Publications by authors named "Lucette Lacomblez"

106 Publications

Anosognosia in amyotrophic lateral sclerosis: A cross-sectional study of 85 individuals and their relatives.

Ann Phys Rehabil Med 2021 Sep 24;64(5):101440. Epub 2021 Sep 24.

Department of Physical Rehabilitation Medicine, Pitié-Salpêtrière hospital (AP-HP) and GRC 24 (Sorbonne Université), 47, boulevard de l'Hôpital, 75013 Paris, France; Laboratoire d'imagerie biomédicale (LIB), Sorbonne université, Paris, France; Global Brain Health Institute, Memory and Aging Center, University of California San Francisco, San Francisco, USA. Electronic address:

Background: Amyotrophic lateral sclerosis (ALS) has long been considered a pure motor neurodegenerative disease. However, now, extra-motor manifestations such as cognitive-behavioral disorders are considered not rare and are even a severity factor of the disease. Experiencing anosognosia (i.e., the inability to recognize neurological symptoms) might affect care and treatment compliance in ALS. Regardless, this pivotal feature has been little investigated.

Objectives: By comparing patients' and caregivers' reports, we analysed whether patients with ALS would experience a lack of awareness about their executive disorders and their apathy symptoms.

Methods: From the ALS reference center in Paris, we included 85 patients (47 men, mean [SD] age 60.5 [12] years and ALS-Functional Rating Scale-revised score 8 to 46) and their primary family caregivers who all completed the Dysexecutive Questionnaire (DEX) and the Apathy Evaluation Scale (AES). Overall scores and answers were compared by agreement/disagreement statistical methods.

Results: Caregivers reported higher levels of cognitive-behavioral disorders than did patients, but reports matched when cognitive-behavioral disorders were absent or mild. With published DEX and AES cutoffs, 32% and 51% of patients had executive disorders and apathy, respectively. In these patients with significant impairment, Bland-Altman plots (i.e., visual display agreement that represents the difference between the patient's and caregiver's scores as a function of their average) showed a strong discrepancy between joint reports: patients underestimated their symptoms by a mean bias of -6.81 DEX points (95% confidence interval -11.88, -1.75) and -8.85 AES points (95% confidence interval -11.72, -5.98). We found no clear relationship between bulbar or spinal ALS subtypes and anosognosia.

Conclusions: ALS patients with a cognitive-behavioral phenotype show anosognosia by a mismatch between self and proxy reports, which warrants further investigation in neuroimaging. Systematic longitudinal screening of anosognosia is needed to propose targeted psychoeducation in patient-caregiver dyads showing disagreement.
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http://dx.doi.org/10.1016/j.rehab.2020.08.004DOI Listing
September 2021

Exome Sequencing Reveals Signal Transduction Genes Involved in Impulse Control Disorders in Parkinson's Disease.

Front Neurol 2020 21;11:641. Epub 2020 Jul 21.

Sorbonne Université, INSERM UMRS 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle, ICM, Paris, France.

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. Thirty-six Parkinsonian patients on DA therapy with ( = 18) and without ICDs ( = 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. 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 ( = 1.6 × 10) was replicated in the PPMI cohort and was significantly associated with ICDs in a pooled analysis (combined value 3.3 × 10). Two of the 10 most associated variants belonged to genes implicated in cAMP and ERK signaling (rs34193571 in = 5 × 10; rs1877652 in = 8 × 10) although non-significant after Bonferroni correction. Our results suggest that genes implicated in the signaling pathways linked to G protein-coupled receptors participate to genetic susceptibility to ICDs in PD.
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http://dx.doi.org/10.3389/fneur.2020.00641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385236PMC
July 2020

Absence of hyperexcitability of spinal motoneurons in patients with amyotrophic lateral sclerosis.

J Physiol 2019 11 26;597(22):5445-5467. Epub 2019 Oct 26.

Sorbonne Université, Inserm, CNRS, Laboratoire d'Imagerie Biomédicale, LIB, Paris, France.

Key Points: •Amyotrophic lateral sclerosis (ALS) motoneurons become hypoexcitable with disease progression in experimental models, raising questions about the neural hyperexcitability supported by clinical observations. •A variant of the ∆F method, based on motor unit discharge frequency modulations during recruitment and derecruitment, has been developed to investigate the motoneuron capacity to self-sustained discharge in patients. •The modulation of motor unit firing rate during ramp contraction and vibration-induced recruitment are modified in ALS, suggesting lower motoneuron capacity to self-sustained discharge, which is a sign of hypoexcitability. •∆F-D decreases with functional impairment and its reduction is more pronounced in fast progressors. •In patients with ALS, motoneurons exhibit hypoexcitability, which increases with disease progression.

