Papers by Graziella Mangone
Parkinson's Disease, 2022
Identification of individual risk factors for motor complications in Parkinson’s disease (PD) can... more Identification of individual risk factors for motor complications in Parkinson’s disease (PD) can help to guide personalised medical treatment, particularly since treatment options are still limited. To determine whether common functional gene polymorphisms in the dopamine metabolism predict the onset of motor complications in PD, we performed a retrospective, observer-blinded follow-up study of 30 PD patients who underwent genotyping of dopa-decarboxylase (DDC; rs921451), monoamine oxidase B (MAOB; rs1799836), catechol-O-methyltransferase (COMT; rs4680), and dopamine transporter (DAT; variable number tandem repeat) polymorphisms. Onset of wearing-off and dyskinesias was determined by blinded clinical assessments. Predictive values of genotypes for motor complications were evaluated using Cox proportional hazard models. During a median follow-up time of 11.6 years, 23 (77%) of 30 PD patients developed wearing-off, 16 (53%) dyskinesias, and 23 (77%) any motor complication. The MAOB (...
Frontiers in Neurology, 2021
Autosomal recessive early-onset parkinsonism is clinically and genetically heterogeneous. Mutatio... more Autosomal recessive early-onset parkinsonism is clinically and genetically heterogeneous. Mutations of three genes, PRKN, PINK1, and DJ-1 cause pure phenotypes usually characterized by levodopa-responsive Parkinson's disease. By contrast, mutations of other genes, including ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, VPS13C, and PTRHD1, cause rarer, more severe diseases with a poor response to levodopa, generally with additional atypical features. We performed data mining on a gene panel or whole-exome sequencing in 460 index cases with early-onset (≤ 40 years) Parkinson's disease, including 57 with autosomal recessive disease and 403 isolated cases. We identified two isolated cases carrying biallelic mutations of SYNJ1 (double-heterozygous p.D791fs/p.Y232H and homozygous p. Y832C mutations) and two siblings with the recurrent homozygous p.R258Q mutation. All four variants were absent or rare in the Genome Aggregation Database, were predicted to be deleterious on in silico analys...
SSRN Electronic Journal, 2019
Background: Genetic mutations causing autosomal recessive Parkinson's disease account for a s... more Background: Genetic mutations causing autosomal recessive Parkinson's disease account for a significant proportion of patients with early-onset disease. However, no large multicentre studies of known recessive Parkinson's disease-linked genes have been performed, to guide genetic testing according to age at onset, family history, ethnic origin, or phenotype. We aimed to evaluate the relative frequencies of mutations in genes causing recessive Parkinson's disease and their associated phenotypes in a large series of European and North African cases. Methods: Clinical data for 1664 patients were collected between 1990 and 2018 from 511 families with recessive Parkinson's disease and/or with consanguinity, and 1098 isolated cases. All the recessively inherited genes were screened by Sanger and/or targeted next-generation sequencing and gene dosage methods. Clinical features were compared between patients with PRKN and those without mutations, by regression analyses adjusted for sex, age at onset, disease duration and levodopa medication. Findings: Biallelic mutations of genes known to cause recessive Parkinson's disease were found in 246 of the 1609 index cases (15·3%): 150 familial (29·4%) and 96 (8·7%) isolated cases. The most frequently mutated genes were PRKN, in 199 cases (12·4%), PINK1, in 23 (1·8%), and DJ-1, in two (0·16%). We screened 675 index cases by targeted sequencing, and 22 were found to have mutations in genes known to cause atypical parkinsonism (3·3%). PRKN and PINK1 mutation frequencies were higher in early-onset (≤40 years) than late-onset Parkinson's disease. The frequency of PRKN mutations in the 1609 index cases decreased with increasing age at onset, from 38% in cases ≤20 years to 4·4% in those with onset at 41 to 60 years. No mutation of PRKN or another recessive Parkinson's disease gene was found in patients with onset above 60. PRKN mutations were more frequent in Caucasians (13·4%) than in North Africans (7·4%). Conversely, PINK1 mutations were more frequent in North Africans (6·3%) than in Caucasians (0·9%). PRKN patients had an earlier age at onset, lower levels of asymmetry, akinesia, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. Interpretation: This is a large study providing information about the frequency of recessive Parkinson's disease genes according to age at onset, family history, ethnic origin, and associated phenotype. Its findings will be useful for genetic testing and counselling. Funding Statement: Fondation de France, France-Parkinson Association, la Federation pour la Recherche sur le Cerveau, the French program "Investissements d'avenir", National Institute for Health Research. Declaration of Interests: SL reports grants from Fondation de France, the French program “Investissements d’avenir” (ANR-10-IAIHU-06), both outside the scope of the submitted work. MA reports grants and personal fees from Abbvie, Teva, Aguettant, Actelion Pharmaceuticals, personal fees from Johnson and Johnson, Merz, Orkyn, all outside the scope of the submitted work. ER reports grants, personal fees and non-financial support from Orkyn, Aguettant, Merz pharma, Everpharma, personal fees and non-financial support from Movement Disorders Society, grants and non-financial support from Elivie, non-financial support from Merck, Dystonia Coalition, Dystonia Medical Research Foundation, grants from Ipsen, Fondation Desmarest, Fonds de dotation Brou de Lauriere, Agence Nationale de la Recherche, AMADYS, personal fees from Medday pharma, Retrophin, European Academy of Neurology, International Association of Parkinsonism and related Disorders, all outside the submitted work. CT received fees from ALLERGAN and from MERZ. J-CC reports grants from Sanofi, personal fees from EverPharma, Denali, BrainEver, Theranexus, Air Liquide, all outside the scope of this work. EB reports grants from Medtronic France, Abbvie, UCB, and Aguettant laboratories but no conflict of interest nor financial concerns about the present research paper submitted for publication. AB reports grants from ANR - Agence nationale de recherche, ARNN - Association pour la Recherche en Neuro-imagerie et Neuropsychologie, France Parkinson, AP-HP, FMR - Fondation Maladies Rares (ex GIS), France Parkinson + FRC (Federation pour la Recherche sur le Cerveau), Universite Mohammed V - Rabat, Prix Allianz Institut de France, RDS (Roger de Spoelberch Foundation), FDF -Fondation de France-, all outside the submitted work. All other authors have no competing interests to declare. Ethics Approval Statement: Informed consent was obtained from all participants, and genetic studies were approved by local ethics committees (INSERM, CCPPRB du Groupe Hospitalier Pitie-Salpetriere, Paris, France).
Global Spine Journal, 2017
Introduction: To report a case of monoparesis caused by a vertebral artery (VA) anomaly and foram... more Introduction: To report a case of monoparesis caused by a vertebral artery (VA) anomaly and foraminal stenosis treated with microvascular decompression by the posterior approach. Material and Methods: A 51-year-old man was referred because of a 4-year history of progressive left shoulder pain refractory to other forms of treatment and a 7-month history of arm weakness. Clinical and radiologic evaluation showed an abnormally tortuous loop of left C5-6 cervical foramina with foraminal stenosis causing direct C6 nerve root compression. Results: Left posterior cervical C5-6 facetectomy and fusion was done to decompress the nerve root. The C6 nerve root was identified and well decompressed. The patient’s symptoms resolved after surgery, supporting the posterior decompression of a cervical nerve root compressed by a vertebral artery loop and stenosis for the relief of pain and weakness. Conclusion: Cervical root compression by an anomalous extracranial VA accompanied with foraminal stenos...
