Serotonergic pathology and disease burden in the premotor and motor phase of A53T α-synuclein parkinsonism: a cross-sectional study.

Adult Aged Brain / metabolism Cross-Sectional Studies Female Humans Male Middle Aged Parkinsonian Disorders / diagnosis Serotonin / metabolism Serotonin Plasma Membrane Transport Proteins / metabolism Severity of Illness Index alpha-Synuclein / genetics

Journal

The Lancet. Neurology
ISSN: 1474-4465
Titre abrégé: Lancet Neurol
Pays: England
ID NLM: 101139309

Informations de publication

Date de publication:
08 2019
Historique:
received: 18 01 2019
revised: 01 04 2019
accepted: 03 04 2019
pubmed: 24 6 2019
medline: 9 6 2020
entrez: 24 6 2019
Statut: ppublish

Résumé

Because of the highly penetrant gene mutation and clinical features consistent with idiopathic Parkinson's disease, carriers of the autosomal dominant Ala53Thr (A53T; 209G→A) point mutation in the α-synuclein (SNCA) gene are an ideal population to study the premotor phase and evolution of Parkinson's pathology. Given the known neurochemical changes in the serotonergic system and their association with symptoms of Parkinson's disease, we hypothesised that carriers of the A53T SNCA mutation might show abnormalities in the serotonergic neurotransmitter system before the diagnosis of Parkinson's disease, and that this pathology might be associated with measures of Parkinson's burden. In this cross-sectional study, we recruited carriers of the A53T SNCA mutation from specialist Movement Disorders clinics in Athens, Greece, and Salerno, Italy, and a cohort of healthy controls with no personal or family history of neurological or psychiatric disorders from London, UK (recruited via public advertisement) who were age matched to the A53T SNCA carriers. We also recruited one cohort of patients with idiopathic Parkinson's disease (cohort 1) from Movement Disorders clinics in London, UK, and retrieved data on a second cohort of such patients (cohort 2; n=40) who had been scanned with a different scanner. 7-day continuous recording of motor function was used to determine the Parkinson's disease status of the A53T carriers. To assess whether serotonergic abnormalities were present, we used [ Between Sept 1, 2016, and Sept 30, 2018, we recruited 14 A53T SNCA carriers, 25 healthy controls, and 25 patients with idiopathic Parkinson's disease. Seven (50%) of 14 A53T SCNA carriers were confirmed to have motor symptoms and confirmed to have Parkinson's disease, and the absence of motor symptoms was confirmed in seven (50%) A53T SCNA carriers (ie, premotor), in whom [ The presence of serotonergic pathology in premotor A53T SNCA carriers preceded development of dopaminergic pathology and motor symptoms and was associated with disease burden, highlighting the potential early role of serotonergic pathology in the progression of Parkinson's disease. Our findings provide evidence that molecular imaging of serotonin transporters could be used to visualise premotor pathology of Parkinson's disease in vivo. Future work might establish whether serotonin transporter imaging is suitable as an adjunctive tool for screening and monitoring progression for individuals at risk or patients with Parkinson's disease to complement dopaminergic imaging, or as a marker of Parkinson's burden in clinical trials. Lily Safra Hope Foundation and National Institute for Health Research (NIHR) Biomedical Research Centre at King's College London.

Sections du résumé

BACKGROUND
Because of the highly penetrant gene mutation and clinical features consistent with idiopathic Parkinson's disease, carriers of the autosomal dominant Ala53Thr (A53T; 209G→A) point mutation in the α-synuclein (SNCA) gene are an ideal population to study the premotor phase and evolution of Parkinson's pathology. Given the known neurochemical changes in the serotonergic system and their association with symptoms of Parkinson's disease, we hypothesised that carriers of the A53T SNCA mutation might show abnormalities in the serotonergic neurotransmitter system before the diagnosis of Parkinson's disease, and that this pathology might be associated with measures of Parkinson's burden.
METHODS
In this cross-sectional study, we recruited carriers of the A53T SNCA mutation from specialist Movement Disorders clinics in Athens, Greece, and Salerno, Italy, and a cohort of healthy controls with no personal or family history of neurological or psychiatric disorders from London, UK (recruited via public advertisement) who were age matched to the A53T SNCA carriers. We also recruited one cohort of patients with idiopathic Parkinson's disease (cohort 1) from Movement Disorders clinics in London, UK, and retrieved data on a second cohort of such patients (cohort 2; n=40) who had been scanned with a different scanner. 7-day continuous recording of motor function was used to determine the Parkinson's disease status of the A53T carriers. To assess whether serotonergic abnormalities were present, we used [
FINDINGS
Between Sept 1, 2016, and Sept 30, 2018, we recruited 14 A53T SNCA carriers, 25 healthy controls, and 25 patients with idiopathic Parkinson's disease. Seven (50%) of 14 A53T SCNA carriers were confirmed to have motor symptoms and confirmed to have Parkinson's disease, and the absence of motor symptoms was confirmed in seven (50%) A53T SCNA carriers (ie, premotor), in whom [
INTERPRETATION
The presence of serotonergic pathology in premotor A53T SNCA carriers preceded development of dopaminergic pathology and motor symptoms and was associated with disease burden, highlighting the potential early role of serotonergic pathology in the progression of Parkinson's disease. Our findings provide evidence that molecular imaging of serotonin transporters could be used to visualise premotor pathology of Parkinson's disease in vivo. Future work might establish whether serotonin transporter imaging is suitable as an adjunctive tool for screening and monitoring progression for individuals at risk or patients with Parkinson's disease to complement dopaminergic imaging, or as a marker of Parkinson's burden in clinical trials.
FUNDING
Lily Safra Hope Foundation and National Institute for Health Research (NIHR) Biomedical Research Centre at King's College London.