Abstract: Experimental models have primarily revealed spinal motoneuron hypoexcitability in amyotrophic lateral sclerosis (ALS), which is contentious considering the role of glutamate-induced excitotoxicity in neurodegeneration and clinical features rather supporting hyperexcitability. This phenomenon was evaluated in human patients by investigating changes in motor unit firing during contraction and relaxation. Twenty-two ALS patients with subtle motor deficits and 28 controls performed tonic contractions of extensor carpi radialis, triceps brachialis, tibialis anterior and quadriceps, aiming to isolate a low-threshold unit (U1) on the electromyogram (EMG). Subsequently, they performed a stronger contraction or tendon vibration was delivered, to recruit higher threshold unit (U2) for 10 s before they relaxed progressively. EMG and motor unit potential analyses suggest altered neuromuscular function in all muscles, including those with normal strength (Medical Research Council score at 5). During the preconditioning tonic phase, U1 discharge frequency did not differ significantly between groups. During recruitment, the increase in U1 frequency (∆F-R) was comparable between groups both during contraction and tendon vibration. During derecruitment, the decrease in U1 frequency (∆F-D) was reduced in ALS regardless of the recruitment mode, particularly for ∆F-R <8 Hz in the upper limbs, consistent with the muscle weakness profile of the group. ∆F-D was associated with functional disability and its reduction was more pronounced in patients with more rapid disease progression rate. This in vivo study has demonstrated reduced motoneuron capacity for self-sustained discharge, and further supports that motoneurons are normo- to hypoexcitable in ALS patients, similar to observations in experimental models.
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http://dx.doi.org/10.1113/JP278117DOI Listing
November 2019

Examining the Reserve Hypothesis in Parkinson's Disease: A Longitudinal Study.

Mov Disord 2019 11 13;34(11):1663-1671. Epub 2019 Sep 13.

CESP, Fac. de médecine - Univ. Paris-Sud, Fac. de médecine - UVSQ, INSERM, Université Paris-Saclay, 94805, Villejuif, France.

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 education level (proxy of reserve) is associated with baseline performance and rate of progression.

Methods: We used data from a longitudinal cohort of PD patients (≤5-year disease duration at baseline) annually followed up to 5 years (n = 393; 41% women; mean age = 62.3 years, standard deviation = 10.0; mean disease duration = 2.6 years, standard deviation = 1.5). We examined the relationship of education with time to reach Hoehn and Yahr stage ≥3 using Cox regression and with baseline severity and progression of motor (Movement Disorder Society-Unified Parkinson's Disease Rating Scale parts II and III, gait speed), cognitive (Mini-Mental State Examination), and nonmotor (depression, anxiety, nonmotor symptoms scale, quality of life) symptoms using mixed models.

Results: Education level was not associated with age at onset or diagnosis. Compared with the low-education group, the incidence of Hoehn and Yahr ≥3.0 was 0.42 times lower (95% confidence interval, 0.22-0.82, P = 0.012) in the high-education group. Higher education was associated with better baseline motor function (P < 0.001), but not with the rate of motor decline (P > 0.15). Similar results were observed for cognition. Education was not associated with nonmotor symptoms.

Conclusions: Higher education is associated with better baseline motor/cognitive function in PD, but not with rate of decline, and with a lower risk of reaching Hoehn and Yahr ≥3 during the follow-up. Our observations are consistent with a passive reserve hypothesis for motor/cognitive symptoms. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27854DOI Listing
November 2019

Are PSP patients included in clinical trials representative of the general PSP population?

Parkinsonism Relat Disord 2019 09 10;66:202-206. Epub 2019 Jul 10.

Sorbonne Université, Assistance Publique Hôpitaux de Paris, Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, Department of Neurology, Hôpital Pitié-Salpêtrière, F-75013, Paris, France. Electronic address:

Background: Progressive supranuclear palsy (PSP) is a rare parkinsonian syndrome with a wide spectrum of clinical presentations. Recently, the MDS published revised diagnosis criteria to provide early and reliable diagnosis of PSP and its variants. Two large randomized clinical trials were initiated in 2017, but the question remains regarding the extrapolation of their results to the general PSP population.

Objective: To determine if PSP patients included in clinical trials are representative of the general PSP population.

Methods: We conducted a single center retrospective study of PSP patients referred to a tertiary department of Neurology (Pitié-Salpêtrière Hospital, Paris) for clinical diagnosis and clinical trial inclusion, over a 12-month period. We collected and analyzed gender, age at examination, age at disease onset, disease duration, and core clinical features regarding oculo-motor dysfunction, postural instability, akinesia and cognitive dysfunction, and inclusion/exclusion criteria of clinical trials to assess eligibility for inclusion. We assessed the relative proportions of different PSP subtypes, as defined by the MDS-PSP criteria, in the whole population compared to patients eligible in trials.

Results: 206 PSP patients were included, among which 175 (85%) were diagnosed with probable PSP-Richardson's syndrome (RS) subtype, with a mean age of 73 and mean disease duration of 5 years. Among those patients, 29 (21%) were eligible (age 71 ± 10.7, disease duration 3.1 ± 1.2 years) and 19 were included in trials, all with a diagnosis of probable PSP-RS. As compared to the whole population, patients included in clinical trials tended to be younger, and showed more PSP-RS subtypes (p < 0.05).