Brain, 2021
In Parkinson’s disease, there is a progressive reduction in striatal dopaminergic function, and l... more In Parkinson’s disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson’s disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system. Patients with Parkinson’s disease (disease duration < 4 years) or idiopathic REM sleep behaviour disorder (a prodromal form of Parkinson’s disease) and healthy controls underwent longitudinal examination (baseline and 2-year follow-up). Neuromelanin and iron sensitive MRI and dopamine transporter single-photon emission tomography were performed to assess nigrostriatal levels of neuromelanin, iron, and dopamine. Fo...
Parkinsonism & Related Disorders, 2020
BACKGROUND Subthalamic nucleus deep brain stimulation (STN-DBS) has demonstrated its efficacy on ... more BACKGROUND Subthalamic nucleus deep brain stimulation (STN-DBS) has demonstrated its efficacy on motor complications in advanced Parkinson's disease (PD) but does not modify disease progression. Genetic forms of PD have been associated with different cognitive progression profiles. OBJECTIVE To assess the effect of PD-related genetic mutations on cognitive outcome after STN-DBS. METHODS Patients with STN-DBS were screened for LRRK2, GBA, and PRKN mutations at the Pitié-Salpêtrière Hospital between 1997 and 2009. Patients with known monogenetic forms of PD from six other centers were also included. The Mattis Dementia Rating Scale (MDRS) was used to evaluate cognition at baseline and one-year post-surgery. The standardized Unified PD Rating Scale (UPDRS) evaluation On and Off medication/DBS was also administered. A generalized linear model adjusted for sex, ethnicity, age at onset, and disease duration was used to evaluate the effect of genetic factors on MDRS changes. RESULTS We analyzed 208 patients (131 males, 77 females, 54.3 ± 8.8 years) including 25 GBA, 18 LRRK2, 22 PRKN, and 143 PD patients without mutations. PRKN patients were younger and had a longer disease duration at baseline. A GBA mutation was the only significant genetic factor associated with MDRS change (β = -2.51, p = 0.009). GBA mutation carriers had a more pronounced post-operative MDRS decline (3.2 ± 5.1) than patients with LRRK2 (0.9 ± 4.8), PRKN (0.5 ± 2.7) or controls (1.4 ± 4.4). The motor response to DBS was similar between groups. CONCLUSION GBA mutations are associated with early cognitive decline following STN-DBS. Neuropsychological assessment and discussions on the benefit/risk ratio of DBS are particularly important for this population.
Brain Communications, 2021
A variety of neuropsychiatric complications has been described in association with COVID-19 infec... more A variety of neuropsychiatric complications has been described in association with COVID-19 infection. Large scale studies presenting a wider picture of these complications and their relative frequency are lacking. The objective of our study was to describe the spectrum of neurological and psychiatric complications in patients with COVID-19 seen in a multidisciplinary hospital centre over 6 months. We conducted a retrospective, observational study of all patients showing neurological or psychiatric symptoms in the context of COVID-19 seen in the medical and university neuroscience department of Assistance Publique Hopitaux de Paris—Sorbonne University. We collected demographic data, comorbidities, symptoms and severity of COVID-19 infection, neurological and psychiatric symptoms, neurological and psychiatric examination data and, when available, results from CSF analysis, MRI, EEG and EMG. A total of 249 COVID-19 patients with a de novo neurological or psychiatric manifestation were...
2017 International Conference on Advanced Technologies for Signal and Image Processing (ATSIP), 2017
Vocal impairments are one of the earliest disrupted modalities in Parkinson's disease (PD). Most ... more Vocal impairments are one of the earliest disrupted modalities in Parkinson's disease (PD). Most of the studies whose aim was to detect Parkinson's disease through acoustic analysis use global parameters. In the meantime, in speaker and speech recognition, analyses are carried out by short-term parameters, and more precisely by Mel-Frequency Cepstral Coefficients (MFCC), combined with Gaussian Mixture Models (GMM). This paper presents an adaptation of the classical methodology used in speaker recognition to the detection of early stages of Parkinson's disease. Automatic analyses were performed during 4 tasks: sustained vowels, fast syllable repetitions, free speech and reading. Men and women were considered separately in order to improve the classification performance. Leave one subject out cross validation exhibits accuracies ranging from 60% to 91% depending on the speech task and on the gender. Best performances are reached during the reading task (91% for men). This accuracy, obtained with a simple and fast methodology, is in line with the best classification results in early PD detection found in literature, obtained with more complex methods.
