Mangone Graziella

• MD, PhD
• Paris Brain Institute, French National Centre for Scientific Research

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting millions worldwide, characterized by a wide range of motor and non-motor symptoms. Among these symptoms, alterations in speech and voice quality stand out as early and prominent indicators of the disease. Recently, the emergence of speech foundation models has revolution...

Studies in animal models of Parkinson′s disease (PD) suggested that the accumulation of the neuromelanin (NM), a pigment contained in nigral dopaminergic neurons, could trigger neurodegeneration above a pathogenic threshold. Here we investigated this hypothesis using NM-sensitive MRI in rodents and in patients with isolated rapid eye movement sleep...

Hypomimia, a symptom of Parkinson's disease (PD), is marked by reduced facial movements and loss of face emotional expressions. This study focuses on identifying hypomimia in individuals with early-stage PD using optical-flow-based video vision transformer. Our study included video recordings from 109 PD and 45 healthy control (HC) subjects with an...

Digital device technologies, such as wearable gait sensors, voice and video recordings, bear potential for monitoring symptoms of chronic and increasingly prevalent diseases, such as Parkinson's Disease. This could facilitate a more personalised and higher quality treatment in the future. As part of the EU-wide project DIGIPD, we confirmed this pot...

Digital device technologies, such as wearable gait sensors, voice and video recordings, bear potential for monitoring symptoms of chronic and increasingly prevalent diseases, such as Parkinson's Disease. This could facilitate a more personalized and higher quality treatment in the future. As part of the EU-wide project DIGIPD, we confirmed this pot...

Background In early‐stage Parkinson's disease (PD), rapid eye movement (REM) sleep behavior disorder (RBD) predicts poor cognitive and motor outcome. However, the baseline significance and disease evolution associated with isolated REM sleep without atonia (iRWA, ie, enhanced muscle tone during 8.7% of REM sleep, but no violent behavior) are not we...

To assess amantadine use and associated factors in the patients with Parkinson’s disease (PD). Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat “levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features o...

Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson’s disease (PD). 647 patients with PRKN -PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN -PD was also assessed. Am...

In Parkinson’s disease (PD), it remains unclear whether sleep disorders including insomnia, REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), restless legs syndrome (RLS) and sleep-disordered breathing (SDB), are isolated or combined, interact with each other and are associated with clinical factors. We sought to determine the...

Background Parkinson's disease psychosis (PDP) is a multidimensional construct that is challenging to measure. Accurate assessment of PDP requires comprehensive and reliable clinical outcome assessment (COA) measures. Objective To identify PDP measurement gaps in available COAs currently used in clinical and research settings. Methods We conducte...

Cognitive decline is common in Parkinson’s disease (PD) and its genetic risk factors are not well known to date, besides variants in the GBA and APOE genes. However, variation in complex traits is caused by numerous variants and is usually studied with genome-wide association studies (GWAS), requiring a large sample size, which is difficult to achi...

Background Clinical presentation and progression dynamics are variable in patients with Parkinson's disease (PD). Disease course mapping is an innovative disease modelling technique that summarizes the range of possible disease trajectories and estimates dimensions related to onset, sequence, and speed of progression of disease markers. Objective...

Background: Longitudinal measures of structural brain changes using MRI in relation to clinical features and progression patterns in PD have been assessed in previous studies, but few were conducted in well-defined and large cohorts, including prospective clinical assessments of both motor and non-motor symptoms. Objective: We aimed to identify...

Background: Hypomimia is a symptom of Parkinson's disease (PD), characterized by a decrease in facial movements and loss of face emotional expressions. This study aims to detect hypomimia in participants with early-stage PD based on facial action units (AUs). Methods: A total of 299 video recordings were included, consisting of 208 PD subjects and...

Introduction: Gait disorders and falls occur early in progressive supranuclear palsy (PSP-RS) and Caribbean atypical parkinsonism (Caribbean AP). However, the link between these signs and brain lesions has never been explored in these patient populations. Here, we investigate and compare the imaging factors that relate to gait and balance disorder...

Objective: Survival of patients with monogenic Parkinson's disease may depend on the causative genes associated with the disease. In this study, we compare survival of patients with Parkinson's disease according to the presence of SNCA, PRKN, LRRK2 or GBA mutations. Methods: Data from the French Parkinson Disease Genetics national multicentre co...

Background: The locus coeruleus/subcoeruleus complex (LC/LsC) is a structure comprising melanized noradrenergic neurons. Objective: To study the LC/LsC damage across Parkinson's disease (PD) and atypical parkinsonism in a large group of subjects. Methods: We studied 98 healthy control subjects, 47 patients with isolated rapid eye movement slee...

