title: The prominent role of serotonergic degeneration in apathy, anxiety and depression in de novo Parkinson's disease.
abstract: SEE SCHRAG AND POLITIS DOI101093/AWW190 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Apathy, which can occur separately or in combination with depression and anxiety, is one of the most frequently encountered neuropsychiatric symptoms in Parkinson's disease. Pathophysiological evidence suggests that parkinsonian apathy is primarily due to a mesolimbic dopaminergic denervation, but the role of the serotonergic alteration has never been examined, despite its well-known involvement in the pathogenesis of depression and anxiety. To fill this gap, we address here the pure model of de novo Parkinson's disease, without the confounding effects of antiparkinsonian treatment. Fifteen apathetic (Lille Apathy Rating Scale scores ≥ -21) and 15 non-apathetic (-36 ≤ Lille Apathy Rating Scale scores ≤ -22) drug-naïve de novo parkinsonian patients were enrolled in the present study and underwent detailed clinical assessment and positron emission tomography imaging, using both dopaminergic [(11)C-N-(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3-beta-(4-methylphenyl)-nortropane (PE2I)] (n = 29) and serotonergic [(11)C-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio)-benzylamine (DASB)] (n = 27) presynaptic transporter radioligands. Apathetic parkinsonian patients presented higher depression (P = 0.0004) and anxiety (P = 0.004) scores - as assessed using the Beck Depression Inventory and the part B of the State-Trait Anxiety Inventory, respectively - compared to the non-apathetic ones - who were not different from the age-matched healthy subjects (n = 15). Relative to the controls, the non-apathetic parkinsonian patients mainly showed dopaminergic denervation (n = 14) within the right caudate nucleus, bilateral putamen, thalamus and pallidum, while serotonergic innervation (n = 15) was fairly preserved. Apathetic parkinsonian patients exhibited, compared to controls, combined and widespread dopaminergic (n = 15) and serotonergic (n = 12) degeneration within the bilateral caudate nuclei, putamen, ventral striatum, pallidum and thalamus, but also a specific bilateral dopaminergic disruption within the substantia nigra-ventral tegmental area complex, as well as a specific serotonergic alteration within the insula, the orbitofrontal and the subgenual anterior cingulate cortices. When comparing the two parkinsonian groups, the apathetic patients mainly displayed greater serotonergic alteration in the ventral striatum, the dorsal and the subgenual parts of the anterior cingulate cortices, bilaterally, as well as in the right-sided caudate nucleus and the right-sided orbitofrontal cortex. Regression analyses also revealed that the severity of apathy was moreover mainly related to specific serotonergic lesions within the right-sided anterior caudate nucleus and the orbitofrontal cortex, while the degree of both depression and anxiety was primarily linked to serotonergic disruption within the bilateral subgenual parts and/or the right dorsal part of the anterior cingulate cortex, without prominent role of the dopaminergic degeneration in the pathogenesis of these three non-motor signs. Altogether, these findings highlight a prominent role of the serotonergic degeneration in the expression of the neuropsychiatric symptoms occurring at the onset of Parkinson's disease.
authors.affiliation: 1 Centre de Neuroscience Cognitive, Institut des Sciences Cognitives Marc Jeannerod, UMR 5229 CNRS, Lyon, France 2 Université Claude Bernard, Lyon I, Lyon, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Maillet
authors.affiliation: 3 Grenoble Institut des Neurosciences, Inserm U1216, Grenoble, France 4 Université Grenoble Alpes, Grenoble I, Grenoble, France 5 Movement Disorders Unit, Neurology Department, CHU de Grenoble, Grenoble, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Krack
authors.affiliation: 3 Grenoble Institut des Neurosciences, Inserm U1216, Grenoble, France 4 Université Grenoble Alpes, Grenoble I, Grenoble, France 5 Movement Disorders Unit, Neurology Department, CHU de Grenoble, Grenoble, France.
