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Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype.

Abstract：

OBJECTIVE:To use a combined neurogenetic-neuroimaging approach to examine the functional consequences of preclinical dopaminergic nigrostriatal dysfunction in the human motor system. Specifically, we examined how a single heterozygous mutation in different genes associated with recessively inherited Parkinson disease alters the cortical control of sequential finger movements. METHODS:Nonmanifesting individuals carrying a single heterozygous Parkin (n = 13) or PINK1 (n = 9) mutation and 23 healthy controls without these mutations were studied with functional MRI (fMRI). During fMRI, participants performed simple sequences of three thumb-to-finger opposition movements with their right dominant hand. Since heterozygous Parkin and PINK1 mutations cause a latent dopaminergic nigrostriatal dysfunction, we predicted a compensatory recruitment of those rostral premotor areas that are normally implicated in the control of complex motor sequences. We expected this overactivity to be independent of the underlying genotype. RESULTS:Task performance was comparable for all groups. The performance of a simple motor sequence task consistently activated the rostral supplementary motor area and right rostral dorsal premotor cortex in mutation carriers but not in controls. Task-related activation of these premotor areas was similar in carriers of a Parkin or PINK1 mutation. CONCLUSION:Mutations in different genes linked to recessively inherited Parkinson disease are associated with an additional recruitment of rostral supplementary motor area and rostral dorsal premotor cortex during a simple motor sequence task. These premotor areas were recruited independently of the underlying genotype. The observed activation most likely reflects a "generic" compensatory mechanism to maintain motor function in the context of a mild dopaminergic deficit.

journal_name

Neurology

journal_title

Neurology

authors

van Nuenen BF,Weiss MM,Bloem BR,Reetz K,van Eimeren T,Lohmann K,Hagenah J,Pramstaller PP,Binkofski F,Klein C,Siebner HR

doi

10.1212/01.wnl.0000338699.56379.11

subject

Has Abstract

pub_date

2009-03-24 00:00:00

pages

1041-7

issue

eissn

0028-3878

issn

1526-632X

pii

01.wnl.0000338699.56379.11

journal_volume

pub_type

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Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype.