR < 30 ml/min/1.73 m2. This association was confirmed across three adjusted models. RCS analysis demonstrated a nonlinear relationship between decreasing eGFR and increasing PD risk. Furthermore, changes in eGFR were correlated with alterations in subcortical gray matter volume in regions such as the frontal cortex, striatum, and cerebellum. The clinical prediction model showed high diagnostic accuracy with AUC values of 0.776, 0.780, and 0.824 for 4-, 8-, and 16-year predictions, respectively.ConclusionRenal insufficiency is significantly associated with an increased risk of PD, highlighting the importance of maintaining good kidney function as a potential preventive measure against PD.

Association of Autoimmune Diseases with the Risk of Parkinson's Disease.

PD is a progressive neurodegeneration disease characterized by cardinal motor symptoms such as bradykinesia and tremor. The pathogenesis of PD remains unclear. It is hypothesized that immune system dysfunction may contribute to PD. Thus, autoimmune diseases may influence the risk of incident PD. We included 398,329 participants without PD at the baseline from UK Biobank. The association between 20 autoimmune diseases with PD was examined using cox hazards regression analyses, adjusting covariates like age, sex, and smoking status in the statistical models. Sensitivity analyses were conducted, adjusting for polygenic risk score and the reported source of PD, to check the robustness. After an average follow-up of 13.1 ± 0.816 years, 2,245 participants were diagnosed with incident PD. After multiple comparison correction, only multiple sclerosis (MS) reached statistical significance and showed an increased risk for incident PD. Compared with non-MS patients, the risk of incident PD in MS patients was 2.57-fold with age and sex being adjusted (95% CI, 1.59-4.14; adjust p value = 0.002). After adjusting lifestyle and other factors, the hazard ratio of incident PD in MS patients was 2.49 (95% CI, 1.55-4.02; adjust p value = 0.004). Excluding the self-reported PD cases in the sensitivity analysis, MS was a detrimental factor for incident PD (HR, 2.06; 95% CI, 1.56-4.05; adjust p value = 0.004). The link between MS and PD did not reach the statistical significance in the sensitivity analysis adjusting the PRS (adjust p value = 0.95). Our study provided evidence from observational analyses that MS was associated with an increased risk of PD. Further investigations should be performed to determine the causal association and potential pathophysiology between MS and PD.

Single-cell sequencing of the substantia nigra reveals microglial activation in a model of MPTP.

N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin widely used to induce PD models, but the effect of MPTP on the cells and genes of PD has not been fully elucidated. Single-nucleus RNA sequencing was performed in the Substantia Nigra (SN) of MPTP mice. UMAP analysis was used for the dimensionality reduction visualization of the SN in the MPTP mice. Known marker genes highly expressed genes in each cluster were used to annotate most clusters. Specific Differentially Expressed Genes (DEGs) and PD risk genes analysis were used to find MPTP-associated cells. GO, KEGG, PPI network, GSEA and CellChat analysis were used to reveal cell type-specific functional alterations and disruption of cell-cell communication networks. Subset reconstruction and pseudotime analysis were used to reveal the activation status of the cells, and to find the transcription factors with trajectory characterized. Initially, we observed specific DEGs and PD risk genes enrichment in microglia. Next, We obtained the functional phenotype changes in microglia and found that IGF, AGRN and PTN pathways were reduced in MPTP mice. Finally, we analyzed the activation state of microglia and revealed a pro-inflammatory trajectory characterized by transcription factors Nfe2l2 and Runx1. Our work revealed alterations in microglia function, signaling pathways and key genes in the SN of MPTP mice.

Association between CD4+ T cells ATP levels and disease progression in patients with non‑small cell lung cancer.