Identifiants

DOI: 10.1016/S1474-4422(19)30140-1 PMID: 31229470
pubmed: 31229470
pii: S1474-4422(19)30140-1
doi: 10.1016/S1474-4422(19)30140-1
pii:
doi:

Substances chimiques

Serotonin Plasma Membrane Transport Proteins 0
alpha-Synuclein 0
Serotonin 333DO1RDJY

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

748-759

Commentaires et corrections

Type : CommentIn
Type : CommentIn
Type : ExpressionOfConcernIn

Informations de copyright

Copyright © 2019 Elsevier Ltd. All rights reserved.

Auteurs

Heather Wilson (H)

Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

George Dervenoulas (G)

Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Gennaro Pagano (G)

Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Christos Koros (C)

University of Athens Medical School, 1st Department of Neurology, University of Athens Hospital Attikon, Greece.

Tayyabah Yousaf (T)

Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Marina Picillo (M)

Center for Neurodegenerative Diseases (CEMAND), Department of Medicine, Neuroscience Section, University of Salerno, Italy.

Sotirios Polychronis (S)

Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Athina Simitsi (A)

University of Athens Medical School, 1st Department of Neurology, University of Athens Hospital Attikon, Greece.

Beniamino Giordano (B)

Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Zachary Chappell (Z)

Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Benjamin Corcoran (B)

Nuclear Medicine Department, King's College Hospital NHS Foundation Trust, London, UK.

Maria Stamelou (M)

University of Athens Medical School, 1st Department of Neurology, University of Athens Hospital Attikon, Greece; Department of Neurology, Philipps University, Marburg, Germany; Parkinson's Disease and Movement Disorders Department, HYGEIA Hospital, Athens, Greece.

Roger N Gunn (RN)

Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK; Invicro LLC, Centre for Imaging Sciences, Hammersmith Hospital, London, UK.

Maria Teresa Pellecchia (MT)

Center for Neurodegenerative Diseases (CEMAND), Department of Medicine, Neuroscience Section, University of Salerno, Italy.

Eugenii A Rabiner (EA)

Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Invicro LLC, Centre for Imaging Sciences, Hammersmith Hospital, London, UK.

Paolo Barone (P)

Center for Neurodegenerative Diseases (CEMAND), Department of Medicine, Neuroscience Section, University of Salerno, Italy.

Leonidas Stefanis (L)

University of Athens Medical School, 1st Department of Neurology, University of Athens Hospital Attikon, Greece; Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.

Marios Politis (M)

Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. Electronic address: marios.politis@kcl.ac.uk.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Serotonergic pathology and disease burden in...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Serotonergic pathology and disease burden in...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Serotonergic pathology and disease burden in...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études transversales › Serotonergic pathology and disease burden in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Serotonergic pathology and disease burden in...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Serotonergic pathology and disease burden in...
questionsmedicales.fr › Maladies du système nerveux › Maladies du système nerveux central › Troubles de la motricité › Syndromes parkinsoniens › Serotonergic pathology and disease burden in...
questionsmedicales.fr › Facteurs biologiques › Médiateurs de l'inflammation › Autacoïdes › Sérotonine › Serotonergic pathology and disease burden in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Protéines transporteurs de solutés › Transporteurs de la sérotonine › Serotonergic pathology and disease burden in...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Collecte de données › Enquêtes et questionnaires › Enquêtes de santé › Indicateurs d'état de santé › Acuité des besoins du patient › Indice de gravité de la maladie › Serotonergic pathology and disease burden in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines associées à la maladie de Parkinson › alpha-Synucléine › Serotonergic pathology and disease burden in...