Objective: To determine whether relatively prevalent variants in the gene for brain-derived neurotrophic factor (Bdnf) are associated with differential efficacy of levodopa or other dopaminergic pharmacotherapies.

Background: The ability to use patient genotype to design optimal antiparkinsonian treatment strategies would be a powerful approach. BDNF is a critical modulator of neurotransmission and plasticity in the basal ganglia. Preclinical work has implicated BDNF signaling in the antiparkinsonian efficacy of both levodopa and deep brain stimulation (DBS). Several single nucleotide polymorphisms (SNPs) exist in the gene Bdnf, one in particular (rs6265) results in reduced activity-dependent BDNF release. Previously we showed that early-stage PD subjects carrying the rs6265 Met66 allele exhibit a less robust response to l-dopa therapy, whereas rs6265 variant status did not alter patient response to STN DBS.

Methods: A retrospective analysis was conducted using data from the NIH Exploratory Trials in PD Long-term Study 1 (NET-PD LS-1). DNA samples (n = 540) were genotyped for the Bdnf rs6265, rs11030094, rs10501087, rs1491850, rs908867 and rs1157659 variants. The primary endpoints were the Unified PD Rating Scale (UPDRS) and its motor component (UPDRS-III) with groups divided by both presence of a risk allele and treatment regimen using baseline data. A second cohort derived from longitudinal data of UPDRS, UPDRS-III and PDQ-39 scores over the course of 36 months of treatment was used for validation.

Results: When treated with levodopa (l-dopa) monotherapy, Met66 carriers for the rs6265 SNP were associated with worse scores compared to non-Met66 carriers. Within the Met66 carrier group, l-dopa monotherapy was associated with worse scores compared to an l-dopa-sparing regimen. These results were validated in the longitudinal cohort. Similar findings were observed in the baseline cohort for the other Bdnf SNPs but to a lesser degree; only the rs11030094 and rs1491850 SNPs’ effects on l-dopa efficacy were validated in the longitudinal cohort.

Conclusions: Data from two distinct cohorts of early-stage PD subjects suggest that Bdnf variants predict the efficacy of l-dopa monotherapy. Risk allele carriers for the rs6265 SNP and others may offer a precision medicine approach to treating PD in reserving l-dopa initiation and dose escalation until after optimized management using other dopamine replacement pharmacotherapies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/bdnf-rs6265-and-other-variants-predict-the-efficacy-of-levodopa-monotherapy-in-early-stage-parkinsons-disease/