Conclusion: The PSP population included in trials is very similar to the general PSP population, but younger, with shorter disease duration. By definition, only probable PSP subtypes are included in clinical trials. The time window for inclusion is short because of diagnosis delay, fast disease progression and old age of the population.
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http://dx.doi.org/10.1016/j.parkreldis.2019.07.012DOI Listing
September 2019

Cursive Eye-Writing With Smooth-Pursuit Eye-Movement Is Possible in Subjects With Amyotrophic Lateral Sclerosis.

Front Neurosci 2019 29;13:538. Epub 2019 May 29.

Laboratoire des Systèmes Perceptifs (UMR 8248), Département d'Études Cognitives de l'École Normale Supérieure, Paris, France.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder causing a progressive motor weakness of all voluntary muscles, whose progression challenges communication modalities such as handwriting or speech. The current study investigated whether ALS subjects can use Eye-On-Line (EOL), a novel eye-operated communication device allowing, after training, to voluntarily control smooth-pursuit eye-movements (SPEM) so as to eye-write in cursive. To that aim, ALS participants ( = 12) with preserved eye-movements but impaired handwriting were trained during six on-site visits. The primary outcome of the study was the recognition of eye-written digits (0-9) from ALS and healthy control subjects by naïve "readers." Changes in oculomotor performance and the safety of EOL were also evaluated. At the end of the program, 69.4% of the eye-written digits from 11 ALS subjects were recognized by naïve readers, similar to the 67.3% found for eye-written digits from controls participants, with however, large inter-individual differences in both groups of "writers." Training with EOL was associated with a transient fatigue leading one ALS subject to drop out the study at the fifth visit. Otherwise, itching eyes was the most common adverse event (3 subjects). This study shows that, despite the impact of ALS on the motor system, most ALS participants could improve their mastering of eye-movements, so as to produce recognizable eye-written digits, although the eye-traces sometimes needed smoothing to ease digit legibility from both ALS subjects and control participants. The capability to endogenously and voluntarily generate eye-traces using EOL brings a novel way to communicate for disabled individuals, allowing creative personal and emotional expression.
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http://dx.doi.org/10.3389/fnins.2019.00538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548885PMC
May 2019

Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients 60 Years of Age and Younger: Results of the Intergroup ANOCEF-GOELAMS Randomized Phase II PRECIS Study.

J Clin Oncol 2019 04 20;37(10):823-833. Epub 2019 Feb 20.

3 Institut Curie, Site Saint-Cloud, Saint-Cloud, France.

Purpose: To determine the efficacy and toxicity of chemoimmunotherapy followed by either whole-brain radiotherapy (WBRT) or intensive chemotherapy and autologous stem-cell transplantation (ASCT) as a first-line treatment of primary CNS lymphoma (PCNSL).

Patients And Methods: Immunocompetent patients (18 to 60 years of age) with untreated PCNSL were randomly assigned to receive WBRT or ASCT as consolidation treatment after induction chemotherapy consisting of two cycles of R-MBVP (rituximab 375 mg/m day (D) 1, methotrexate 3 g/m D1; D15, VP16 100 mg/m D2, BCNU 100 mg/m D3, prednisone 60 mg/kg/d D1-D5) followed by two cycles of R-AraC (rituximab 375 mg/m D1, cytarabine 3 g/m D1 to D2). Intensive chemotherapy consisted of thiotepa (250 mg/m/d D9; D8; D7), busulfan (8 mg/kg D6 through D4), and cyclophosphamide (60 mg/kg/d D3; D2). WBRT delivered 40 Gy (2 Gy/fraction). The primary end point was 2-year progression-free survival. Cognitive outcome was the main secondary end point. Analysis was intention to treat in a noncomparative phase II trial.

Results: Between October 2008 and February 2014, 140 patients were recruited from 23 French centers. Both WBRT and ASCT met the predetermined threshold (among the first 38 patients in each group, at least 24 patients were alive and disease free at 2 years). The 2-year progression-free survival rates were 63% (95% CI, 49% to 81%) and 87% (95% CI, 77% to 98%) in the WBRT and ASCT arms, respectively. Toxicity deaths were recorded in one and five patients after WBRT and ASCT, respectively. Cognitive impairment was observed after WBRT, whereas cognitive functions were preserved or improved after ASCT.

Conclusion: WBRT and ASCT are effective consolidation treatments for patients with PCNSL who are 60 years of age and younger. The efficacy end points tended to favor the ASCT arm. The specific risk of each procedure should be considered.
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http://dx.doi.org/10.1200/JCO.18.00306DOI Listing
April 2019

The spinal and cerebral profile of adult spinal-muscular atrophy: A multimodal imaging study.

Neuroimage Clin 2019 28;21:101618. Epub 2018 Nov 28.