Frontiers in Neurology, 2020
LRRK2, SNCA, and VPS35 are unequivocally associated with autosomal dominant Parkinson's disease (... more LRRK2, SNCA, and VPS35 are unequivocally associated with autosomal dominant Parkinson's disease (PD). We evaluated the prevalence of LRRK2, SNCA, and VPS35 mutations and associated clinical features in a large French multi-center cohort of PD patients. Demographic and clinical data were collected for 1,805 index cases (592 with autosomal dominant inheritance and 1,213 isolated cases) since 1990. All probands were Lesage et al. Characterization of Dominant Parkinson's Disease screened with TaqMan assays for LRRK2 Gly2019Ser. In the absence of this mutation, the coding sequences of the three genes were analyzed by Sanger sequencing and/or next-generation sequencing. The data for the three genes were analyzed according to age at onset, family history, ethnic origin and clinical features. We identified 160 index cases (8.9%) with known pathogenic variants: 138 with pathogenic LRRK2 variants (7.6%), including 136 with the Gly2019Ser mutation, 19 with SNCA point mutations or genomic rearrangements (1.1%), and three with the VPS35 Asp620Asn mutation (0.16%). Mutation frequencies were higher in familial than isolated cases, consistent with autosomal dominant inheritance (12.0 vs. 7.3%; OR 1.7, 95% CI [1.2-2.4], p = 0.001). PD patients with LRRK2 variants were more likely to have higher rates of late-onset PD (>50 years; OR 1.5, 95% CI [1.0-2.1], p = 0.03), whereas those with SNCA mutations tended to have earlier age at onset disease (≤50 years, p = 0.06). The clinical features of LRRK2 carriers and those without any pathogenic variants in known PD-associated genes were similar. The likelihood of detecting disease-causing mutations was higher in cases compatible with autosomal dominant inheritance.
Brain, 2020
This study aimed to investigate the spatiotemporal changes in neuromelanin-sensitive MRI signal i... more This study aimed to investigate the spatiotemporal changes in neuromelanin-sensitive MRI signal in the substantia nigra and their relation to clinical scores of disease severity in patients with early or progressing Parkinson’s disease and patients with idiopathic rapid eye movement sleep behaviour disorder (iRBD) exempt of Parkinsonian signs compared to healthy control subjects. Longitudinal T1-weighted anatomical and neuromelanin-sensitive MRI was performed in two cohorts, including patients with iRBD, patients with early or progressing Parkinson’s disease, and control subjects. Based on the aligned substantia nigra segmentations using a study-specific brain anatomical template, parametric maps of the probability of a voxel belonging to the substantia nigra were calculated for patients with various degrees of disease severity and controls. For each voxel in the substantia nigra, probability map of controls, correlations between signal-to-noise ratios on neuromelanin-sensitive MRI ...
Annals of Neurology, 2020
Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are re... more Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene-targeting approaches for Parkinson's disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ-1 mutations in a cohort of 1587 cases. Mutations were found in 14.1% of patients: 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians whereas PINK1 mutations predominated in Arab-Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations.
