Pr. Stéphane THOBOIS
Neurology department – movement disorders and neuromuscular pathologies
The neurology department – movement disorders and muscular pathologies is particularly involved in certain subspecialties of neurology: Parkinson’s disease and abnormal movements on the one hand; ALS (Amyotrophic Lateral Sclerosis or Charcot’s disease) and neuromuscular pathologies on the other hand.
To phenotype patients with Parkinson disease much more precisely in terms of their clinical characteristics, particularly non-motor (anxiety, apathy, impulsivity, cognition, sleep, etc.), then correlate this with physiopathological processes via multimodal imaging approaches (multi-tracer PET, MRI). Use the non-human primate parkinson model to analyze how the modulations or lesions of these systems or regions impact behavior and finally propose new therapeutic axes (clinical trials).
At the same time, our team is very involved in the national NS-Park database and is piloting the project to implement an MRI database in addition to the clinico-genetic database (PRECISE-PD study)
Finally, we are working to better understand the mechanisms of plasticity or the impact of therapies such as intensive rehabilitation (SIROCCO program) or deep brain stimulation. Research team: ISC Marc Jeannerod, CNRS, UMR 5229, “Physiopathology of the Basal Ganglia Team” (Dir Léon Tremblay)
1. Honeymoon study group. Early Parkinson’s Disease Phenotypes Tailored by Personality, Behavior, and Motor Symptoms
Meira B, Lhommée E, Schmitt E, Klinger H, Bichon A, Pélissier P, Anheim M, Tranchant C, Fraix V, Meoni S, Durif F, Houeto JL, Azulay JP, Moro E, Thobois S, Krack P, Castrioto A;
J Parkinsons Dis (2022) — Abstract
Background: Previous studies described a parkinsonian personality characterized as rigid, introverted, and cautious; however, little is known about personality traits in de novo Parkinson’s disease (PD) patients and their relationships with motor and neuropsychiatric symptoms. Objective: To investigate personality in de novo PD and explore its relationship with PD symptoms. Methods: Using Cloninger’s biosocial model, we assessed personality in 193 de novo PD patients. Motor and non-motor symptoms were measured using several validated scales. Cluster analysis was conducted to investigate the interrelationship of personality traits, motor, and non-motor symptoms. Results: PD patients showed low novelty seeking, high harm avoidance, and normal reward dependence and persistence scores. Harm avoidance was positively correlated with the severity of depression, anxiety, and apathy (rs = [0.435, 0.676], p < 0.001) and negatively correlated with quality of life (rs = -0.492, p < 0.001). Novelty seeking, reward dependence, and persistence were negatively correlated with apathy (rs = [-0.274, -0.375], p < 0.001). Classification of patients according to personality and PD symptoms revealed 3 distinct clusters: i) neuropsychiatric phenotype (with high harm avoidance and low novelty seeking, hypodopaminergic neuropsychiatric symptoms and higher impulsivity), ii) motor phenotype (with low novelty seeking and higher motor severity), iii) benign phenotype (with low harm avoidance and high novelty seeking, reward dependence, and persistence traits clustered with lower symptoms severity and low impulsivity). Conclusion: Personality in early PD patients allows us to recognize 3 patients’ phenotypes. Identification of such subgroups may help to better understand their natural history. Their longitudinal follow-up will allow confi
2. Limbic Serotonergic Plasticity Contributes to the Compensation of Apathy in Early Parkinson’s Disease
Prange S, Metereau E, Maillet A, Klinger H, Schmitt E, Lhommée E, Bichon A, Lancelot S, Meoni S, Broussolle E, Castrioto A, Tremblay L, Krack P, Thobois S
Mov Disord (2022) — Abstract
Background: De novo Parkinson’s disease (PD) patients with apathy exhibit prominent limbic serotonergic dysfunction and microstructural disarray. Whether this distinctive lesion profile at diagnosis entails different prognosis remains unknown. Objectives: To investigate the progression of dopaminergic and serotonergic dysfunction and their relation to motor and nonmotor impairment in PD patients with or without apathy at diagnosis. Methods: Thirteen de novo apathetic and 13 nonapathetic PD patients were recruited in a longitudinal double-tracer positron emission tomography cohort study. We quantified the progression of presynaptic dopaminergic and serotonergic pathology using [11 C]PE2I for dopamine transporter and [11 C]DASB for serotonin transporter at baseline and 3 to 5 years later, using linear mixed-effect models and mediation analysis to compare the longitudinal evolution between groups for clinical impairment and region-of-interest-based analysis. Results: After the initiation of dopamine replacement therapy, apathy, depression, and anxiety improved at follow-up in patients with apathy at diagnosis (n = 10) to the level of patients without apathy (n = 11). Patients had similar progression of motor impairment, whereas mild impulsive behaviors developed in both groups. Striato-pallidal and mesocorticolimbic presynaptic dopaminergic loss progressed similarly in both groups, as did serotonergic pathology in the putamen, caudate nucleus, and pallidum. Contrastingly, serotonergic innervation selectively increased in the ventral striatum and anterior cingulate cortex in apathetic patients, contributing to the reversal of apathy besides dopamine replacement therapy. Conclusion: Patients suffering from apathy at diagnosis exhibit compensatory changes in limbic serotonergic innervation within 5 years of diagnosis, with promising evidence that serotonergic plasticity contributes to the reversal of apathy. The relationship between serotonergic plasticity and dopaminergic treatments warrants further longitudinal investigations. © 2022 International Parkinson and Movement Disorder Society.
