title: Neuroimaging and clinical features in adults with a 22q11.2 deletion at risk of Parkinson's disease.
abstract: The recurrent 22q11.2 deletion is a genetic risk factor for early-onset Parkinson's disease. Adults with the associated 22q11.2 deletion syndrome (22q11.2DS) may exhibit phenotypes that could help identify those at highest risk and reveal disease trajectories. We investigated clinical and neuroimaging features relevant to Parkinson's disease in 26 adults: 13 with 22q11.2DS at genetic risk of Parkinson's disease (mean age = 41.5 years, standard deviation = 9.7), 12 healthy age and sex-matched controls, and a 22q11.2DS patient with l-DOPA-responsive early-onset Parkinson's disease. Neuroimaging included transcranial sonography and positron emission tomography using 11C-dihydrotetrabenazine (11C-DTBZ), a radioligand that binds to the presynaptic vesicular monoamine transporter. The 22q11.2DS group without Parkinson's disease demonstrated significant motor and olfactory deficits relative to controls. Eight (61.5%) were clinically classified with parkinsonism. Transcranial sonography showed a significantly larger mean area of substantia nigra echogenicity in the 22q11.2DS risk group compared with controls (P = 0.03). The 22q11.2DS patient with Parkinson's disease showed the expected pattern of severely reduced striatal 11C-DTBZ binding. The 22q11.2DS group without Parkinson's disease however showed significantly elevated striatal 11C-DTBZ binding relative to controls (∼33%; P < 0.01). Results were similar within the 22q11.2DS group for those with (n = 7) and without (n = 6) psychotic illness. These findings suggest that manifestations of parkinsonism and/or evolution to Parkinson's disease in this genetic at-risk population may include a hyperdopaminergic mechanism. Adequately powered longitudinal studies and animal models are needed to evaluate the relevance of the observed clinical and imaging phenotypes to Parkinson's disease and other disorders that are more prevalent in 22q11.2DS, such as schizophrenia.
authors.affiliation: Clinical Genetics Research Program and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, Ontario, Canada.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Butcher
authors.affiliation: Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital and the Edmond J. Safra Program in Parkinson's Disease Research, University of Toronto, Toronto, Ontario, Canada.|Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Connie
authors.initials: C
authors.lastname: Marras
authors.affiliation: Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital and the Edmond J. Safra Program in Parkinson's Disease Research, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Margarita
authors.initials: M
authors.lastname: Pondal
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Pablo
authors.initials: P
authors.lastname: Rusjan
authors.affiliation: Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.|The Dalglish Family 22q Clinic for Adults with 22q11.2 Deletion Syndrome, and Department of Psychiatry, University Health Network, Toronto, Ontario, Canada.
authors.forename: Erik
authors.initials: E
authors.lastname: Boot
authors.affiliation: Institute of Medical Science, University of Toronto, Ontario, Canada.|Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital and the Edmond J. Safra Program in Parkinson's Disease Research, University of Toronto, Toronto, Ontario, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Division of Brain, Imaging and Behaviour-Systems Neuroscience, Toronto Western Research Institute, University Hospital Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Leigh
authors.initials: L
authors.lastname: Christopher
authors.affiliation: Centre for Genetics and Genomics, Facultad de Medicina, Clinica Alemana Universidad del Desarrollo, Santiago, Chile.
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Repetto
authors.affiliation: Departamento de Psiquiatría y Salud Mental, Clínica Psiquiátrica Recoleta, Universidad de Chile, Santiago, Chile.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Fritsch
authors.affiliation: Clinical Genetics Research Program and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Eva W C
authors.initials: EWC
authors.lastname: Chow
authors.affiliation: Sunnybrook Health Sciences Research Centre, Toronto, Ontario, Canada.
authors.forename: Mario
authors.initials: M
authors.lastname: Masellis
authors.affiliation: Institute of Medical Science, University of Toronto, Ontario, Canada.|Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital and the Edmond J. Safra Program in Parkinson's Disease Research, University of Toronto, Toronto, Ontario, Canada.|Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Division of Brain, Imaging and Behaviour-Systems Neuroscience, Toronto Western Research Institute, University Hospital Network, University of Toronto, Toronto, Ontario, Canada.|Toronto Western Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Antonio P
authors.initials: AP
authors.lastname: Strafella
authors.affiliation: Institute of Medical Science, University of Toronto, Ontario, Canada.|Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital and the Edmond J. Safra Program in Parkinson's Disease Research, University of Toronto, Toronto, Ontario, Canada.|Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.|Toronto Western Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.|Tanz Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Lang
authors.affiliation: Clinical Genetics Research Program and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.|The Dalglish Family 22q Clinic for Adults with 22q11.2 Deletion Syndrome, and Department of Psychiatry, University Health Network, Toronto, Ontario, Canada.|Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.|Division of Cardiology, Department of Medicine, University Health Network, Toronto, Ontario, Canada.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Bassett
mesh_terms: D000328:Adult; D002250:Carbon Radioisotopes / Q000378:metabolism; D016022:Case-Control Studies; D003342:Corpus Striatum / Q000378:metabolism; D004062:DiGeorge Syndrome / Q000150:complications* / Q000235:genetics / Q000503:physiopathology*; D005260:Female; D059907:Functional Neuroimaging; D006801:Humans; D006984:Hypertrophy / Q000473:pathology; D008297:Male; D010302:Parkinson Disease, Secondary / Q000150:complications / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology*; D049268:Positron-Emission Tomography; D013378:Substantia Nigra / Q000473:pathology; D013747:Tetrabenazine / Q000031:analogs & derivatives / Q000378:metabolism; D017585:Ultrasonography, Doppler, Transcranial
chemical_list: D002250:Carbon Radioisotopes; C032811:dihydrotetrabenazine; D013747:Tetrabenazine
keywords: 11C-DTBZ PET; 22q11.2 deletion syndrome; Parkinson’s disease; dopamine; neurotoxicity