Introducing the exploration of stimulated CD4+ cells adenosine triphosphate (sATPCD4) levels for immune monitoring post non-small cell lung cancer (NSCLC) chemotherapy, the present study aimed to investigate its efficacy in gauging the potential risk of disease progression (PD) in patients with NSCLC. Therefore, a total of 89 patients with advanced NSCLC, who underwent chemotherapy between August 15 2022 and August 30 2023 at the Fifth Affiliated Hospital of Guangzhou Medical University (Guangzhou, China), were retrospectively studied. Patients were divided into the PD (n=21) and disease stability (non-PD; n=68) groups and their clinical data were compared. The thresholds for predicting PD were identified using receiver operating characteristics (ROC) curves. Multivariate logistic regression analysis was carried out to assess the association between peripheral blood markers and the incidence of PD. Therefore, post-chemotherapy, significant differences in white blood cell count, non-stimulated CD4+ cells ATP and sATPCD4 levels were obtained between patients in the PD and non-PD groups (P<0.05). In addition, sATPCD4 levels were notably decreased in the PD group compared with the non-PD group. Furthermore, ROC analysis revealed that the predictive threshold for PD was 224.5 ng/ml [area under the curve=0.887; 95% confidence interval, 0.811-0.963]. Additionally, patients with low immunity (ATP <224.5 ng/ml) exhibited a higher risk of PD compared with the high-immunity group (ATP >224.5 ng/ml; P<0.0001). Finally, multivariate logistic regression analysis suggested that sATPCD4 could serve as an independent factor for predicting NSCLC progression. Overall, the current study predicted that immune function could be possibly associated with the risk of PD in patients with NSCLC.

Non-linear relationship between TSH and psychotic symptoms on first episode and drug naïve major depressive disorder patients: a large sample sized cross-sectional study in China

IntroductionPsychotic depression (PD) is characterized by the co-occurrence of emotional dysfunction and psychotic symptoms such as delusions and hallucinations with poor clinical outcomes. TSH may involve in the development of PD. This study aims to explore relationship between TSH and PD.MethodsA total of 1718 outpatients diagnosed as FEDN MDD were recruited in this study. The relationship between PD and TSH was evaluated using multivariable binary logistic regression analysis. To assess the presence of non-linear associations, a two-piecewise linear regression model was employed. Furthermore, interaction and stratified analyses were conducted with respect to sex, education, marital status, comorbid anxiety, and suicide attempt.ResultsMultivariable logistic regression analysis revealed that TSH was positively associated with the risk of PD after adjusting for confounders (OR = 1.26, 95% CI: 1.11 to 1.43; p < 0.05). Smoothing plots showed a nonlinear relationship between TSH and PD, with the inflection point of TSH being 4.94 mIU/L. On the right of the inflection point, for each unit increase in serum TSH level on the right side of the inflection point, the probability of PD increased substantially by 47% (OR = 1.47, 95% CI: 1.25 to 1.73, p < 0.001), while no significant association was observed on the left side of the inflection point (OR = 0.87, 95% CI: 0.67 to 1.14, p = 0.32).ConclusionOur investigation showed a nonlinear TSH-PD relationship in FEDN MDD patients, thus contributing to effective intervention strategies for psychotic symptoms in depression patients.

Low-dose radiation decreases Lrrk2 levels in the striatum of large mammalian brains: New venues to treat Parkinson's disease?

IntroductionAmong gene mutations and variants linked to an increased risk of PD, mutations of leucine-rich repeat kinase 2 gene (LRRK2) are among the most frequently associated with early- and late-onset PD. Clinical and neuropathological characteristics of idiopathic-PD (iPD) and LRRK2-PD are similar, and these similarities suggest that the pathomechanisms between these two conditions are shared. LRRK2 mutations determine a gain-of-function and yield higher levels of lrrk2 across body tissues, including brain. On another side, recent animal studies supported the potential use of low dose radiation (LDR) to modify the pathomechanisms of diseases such as Alzheimer's disease (AD). MethodsWe assessed if a single total-body LDR (sLDR) exposure in normal swine could alter expression levels of the following PD-associated molecules: alpha-synuclein (α-syn), phosphorylated-α-synuclein (pα-syn), parkin, tyrosine hydroxylase (th), lrrk2, phosphorylated-lrrk2 (pS935-lrrk2), and some LRRK2 substrates (Rab8a, Rab12) across different brain regions. These proteins were measured in frontal cortex, hippocampus, striatum, thalamus/hypothalamus, and cerebellum of 9 radiated (RAD) vs. 6 sham (SH) swine after 28 days from a sLDR of 1.79Gy exposure. ResultsWestern Blot analyses showed lowered lrrk2 levels in the striatum of RAD vs. SH swine (p < 0.05), with no differences across the remaining brain regions. None of the other protein levels differed between RAD and SH swine in any examined brain regions. No lrrk2 and p-lrrk2 (S935) levels differed in the lungs of RAD vs. SH swine. ConclusionsThese findings show a specific striatal lrrk2 lowering effect due to LDR and support the potential use of LDR to interfere with the pathomechanisms of PD.