Movement Disorders, 2020
Background: Cognitive impairment is common in patients with PD. Core markers of Alzheimer's demen... more Background: Cognitive impairment is common in patients with PD. Core markers of Alzheimer's dementia have been related also to PD dementia, but no disease-specific signature to predict PD dementia exists to date. Objectives: The aim of this study was to investigate CSF markers associated with cognition in early PD. Methods: A high-throughput suspension bead array examined 216 proteins in CSF of 74 PD patients in the AETIONOMY project. Cognitive function was assessed with Repeatable Battery for the Assessment of the Neuropsychological Status, Montreal Cognitive Assessment, and Mini-Mental State Examination. Results: Of 69 patients with complete data, 34 had high (≥90) and 35 had low Repeatable Battery for the Assessment of the Neuropsychological Status total score (<90). Of 14 proteins in CSF that differed in levels between groups, increased kininogen-1, validated with several antibodies, was independently associated with lower Repeatable Battery for the Assessment of the Neuropsychological Status and Montreal Cognitive Assessment scores after adjustment for confounders. Conclusions: Kininogen-1 levels in CSF may serve as a marker of cognitive impairment in PD.
Frontiers in Neurology, 2020
Introduction: Impulse control disorders (ICDs) frequently complicate dopamine agonist (DA) therap... more Introduction: Impulse control disorders (ICDs) frequently complicate dopamine agonist (DA) therapy in Parkinson's disease (PD). There is growing evidence of a high heritability for ICDs in the general population and in PD. Variants on genes belonging to the reward pathway have been shown to account for part of this heritability. We aimed to identify new pathways associated with ICDs in PD. Methods: Thirty-six Parkinsonian patients on DA therapy with (n = 18) and without ICDs (n = 18) matched on age at PD's onset, and gender was selected to represent the most extreme phenotypes of their category. Exome sequencing was performed, and variants with a strong functional impact in brain-expressed genes were selected. Allele frequencies and their distribution in genes and pathways were analyzed with single variant and SKAT-O tests. The 10 most associated variants, genes, and pathways were retained for replication in the Parkinson's progression markers initiative (PPMI) cohort. Results: None of markers tested passed the significance threshold adjusted for multiple comparisons. However, the "Adenylate cyclase activating" pathway, one of the top associated pathways in the discovery data set (p = 1.6 × 10 −3) was replicated in the PPMI cohort and was significantly associated with ICDs in a post hoc pooled analysis (combined p-value 3.3 × 10 −5). Two of the 10 most associated variants belonged to genes implicated in cAMP and ERK signaling (rs34193571 in RasGRF2, p = 5 × 10 −4 ; rs1877652 in PDE2A, p = 8 × 10 −4) although non-significant after Bonferroni correction. Conclusion: Our results suggest that genes implicated in the signaling pathways linked to G protein-coupled receptors participate to genetic susceptibility to ICDs in PD.
Alzheimer's & Dementia, 2019
Introduction: Multiple immunity biomarkers have been suggested as tracers of neuroinflammation in... more Introduction: Multiple immunity biomarkers have been suggested as tracers of neuroinflammation in neurodegeneration. This study aimed to verify findings in cerebrospinal fluid (CSF) samples of Alzheimer's disease (AD) and Parkinson's disease (PD) subjects from the network of the European, Innovative Medicines Initiative-funded project AETIONOMY. Methods: A total of 227 samples from the studies/centres AETIONOMY, ICEBERG, and IDIBAPS were used to analyse 21 selected immunity biomarkers in CSF. Results were compared to data of an independent cohort of 399 subjects previously published. Results: Immunity markers were predominantly and reproducibly associated with pathological levels of tau isoforms, but also with amyloid levels, aging, sex, APOE genotype, and center-specific factors. Discussion: Immunity biomarker levels in CSF reflect molecular and cellular pathology rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariates could improve the power of such markers in clinical applications or intervention studies targeting immune responses in neurodegeneration. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. c
Interspeech 2019, 2019
Vocal impairments are among the earliest symptoms in Parkinson's Disease (PD). We adapted a metho... more Vocal impairments are among the earliest symptoms in Parkinson's Disease (PD). We adapted a method classically used in speech and speaker recognition, based on Mel-Frequency Cepstral Coefficients (MFCC) extraction and Gaussian Mixture Model (GMM) to detect recently diagnosed and pharmacologically treated PD patients. We classified early PD subjects from controls with an accuracy of 83%, using recordings obtained with a professional microphone. More interestingly, we were able to classify PD from controls with an accuracy of 75 % based on telephone recordings. As far as we know, this is the first time that audio recordings from telephone network have been used for early PD detection. This is a promising result for a potential future telediagnosis of Parkinson's disease.