authors.forename: Eugénie
authors.initials: E
authors.lastname: Lhommée
authors.affiliation: 1 Centre de Neuroscience Cognitive, Institut des Sciences Cognitives Marc Jeannerod, UMR 5229 CNRS, Lyon, France 2 Université Claude Bernard, Lyon I, Lyon, France 6 Hospices Civils de Lyon, Hôpital Neurologique et Neurochirurgical Pierre Wertheimer, Service de Neurologie C - Pathologies du Mouvement, Lyon, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Météreau
authors.affiliation: 6 Hospices Civils de Lyon, Hôpital Neurologique et Neurochirurgical Pierre Wertheimer, Service de Neurologie C - Pathologies du Mouvement, Lyon, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Klinger
authors.affiliation: 6 Hospices Civils de Lyon, Hôpital Neurologique et Neurochirurgical Pierre Wertheimer, Service de Neurologie C - Pathologies du Mouvement, Lyon, France 7 Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Service de Gastroentérologie, Hépatologie et Nutrition pédiatrique, Centre National de Référence pour la maladie de Wilson, Lyon, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Favre
authors.affiliation: 2 Université Claude Bernard, Lyon I, Lyon, France 8 CERMEP, Imagerie du Vivant, Lyon, France 9 Institut de Chimie et de Biochimie Moléculaires et Supramoléculaires, UMR 5246 CNRS, Université Lyon I, Lyon, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Le Bars
authors.affiliation: 3 Grenoble Institut des Neurosciences, Inserm U1216, Grenoble, France 4 Université Grenoble Alpes, Grenoble I, Grenoble, France 5 Movement Disorders Unit, Neurology Department, CHU de Grenoble, Grenoble, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Schmitt
authors.affiliation: 3 Grenoble Institut des Neurosciences, Inserm U1216, Grenoble, France 4 Université Grenoble Alpes, Grenoble I, Grenoble, France 5 Movement Disorders Unit, Neurology Department, CHU de Grenoble, Grenoble, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bichon
authors.affiliation: 3 Grenoble Institut des Neurosciences, Inserm U1216, Grenoble, France 4 Université Grenoble Alpes, Grenoble I, Grenoble, France 5 Movement Disorders Unit, Neurology Department, CHU de Grenoble, Grenoble, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Pelissier
authors.affiliation: 3 Grenoble Institut des Neurosciences, Inserm U1216, Grenoble, France 4 Université Grenoble Alpes, Grenoble I, Grenoble, France 5 Movement Disorders Unit, Neurology Department, CHU de Grenoble, Grenoble, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Fraix
authors.affiliation: 3 Grenoble Institut des Neurosciences, Inserm U1216, Grenoble, France 4 Université Grenoble Alpes, Grenoble I, Grenoble, France 5 Movement Disorders Unit, Neurology Department, CHU de Grenoble, Grenoble, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Castrioto
authors.affiliation: 1 Centre de Neuroscience Cognitive, Institut des Sciences Cognitives Marc Jeannerod, UMR 5229 CNRS, Lyon, France 2 Université Claude Bernard, Lyon I, Lyon, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Sgambato-Faure
authors.affiliation: 1 Centre de Neuroscience Cognitive, Institut des Sciences Cognitives Marc Jeannerod, UMR 5229 CNRS, Lyon, France 2 Université Claude Bernard, Lyon I, Lyon, France 6 Hospices Civils de Lyon, Hôpital Neurologique et Neurochirurgical Pierre Wertheimer, Service de Neurologie C - Pathologies du Mouvement, Lyon, France 10 Faculté de Médecine Lyon Sud Charles Mérieux, Université Lyon I, Lyon, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Broussolle
authors.affiliation: 1 Centre de Neuroscience Cognitive, Institut des Sciences Cognitives Marc Jeannerod, UMR 5229 CNRS, Lyon, France 2 Université Claude Bernard, Lyon I, Lyon, France.
authors.forename: Léon
authors.initials: L
authors.lastname: Tremblay
authors.affiliation: 1 Centre de Neuroscience Cognitive, Institut des Sciences Cognitives Marc Jeannerod, UMR 5229 CNRS, Lyon, France 2 Université Claude Bernard, Lyon I, Lyon, France 6 Hospices Civils de Lyon, Hôpital Neurologique et Neurochirurgical Pierre Wertheimer, Service de Neurologie C - Pathologies du Mouvement, Lyon, France 10 Faculté de Médecine Lyon Sud Charles Mérieux, Université Lyon I, Lyon, France stephane.thobois@chu-lyon.fr dr.audrey.maillet@gmail.com.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Thobois
mesh_terms: D000328:Adult; D000368:Aged; D001007:Anxiety / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D057565:Apathy / Q000502:physiology*; D003863:Depression / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D049268:Positron-Emission Tomography / Q000379:methods*; D012701:Serotonin / Q000378:metabolism*
chemical_list: D012701:Serotonin
keywords: apathy; depression; dopamine; drug-naïve de novo Parkinson’s disease; serotonin