Here, we characterised gait and balance disorders in 16 Caribbean AP patients (mean age = 64.3 ± 6.8 years, 9F/7M), which we compared to 15 PSP-RS patients (mean age = 66.2 ± 5.9 years, 6F/9M), and 17 controls (mean age = 64.6 ± 5.1 years, 12F/5M) (Table S1), using clinical scales and gait initiation recordings. We also recorded oculomotor paramete...

Several postmortem studies have shown iron accumulation in the substantia nigra of Parkinson’s disease patients. Iron concentration can be estimated via MRI-R2∗ mapping. To assess the changes in R2∗ occurring in Parkinson’s disease patients compared to controls, a multicentre transversal study was carried out on a large cohort of Parkinson’s diseas...

Background Parkinson’s disease (PD) demonstrates neurodegenerative changes in the substantia nigra pars compacta (SNc) using neuromelanin-sensitive (NM)-MRI. As SNc manual segmentation is prone to substantial inter-individual variability across raters, development of a robust automatic segmentation framework is necessary to facilitate nigral neurom...

We investigated the presence of misfolded alpha-Synuclein (α-Syn) in minor salivary gland biopsies in relation to substantia nigra pars compacta (SNc) damage measured using magnetic resonance imaging in patients with isolated rapid eye movement sleep behavior disorder (iRBD) and Parkinson’s disease (PD) as compared to healthy controls. Sixty-one pa...

italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Goal : Impulse control disorders (ICDs) are frequent non-motor symptoms occurring during the course of Parkinson’s disease (PD). The objective of this study was to estimate the predictability of the future occurrence of these disorders using longitudin...

Background: Isolated REM sleep behavior disorder (iRBD) is considered a prodromal stage of parkinsonism. Neurodegenerative changes in the substantia nigra pars compacta (SNc) in parkinsonism can be detected using neuromelanin-sensitive MRI. Objective: To investigate SNc neuromelanin changes in iRBD patients using fully automatic segmentation. M...

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 re...

Background Speech disorders are amongst the first symptoms to appear in Parkinson's disease (PD). Objectives We aimed to characterize PD voice signature from the prodromal stage (isolated rapid eye movement sleep behavior disorder, iRBD) to early PD using an automated acoustic analysis and compare male and female patients. We carried out supervise...

Objective To compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and non-carriers with and without subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD). Methods Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating...

COVID-19, caused by the SARS-CoV-2 virus, has spread since December 2019 and was declared a pandemic by the World Health Organization. An initial Chinese cohort of 214 COVID-19 patients reported a high frequency of neurological symptoms (36%), including non-specific manifestations such as headache, confusion and myalgia, but also strokes and seizur...

Current quantification methods of 123 I-FP-CIT SPECT rely on anatomical parcellation of the striatum. We propose here to implement a new method based on MRI segmentation and functional atlas of the basal ganglia (MR-ATLAS) that could provide a reliable quantification within the sensorimotor, associative, and limbic territories of the striatum. Pati...

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 key driver of patients’ well-being and clinical trials for Parkinson’s disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 1...

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...

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, mor...

Background: Development of reliable and accurate imaging biomarkers of dopaminergic cell neurodegeneration is necessary to facilitate therapeutic drug trials in Parkinson's disease (PD). Neuromelanin-sensitive MRI techniques have been effective in detecting neurodegeneration in the substantia nigra pars compacta (SNpc). The objective of the curren...

Introduction Growing evidence highlighting a social cognition (SC) deficit in Parkinson’s disease (PD) have recently emerged, while pointing to ambiguous findings. Our objective was to determine if SC abilities impairment is frequent at the early stages of PD. Methods 109 patients with idiopathic PD diagnosed within the past four years (ICEBERG co...

Many articles have used voice analysis to detect Parkinson's disease (PD), but few have focused on the early stages of the disease and the gender effect. In this article, we have adapted the latest speaker recognition system, called x-vectors, in order to detect PD at an early stage using voice analysis. X-vectors are embeddings extracted from Deep...

Objective To examine the longitudinal relation of dopamine agonists (DA) use with body mass index (BMI) change and weight gain in Parkinson's disease (PD). Methods In a cohort of 356 patients with PD annually followed up to 6 years, BMI, antiparkinsonian drugs use, and impulse control disorders (ICDs) were assessed at each visit. DA dose trajector...

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 compa...

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 suspens...

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 i...

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 identif...

Many articles have used voice analysis to detect Parkinson's disease (PD), but few have focused on the early stages of the disease and the gender effect. In this article, we have adapted the latest speaker recognition system, called x-vectors, in order to detect an early stage of PD from voice analysis. X-vectors are embeddings extracted from a dee...

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...

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...

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....

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...

Background: Although 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...

Background: Whether reserve plays a role in Parkinson's disease (PD) patients has received less attention than in dementia and has been mainly examined in relation with cognitive function. Objective: To investigate whether reserve plays a role in the severity and progression of motor, cognitive, and nonmotor PD symptoms by examining whether educ...

