Tumor Necrosis Factor Inhibition and Parkinson Disease

Kang, Xiaoying; Ploner, Alexander; Pedersen, Nancy L.; Bandrés‐Ciga, Sara; Noyce, Alastair J.; Wirdefeldt, Karin; Williams, Dylan M

doi:10.1212/wnl.0000000000011630

Cited by 27 publications

(17 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Data on select variants was then combined with corresponding association statistics from GWAS of PD traits, including age at disease onset and risk of PD (measured as self-reported or clinically ascertained disease). TNF-TNFR1 signaling inhibition was not estimated to affect PD risk or age at onset [ 58 ]. One important caveat is that TNF inhibition on direct measures of PD progression were not tested in this study, it still highlights the value of MR studies as an approach to help answer these questions.…”

Section: Immunosuppressant and Anti-inflammatory Drugs And Pdmentioning

confidence: 99%

Epidemiological Evidence for an Immune Component of Parkinson’s Disease

Gonzàlez‐Latapi

Marras

2022

JPD

View full text Add to dashboard Cite

There is a growing interest in the role the immune system and inflammatory response play on the pathophysiology of Parkinson’s disease (PD). Epidemiological evidence lends support for the hypothesis that PD is an immune-mediated condition. An association between inflammatory bowel disease, including Crohn’s and Ulcerative colitis, and the risk of PD has been described and replicated in several population-based cohorts. Other autoimmune conditions, such as Sjogren syndrome, ankylosing spondylitis, and rheumatoid arthritis also seem to be associated with an increased risk of PD. Immunosuppressant medications seem to be associated with a decreased risk of PD. Finally, variants in genes involved in immune system regulation are also shared between PD and autoimmune conditions. In this review, we will provide an overview of epidemiological evidence from population-based cohort studies, meta-analyses, and genome-wide association studies that analyze the association between the immune system and PD, discuss current gaps in the literature and future research directions in this field.

show abstract

Section: Immunosuppressant and Anti-inflammatory Drugs And Pdmentioning

confidence: 99%

Epidemiological Evidence for an Immune Component of Parkinson’s Disease

Gonzàlez‐Latapi

Marras

2022

JPD

View full text Add to dashboard Cite

show abstract

“…Following the analytical protocol we previously validated, the statistical analysis was performed in three sections. 25 Using the independent single SNP (r 2 < 0.001) with smallest association p values for CRP (rs767455, F statistics = 28.9; Table 1), we fit the main model with Wald ratio estimator. In the secondary MR analysis, 3 partially correlated SNPs (r 2 < 0.8), including rs767455, were included in the inverse variance weighting-based estimation to improve statistical power.…”

Section: Discussionmentioning

confidence: 99%

“…41 Validity of all the four analyzed SNPs and the analytical protocol was previously shown by positive control analysis on Crohn disease, ulcerative colitis and multiple sclerosis, and can be found in our previous publication. 25 Causal estimates of TNF/TNFR1 inhibition on the binary disease outcomes from the primary and secondary MR models were presented as odds ratios (ORs) and 95% confidence intervals (CIs) for every 10% decrease of circulating CRP. Statistical significance was determined as two-sided p < 0.05 without multiple correction.…”

Section: Discussionmentioning

confidence: 99%

“…The selective choice of TNFR1 as the drug target was explained in our earlier publication. 25 Briefly, the pathogenic role of TNF in CAD and IS is mainly thought of as a consequence of its pro-inflammatory effect activated by the binding of TNF to TNFR1. 19,26 Moreover, the other receptor, TNF receptor 2, has been increasingly demonstrated to be cardio-and neuro-protective and should therefore not be antagonized in novel anti-TNF strategies.…”

Section: Implications Of All the Available Evidencementioning

confidence: 99%

“…A total of 4 single nucleotide polymorphisms (SNPs) that have been previously validated by Kang et al were used to instrument the pharmacologic inhibition of TNF/TNFR1 pathway. 25 In essence, the instrumental variants were selected based on two criteria. First, the SNPs must be located within or §1kb around TNFRSF1A (chromosome and base pairs per GRCh37, 12:6437923-6451280), the gene encoding TNFR1.…”

Section: Instrumentation Of Tnf/tnfr1 Inhibitionmentioning

confidence: 99%

See 2 more Smart Citations

Mendelian randomization study on the causal effects of tumor necrosis factor inhibition on coronary artery disease and ischemic stroke among the general population

