Abnormal premotor-motor interaction in heterozygous Parkin- and Pink1 mutation carriers

- Asymptomatic heterozygous Parkin/PINK1 mutation carriers show altered premotor-motor inhibition.
- A single l-dopa administration could partly reverse this alteration.
- These mutation carriers can serve as in vivo models to study pre-symptomatic stages of Parkinsonism.

ObjectivesMutations in the Parkin and PINK1 gene account for the majority of autosomal recessive early-onset Parkinson cases. There is increasing evidence that clinically asymptomatic subjects with single heterozygous mutations have a latent nigrostriatal dopaminergic deficit and could be taken as in vivo model of pre-symptomatic phase of Parkinsonism.MethodsWe charted premotor-motor excitability changes as compensatory mechanisms for subcortical dopamine depletions using transcranial magnetic stimulation by applying magnetic resonance-navigated premotor-motor cortex conditioning in 15 asymptomatic, heterozygous Parkin and PINK1 mutation carriers (2 female; mean age 53 ± 8 years) and 16 age- and sex-matched controls (5 female; mean age 57 ± 9 years). Participants were examined at baseline and after acute l-dopa challenge.ResultsThere were l-dopa and group specific effects during premotor-motor conditioning at an interstimulus interval of 6 ms indicating a normalisation of premotor-motor interactions in heterozygous Parkin and PINK1 mutation carriers after l-dopa intake. Non-physiologically high conditioned MEP amplitudes at this interval in mutation carriers decreased after l-dopa intake but increased in controls.ConclusionPremotor-motor excitability changes are part of the cortical reorganization in asymptomatic heterozygous Parkin- and PINK1 mutation carriers.SignificanceThese subjects offer opportunities to delineate motor network adaptation in pre-symptomatic Parkinsonism.