Les modifications de la voix, connues sous le terme de dysarthrie hypokinétique, sont un des premiers symptômes à apparaître dans la maladie de Parkinson. Les corrélations entre des paramètres vocaux et les atteintes du système dopaminergique mises en évidence par la 123-I Ioflupane tomoscintigraphie d'émission monophotonique (DAT) ou l'IRM sensibl...

Introduction: The management of impulse control disorders (ICDs) in Parkinson's disease (PD) relies on their early identification, allowing adjustment of antiparkinsonian treatment before these manifestations lead to major social, financial or legal consequences. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Sc...

Background: Impulse control disorders are frequently associated with dopaminergic therapy in Parkinson's disease. Genetic studies have suggested a high heritability of impulse control disorders in the general population and in PD. The aim of this study was to identify candidate gene variants associated with impulse control disorders and related beh...

Although accumulating data indicate that increased α-synuclein expression is crucial for Parkinson disease (PD), mechanisms regulating the transcription of its gene, SNCA, are largely unknown. Here, we describe a pathway regulating α-synuclein expression. Our data show that ZSCAN21 stimulates SNCA transcription in neuronal cells and that TRIM41 is...

Objective: The objective of this study was to evaluate the effects of common functional polymorphisms in genes involved in dopamine metabolism on striatal dopamine turnover in de novo Parkinson's disease (PD). Methods: This was an observer‐blinded cohort study investigating effects of common functional polymorphisms in dopa decarboxylase (DDC, rs92...

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There is currently no cure for Parkinson’s disease. The symptomatic therapeutic strategy essentially relies on dopamine replacement whose efficacy was demonstrated more than 50 years ago following the introduction of the dopamine precursor, levodopa. The spectacular antiparkinsonian effect of levodopa is, however, balanced by major limitations incl...

Objective: To investigate the longitudinal dose-effect relationship between dopamine replacement therapy and impulse control disorders (ICDs) in Parkinson disease (PD). Methods: We 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...

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...

Background: The relationship between Health-Related Quality of Life (HRQoL) and MDS-UPDRS has not been fully studied so far. The aim of this study was to evaluate the relationship between all MDS-UPDRS components and HRQoL in a representative international cohort of PD patients. Methods: We collected demographic and disease-related data as well...

Background: Patients with Parkinson's disease often present abnormal posture or severe sagittal malalignment, causing significant disability. Surgical fusion is these cases shows high rates of complications, but may nevertheless provide functional benefit; however, this remains to be assessed. Hypothesis: Long fusion for patients with Parkinson'...

Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical-genetic score to predict global cognitive impairment in patients with the disease.In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MM...

Background: Penetrance estimates of the leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation for PD vary widely (24%-100%). The p.G2019S penetrance in individuals of Ashkenazi Jewish ancestry has been estimated as 25%, adjusted for multiple covariates. It is unknown whether penetrance varies among different ethnic groups. The objective of this s...

Background Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical–genetic score to predict global cognitive impairment in patients with the disease. Methods In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental...

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 Cepstr...

Background: The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a newly developed tool to assess Parkinson's disease (PD). Changes in scores on the scale over the course of PD, including increasing disease duration and Hoehn and Yahr (HY) stages, have not been described. The objectives of this study were to analyz...

Supporting Information

Mutations in TMEM230 have recently been associated to Parkinson’s disease (PD). To further understand the role of this gene in the Caucasian population, we interrogated our large repository of next generation sequencing data from unrelated PD cases and controls, as well as multiplex families with autosomal dominant PD. We identified 2 heterozygous...

An observation/execution matching system for walking has not been assessed yet. The present fMRI study was aimed at assessing whether, as for object-directed actions, an observation/execution matching system is active for walking and whether the spatial context of walking (open or narrow space) recruits different neural correlates. Two experimental...

Background: Parkinson’s disease is primarily a disorder of response initiation characterized by an excessive motor inhibition, whereas levodopainduced dyskinesias are clearly a clinical expression of disinhibition of movements. Objective: That levodopa-induced dyskinesias are linked to dysfunctions of inhibitory brain network has recently been prop...

Levodopa-induced dyskinesias are disabling motor complications of long-term dopamine replacement in patients with Parkinson’s disease. In recent years, several alternative models have been proposed to explain the pathophysiological mechanisms underlying this hyperkinetic motor disorder. In particular, our group has shed new light on the role of the...

Genetic variants within the serotonin transporter gene (5-HTTLPR) impact the neurobiology and risk for anxiety-related behaviours. There are also gender differences in the prevalence of anxiety-related behaviours. Although numerous studies have investigated the influence of 5-HTTLPR genotype on the neural systems involved in emotional regulation, n...