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

• Published in: Brain (London, England : 1878) England : 1878), 2005-12, Vol.128 (12), p.2777-2785
• Main Authors: Adams, John R., van Netten, Hinke, Schulzer, Michael, Mak, Edwin, Mckenzie, Jessamyn, Strongosky, Audrey, Sossi, Vesna, Ruth, Thomas J., Lee, Chong S., Farrer, Matthew, Gasser, Thomas, Uitti, Ryan J., Calne, Donald B., Wszolek, Zbigniew K., Stoessl, A. Jon
• Format: Article
• Language: English
• Subjects: 11C-DTBZ = 11C-(±)α-dihydrotetrabenazine; 11C-MP = 11C-d-threo-methylphenidate; 11C-RAC = 11C-raclopride; 18F-dopa = 18F-6-fluoro-l-dopa; Adult; Age Factors; Aged; Biological and medical sciences; BP = binding potential; Brain - diagnostic imaging; Brain - metabolism; Carbon Radioisotopes; Carboxy-Lyases - metabolism; Case-Control Studies; DAT = dopamine transporter; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dopamine Plasma Membrane Transport Proteins - metabolism; Fluorine Radioisotopes; genetics; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; Image Processing, Computer-Assisted; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Levodopa - metabolism; LRRK2 = leucine-rich repeat kinase 2; Medical sciences; Methylphenidate; Middle Aged; Mutation; Nervous system (semeiology, syndromes); Neurology; Parkinson Disease - diagnostic imaging; Parkinson Disease - genetics; Parkinson's disease; pathophysiology; PET = positron emission tomography; Phenotype; Positron-Emission Tomography; Protein-Serine-Threonine Kinases - genetics; Radiopharmaceuticals; Receptors, Dopamine D2 - metabolism; Regression Analysis; sPD = sporadic Parkinson's disease; Tetrabenazine - analogs & derivatives; Tetrabenazine - metabolism; UPDRS = Unified Parkinson's Disease Rating Scale; VMAT2 = vesicular monoamine transporter
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awh607

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-(±)α-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.