BackgroundAlthough advances in the understanding of neurodegenerative diseases (NDDs) have led to... more BackgroundAlthough advances in the understanding of neurodegenerative diseases (NDDs) have led to improvements in classification and diagnosis and most importantly to new therapies, the unmet medical needs remain significant due to high treatment failure rates. The AETIONOMY project funded by the Innovative Medicine Initiative (IMI) aims at using multi-OMICs and bioinformatics to identify new classifications for NDDs based on common molecular pathophysiological mechanisms in view of improving the availability of personalised treatments.ObjectivesThe purpose of the AETIONOMY cross-sectional study is to validate novel patient classification criteria provided by these tools.MethodsThis was a European multi centre, cross-sectional, clinical study conducted at 6 sites in 3 countries. Standardised clinical data, biosamples from peripheral blood, cerebrospinal fluid, skin biopsies, and data from a multi-OMICs approach were collected in patients suffering from Alzheimer’s and Parkinson’s di...
Parkinsonism & Related Disorders, 2019
HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Distributed under a Creative Commons Attribution-NonCommercial| 4.0 International License
Cell Reports, 2018
Highlights d The transcription factor ZSCAN21 induces a-synuclein expression in neuronal cells d ... more Highlights d The transcription factor ZSCAN21 induces a-synuclein expression in neuronal cells d TRIM41 ubiquitinates ZSCAN21 and TRIM17 inhibits its activity d Variants of TRIM41 and ZSCAN21 in patients with familial PD co-segregate with PD d These genetic variations result in stabilization of the ZSCAN21 protein
Neurology, 2018
ObjectiveTo investigate the longitudinal dose-effect relationship between dopamine replacement th... more ObjectiveTo investigate the longitudinal dose-effect relationship between dopamine replacement therapy and impulse control disorders (ICDs) in Parkinson disease (PD).MethodsWe used data from a multicenter longitudinal cohort of consecutive patients with PD with ≤5 years' disease duration at baseline followed up annually up to 5 years. ICDs were evaluated during face-to-face semistructured interviews with movement disorder specialists. Generalized estimating equations and Poisson models with robust variance were used to study the association between several time-dependent definitions of dopamine agonist (DA) use, taking dose and duration of treatment into account, and ICDs at each visit. Other antiparkinsonian drugs were also examined.ResultsAmong 411 patients (40.6% women, mean age 62.3 years, average follow-up 3.3 years, SD 1.7 years), 356 (86.6%) took a DA at least once since disease onset. In 306 patients without ICDs at baseline, the 5-year cumulative incidence of ICDs was 4...
Glia, Jan 17, 2018
Neuroinflammation and mitochondrial dysfunction, key mechanisms in the pathogenesis of Parkinson&... more Neuroinflammation and mitochondrial dysfunction, key mechanisms in the pathogenesis of Parkinson's disease (PD), are usually explored independently. Loss-of-function mutations of PARK2 and PARK6, encoding the E3 ubiquitin protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1, account for a large proportion of cases of autosomal recessive early-onset PD. PINK1 and Parkin regulate mitochondrial quality control and have been linked to the modulation of innate immunity pathways. We report here an exacerbation of NLRP3 inflammasome activation by specific inducers in microglia and bone marrow-derived macrophages from Park2 and Pink1 mice. The caspase 1-dependent release of IL-1β and IL-18 was, therefore, enhanced in Park2 and Pink1 cells. This defect was confirmed in blood-derived macrophages from patients with PARK2 mutations and was reversed by MCC950, which specifically inhibits NLRP3 inflammasome complex formation. Enhanced NLRP3 signaling in Parkin-deficient c...
Uploads
Papers by Graziella Mangone