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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.
Highlights
Dyskinesia is characterized by involuntary dystonic and/or choreic movements of the trunk, limbs, and face (Finlay et al, 2014)
The multivariable Cox Proportional Hazard (PH) regression analyzing the association of non-genetic factors with the incident risk of L-Dopa Induced Dyskinesia (LID) was performed in 460 Parkinson’s disease (PD) cases for which all phenotypic, clinical and pharmacological information was available after imputation, TABLE 2 | Results of the stepwise multivariable Cox PH regression modeling LID onset vs non-genetic factors
This discrepancy may be explained by the multivariable setting of our exploratory analysis, where age at onset (AAO) showed a significant association with incident LID risk, in the expected direction
Summary
Dyskinesia is characterized by involuntary dystonic and/or choreic movements of the trunk, limbs, and face (Finlay et al, 2014). Women generally show a greater incidence of dyskinesia than men (Zappia et al, 2005; Warren et al, 2013) and tend to develop dyskinesia earlier in relation to time of L-Dopa administration (Hassin-Baer et al, 2011) This may be due to a higher bioavailability of L-Dopa in women, which may be in turn be due to their usually lower body weight (Coelho and Ferreira, 2014). A recent analysis of Chinese PD patients revealed a positive association of prevalent LID risk with high HY scores and low Unified Parkinson’s disease Rating Scale part III (UPDRS-III) under active L-Dopa treatment, which suggested progression of the disease and severity of motor symptoms as risk factors, in addition to early AAO, long disease duration, gender (women being more affected), and high L-Dopa equivalent dose (Zhou et al, 2019). 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
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