Kang

Jiao²,

Wang³

et al. 2022

eBioMedicine

Self Cite

View full text Add to dashboard Cite

Background Tumor necrosis factor (TNF) is a potent inflammatory cytokine that has been causally associated with coronary artery disease (CAD) and ischemic stroke (IS), implying opportunities for disease prevention by anti-TNF therapeutics.Methods Leveraging summary statistics of several genome-wide association studies (GWAS), we assessed the repurposing potential of TNF inhibitors for CAD and IS using drug-target Mendelian randomization (MR) design. Pharmacologic blockade of the pro-inflammatory TNF signalling mediated by TNF receptor 1 (TNFR1) was instrumented by four validated variants. Causal effects of TNF/TNFR1 blockade on CAD (N case/control upto 122,733/424,528) and IS (N case/control upto 60,341/454,450) were then estimated via various MR estimators using circulating C-reactive protein (CRP; N GWAS =204,402) as downstream biomarker to reflect treatment effect. Associations of a functional variant, rs1800693, with CRP, CAD and IS were also examined.Findings No protective effect of TNF/TNFR1 inhibition on CAD or IS was observed. For every 10% decrease of circulating CRP achieved by TNF/TNFR1 blockade, odds ratio was 0.98 (95% confidence interval [CI]: 0.60-1.60) for CAD and 0.77 (95% CI: 0.36-1.63) for IS. Findings remained null in all supplement analyses. Interpretation Our findings do not support TNFR1 as a promising target for CAD or IS prevention among the general population. Future research is warranted to investigate whether the detrimental effect of circulating TNF on CAD and IS might be counteracted by modulating other relevant drug targets.Funding No.

show abstract

Blood Markers of Inflammation, Neurodegeneration, and Cardiovascular Risk in Early Parkinson's Disease

Bartl¹,

Dakna²,

Schade

et al. 2022

Movement Disorders

View full text Add to dashboard Cite

Background Recent studies point toward a significant impact of cardiovascular processes and inflammation on Parkinson's disease (PD) progression. Objective The aim of this study was to assess established markers of neuronal function, inflammation, and cardiovascular risk by high‐throughput sandwich immune multiplex panels in deeply phenotyped PD. Methods Proximity Extension Assay technology on 273 markers was applied in plasma of 109 drug‐naive at baseline (BL) patients with PD (BL, 2‐, 4‐, and 6‐year follow‐up [FU]) and 96 healthy control patients (HCs; 2‐ and 4‐year FU) from the de novo Parkinson's cohort. BL plasma from 74 individuals (37 patients with PD, 37 healthy control patients) on the same platform from the Parkinson Progression Marker Initiative was used for independent validation. Correlation analysis of the identified markers and 6 years of clinical FU, including motor and cognitive progression, was evaluated. Results At BL, 35 plasma markers were differentially expressed in PD, showing downregulation of atherosclerotic risk markers, eg, E‐selectin and ß2‐integrin. In contrast, we found a reduction of markers of the plasminogen activation system, eg, urokinase plasminogen activator. Neurospecific markers indicated increased levels of peripheral proteins of neurodegeneration and inflammation, such as fibroblast growth factor 21 and peptidase inhibitor 3. Several markers, including interleukin‐6 and cystatin B, correlated with cognitive decline and progression of motor symptoms during FU. These findings were independently validated in the Parkinson Progression Marker Initiative. Conclusions We identified and validated possible PD plasma biomarker candidates for state, fate, and disease progression, elucidating new molecular processes with reduced endothelial/atherosclerotic processes, increased thromboembolic risk, and neuroinflammation. Further investigations and validation in independent and larger longitudinal cohorts are needed. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

show abstract

Tumor Necrosis Factor Inhibition and Parkinson Disease

Cited by 27 publications

References 41 publications

Epidemiological Evidence for an Immune Component of Parkinson’s Disease

Epidemiological Evidence for an Immune Component of Parkinson’s Disease

Mendelian randomization study on the causal effects of tumor necrosis factor inhibition on coronary artery disease and ischemic stroke among the general population

Blood Markers of Inflammation, Neurodegeneration, and Cardiovascular Risk in Early Parkinson's Disease

Contact Info

Product

Resources

About