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Brain Advance Access originally published online on August 4, 2005
Brain 2005 128(12):2777-2785; doi:10.1093/brain/awh607
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© The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation

John R. Adams1, Hinke van Netten1, Michael Schulzer1, Edwin Mak1, Jessamyn Mckenzie1, Audrey Strongosky4, Vesna Sossi2, Thomas J. Ruth3, Chong S. Lee1, Matthew Farrer4, Thomas Gasser5, Ryan J. Uitti4, Donald B. Calne1, Zbigniew K. Wszolek4,* and A. Jon Stoessl1,*

1 Pacific Parkinson's Research Centre and 2 Department of Physics and Astronomy, University of British Columbia, 3 TRIUMF, Vancouver, BC, Canada, 4 Mayo Clinic, Jacksonville, FL, USA and 5 Department of Neurodegenerative disorders, Hertie Institute for Clinical Brain Research, Center of Neurology, University of Tubingen, Tubingen, Germany

Correspondence to: Dr A. J. Stoessl, Pacific Parkinson's Research Centre, Purdy Pavilion, 2221 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5 E-mail: jstoessl{at}interchange.ubc.ca

Parkinson's disease may arise from multiple aetiologies, including genetic mutations that are for the most part uncommon. We describe here the positron emission tomography (PET) findings in clinically affected and asymptomatic, high-risk members of two autosomal dominantly inherited Parkinson's disease kindreds with recently described mutations at the PARK8 locus, in a novel gene encoding a leucine-rich repeat kinase (LRRK2). Affected family members have L-dopa-responsive parkinsonism with loss of dopaminergic nigral neurons and pleomorphic subcellular pathology. Fifteen family members underwent PET using: 18F-6-fluoro-L-dopa (18F-dopa) to assess dopamine (DA) synthesis and storage, 11C-(±){alpha}-dihydrotetrabenazine (11C-DTBZ) for the vesicular monoamine transporter, and 11C-d-threo-methylphenidate (11C-MP) for the membrane dopamine transporter (DAT). Measurements were compared with normal (n = 33) and sporadic Parkinson's disease (sPD) (n = 67) control groups. Four clinically affected members had findings similar to sPD, with impaired presynaptic DA function affecting the putamen more than the caudate. In two affected members, D2 dopamine receptor binding was intact. Two asymptomatic mutation carriers had abnormal DAT binding with another two developing such abnormalities over 4 years of follow-up. In these individuals, 18F-dopa uptake remained normal, although two of them also displayed abnormal 11C-DTBZ binding. Our study demonstrates that the in vivo neurochemical phenotype of LRRK2 mutations is indistinguishable from that of sPD, despite the pathological heterogeneity of the condition. Furthermore, we suggest that compensatory changes including downregulation of the DAT and upregulation of decarboxylase activity may delay the onset of parkinsonian symptoms.

Key Words: genetics; Parkinson's disease; pathophysiology; positron emission tomography

Abbreviations: 11C-DTBZ = 11C-(±){alpha}-dihydrotetrabenazine; 11C-MP = 11C-d-threo-methylphenidate; 11C-RAC = 11C-raclopride; 18F-dopa = 18F-6-fluoro-L-dopa; BP = binding potential; DAT = dopamine transporter; LRRK2 = leucine-rich repeat kinase 2; PET = positron emission tomography; sPD = sporadic Parkinson's disease; UPDRS = Unified Parkinson's Disease Rating Scale; VMAT2 = vesicular monoamine transporter

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Received February 10, 2005. Revised May 30, 2005. Accepted July 4, 2005.

* These authors contributed equally to this work


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