Sorbonne Université, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, Paris, France; APHP, Département de Neurologie, Hôpital Pitié-Salpêtrière, Centre référent SLA, Paris, France; Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute Ulster University, C-TRIC, Altnagelvin Hospital, Derry, Londonderry, United Kingdom. Electronic address:

Spinal muscular atrophy (SMA) type III and IV are autosomal recessive, slowly progressive lower motor neuron syndromes. Nevertheless, wider cerebral involvement has been consistently reported in mouse models. The objective of this study is the characterisation of spinal and cerebral pathology in adult forms of SMA using multimodal quantitative imaging.

Methods: Twenty-five type III and IV adult SMA patients and 25 age-matched healthy controls were enrolled in a spinal cord and brain imaging study. Structural measures of grey and white matter involvement and diffusion parameters of white matter integrity were evaluated at each cervical spinal level. Whole-brain and region-of-interest analyses were also conducted in the brain to explore cortical thickness, grey matter density and tract-based white matter alterations.

Results: In the spinal cord, considerable grey matter atrophy was detected between C2-C6 vertebral levels. In the brain, increased grey matter density was detected in motor and extra-motor regions of SMA patients. No white matter pathology was identified neither at brain and spinal level.

Conclusions: Adult forms of SMA are associated with selective grey matter degeneration in the spinal cord with preserved white matter integrity. The observed increased grey matter density in the motor cortex may represent adaptive reorganisation.
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http://dx.doi.org/10.1016/j.nicl.2018.101618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413472PMC
December 2019

Suggestive association between OPRM1 and impulse control disorders in Parkinson's disease.

Mov Disord 2018 12 16;33(12):1878-1886. Epub 2018 Nov 16.

Assistance Publique Hôpitaux de Paris, CHU Pitié-Salpêtrière, Pharmacie, Paris, France.

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 behaviors in PD.

Methods: We performed a multicenter case-control study in PD patients with (cases) or without impulse control disorders and related behaviors despite significant dopamine agonist exposure of >300 mg levodopa-equivalent daily dose during 12 months (controls). Behavioral disorders were assessed using the Ardouin scale. We investigated 50 variants in 24 candidate genes by a multivariate logistic regression analysis adjusted for sex and age at PD onset.

Results: The analysis was performed on 172 cases and 132 controls. Cases were younger (60 ± 8 vs 63 ± 8 years; P < 0.001) and had a higher family history of pathological gambling (12% vs 5%, P = 0.03). No variant was significantly associated with impulse control disorders or related behaviors after correction for multiple testing, although the 2 top variants were close to significant (OPRM1 rs179991, OR, 0.49; 95%CI, 0.32-0.76; P = 0.0013; Bonferroni adjusted P = 0.065; DAT1 40-base pair variable number tandem repeat, OR, 1.82; 95%CI, 1.24-2.68; P = 0.0021; Bonferroni adjusted P = 0.105).

Conclusions: Our results are suggestive of a novel association of the opioid receptor gene OPRM1 with impulse control disorders and related behaviors in PD and confirm a previous association with DAT1. Although replication in independent studies is needed, our results bring potential new insights to the understanding of molecular mechanisms of impulse control disorders. © 2018 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27519DOI Listing
December 2018

Emotional feeling in patients suffering from amyotrophic lateral sclerosis.

Geriatr Psychol Neuropsychiatr Vieil 2018 Dec;16(4):414-422

Département de neurologie, Centre référent SLA, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France, CNRS, Inserm, Laboratoire d'imagerie biomédicale (LIB), CIC-1422, Sorbonne Universités, UPMC Université Paris 06, Paris, France.

Objective: Amyotrophic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disorder involving motor neurons of the cerebral cortex, brain stem and spinal cord. Besides the motor signs, cognitive disorders and apathy may be present and may impact the survival time. These elements are therefore to be taken into consideration for medical care because they can influence the disease evolution. The literature shows low psychopathological disorders in this population despite its poor prognosis. The main objective of this study is to explore the emotional feeling in apathetic and non-apathetic patients in relation to their anxiety and depressive symptoms.

Methods: We included 152 patients at the day hospital for the follow-up of their illness, with an average age of 61±12.2 years. All filled the following self-administered questionnaires: EPN-31 (emotional feeling), HADS (for anxiety and depressive symptoms) and the Marin's apathy evaluation scale. Most of the patients (n=110) had also a cognitive assessment with the ALS-CBS scale.

Results: 42% of patients could be considered as apathetic and they felt both positive and negative emotions whose frequency was related to the presence and intensity of anxiety and depressive symptoms. The only significant differences were that apathetic and anxious patients experienced more negative emotions including sadness, shame and anger than non-apathetic and anxious patients. Apathy was negatively correlated with cognitive functioning and survival time.

Conclusions: These results highlighted the negative impact that apathy seemed to have on the evolution of this disease. However, apathetic patients didn't show emotional blunting and were able to name and feel positive and negative emotions; and even feel more negative emotions than non-apathetic patients when they were anxious. A better understanding of apathetic and no apathetic patients' emotional feelings should lead to a more personalized care for the ALS patients.
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http://dx.doi.org/10.1684/pnv.2018.0762DOI Listing
December 2018

Atrophy, metabolism and cognition in the posterior cortical atrophy spectrum based on Alzheimer's disease cerebrospinal fluid biomarkers.

Neuroimage Clin 2018 10;20:1018-1025. Epub 2018 Oct 10.

FrontLab, Institut du Cerveau et de la Moelle épinière (ICM), 75013 Paris, France; INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, Université Pierre et Marie Curie-Paris 6, UMR S1127, Institut du Cerveau et de la Moelle épinière (ICM), Pitié-Salpêtrière hospital, 75013 Paris, France; Department of Nervous system diseases, Institut de la mémoire et de la maladie d'Alzheimer (IM2A), Neurology, Pitié-Salpêtrière hospital, 75013 Paris, France. Electronic address:

Introduction: In vivo clinical, anatomical and metabolic differences between posterior cortical atrophy (PCA) patients presenting with different Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers profiles are still unknown.

Methods: Twenty-seven PCA patients underwent CSF examination and were classified as 1) PCA with a typical CSF AD profile (PCA-tAD; abnormal amyloid and T-tau/P-tau biomarkers, n = 13); 2) PCA with an atypical AD CSF profile (PCA-aAD; abnormal amyloid biomarker only, n = 9); and 3) PCA not associated with AD (PCA-nonAD; normal biomarkers, n = 5). All patients underwent clinical and cognitive assessment, structural MRI, and a subset of them underwent brain F-FDG PET.

Results: All patients' groups showed a common pattern of posterior GM atrophy and hypometabolism typical of PCA, as well as equivalent demographics and clinical/cognitive profiles. PCA-tAD patients showed a group-specific pattern of hypometabolism in the left fusiform gyrus and inferior temporal gyrus. PCA-aAD did not present a group-specific atrophy pattern. Finally, group-specific gray matter atrophy in the right dorsolateral prefrontal cortex, left caudate nucleus and right medial temporal regions and hypometabolism in the right supplementary motor area and paracentral lobule were observed in PCA-nonAD patients.

Conclusion: Our findings suggest that both PCA-tAD and PCA-aAD patients are on the AD continuum, in agreement with the recently suggested A/T/N model. Furthermore, in PCA, the underlying pathology has an impact at least on the anatomo-functional presentation. Brain damage observed in PCA-tAD and PCA-aAD was mostly consistent with the well-described presentation of the disease, although it was more widespread in PCA-tAD group, especially in the left temporal lobe. Additional fronto-temporal (especially dorsolateral prefrontal) damage seems to be a clue to underlying non-AD pathology in PCA, which warrants the need for longitudinal follow-ups to investigate frontal symptoms in these patients.
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http://dx.doi.org/10.1016/j.nicl.2018.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197495PMC
February 2019

Naftazone in advanced Parkinson's disease: An acute L-DOPA challenge randomized controlled trial.

Parkinsonism Relat Disord 2019 03 4;60:51-56. Epub 2018 Oct 4.

Clinical Investigation Center CIC-1436, Departments of Clinical Pharmacology and Neurosciences, University Hospital of Toulouse, INSERM, University of Toulouse 3, Toulouse, France; F-CRIN, UMS 015, Toulouse, France.

Introduction: There is an unmet need to better control motor complications in Parkinson's disease (PD). Naftazone, which exhibits glutamate release inhibition properties, has shown antiparkinsonian and antidyskinetic activity in preclinical models of PD and in a clinical proof of concept study.

Methods: We conducted a double-blind randomized placebo-controlled cross-over trial in PD patients with motor fluctuations and dyskinesia testing naftazone 160 mg/day versus placebo for 14 days. The two co-primary endpoints were the area under curve (AUC) of motor (MDS-UPDRS part III) and dyskinesia (AIMS) scores during an acute levodopa challenge performed at the end of each period. Secondary endpoints were UDysRS and axial symptoms scores during the challenge; AIMS, UDysRS, and time spent with or without dyskinesia the day before the challenge. The primary analysis was performed in the per protocol population.

Results: Sixteen patients were included in the analysis. There was no difference between naftazone and placebo for the AUC of MDS-UPDRS III (-89, 95%CI[-1071; 893], p = 0.85), and AIMS (70, 95%CI[-192; 332], p = 0.57). At the end of treatment periods, AIMS score tended to be lower with naftazone than placebo (4.4 ± 3.4 versus 6.7 ± 4.4, p = 0.07), but UDysRS scores and other secondary outcomes were not different. Naftazone was safe and well tolerated.

Conclusions: This study did not confirm previous results on the efficacy of naftazone on dyskinesia nor motor fluctuations highlighting the problem of translating results obtained in preclinical models into clinical trials. Further investigation of naftazone may be conducted in PD with longer treatment duration.
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http://dx.doi.org/10.1016/j.parkreldis.2018.10.005DOI Listing
March 2019

The motor unit number index (MUNIX) profile of patients with adult spinal muscular atrophy.

Clin Neurophysiol 2018 11 13;129(11):2333-2340. Epub 2018 Sep 13.

Sorbonne Université, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, Paris, France; APHP, Département de Neurologie, Hôpital Pitié-Salpêtrière, Centre référent SLA, Paris, France; Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute Ulster University, C-TRIC, Altnagelvin Hospital, Derry/Londonderry, United Kingdom. Electronic address:

Objective: Objective of this study is the comprehensive characterisation of motor unit (MU) loss in type III and IV Spinal Muscular Atrophy (SMA) using motor unit number index (MUNIX), and evaluation of compensatory mechanisms based on MU size indices (MUSIX).

Methods: Nineteen type III and IV SMA patients and 16 gender- and age-matched healthy controls were recruited. Neuromuscular performance was evaluated by muscle strength testing and functional scales. Compound motor action potential (CMAP), MUNIX and MUSIX were studied in the abductor pollicis brevis (APB), abductor digiti minimi (ADM), deltoid, tibialis anterior and trapezius muscles. A composite MUNIX score was also calculated.

Results: SMA patients exhibited significantly reduced MUNIX values (p < 0.05) in all muscles, while MUSIX was increased, suggesting active re-innervation. Significant correlations were identified between MUNIX/MUSIX and muscle strength. Similarly, composite MUNIX scores correlated with disability scores. Interestingly, in SMA patients MUNIX was much lower in the ADM than in the ABP, a pattern which is distinctly different from that observed in Amyotrophic Lateral Sclerosis.

Conclusions: MUNIX is a sensitive measure of MU loss in adult forms of SMA and correlates with disability.

Significance: MUNIX evaluation is a promising candidate biomarker for longitudinal studies and pharmacological trials in adult SMA patients.
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http://dx.doi.org/10.1016/j.clinph.2018.08.025DOI Listing
November 2018

Extrapyramidal deficits in ALS: a combined biomechanical and neuroimaging study.

J Neurol 2018 Sep 11;265(9):2125-2136. Epub 2018 Jul 11.

Laboratoire CeRSM - EA 2931 Paris Ouest, Nanterre, France.

Introduction: Extrapyramidal deficits are poorly characterised in amyotrophic lateral sclerosis (ALS) despite their contribution to functional disability, increased fall risk and their quality-of-life implications. Given the concomitant pyramidal and cerebellar degeneration in ALS, the clinical assessment of extrapyramidal features is particularly challenging.

Objective: The comprehensive characterisation of postural instability in ALS using standardised clinical assessments, gait analyses and computational neuroimaging tools in a prospective study design.

Methods: Parameters of gait initiation in the anticipatory postural adjustment phase (APA) and execution phase (EP) were evaluated in ALS patients with and without postural instability and healthy controls. Clinical and gait analysis parameters were interpreted in the context of brain imaging findings.

Results: ALS patients with postural instability exhibit impaired gait initiation with an altered APA phase, poor dynamic postural control and significantly decreased braking index. Consistent with their clinical profile, "unsteady" ALS patients have reduced caudate and brain stem volumes compared to "steady" ALS patients.

Interpretation: Our findings highlight that the ALS functional rating scale (ALSFRS-r) does not account for extrapyramidal deficits, which are major contributors to gait impairment in a subset of ALS patients. Basal ganglia degeneration in ALS does not only contribute to cognitive and behavioural deficits, but also adds to the heterogeneity of motor disability.
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http://dx.doi.org/10.1007/s00415-018-8964-yDOI Listing
September 2018

Longitudinal analysis of impulse control disorders in Parkinson disease.

Neurology 2018 07 20;91(3):e189-e201. Epub 2018 Jun 20.

From the Assistance Publique Hôpitaux de Paris (J.-C.C., F.C.-D., L.L., C.B., D.G., S.K., G.M., H.Y., A.B., M.V.); Sorbonne Université (J.-C.C., F.C.-D., L.L., C.B., D.G., S.K., G.M., H.Y., A.B., M.V.); INSERM (J.-C.C., F.C.-D., L.L., C.B., D.G., S.K., G.M., H.Y., A.B., M.V.), Institut du cerveau et de la Moelle, Centre d'Investigation Clinique Neurosciences, NS-PARK/FCRIN Network; CNRS (J.-C.C., F.C.-D., L.L., C.B., D.G., S.K., G.M., H.Y., A.B., M.V.); Departments of Neurology and Genetics (J.-C.C., F.C.-D., L.L., C.B., D.G., S.K., G.M., H.Y., A.B., M.V.), Hôpital Pitié-Salpêtrière, Paris; CESP (F.A., A.E.), Faculte de médecine, Université Paris-Sud; Faculte de médecine (F.A., A.E.), UVSQ, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Villejuif; University of Toulouse 3 (O.R., C.B.-C., F.O.-M), Centre Hospitalo-Universitaire de Toulouse and INSERM; Centre d'Investigation Clinique CIC1436 (O.R., C.B.-C., F.O.-M), NS-PARK/FCRIN Network, Départements de Neurosciences et de Pharmacologie Clinique, NeuroToul COEN Center, Toulouse; Department of Neurology (F.D., A.-R.M.), NS-PARK/FCRIN Network, Centre Hospitalo-Universitaire de Clermont-Ferrand; Department of Neurology (P.D.), NS-PARK/FCRIN Network, Centre Hospitalo-Universitaire de Nantes; Department of Neurology (F.B.), Hôpital Foch, Suresnes; Department of Neurology (J.-P.B.), Fondation Rothschild, Paris; Department of Neurology (F.P.), Centre Hospitalier de Versailles; Université Versailles Saint Quentin en Yvelines et Paris Saclay (F.P.), Versailles; Department of Neurology (V.M.), Centre Hospitalo-Universitaire Saint-Antoine, Paris, France; and Department of Health Care Management (P.-C.L.), College of Health Technology, National Taipei University of Nursing and Health Sciences, Taiwan.

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 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.

Results: Among 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 46.1% (95% confidence interval [CI] 37.4-55.7, DA ever users 51.5% [95% CI 41.8-62.1], DA never users 12.4% [95% CI 4.8-30.0]). ICD prevalence increased from 19.7% at baseline to 32.8% after 5 years. ICDs were associated with ever DA use (prevalence ratio 4.23, 95% CI 1.78-10.09). Lifetime average daily dose and duration of treatment were independently associated with ICDs with significant dose-effect relationships. Similar analyses for levodopa were not in favor of a strong association. ICDs progressively resolved after DA discontinuation.

Conclusion: In this longitudinal study of patients with PD characterized by a high prevalence of DA treatment, the 5-year cumulative incidence of ICDs was ≈46%. ICDs were strongly associated with DA use with a dose-effect relationship; both increasing duration and dose were associated with ICDs. ICDs progressively resolved after DA discontinuation.

Clinicaltrialsgov Identifier: NCT01564992.
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http://dx.doi.org/10.1212/WNL.0000000000005816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059034PMC
July 2018

Posterior cortical atrophy: from vision to emotion.

Geriatr Psychol Neuropsychiatr Vieil 2018 Mar;16(1):57-66

Inserm, U1127, Institut du cerveau et de la moelle épinière (ICM), Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France, Département de neurologie, Institut de la mémoire et de la maladie d'Alzheimer, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France.

In this review of the literature on posterior cortical atrophy (PCA), the history of the disease is first told through the studies of Frank Benson and Oliver Sacks. Then, we detail the possible underlying pathologies, Alzheimer's disease being the most common cause. Clinical, cognitive, and biological features are described, with a specific focus on the neuroimaging. We also describe the emotional aspects of PCA. These aspects are often overlooked, but deserve a particular attention due to their impact on the quality of life and prognostic implications for the patients. A multilevel care strategy for PCA patients is suggested.
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http://dx.doi.org/10.1684/pnv.2017.0717DOI Listing
March 2018

Sleep and REM sleep behaviour disorder in Parkinson's disease with impulse control disorder.

J Neurol Neurosurg Psychiatry 2018 03 24;89(3):305-310. Epub 2017 Oct 24.

EA7820 UFR Medecine, Universite Clermont Auvergne, Clermont-Ferrand, France.

Introduction: Because the association between rapid eye movement sleep behaviour disorder (RBD) and impulse control disorders (ICDs) in Parkinson's disease (PD) has been debated, we assessed the sleep characteristics and the frequency of RBD using video-polysomnography (v-PSG) in patients with PD with versus without ICDs.

Methods: Eighty non-demented patients with PD consecutively identified during routine evaluation at three movement disorders centres were enrolled in a case-control study. Forty patients (22 men; mean age: 62.6±9.7 years, Hoehn & Yahr: 2.1±0.6) with one or more current ICDs were age-matched and sex-matched with 40 patients with no history of ICDs (22 men, mean age: 64.9±7.8 years, Hoehn & Yahr: 2.2±0.6). They underwent a detailed sleep interview followed by a full-night in-lab v-PSG. Sleep was scored blindly to ICDs condition and RBD diagnosis included a clinical complaint of enacted dreams and/or documented behaviour during rapid eye movement (REM) sleep, with the presence of quantified REM sleep without atonia (RSWA).

Results: Patients with ICDs had a higher arousal index and higher RSWA than those without ICDs (51.9%±28.2%vs 32.2±27.1%, p=0.004). In addition, RBD was more frequent in the ICD group (85%vs53%, p=0.0001). RBD was still associated with ICDs in a multivariate regression analysis including age of onset, PD duration and severity, treatment duration, levodopa-equivalent and dopamine agonist-equivalent daily doses and antidepressant use (OR: 4.9 (95% CI 1.3 to 18.5), p=0.02).

Conclusions: This large, controlled series of patients with PD with ICDs assessed by v-PSG confirms the association between ICDs and RBD. Increased surveillance of symptoms of ICDs should be recommended in patients with PD with RBD.
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http://dx.doi.org/10.1136/jnnp-2017-316576DOI Listing
March 2018

Outcome of gastrostomy in parkinsonism: A retrospective study.

