We demonstrate the feasibility of a clustering approach resulting in three distinct iPS patient subgroups. Extending earlier studies, describing motor and non-motor characteristics in their clustering approaches, we also considered parameters for (1) gender and (2) D2 gene polymorphism. The results of our analyses suggest, that these additional features might also have an impact on the development of Parkinson’s disease affecting the treatment response to dopamine or dopamine equivalents.
An extensive body of literature exists on the association of gender and iPD (for review e.g. see Picillo et al., 201622). A clear trend of a 1.5 times higher incidence of iPD in men is well described14; here the neuroprotective influence of estrogen, the genetically determined structural and functional cerebral differences as well as environmental factors are stated as putative mechanisms. Considering the fact that two out three clusters consisted only of men or women, gender seems to be a highly predictive factor in iPD and should be generally considered in the analysis of parkinsonian data.
As recently shown in Pelzer et al., 201923, D2 polymorphism seems to have a neuroprotective influence on neurons in the nigro-striatal and satellite systems for patients with Parkinson’s disease. Besides, the current study emphasizes an impact of D2 polymorphism also on the treatment response to dopaminergic drugs: (1) We were able to predict the daily levodopa intake of the individual patients in cluster 1 with very high significance. (2) Our findings, especially in cluster 2, fit well to previous studies, describing a rapid-disease progression in patients with right-dominant symptom onset compared to those with left-sided symptom onset, as shown in a large scale prospective study24. These patients were all D2 negative.
An altered anatomical background in basal ganglia loops for right- or left-affected parkinsonian patients has already been confirmed in a recent support vector machine analysis25. In this study right-dominant expression of iPD has been connected to faster disease progression26, indicating a different degeneration pattern with altered neuronal firing rates in oscillatory networks. However, the role of the D2 receptor polymorphism in these different clinical situations is still unclear. Other studies investigating the association of iPD with the D2 genotype published contradictory findings. Whereas one study could show an increased risk of motor fluctuations27, another study could not state any influence of D2 gene polymorphism on dyskinesia28. An effect of D2 polymorphism on structural brain connectivity has been shown in Pelzer et al., 201923 in patients with the wild type compared to the D2 risk type. This correlation of structural changes in brain connectivity due to D2 genotypes can further be linked to differences in the treatment response of individual genotypes. Hence, it might explain differences in the development of side effects like motor fluctuations in Parkinson’s disease. Herewith these results indicate the relevance of the D2 receptor polymorphism for future studies investigating dopaminergic side effects.
In conclusion, we consider these results as a major step to further establish predictive clinical models of iPD. In contrast to previous studies identifying subtypes of Parkinson’s disease8,12, we ignored non-motor scales and only focused on the implementation of parameters usually assessed in clinical routine (like age, gender, symptom onset side, motor scales, levodopa dosage per day). However, these features plus information about D2 receptor polymorphism provide sufficient information for building adequate models to predict the daily dosage of levodopa necessary to elevate parkinsonian symptoms. Based on this information the medical treatment and levodopa dosage could be individually customized to relief parkinsonian symptoms more efficient while reducing potential side effects.