The causal effects of intelligence and fluid intelligence on Parkinson’s disease: a Mendelian randomization study

BackgroundParkinson’s disease (PD) is a chronic neurodegenerative disease that affects the central nervous system, primarily the motor nervous system, and occurs most often in older adults. A large number of studies have shown that high intelligence leads to an increased risk of PD. However, whether there is a causal relationship between intelligence on PD has not yet been reported.MethodsIn this study, Mendelian randomization (MR) analysis was performed with intelligence (ebi-a-GCST006250) and fluid intelligence score (ukb-b-5238) as exposure factors and PD (ieu-b-7) as an outcome, which the datasets were mined from the IEU OpenGWAS database. MR analysis was performed through 3 methods [MR Egger, weighted median, inverse variance weighted (IVW)], of which IVW was the primary method. In addition, the reliability of the results of the MR analysis was assessed via the heterogeneity test, the horizontal polytropy test, and Leave-One-Out (LOO). Finally, based on gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, the genes corresponding to intelligence and fluid intelligence score related to SNPs were enriched for functional features and pathways.ResultsThe results of MR analysis suggested that elevated intelligence indicators can increase the risk of PD [p = 0.015, Odd Ratio (OR) = 1.316]. Meanwhile, fluid intelligence score was causally associated with the PD (p = 0.035), which was a risk factor (OR = 1.142). The reliability of the results of MR analysis was demonstrated by sensitivity analysis. Finally, the results of GO enrichment analysis for 87 genes corresponding to intelligence related SNPs mainly included regulation of synapse organization, developmental cell growth, etc. These genes were enriched in the synaptic vessel cycle, polycomb expressive complex in KEGG. Similarly, 44 genes corresponding to SNPs associated with fluid intelligence score were used for enrichment analysis. Based on the GO database, these genes were mainly enriched in regulation of developmental growth, negative regulation of neuron projection development, etc. In KEGG, 44 genes corresponding to SNPs associated with fluid intelligence score were enriched in signaling pathways including Alzheimer’s disease, the cellular senescence, etc.ConclusionThe causal relationships between intelligence and fluid intelligence scores, and PD were demonstrated through MR analysis, providing an important reference and evidence for the study of PD.

Polygenic Risk Scores Validated in Patient-Derived Cells Stratify for Mitochondrial Subtypes of Parkinson's Disease.

The aim of our study is to better understand the genetic architecture and pathological mechanisms underlying neurodegeneration in idiopathic Parkinson's disease (iPD). We hypothesized that a fraction of iPD patients may harbor a combination of common variants in nuclear-encoded mitochondrial genes ultimately resulting in neurodegeneration. We used mitochondria-specific polygenic risk scores (mitoPRSs) and created pathway-specific mitoPRSs using genotype data from different iPD case-control datasets worldwide, including the Luxembourg Parkinson's Study (412 iPD patients and 576 healthy controls) and COURAGE-PD cohorts (7,270 iPD cases and 6,819 healthy controls). Cellular models from individuals stratified according to the most significant mitoPRS were subsequently used to characterize different aspects of mitochondrial function. Common variants in genes regulating Oxidative Phosphorylation (OXPHOS-PRS) were significantly associated with a higher PD risk in independent cohorts (Luxembourg Parkinson's Study odds ratio, OR = 1.31[1.14-1.50], p-value = 5.4e-04; COURAGE-PD OR = 1.23[1.18-1.27], p-value = 1.5e-29). Functional analyses in fibroblasts and induced pluripotent stem cells-derived neuronal progenitors revealed significant differences in mitochondrial respiration between iPD patients with high or low OXPHOS-PRS (p-values < 0.05). Clinically, iPD patients with high OXPHOS-PRS have a significantly earlier age at disease onset compared to low-risk patients (false discovery rate [FDR]-adj p-value = 0.015), similar to prototypic monogenic forms of PD. Finally, iPD patients with high OXPHOS-PRS responded more effectively to treatment with mitochondrially active ursodeoxycholic acid. OXPHOS-PRS may provide a precision medicine tool to stratify iPD patients into a pathogenic subgroup genetically defined by specific mitochondrial impairment, making these individuals eligible for future intelligent clinical trial designs. ANN NEUROL 2024;96:133-149.