3. Safety and efficacy of riluzole in spinocerebellar ataxia type 2 in France (ATRIL): a multicentre, randomised, double-blind, placebo-controlled trial
Coarelli G, Heinzmann A, Ewenczyk C, Fischer C, Chupin M, Monin ML, Hurmic H, Calvas F, Calvas P, Goizet C, Thobois S, Anheim M, Nguyen K, Devos D, Verny C, Ricigliano VAG, Mangin JF, Brice A, Tezenas du Montcel S, Durr A
Lancet neurol (2022) — Abstract
Background Riluzole has been reported to be beneficial in patients with cerebellar ataxia; however, effectiveness in individual subtypes of disease is unclear due to heterogeneity in participants’ causes and stages of disease. Our aim was to test riluzole in a single genetic disease, spinocerebellar ataxia type 2. Methods We did a randomised, double-blind, placebo-controlled, multicentre trial (the ATRIL study) at eight national reference centres for rare diseases in France that were part of the Neurogene National Reference Centre for Rare Diseases. Participants were patients with spinocerebellar ataxia type 2 with an age at disease onset of up to 50 years and a scale for the assessment and rating of ataxia (SARA) score of at least 5 and up to 26. Patients were randomly assigned centrally (1:1) to receive either riluzole 50 mg orally or placebo twice per day for 12 months. Two visits, at baseline and at 12 months, included clinical measures and 3T brain MRI. The primary endpoint was the proportion of patients whose SARA score improved by at least 1 point. Analyses were done in the intention-to-treat population (all participants who were randomly assigned) and were done with only the observed data (complete case analysis). This trial is registered at ClinicalTrials.gov (NCT03347344) and has been completed.
4. Isolated parkinsonism is an atypical presentation of GRN and C9orf72 gene mutations
Carneiro F, Saracino D, Huin V, Clot F, Delorme C, Méneret A, Thobois S, Cormier F, Corvol JC, Lenglet T, Vidailhet M, Habert MO, Gabelle A, Beaufils É, Mondon K, Tir M, Andriuta D, Brice A, Deramecourt V, Le Ber I
Parkinsonism Relat Disord (2021) — Abstract
Introduction: A phenotype of isolated parkinsonism mimicking Idiopathic Parkinson’s Disease (IPD) is a rare clinical presentation of GRN and C9orf72 mutations, the major genetic causes of frontotemporal dementia (FTD). It still remains controversial if this association is fortuitous or not, and which clinical clues could reliably suggest a genetic FTD etiology in IPD patients. This study aims to describe the clinical characteristics of FTD mutation carriers presenting with IPD phenotype, provide neuropathological evidence of the mutation’s causality, and specifically address their red flags according to current IPD criteria. Methods: Seven GRN and C9orf72 carriers with isolated parkinsonism at onset, and three patients from the literature were included in this study. To allow better delineation of their phenotype, the presence of supportive, exclusion and red flag features from MDS criteria were analyzed for each case. Results: Amongst the ten patients (5 GRN, 5 C9orf72), seven fulfilled probable IPD criteria during all the disease course, while behavioral/language or motoneuron dysfunctions occurred later in three. Disease duration was longer and dopa-responsiveness was more sustained in C9orf72 than in GRN carriers. Subtle motor features, cognitive/behavioral changes, family history of dementia/ALS were suggestive clues for a genetic diagnosis. Importantly, neuropathological examination in one patient revealed typical TDP-43-inclusions without alpha-synucleinopathy, thus demonstrating the causal link between FTD mutations, TDP-43-pathology and PD phenotype. Conclusion: We showed that, altogether, family history of early-onset dementia/ALS, the presence of cognitive/behavioral dysfunction and subtle motor characteristics are atypical features frequently present in the parkinsonian presentations of GRN and C9orf72 mutations.
