A Multitracer Dopaminergic PET Study of Young-Onset Parkinsonian Patients With and Without Parkin Gene Mutations

¹ CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France
² University of Lyon; Hospices Civils de Lyon, Neurological Hospital, Lyon, France
³ INSERM, Paris, France; Department of the Nervous System Disorders, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; UPMC University of Paris, Paris, France
⁴ Unit of de Biostatistics and Medical Information and Unit of Medical Research, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; Modelisation in Clinical Research, UPMC University of Paris, Paris, France
⁵ INSERM, Paris, France; UPMC University of Paris, Paris, France
⁶ Department of Psychiatry, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
⁷ INSERM, Paris, France; UPMC University of Paris, Paris, France; Centre de Référence sur la Maladie de Pick, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
⁸ Behaviour, Emotion and Basal Ganglia, Center of Clinical Investigation, INSERM Avenir Group, Paris, France
⁹ Department of Clinical and Biological Neurosciences, University Hospital of Grenoble, Grenoble, France
¹⁰ INSERM, Paris, France; Department of the Nervous System Disorders, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; UPMC University of Paris, Paris, France; Clinical Investigation Center, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
¹¹ INSERM, Paris, France; Department of the Nervous System Disorders, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; UPMC University of Paris, Paris, France; Department of Genetics and Cytogenetics, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
¹² CEA, I2BM, MIRCEN, URA CEA-CNRS 2210, Orsay, France; CHU Henri Mondor, AP-HP and Faculté de Médecine Paris 12, Créteil, France

^* To whom correspondence should be addressed. E-mail: maria-joao.ribeiro{at}cea.fr.

	Abstract

The impact of parkin gene mutations on nigrostriatal dopaminergic degeneration is not well established. The purpose of this study was to characterize by PET using ¹⁸F-fluoro-L-3,4-dihydroxyphenylalanine (¹⁸F-fluoro-L-DOPA), ¹¹C-PE2I, and ¹¹C-raclopride the pattern of dopaminergic lesions in young-onset Parkinson disease (YOPD) patients with or without mutations of the parkin gene and to correlate the clinical and neuropsychologic characteristics of these patients with PET results. Methods: A total of 35 YOPD patients were enrolled (16 with parkin mutation, 19 without). The uptake constant (K_i) of ¹⁸F-fluoro-L-DOPA and the binding potential (BP) of ¹¹C-PE2I (BP_DAT) and of ¹¹C-raclopride (BP_D2) were calculated in the striatum. Comparisons were made between the 2 groups of YOPD and between controls and patients. For each radiotracer, parametric images were obtained, and statistical parametric mapping (SPM) analysis using a voxel-by-voxel statistical t test was performed. Correlations between the cognitive and motor status and PET results were analyzed. Results: In YOPD patients, ¹⁸F-fluoro-L-DOPA K_i values were reduced to 68% (caudate) and 40% (putamen) of normal values (P < 0.0001). This decrease was symmetric and comparable for nonparkin and parkin patients. No correlation was found between the K_i values and cognitive or motor status. ¹¹C-PE2I BP_DAT values in YOPD patients were decreased to 56% (caudate) and 41% (putamen) of normal values (P < 0.0001) and did not differ between the 2 YOPD populations. The mean ¹¹C-raclopride BP_D2 values were reduced to 72% (caudate) and 84% (putamen) of the normal values (P < 0.02) and did not differ between nonparkin and parkin patients. SPM analyses showed in patients an additional decrease of ¹¹C-raclopride in the frontal cortex and a decrease of ¹⁸F-fluoro-L-DOPA and ¹¹C-PE2I uptake in the substantia nigra bilaterally (P < 0.05, false-discovery rate–corrected). Conclusion: Carriers of parkin mutations are indistinguishable on PET markers of dopaminergic dysfunction from other YOPD patients with long disease duration.

Key Words: Parkinson, parkin gene, PET, ¹⁸F-fluoro-L-DOPA, ¹¹C-PE2I, ¹¹C-raclopride