Gene expression markers in peripheral blood and outcome in patients with platinum-resistant ovarian cancer: A study of the European GANNET53 consortium.

Disease progression is a major problem in ovarian cancer. There are very few treatment options for patients with platinum-resistant ovarian cancer (PROC), and therefore, these patients have a particularly poor prognosis. The aim of the present study was to identify markers for monitoring the response of 123 PROC patients enrolled in the Phase I/II GANNET53 clinical trial, which evaluated the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone. In total, 474 blood samples were collected, comprising baseline samples taken before the first administration of the study drugs and serial samples taken during treatment until further disease progression (PD). After microfluidic enrichment, 27 gene transcripts were analyzed using quantitative polymerase chain reaction and their utility for disease monitoring was evaluated. At baseline, ERCC1 was associated with an increased risk of PD (hazard ratio [HR] 1.75, 95% confidence interval [CI]: 1.20-2.55; p = 0.005), while baseline CDH1 and ESR1 may have a risk-reducing effect (CDH1 HR 0.66, 95% CI: 0.46-0.96; p = 0.024; ESR1 HR 0.58, 95% CI: 0.39-0.86; p = 0.002). ERCC1 was observed significantly more often (72.7% vs. 53.9%; p = 0.032) and ESR1 significantly less frequently (59.1% vs. 78.3%; p = 0.018) in blood samples taken at radiologically confirmed PD than at controlled disease. At any time during treatment, ERCC1-presence and ESR1-absence were associated with short PFS and with higher odds of PD within 6 months (odds ratio 12.77, 95% CI: 4.08-39.97; p < 0.001). Our study demonstrates the clinical relevance of ESR1 and ERCC1 and may encourage the analysis of liquid biopsy samples for the management of PROC patients.

33 Risk and protective factors for persistent depressive symptoms among transgender and non-binary youth: A prospective cohort study

OBJECTIVES/GOALS: While most transgender and non-binary (TNB) youth experience improved mental health post-initiating gender-affirming hormones (GAH), some continue to experience persistent, significant depressive symptoms two years post-GAH. Importantly, few studies have examined this issue given the lack of existing longitudinal studies. METHODS/STUDY POPULATION: We aimed to identify intervenable factors predicting persistent clinical depressive symptoms (PD) among TNB youth two years post-initiation of GAH utilizing the Trans Youth Care U.S. Study, an ongoing, multisite, observational study of TNB youth from four major pediatric hospitals across the U.S. We compared TNB youth (ages 12-20 at baseline) with persisting depression symptoms (PD) two-years post-GAH (i.e., PD; N=59) and those youth without (non-PD; n=215). Logistic regression estimated the association between PD and risk (e.g., negative expectations) and protective factors (e.g., parental acceptance, self-efficacy), measured at baseline and longitudinally. A mixed-effects model compared the rate of change of these factors between PD and non-PD youth. Models controlled for birth sex. RESULTS/ANTICIPATED RESULTS: Participants (Mean age=16) identified as transmasculine, then transfeminine, followed by non-binary. PD youth had higher negative expectations at baseline and internalized transphobia by 2-years, while non-PD youth reported greater parental acceptance over 2-years. The odds of PD compared to non-PD decreased with increasing self-efficacy at baseline (OR=0.7, 95% CI:0.5-0.9), whereas negative expectation for the future was associated with increased odds (OR=1.3, 95% CI:0.9,1.8). Moreover, the odds of PD increased 50% with increased rate of change in negative expectations, and odds decreased 50% with increased rate of change in self-efficacy, after adjusting for baseline negative expectations and self-efficacy, respectively. DISCUSSION/SIGNIFICANCE: We identified key intervenable factors for mental health treatment for TNB youth with PD; specifically, negative expectations increased risk for PD while self-efficacy appeared to buffer against PD risk. These findings also support assessment of youth for negative expectations for the future conferring greater risk for later PD.