5. Clinical and Molecular Landscape of ALS Patients with SOD1 Mutations: Novel Pathogenic Variants and Novel Phenotypes. A Single ALS Center Study
Bernard E, Pegat A, Svahn J, Bouhour F, Leblanc P, Millecamps S, Thobois S, Guissart C, Lumbroso S, Mouzat K
Int J Mol Sci (2020) — Abstract
Mutations in the copper zinc superoxide dismutase 1 (SOD1) gene are the second most frequent cause of familial amyotrophic lateral sclerosis (ALS). Nearly 200 mutations of this gene have been described so far. We report all SOD1 pathogenic variants identified in patients followed in the single ALS center of Lyon, France, between 2010 and 2020. Twelve patients from 11 unrelated families are described, including two families with the not yet described H81Y and D126N mutations. Splice site mutations were detected in two families. We discuss implications concerning genetic screening of SOD1 gene in familial and sporadic ALS.
6. Deep Brain Stimulation for Freezing of Gait in Parkinson’s Disease With Early Motor Complications
Barbe MT, Tonder L, Krack P, Debû B, Schüpbach M, Paschen S, Dembek TA, Kühn AA, Fraix V, Brefel-Courbon C, Wojtecki L, Maltête D, Damier P, Sixel-Döring F, Weiss D, Pinsker M, Witjas T, Thobois S, Schade-Brittinger C, Rau J, Houeto JL, Hartmann A, Timmermann L, Schnitzler A, Stoker V, Vidailhet M, Deuschl G; EARLYSTIM study group
Mov Disord (2020) — Résumé
Background: Effects of DBS on freezing of gait and other axial signs in PD patients are unclear. Objective: Secondary analysis to assess whether DBS affects these symptoms within a large randomized controlled trial comparing DBS of the STN combined with best medical treatment and best medical treatment alone in patients with early motor complications (EARLYSTIM-trial). Methods: One hundred twenty-four patients were randomized in the stimulation group and 127 patients in the best medical treatment group. Presence of freezing of gait was assessed in the worst condition based on item-14 of the UPDRS-II at baseline and follow-up. The posture, instability, and gait-difficulty subscore of the UPDRS-III, and a gait test including quantification of freezing of gait and number of steps, were performed in both medication-off and medication-on conditions. Results: Fifty-two percent in both groups had freezing of gait at baseline based on UPDRS-II. This proportion decreased in the stimulation group to 34%, but did not change in the best medical treatment group at 24 months (P = 0.018). The steps needed to complete the gait test decreased in the stimulation group and was superior to the best medical treatment group (P = 0.016). The axial signs improved in the stimulation group compared to the best medical treatment group (P < 0.01) in both medication-off and medication-on conditions. Conclusions: Within the first 2 years of DBS, freezing of gait and other axial signs improved in the medication-off condition compared to best medical treatment in these patients. © 2019 International Parkinson and Movement Disorder Society.
7. Early limbic microstructural alterations in apathy and depression in de novo Parkinson’s disease
Prange S, Metereau E, Maillet A, Lhommée E, Klinger H, Pelissier P, Ibarrola D, Heckemann RA, Castrioto A, Tremblay L, Sgambato V, Broussolle E, Krack P, Thobois S
Mov Disord (2019) — Abstract
Background: Whether structural alterations underpin apathy and depression in de novo parkinsonian patients is unknown. The objectives of this study were to investigate whether apathy and depression in de novo parkinsonian patients are related to structural alterations and how structural abnormalities relate to serotonergic or dopaminergic dysfunction. Methods: We compared the morphological and microstructural architecture in gray matter using voxel-based morphometry and diffusion tensor imaging coupled with white matter tract-based spatial statistics in a multimodal imaging case-control study enrolling 14 apathetic and 13 nonapathetic patients with de novo Parkinson’s disease and 15 age-matched healthy controls, paired with PET imaging of the presynaptic dopaminergic and serotonergic systems. Results: De novo parkinsonian patients with apathy had bilateral microstructural alterations in the medial corticostriatal limbic system, exhibiting decreased fractional anisotropy and increased mean diffusivity in the anterior striatum and pregenual anterior cingulate cortex in conjunction with serotonergic dysfunction. Furthermore, microstructural alterations extended to the medial frontal cortex, the subgenual anterior cingulate cortex and subcallosal gyrus, the medial thalamus, and the caudal midbrain, suggesting disruption of long-range nondopaminergic projections originating in the brainstem, in addition to microstructural alterations in callosal interhemispheric connections and frontostriatal association tracts early in the disease course. In addition, microstructural abnormalities related to depressive symptoms in apathetic and nonapathetic patients revealed a distinct, mainly right-sided limbic subnetwork involving limbic and frontal association tracts. Conclusions: Early limbic microstructural alterations specifically related to apathy and depression emphasize the role of early disruption of ascending nondopaminergic projections and related corticocortical and corticosubcortical networks which underpin the variable expression of nonmotor and neuropsychiatric symptoms in Parkinson’s disease. © 2019 International Parkinson and Movement Disorder Society.
