Study Rationale:
A relatively common mutation in the brain derived neurotrophic factor (BDNF) gene exists in the human population. Neurotrophic factors are like brain fertilizers that help neurons grow and stay healthy. This specific mutation — called rs6265 — results in a disruption of release of BDNF. Although the BDNF mutation does not increase the risk of developing Parkinson’s disease (PD), it is possible that those with this mutation and with PD could become more susceptible to dysfunction or degeneration once the disease process begins. We will examine whether this mutation impacts the progression of PD symptoms in early, un-medicated PD subjects from the DATATOP clinical trial.
Hypothesis:
PD progression will be accelerated in patients possessing the BDNF rs6265 mutation.
Study Design:
Existing DNA samples from DATATOP subjects will be genotyped for the rs6265 genetic mutation. We also will genotype for other BDNF mutations that have been associated with brain dysfunction, specifically: rs908867, rs11030094, rs10501087, rs1157659 and rs1491850. We will then stratify by mutation status and compare to clinical metrics (UPDRS, time to levodopa therapy, neuropsychological assessments).
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Results will determine whether screening for the rs6265 mutation (possessed by one in three people with PD) has potential to serve as a biomarker to predict the rate of PD progression as well as to screen for subjects for clinical trials.
Next Steps for Development:
Next steps could include genotyping additional clinical trial cohorts to determine whether possession of the BDNF rs6265 mutation impacted results of previously studied therapies as well as a prospective clinical trial to determine whether subject BDNF rs6265 status is truly predictive of rate of PD progression.
Final Outcome
Early, unmedicated Parkinson’s disease (PD) subjects from the DATATOP trial (n=217) were genotyped for the brain derived trophic factor (BDNF) rs6265 single nucleotide polymorphism (SNP). Approximately 4% of subjects possessed the minor/minor genetic variant of the rs6265 SNP and 31% the major/minor rs6265 variant. A significant protective effect of the minor/minor rs6265 variant was observed in time to needing dopaminergic therapy. Specifically, major/major and major/minor rs6265 subjects were approximately five times more likely to require dopaminergic therapy than minor/minor subjects at any given time a during the course of the study. These results suggest that PD subjects with the minor/minor rs6265 genetic variant experience a slower progression of PD symptoms that delays need for dopaminergic medications. Validation of this finding in an additional cohort of early, unmedicated PD subjects is warranted.