Increased Risk of New-Onset Parkinson's Disease Following a Diagnosis of Retinal Vascular Occlusion: A 14-Year Cohort Study.

Although the role of the vascular component in the pathophysiology of Parkinson's disease is widely accepted and retinal vascular abnormalities are commonly observed in Parkinson's disease patients, evidence connecting retinal vascular disorders with the risk of developing Parkinson's disease is limited. We aimed to investigate the association between retinal vascular occlusion (RVO) and the risk of developing Parkinson's disease in people over 60 years using a nationwide cohort. From the 14-year South Korean National Health Insurance Service-Senior cohort, 11210 incident RVO patients and 11210 propensity scores, risk-matched controls were included. The incidence of Parkinson's disease was estimated with a Poisson regression. A Cox proportional hazards regression model was used to investigate the associations between RVO and the risk of Parkinson's disease. The incidence of Parkinson's disease was 664.4 cases per 100000 person-years (95% confidence interval [CI], 599.7-736.0) in the RVO cohort. Individuals with RVO had an increased incidence of Parkinson's disease (hazard ratio [HR], 1.28; 95% CI: 1.10-1.49). Increased PD risk was predominantly observed in retinal artery occlusion patients (HR, 1.53; 95% CI: 1.11-2.12), male patients (HR, 1.67; 95% CI: 1.29-2.17), and 5 years after diagnosis (HR, 1.46; 95% CI: 1.10-1.93). Our findings suggest that a common pathophysiological pathway, such as vasculature changes, may exist between RVO and Parkinson's disease. RVO may be one of the risk factors associated with future development of Parkinson's disease. The nature of this association warrants further investigation.

Evidence for genetic causality between iron homeostasis and Parkinson's disease: A two-sample Mendelian randomization study

BackgroundParkinson's disease (PD) is a degenerative disease of the central nervous system, and its specific etiology is still unclear. At present, it is believed that the main pathological basis is the reduction of dopamine concentration in the brain striatum. Although many previous studies have believed that iron as an important nutrient element participates in the occurrence and development of PD, whether there is a causal correlation between total iron binding capacity(TIBC), transferring saturation(TSAT), ferritin and serum iron in iron homeostasis indicators and PD, there has been a lack of effective genetic evidence. MethodsWe used Mendelian randomization (MR) as an analytical method to effectively evaluate the genetic association between exposure and outcome, based on the largest genome-wide association study (GWAS) data to date. By using randomly assigned genetic instrumental variables (SNPs, Single Nucleotide Polymorphisms) that are not affected by any causal relationship, we effectively evaluated the causal relationship between iron homeostasis indicators and PD while controlling for confounding factors. ResultsBy coordinated analysis of 86 SNPs associated with iron homeostasis markers and 12,858,066 SNPs associated with PD, a total of 56 SNPs were finally screened for genome-wide significance of iron homeostasis associated with PD. The results of inverse variance weighting(IVW) analysis suggested that iron（ β = - 0.524; 95%cl=-0.046 to −0.002; P=0.032) was considered to have a genetic causal relationship with PD. Cochran's Q, Egger intercept and MR-PRESSO global tests did not detect the existence of heterogeneity and pleiotropy (P>0.05). Mr Steiger directionality test further confirmed our estimation of the potential causal direction of iron and PD (P=0.001). In addition, TIBC (β=-0.142; 95%Cl=-0.197–0.481; P=0.414), TSAT (β=-0.316; 95%Cl=-0.861–0.229; P=0.255), and ferritin (β=-0.387; 95%Cl=-1.179–0.405; P=0.338) did not have genetic causal relationships with PD, and the results were not heterogeneous and pleiotropic (P>0.05). In addition, TIBC (β=-0.142; 95%Cl=-0.197–0.481; P=0.414), TSAT (β=-0.316; 95%Cl=-0.861–0.229; P=0.255), and ferritin (β=-0.101; 95%Cl=--0.987 to −0.405; P=0.823) did not have genetic causal relationships with PD, and the results were not heterogeneous and pleiotropic (P>0.05). TIBC (P=0.008), TSAT (P=0.000) and ferritin (P=0.013) were all consistent with the estimation of MR Steiger directivity test. ConclusionOur study found that among the four iron homeostasis markers, there was a genetic causal association between serum iron and PD, and the serum iron level was negatively correlated with the risk of PD. In addition, TIBC, TSAT, ferritin had no genetic causal relationship with PD.