8. Neuroimaging biomarkers for clinical trials in atypical parkinsonian disorders: Proposal for a Neuroimaging Biomarker Utility System
van Eimeren T, Antonini A, Berg D, Bohnen N, Ceravolo R, Drzezga A, Höglinger GU, Higuchi M, Lehericy S, Lewis S, Monchi O, Nestor P, Ondrus M, Pavese N, Peralta MC, Piccini P, Pineda-Pardo JÁ, Rektorová I, Rodríguez-Oroz M, Rominger A, Seppi K, Stoessl AJ, Tessitore A, Thobois S, Kaasinen V, Wenning G, Siebner HR, Strafella AP, Rowe JB
Alzheimers Dement (Amst) (2019) — Abstract
Introduction Therapeutic strategies targeting protein aggregations are ready for clinical trials in atypical parkinsonian disorders. Therefore, there is an urgent need for neuroimaging biomarkers to help with the early detection of neurodegenerative processes, the early differentiation of the underlying pathology, and the objective assessment of disease progression. However, there currently is not yet a consensus in the field on how to describe utility of biomarkers for clinical trials in atypical parkinsonian disorders. Methods To promote standardized use of neuroimaging biomarkers for clinical trials, we aimed to develop a conceptual framework to characterize in more detail the kind of neuroimaging biomarkers needed in atypical parkinsonian disorders, identify the current challenges in ascribing utility of these biomarkers, and propose criteria for a system that may guide future studies. Results As a consensus outcome, we describe the main challenges in ascribing utility of neuroimaging biomarkers in atypical parkinsonian disorders, and we propose a conceptual framework that includes a graded system for the description of utility of a specific neuroimaging measure. We included separate categories for the ability to accurately identify an intention-to-treat patient population early in the disease (Early), to accurately detect a specific underlying pathology (Specific), and the ability to monitor disease progression (Progression). Discussion We suggest that the advancement of standardized neuroimaging in the field of atypical parkinsonian disorders will be furthered by a well-defined reference frame for the utility of biomarkers. The proposed utility system allows a detailed and graded description of the respective strengths of neuroimaging biomarkers in the currently most relevant areas of application in clinical trials. Keywords: Biomarker, Trials, PSP, MSA, CBD, CBS, Neurodegeneration, Biomarker, Multicentric,
9. Wait and you shall see: sexual delay discounting in hypersexual Parkinson’s disease
Girard R, Obeso I, Thobois S, Park SA, Vidal T, Favre E, Ulla M, Broussolle E, Krack P, Durif F, Dreher JC
Brain (2019) — Abstract
Patients with Parkinson’s disease may develop impulse control disorders under dopaminergic treatments. Impulse control disorders include a wide spectrum of behaviours, such as hypersexuality, pathological gambling or compulsive shopping. Yet, the neural systems engaged in specific impulse control disorders remain poorly characterized. Here, using model-based functional MRI, we aimed to determine the brain systems involved during delay-discounting of erotic rewards in hypersexual patients with Parkinson’s disease (PD+HS), patients with Parkinson’s disease without hypersexuality (PD – HS) and controls. Patients with Parkinson’s disease were evaluated ON and OFF levodopa (counterbalanced). Participants had to decide between two options: (i) wait for 1.5 s to briefly view an erotic image; or (ii) wait longer to see the erotic image for a longer period of time. At the time of decision-making, we investigated which brain regions were engaged with the subjective valuation of the delayed erotic reward. At the time of the rewarded outcome, we searched for the brain regions responding more robustly after waiting longer to view the erotic image. PD+HS patients showed reduced discounting of erotic delayed rewards, compared to both patients with Parkinson’s disease and controls, suggesting that they accepted waiting longer to view erotic images for a longer period of time. Thus, when using erotic stimuli that motivate PD+HS, these patients were less impulsive for the immediate reward. At the brain system level, this effect was paralleled by the fact that PD+HS, as compared to controls and PD – HS, showed a negative correlation between subjective value of the delayed reward and activity of medial prefrontal cortex and ventral striatum. Consistent with the incentive salience hypothesis combining learned cue-reward associations with current relevant physiological state, dopaminergic treatment in PD+HS boosted excessive ‘wanting’ of rewards and heightened activity in the anterior medial prefrontal cortex and the posterior cingulate cortex, as reflected by higher correlation with subjective value of the option associated to the delayed reward when ON medication as compared to the OFF medication state. At the time of outcome, the anterior medial prefrontal/rostral anterior cingulate cortex showed an interaction between group (PD+HS versus PD – HS) and medication (ON versus OFF), suggesting that dopaminergic treatment boosted activity of this brain region in PD+HS when viewing erotic images after waiting for longer periods of time. Our findings point to reduced delay discounting of erotic rewards in PD+HS, both at the behavioural and brain system levels, and abnormal reinforcing effect of levodopa when PD+HS patients are confronted with erotic