In a recent study published in Scientific Reports, researchers performed a two-sample Mendelian randomization (MR) analysis to explore causal associations between Parkinson’s disease (PD) and cardio-cerebrovascular diseases.
Background
Bradykinesia, resting tremors, and stiffness are clinical symptoms of PD, a common senile condition. Cardiovascular disorders, which are a primary cause of mortality in geriatric individuals, are also common. However, the link between PD and cardio-cerebrovascular disorders is uncertain. Recent research indicates that cardiovascular dysfunction may be a precursor to Parkinson’s disease, with symptoms intensifying as the disease develops. Previous research has generated considerable debate.
About the study
In the present study, researchers evaluated the impact of PD on cardio-cerebrovascular diseases.
PD-associated single-nucleotide polymorphisms (SNPs) were chosen from the International PD Genomics Consortium publicly accessible genome-wide association studies (GWAS) database, including data from 482,730 Europeans, comprising 33,647 patients with 449,056 control individuals. The team analyzed five GWAS datasets to obtain SNP outcome data.
Cardio-cerebrovascular disorders investigated included myocardial infarction (MI), coronary artery disease (CAD), heart failure (HF), atrial fibrillation (AF), stroke, cardioembolic stroke (CES), large artery stroke (LAS), and ischemic stroke (IS). CAD-related SNP dataset (29,319 CAD patients, 183,134 control individuals), MI-related SNP dataset (the CARDIoGRAMplusC4D study participants; 43,676 cases, 128,199 control individuals), AF-related SNP dataset (60,620 AF patients, 970,216 control individuals), and the HF-related SNP dataset (47,309 HF patients, 930,014 healthy individuals) were analyzed.
In addition, the team analyzed the MEGASTROKE consortium findings to obtain stroke subtype data. The team searched the phenotypes database for second phenotypes of single-nucleotide polymorphisms analyzed and excluded the SNPs related to outcome data. The researchers performed the MR analysis using the inverse variance weighted (IVW), weighted median, and MR-Egger methods and a reverse MR analysis to assess reverse causation.
The Cochran’s Q statistic values indicated heterogeneity. A regression analysis was performed to calculate the odds ratios (ORs), indicating the robustness of the link between exposure and outcome. The statistical significance of the findings was determined using the F-statistic. Further, sensitivity analyses were performed using the MR-PRESSO approach to assess horizontal pleiotropy and the eliminate-one-out method to evaluate MR estimation bias.
Results
In total, 23 SNPs were significantly associated with Parkinson’s disease (p-value below 5.0 × 10–8) and independent of each other (R2 below 0.001). The F-statistic was above 10, indicating strong associations between the SNPs and the study exposure. The primary inverse variance-weighted analysis findings showed that Parkinson’s disease was related to an increased risk of coronary artery disease (OR, 1.1), stroke (OR, 1.0), IS (OR, 1.0), and CES (OR, 1.1). The other methods, i.e., the Mendelian randomization-Egger, weighted mean, and the simple and weighted modes, showed similar results.
However, there were no associations between Parkinson’s disease and other cardio-cerebrovascular diseases. The team included 22, 16, 22, and 20 single-nucleotide polymorphisms in the IVW analysis of LAS, HF, AF, and MI, respectively, and OR values of 0.98, 0.97, 0.97, and 1.1 for MI, AF, HF, and LAS, indicating no causal associations with PD. The reverse MR analysis showed similar results. The Mendelian randomization-PRESSO analysis showed no horizontal pleiotropy in the integrated single-nucleotide polymorphisms, and Cochran’s Q values indicated no heterogeneity in the Mendelian randomization analysis estimates. In addition, sensitivity analysis showed reliable outcomes. Eliminating a single-nucleotide polymorphism from the primary study did not significantly impact outcomes.
PD, a Lewy body disease, is linked to an increased CAD incidence due to several mechanisms. Excessive Lewy body deposition in PD patients can lead to cardiac sympathetic denervation, reduced sympathetic innervation, and abnormal function of residual noradrenergic endings. Ankylosis, bradykinesia, tremor, dementia, and depression exacerbate severe cardiac norepinephrine deficiencies reported in PD patients. With disease progression, the mobility of the patient increases CAD risk. Orthostatic hypotension is associated with CAD development risk. PD affects lipid metabolism, which in turn affects cardiovascular disease course.
Parkinson’s disease is associated with an increased stroke risk due to irregularities in α-synuclein metabolism, which over-accumulates in Lewy bodies and can cause ischemic brain damage. Alpha-synuclein causes neuronal death through inflammation, oxidative stress, mitochondrial breakage, and autophagy, increasing stroke risk. Glutathione peroxidase 7 (GPX7) expression in PD patients is comparable to that in stroke patients, presumably aggravating endoplasmic reticulum oxidative stress and causing the stroke. Iron metabolism in PD patients may play a role in the relationship between PD and CES, resulting in fibrin-like substance formation and thrombosis.
Overall, the study findings showed that PD is associated with an increased risk of coronary artery disease, stroke, ischemic stroke, and cardioembolic stroke, in line with previous animal and clinical observation studies. The findings indicated that it is crucial to achieve early screening and treatment of stroke and CAD in PD patients.