Sex-related differences in serum biomarker levels predict the activity and efficacy of immune checkpoint inhibitors in advanced melanoma and non-small cell lung cancer patients

BackgroundImmune Checkpoint Inhibitors (ICIs) lead to durable response and a significant increase in long-term survival in patients with advanced malignant melanoma (MM) and Non-Small Cell Lung Cancer (NSCLC). The identification of serum cytokines that can predict their activity and efficacy, and their sex interaction, could improve treatment personalization.MethodsIn this prospective study, we enrolled immunotherapy-naïve patients affected by advanced MM and NSCLC treated with ICIs. The primary endpoint was to dissect the potential sex correlations between serum cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, GM-CSF, MCP-1, TNF-ɑ, IP-10, VEGF, sPD-L1) and the objective response rate (ORR). Secondly, we analyzed biomarker changes during treatment related to ORR, disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Blood samples, collected at baseline and during treatment until disease progression (PD) or up to 2 years, were analyzed using Luminex xMAP or ELLA technologies.ResultsSerum samples from 161 patients (98 males/63 females; 92 MM/69 NSCLC) were analyzed for treatment response. At baseline, IL-6 was significantly lower in females (F) versus males (M); lower levels of IL-4 in F and of IL-6 in both sexes significantly correlated with a better ORR, while higher IL-4 and TNF-ɑ values were predictive of a lower ORR in F versus M. One hundred and sixty-five patients were evaluable for survival analysis: at multiple Cox regression, an increased risk of PD was observed in F with higher baseline values of IL-4, sPD-L1 and IL-10, while higher IL-6 was a negative predictor in males. In males, higher levels of GM-CSF predict a longer survival, whereas higher IL-1β predicts a shorter survival. Regardless of sex, high baseline IL-8 values were associated with an increased risk of both PD and death, and high IL-6 levels only with shorter OS.ConclusionsSerum IL-1β, IL-4, IL-6, IL-10, GM-CSF, TNF-ɑ, and sPD-L1 had a significant sex-related predictive impact on ORR, PFS and OS in melanoma and NSCLC patients treated with ICIs. These results will potentially pave the way for new ICI combinations, designed according to baseline and early changes of these cytokines and stratified by sex.

A190 HELICOBACTER PYLORI INDUCES AN AUTO-REACTIVE PHENOTYPE IN PINK1 DEFICIENT MICE THAT CORRELATES WITH MOTOR DYSFUNCTION

Abstract Background Parkinson’s disease (PD) is a chronic neurodegenerative disorder. Several genetic predispositions, including the PTEN-induced kinase 1 (PINK1) mutation, have been implicated in early onset family cases. Besides the loss of dopaminergic neurons in the brain, PD patients have a unique immune phenotype that includes increased inflammation, blood serum, brain levels of proinflammatory cytokines, brain infiltration with cytotoxic CD8 T cells, and loss of regulatory T cells (Treg) and their anti-inflammatory phenotype. The role of the gut microbiota and gastrointestinal infections are increasingly recognized as a cofactor in PD. One of pathogens associated with the risk of PD is Helicobacter pylori. The prevalence of this Gram-negative bacteria in PD patients is higher than in the general population and its eradication in PD patients improves motor function. Loss of the PD-associated PINK1 alters induced Treg function in vitro. We previously have shown that in PINK1 knock-out (KO) mice, gut infection with Gram-negative bacteria, Citrobacter rodentium, induces mitochondrial antigen presentation (MitAP) to the CD8 T cells that later infiltrate the brain. In this model, PINK1 KO mice develop a Parkinson-like L-DOPA-responsive motor phenotype after four C. rodentium infections. Aims Here we aimed to scrutinize potential role of the H. pylori infection in the induction of motor dysfunction and disbalanced immune tolerance in PINK1 KO mice. Methods In addition to standard behavioural testing, at 2- and 6-months post-infection we performed a multiplex cytokine analysis of gastric homogenates and spectral flow cytometry of gastric lamina propria, mesenteric lymph nodes, blood, spleen, and brain infiltrating immunocytes. As well as in vitro immunocytes response and function assays to H.pylori exposure in PINK1 KO and wild-type (WT) littermate controls. Results We show that infection with H. pylori causes a long-lasting inflammation in the stomach; and local and systemic immune phenotype that remains 6 months post-infection. This phenotype, though present in some WT infected mice, is higher in PINK1 KOs and similarly to PD patients includes a decrease in Treg proportion, FoxP3 downregulation in regulatory T cells, Gata3+ CD4 T cell loss, as well as increase of circulating mitochondrial antigen-specific CD8 T cells. Moreover, the immune phenotype in the H. pylori infected PINK1 KO mice correlates with motor dysfunction and CD8 T cell brain infiltration with no such association seen in the WT mice. Conclusions These results provide insight to the gut-immunity-brain axis in the pathogenesis of Parkinson’s disease, and further investigate the role of Gram-negative bacteria in the establishment of immune tolerance-autoreactivity balance. Funding Agencies ASAP

