Reply to: "Increased Stroke Risk in Patients with Parkinson's Disease with LRRK2 Mutations"

Parkinson's disease (PD) is associated with an increased stroke risk, however, no relationship between coronary artery disease (CAD) and PD was found.1 To date, little is known about the influence of PD-related genes, such as the leucine-rich repeat kinase 2 (LRRK2), the parkin (PRKN) and the glucocerebrosidase (GBA) genes, in the vascular risk of these patients. This work aims to determine whether the vascular risk differs between sporadic/familial PD forms and controls. We recruited 355 patients with sporadic PD (sPD), 38 with GBA-associated PD (GBA-PD), 36 with LRRK2-associated PD (LRRK2-PD), and 23 with PRKN-associated PD (PRKN-PD) and 620 controls. Demographic, clinical, and vascular risk factors data were collected. The presence of vascular events (ischemic stroke and CAD) were determined by clinical interview and consulting electronic medical records. We applied multivariate logistic regression and Cox regression analyses. In a confirmatory analysis, we repeated our multivariate analysis only with subjects who had a neuroimaging test (computed tomography or magnetic resonance imaging) available in their electronic records. The mutational screening of PRKN, GBA, and LRRK2 genes was previously performed using a combination of high-resolution melting and direct DNA resequencing (Appendix S1).2, 3 Patients with sPD were significantly older than controls and patients with GBA-PD. Patients with PRKN-PD had a lower rate of arterial hypertension. There were no other differences in vascular risk factors among the groups (Table S1). PRKN-PD showed a significantly younger PD onset and longer disease duration than the other groups, and GBA-PD had a younger disease onset than sPD (Tables S4–S6). However, there were no differences in other PD features. The prevalence of ischemic stroke differed among groups, and this difference was statistically significant after controlling for sex, age, and vascular risk factors (Tables S7 and S8). However, no differences in CAD were found among groups. LRRK2-PD had the highest proportion of stroke (13.8%), followed by PRKN-PD and sPD (8.6% and 5.6%, respectively). LRRK2-PD showed a significantly increased risk of stroke compared with controls (odds ratio [OR], 5.1; 95% confidence interval [CI], 1.7–15.3; P = 0.004), whereas there were no significant differences in the other PD cohorts (Fig. 1A). In our confirmatory analysis, we corroborated the previous finding. Interestingly, in this analysis sPD also showed a marginally significant increased risk of stroke compared with controls (OR, 1.8; 95% CI, 0.99–3.2; P = 0.05; Fig. 1B). There was a statistically significant difference in the survival distribution for ischemic stroke among groups (Fig. 1C). The increased risk of stroke in LRRK2-PD was associated with a younger age at stroke compared with controls, a finding supported by our confirmatory analysis (Fig. 1D). Our results are aligned with previous studies.4, 5 A meta-analysis concluded that the overall PD group had a 1.7-fold increase in the risk of stroke compared with controls, without differences in CAD.1 In our study, sPD showed a similar increase in the stroke risk, although this association was marginally significant. LRRK2-PD showed a 5.1-fold increase in the risk of ischemic stroke after controlling for potential confounding factors. These results might be related to a different pathophysiology of stroke in certain PD subtypes compared with controls. A link between these brain disorders has been proposed, beyond the classical risk factors, considering the role of oxidative stress, neuroinflammation, and altered lipid metabolism among others.6 Interestingly, it has been suggested that pathogenic variants of LRRK2 might contribute to postischemic brain damage and neuroinflammation.7 In conclusion, patients with LRRK2-PD may show an increased risk of ischemic stroke, with no differences in CAD. The sporadic forms of PD might have a higher cerebrovascular risk than controls. Conversely, patients with GBA-PD and PRKN-PD showed a similar vascular risk to controls. Our results support the idea that mechanisms other than classical vascular risk factors might be involved in the cerebrovascular disease of those patients. Prospective studies are needed to confirm these findings. Detailed introduction, methods, results, and discussion are included in Appendix S1. We thank the donors and the Hospital Universitario Virgen del Rocío-Instituto Biomedicina de Sevilla Biobank (Andalusian Public Health System Biobank and Instituto de Salud Carlos III-Biobank Network PT17/0015/0041) for the human specimens used in this study. D. Macías-García has received honoraria from Abbvie, Teva, and Zambon. L. Muñoz-Delgado has received honoraria from Teva. S. Jesús has received honoraria from Abbvie, Bial, Merz, UCB, Italfarmaco, and Zambon. A.D. Adarmes-Gómez has received honoraria from Abbvie, Italfarmaco, Zambon, Bial, and Teva. F. Carrillo has received honoraria from Abbvie, Abbott, UCB, and Zambon. P. Mir has received honoraria from Abbott, Allergan, Abbvie, Bial, Britannia, Italfarmaco, Merz, UCB, Teva, and Zambon. M.T. Periñan, M.V. Jimenez-Jaraba, D. Buiza-Rueda, M. Bonilla-Toribio, and P. Goméz-Garre having nothing to report. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. D.M.-G.: 1A, 1B, 1C, 2A, 2B, 2C, 3A M.T.P.: 1C, 2B, 2C, 3B L.M.-D.: 1B, 1C, 3B S.J.: 1B, 1C, 3B M.V.J.-J.: 2B, 2C, 3B D.B.-R.: 1B, 1C, 3B M.B.-T.: 1B, 1C, 3B A.D.A.-G.: 1B, 1C, 3B F.C.: 1B, 1C, 3B P.G.-G.: 1B, 1C, 2C, 3B P.M.: 1A, 1B, 1C, 2A, 2C, 3B The data that support the findings of this study are available from the corresponding author upon reasonable request. Appendix S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.