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

From the Department of Neurology (B.F.L.v.N., M.M.W., H.R.S.), Christian-Albrechts University, Kiel, Germany; Department of Neurology and Donders Centre for Neuroscience (B.F.L.v.N., B.R.B.), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of Neurology (K.R., K.L., J.H., F.B., C.K.), University of Lübeck, Germany; NeuroImage-Nord (K.R., T.v.E., F.B., H.R.S.), Hamburg-Kiel-Lübeck, Germany; Toronto Western Hospital-Research Institute (T.v.E.), CAMH-PET Centre, University of Toronto, Canada; Department of Neurology (P.P.P.), Central Hospital and Institute of Genetic Medicine, Eurac-Research, Bolzano-Bozen, Italy; and Danish Research Centre for Magnetic Resonance (H.R.S.), Hvidovre University Hospital, Copenhagen, Denmark.

Address correspondence and reprint requests to Dr. Hartwig Siebner, Danish Research Centre for Magnetic Resonance, Hvidovre University Hospital, Kettegaard Allé 30, DK-2650 Hvidovre, Denmark hartwig.siebner{at}drcmr.dk

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.

Abbreviations: BOLD = blood oxygen level–dependent; CMA = cingulate motor area; FDR = false discovery rate; fMRI = functional MRI; HRF = hemodynamic response function; IPS = intraparietal sulcus; M1_HAND = primary motor hand area; PD = Parkinson disease; PMd = dorsal premotor cortex; SMA = supplementary motor area; SPM = statistical parametric mapping; SVC = small volume correction; TE = echo time; TMS = transcranial magnetic stimulation; TR = repetition time; VOI = volumes of interest.

Supplemental data at www.neurology.org

Editorial, page 1036

e-Pub ahead of print on November 26, 2008, at www.neurology.org.

Supported by a BMBF grant to H.R.S. (01 GO 0511) and F.B. (01 GO 0512) (NeuroImage-Nord) and by the 6th European Framework (EU-LSHB-CT-2006-037544-GENEPARK). C.K., F.B., and H.S. have been supported by the Volkswagenstiftung. B.F.L.v.N. and B.R.B. were supported by a NWO VIDI research grant (number: 917.76.352).

Disclosure: The authors report no disclosures.

Received May 2, 2008. Accepted in final form September 26, 2008.

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