title: PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation.
abstract: 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-(+/-)-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.
authors.affiliation: Pacific Parkinson's Research Centre, TRIUMF, Vancouver, BC, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Adams
authors.forename: Hinke
authors.initials: H
authors.lastname: van Netten
authors.forename: Michael
authors.initials: M
authors.lastname: Schulzer
authors.forename: Edwin
authors.initials: E
authors.lastname: Mak
authors.forename: Jessamyn
authors.initials: J
authors.lastname: Mckenzie
authors.forename: Audrey
authors.initials: A
authors.lastname: Strongosky
authors.forename: Vesna
authors.initials: V
authors.lastname: Sossi
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Ruth
authors.forename: Chong S
authors.initials: CS
authors.lastname: Lee
authors.forename: Matthew
authors.initials: M
authors.lastname: Farrer
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Uitti
authors.forename: Donald B
authors.initials: DB
authors.lastname: Calne
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: A Jon
authors.initials: AJ
authors.lastname: Stoessl
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D002250:Carbon Radioisotopes; D002262:Carboxy-Lyases / Q000378:metabolism; D016022:Case-Control Studies; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005462:Fluorine Radioisotopes; D006801:Humans; D007091:Image Processing, Computer-Assisted; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D007980:Levodopa / Q000378:metabolism; D008774:Methylphenidate; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000000981:diagnostic imaging* / Q000235:genetics*; D010641:Phenotype; D049268:Positron-Emission Tomography; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012044:Regression Analysis; D013747:Tetrabenazine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D002250:Carbon Radioisotopes; D050483:Dopamine Plasma Membrane Transport Proteins; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D008774:Methylphenidate; C032811:dihydrotetrabenazine; D007980:Levodopa; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D002262:Carboxy-Lyases; D013747:Tetrabenazine