Analysis of Genetic and Non-genetic Predictors of Levodopa Induced Dyskinesia in Parkinson's Disease.
Front Pharmacol
; 12: 640603, 2021.
Article
em En
| MEDLINE
| ID: mdl-33995045
ABSTRACT
Background:
Levodopa (L-Dopa), representing the therapeutic gold standard for the treatment of Parkinson disease (PD), is associated with side effects like L-Dopa induced dyskinesia (LID). Although several non-genetic and genetic factors have been investigated for association with LID risk, contrasting results were reported and its genetic basis remain largely unexplored.Methods:
In an Italian PD cohort (N = 460), we first performed stepwise multivariable Cox Proportional Hazard regressions modeling LID risk as a function of gender, PD familiarity, clinical subtype, weight, age-at-onset (AAO) and years-of-disease (YOD), L-Dopa dosage, severity scores, and scales assessing motor (UPDRS-III), cognitive (MoCA), and non-motor symptoms (NMS). Then we enriched the resulting model testing two variants-rs356219 and D4S3481-increasing the expression of the SNCA gene, previously suggested as a potential mechanism of LID onset. To account for more complex (non-linear) relations of these variables with LID risk, we built a survival random forest (SRF) algorithm including all the covariates mentioned above.Results:
Among tested variables (N = 460 case-complete, 211 LID events; total follow-up 31,361 person-months, median 61 months), disease duration showed significant association (p < 0.005), with 6 (3-8)% decrease of LID risk per additional YOD. Other nominally significant associations were observed for gender-with women showing a 39 (5-82)% higher risk of LID-and AAO, with 2 (0.3-3)% decrease of risk for each year increase of PD onset. The SRF algorithm confirmed YOD as the most prominent feature influencing LID risk, with a variable importance of about 8% in the model. In genetic models, no statistically significant effects on incident LID risk was observed.Conclusions:
This evidence supports a protective effect of late PD onset and gender (men) against LID risk and suggests a new independent protective factor, YOD. Moreover, it underlines the importance of personalized therapeutic protocols for PD patients in the future.
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Base de dados:
MEDLINE
Tipo de estudo:
Guideline
/
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article