Analysis of Genetic and Non-genetic Predictors of Levodopa Induced Dyskinesia in Parkinson’s Disease

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.

Dopamine pathway and Parkinson’s risk variants are associated with levodopa-induced dyskinesia

“…Albeit some studies found contradictory results on the association between the GBA1 and LRRK2 variants and LID, [39][40][41][42] many others have shown that these variants play a role in LID development, [27][28][29][30][31][32] and in this study we also demonstrated that LRRK2 variants might also affect the and disease-related factors. [9][10][11][12][13] The significant association between the two PRS analyses suggests that aggregating multiple common variants that might have a scarce effect on LID individually could contribute to uncovering the overall genetic impact on LID.…”

“…38 However, the association between LID and most of the abovementioned putative genetic risk factors is still controversial, with most findings reported deriving from candidate genes studies that failed to be confirmed in replication studies. [39][40][41][42][43][44] Here, we aimed to systematically evaluate how genetics affect the risk and rate of progression to LID including a total of 4,787 PD patients from multiple centers. For this purpose, we performed genome-wide association studies (GWAS) and downstream analyses focused on specific genes previously implicated in LID.…”

Common and Rare Variants in TMEM175 Gene Concur to the Pathogenesis of Parkinson’s Disease in Italian Patients

“…All subjects were of European ancestry and were evaluated by qualified neurologist of the Parkinson Centre from June 2015 to December 2017, with a thorough protocol comprising neurological examination and evaluation of non-motor domains. Information about family history, demographic characteristics, anamnesis, and pharmacological therapy was also collected [ 8 , 20 , 21 ].…”

In silico,neuroprotective effect of phenyl-methanol based benzylidenehydrazineyl derivatives by scavenging reactive oxygen species via sirtuin 3 in Parkinson's disease

“…Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the brain's substantia nigra (SN); proper treatment employs synthetic molecules 1 . These molecules are neuroprotective but can cause psychosis and hallucinations by creating a large number of reactive oxygen species that disrupt mitochondrial activity 2 . As a polygenic disease, PD involves several genes in its development; modifying the function of a single protein largely activates various pathways, which has synergistic effects on the disease process.…”