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

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&#...

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Bibliographic Details
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
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Summary: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.
ISSN:0006-8950
1460-2156
DOI:10.1093/brain/awh607