Association of grip strength and walking pace with the risk of incident Parkinson's disease: a prospective cohort study of 422,531 participants.

Muscle weakness is a prominent feature of Parkinson's disease, but whether the occurrence of this deficit in healthy adults is associated with subsequent PD diagnosis remains unclear. This study sought to examine the relationship between muscle strength, represented by grip strength and walking pace, and the risk of incident PD. A total of 422,531 participants from the UK biobank were included in this study. Longitudinal associations of grip strength and walking pace with the risk of incident PD were investigated by Cox proportional hazard models adjusting for several well-established risk factors. Subgroup and sensitivity analyses were also conducted for further validation. After a median follow-up of 9.23years, 2,118 (0.5%) individuals developed incident PD. For per 5kg increment of absolute grip strength, there was a significant 10.2% reduction in the risk of incident PD (HR = 0.898, 95% CI [0.872-0.924], P < 0.001). Similarly, per 0.05kg/kg increment of relative grip strength was related to a 9.2% reduced risk of incident PD (HR = 0.908, 95% CI [0.887-0.929], P < 0.001). Notably, the associations remained consistent when grip strength was calculated as quintiles. Moreover, participants with a slower walking pace demonstrated an elevated risk of incident PD (HR = 1.231, 95%CI [1.075-1.409], P = 0.003). Subgroup and sensitivity analyses further validated the robustness of the observed associations. Our findings showed a negative association of grip strength and walking pace with the risk of incident PD independent of important confounding factors. These results hold potential implications for the early screening of people at high-risk of PD.

The potential role of chronic pain and the polytrauma clinical triad in predicting prodromal PD: A cross-sectional study of U.S. Veterans

IntroductionThe research criteria for prodromal Parkinson disease (pPD) depends on prospectively validated clinical inputs with large effect sizes and/or high prevalence. Neither traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), nor chronic pain are currently included in the calculator, despite recent evidence of association with pPD. These conditions are widely prevalent, co-occurring, and already known to confer risk of REM behavior disorder (RBD) and PD. Few studies have examined PD risk in the context of TBI and PTSD; none have examined chronic pain. This study aimed to measure the risk of pPD caused by TBI, PTSD, and chronic pain. Methods216 US Veterans were enrolled who had self-reported recurrent or persistent pain for at least three months. Of these, 44 met criteria for PTSD, 39 for TBI, and 41 for all three conditions. Several pain, sleep, affective, and trauma questionnaires were administered. Participants’ history of RBD was determined via self-report, with a subset undergoing confirmatory video polysomnography. ResultsA greater proportion of Veterans with chronic pain met criteria for RBD (36 % vs. 10 %) and pPD (18.0 % vs. 8.3 %) compared to controls. Proportions were increased in RBD (70 %) and pPD (27 %) when chronic pain co-occurred with TBI and PTSD. Partial effects were seen with just TBI or PTSD alone. When analyzed as continuous variables, polytrauma symptom severity correlated with pPD probability (r = 0.28, P = 0.03). ConclusionThese data demonstrate the potential utility of chronic pain, TBI, and PTSD in the prediction of pPD, and the importance of trauma-related factors in the pathogenesis of PD.

Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations.