BDNF rs6265 Variant Alters Outcomes with Levodopa in Early-Stage Parkinson's Disease

Abstract

Disease outcomes are heterogeneous in Parkinson's disease and may be predicted by gene variants. This study investigated if the BDNF rs6265 single nucleotide polymorphism (SNP) is associated with differential outcomes with specific pharmacotherapy treatment strategies in the "NIH Exploratory Trials in PD Long-term Study 1" (NET-PD LS-1, n = 540). DNA samples were genotyped for the rs6265 SNP and others (rs11030094, rs10501087, rs1491850, rs908867, and rs1157659). The primary measures were the Unified Parkinson's Disease Rating Scale (UPDRS) and its motor component (UPDRS-III). Groups were divided by genotype and treatment regimen (levodopa monotherapy vs levodopa with other medications vs no levodopa). T allele carriers were associated with worse UPDRS outcomes compared to C/C subjects when treated with levodopa monotherapy (+ 6 points, p = 0.02) and to T allele carriers treated with no levodopa treatment strategies (UPDRS: + 8 points, p = 0.01; UPDRS-III: + 6 points, p = 0.01). Similar effects of worse outcomes associated with levodopa monotherapy were observed in the BDNF rs11030094, rs10501087, and rs1491850 SNPs. This study suggests the levodopa monotherapy strategy is associated with worse disease outcomes in BDNF rs6265 T carriers. Pending prospective validation, BDNF variants may be precision medicine factors to consider for symptomatic treatment decisions for early-stage PD patients.

Keywords: Brain-derived neurotrophic factor; Levodopa; Parkinson disease; Subthalamic nucleus deep brain stimulation; rs6265.

Fig. 1

Baseline and longitudinal analyses of NET-PD LS-1. A schematic showing the number of subjects by group for the baseline and longitudinal analyses. Dopaminergic medications prescribed other than levodopa are listed

Fig. 2

BDNF rs6265 SNP and others in the NET-PD LS-1 baseline analysis are associated with differences in outcomes with specific treatment strategies. In subjects on levodopa monotherapy (“LD”), the BDNF rs6265 T allele (C/T or T/T) is associated with worse UPDRS total (a) and part III (b) scores (p = 0.02 and p = 0.03, respectively). Within rs6265 T allele carriers, LD was associated with a worse UPDRS than a no levodopa regimen (“No LD”, A, p = 0.01); similarly, No LD was superior to LD by UPDRS-III in T allele carriers (b, p = 0.01). The rs11030094 G allele also showed a within-genotype difference, where LD is worse than No LD by UPDRS (c, p = 0.002) and UPDRS-III (d, p = 0.01); further, LD plus was worse than No LD by UPDRS (c, p = 0.01). The rs10501087 C/T or C/C subjects show a worse score in association with LD by both UPDRS (e, p = 0.01) and UPDRS-III (F, p = 0.001). In T/T subjects, LD Plus was worse than No LD by UDPRS (e, p = 0.01). For the rs1491850 SNP, LD was worse than No LD within T/C or C/C subjects by UPDRS (g, p = 0.002) and UPDRS-III (h, p = 0.01); further, LD Plus was worse than No LD (g, p = 0.01). Values represent the mean ± SEM. * represents a significant comparison. Darkened bars correspond to “risk” allele carriers; clear bars correspond to no risk allele. Group n values are listed within corresponding bars

Fig. 3

The BDNF rs6265 SNP in the longitudinal analysis. With levodopa monotherapy, carrying the rs6265 T allele (C/T or T/T) was not associated with statistically significant differences between genotypes by UPDRS, its parts I–III, or PDQ-39 (a, c, e, g, i, respectively). For subjects treated with strategies other than levodopa monotherapy, no differences between rs6265 genotypes were observed by UPDRS, its parts I–III, or PDQ-39 (b, d, f, h, j, respectively). Values represent the mean ± SEM. Gray boxes correspond to T allele carriers; black boxes correspond to C/C subjects

Fig. 4

The BDNF rs11030094 SNP in the longitudinal analysis. Possession of the rs11030094 G allele (A/G or G/G) is associated with worse performance on UPDRS when treated with levodopa monotherapy, becoming significant at 24 months (a, p = 0.02), and this difference is also significant at 24 months in UPDRS-I (c, p = 0.02) but not UPDRS-II (e) or UPDRS-III (g). A difference is observed in PDQ-39 scores at baseline between genotypes (i, p = 0.04). For subjects treated with strategies other than levodopa monotherapy, A/A subjects have lower UPDRS score at 36 months compared to G allele carriers (b, p < 0.05); further, a difference was observed in UPDRS-II at 24 months (f, p = 0.04). No differences between genotypes are observed by UPDRS-I, UPDRS-III, or PDQ-39 (d, h, j, respectively). Values represent the mean ± SEM. * represents a significant comparison. Black boxes correspond to G allele carriers; gray boxes correspond to A/A subjects

Fig. 5

The BDNF rs1491850 SNP in the longitudinal analysis. Carrying the rs1491850 C allele (T/C or C/C) is associated with worse performance on UPDRS when treated with levodopa monotherapy, becoming significant at 12 and 24 months (a, p = 0.04 and p = 0.02, respectively), and this difference is also significant at 12 months in UPDRS-I (c, p = 0.04) but not UPDRS-II (e), UPDRS-III (g), or PDQ-39 (i). For subjects treated with strategies other than levodopa monotherapy, no differences between genotypes are observed by UPDRS, its parts I–III, or PDQ-39 (b, d, f, h, j, respectively). Values represent the mean ± SEM. * represents a significant comparison. Gray boxes correspond to C allele carriers; black boxes correspond to T/T subjects