Parkinsonism Relat Disord 2017 Oct 23;43:110-113. Epub 2017 Jun 23.

Assistance Publique Hôpitaux de Paris, Département de Neurologie, Hôpital Pitié-Salpêtrière, F-75013 Paris, France; Institut National de Santé et en Recherche Médicale U 1127 and Centre d'Investigation Clinique 1422, F-75013 Paris, France; Centre National de Recherche Scientifique U 7225, F-75013 Paris, France; Institut du Cerveau et de la Moelle Epinière, F-75013 Paris, France. Electronic address:

Objective: To investigate the indications and the outcomes of gastrostomy tube insertion in patients with parkinsonian syndromes.

Methods: Consecutive patients with Parkinson's disease or atypical parkinsonism, seen in two French tertiary referral movement disorders centers, that received gastrostomy tube insertion (GTI) for feeding between 2008 and 2014 were included in this retrospective study. Data regarding clinical status, indications and outcomes were retrieved from medical files. The main outcome measure was survival duration following gastrostomy insertion according to Kaplan-Meier estimate. Cox analysis was also performed to identify factors associated with survival. Finally, we described short term and long term adverse effects occurring during the follow-up period.

Results: We identified 33 patients with Parkinsonism that received GTI during the study period. One patient was excluded from the analysis because of missing data. Among 32 patients, 7 (22%) had Parkinson's disease and 25 (78%) had atypical parkinsonism. The median survival following the procedure was 186 days (CI 95% [62-309]). In Cox model analysis, total dependency was the only factor negatively associated with survival (HR 0.1; 95% CI [0.02-0.4], p = 0.001). Pneumonia was the most frequent adverse event.

Conclusion: In this sample of patients with parkinsonian syndromes, survival after GTI was short particularly in totally dependent subjects. Aspiration pneumonia was not prevented by GTI. A larger prospective study is warranted to assess the potential benefits of gastrostomy, in order to identify the most appropriate indications and timing for the procedure.
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http://dx.doi.org/10.1016/j.parkreldis.2017.06.012DOI Listing
October 2017

Cholinergic Changes in Aging and Alzheimer Disease: An [18F]-F-A-85380 Exploratory PET Study.

Alzheimer Dis Assoc Disord 2017 Jan-Mar;31(1):8-12

*Neurology of Memory and Language Unit, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMR S894, Sainte-Anne hospital ‡Department of Neurology, Saint-Antoine hospital, APHP §Sorbonne universités, UPMC Univ Paris 06, Inserm U 1127, and CNRS UMR 7225 ∥Department of Nuclear Medicine, APHP, Pitié-Salpêtrière Hospital ¶Department of Neurology, Pitié-Salpêtrière hospital APHP, Paris #IMIV, CEA, INSERM, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay †Department of Neurology, CHU d'Angers, Angers **Neurospin, I2BM, DRF, CEA, Gif-sur-Yvette, France.

The central cholinergic system undergoes changes during the physiological process of aging and the pathologic process of Alzheimer disease (AD). We aimed to analyze the impairment of cholinergic pathways by positron emission tomography using the [F]-F-A-85380 (FA85) tracer, which has a high affinity for nicotinic acetylcholine receptors (nAChRs). Aging was assessed by comparing young (n=10) and elderly (n=4) healthy subjects, and the pathologic process of AD was assessed by comparing elderly controls and age-matched AD patients (n=8). We measured an index of the nAChR density in the cortex and the hippocampus and the total number of FA85-binding sites by taking into account the volume changes. In AD, the nAChR density was preserved in both the cortex and hippocampus. The total estimated number of FA85-binding sites was decreased in the hippocampus despite the lack of a significant loss of volume, whereas the difference in the cortex did not withstand the adjustment for multiple comparisons despite a significant loss of volume. In contrast, in aging, the estimated number of FA85-binding sites was decreased in both the cortex and hippocampus with significant hippocampal atrophy. These findings suggest a preferential impairment of cholinergic pathways in the cortex during aging, whereas in AD, this damage predominated in the hippocampus with a potential compensatory cholinergic effect in the cortex.
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http://dx.doi.org/10.1097/WAD.0000000000000163DOI Listing
November 2017

Bee Venom for the Treatment of Parkinson Disease - A Randomized Controlled Clinical Trial.

PLoS One 2016 12;11(7):e0158235. Epub 2016 Jul 12.

Assistance Publique Hôpitaux de Paris (APHP), UPMC, INSERM, ICM, Centre d'Investigation Clinique Pitié Neurosciences, CIC-1422, Département des Maladies du Système Nerveux, Hôpital Pitié-Salpêtrière, Paris, France.

In the present study, we examined the potential symptomatic and/or disease-modifying effects of monthly bee venom injections compared to placebo in moderatly affected Parkinson disease patients. We conducted a prospective, randomized double-blind study in 40 Parkinson disease patients at Hoehn & Yahr stages 1.5 to 3 who were either assigned to monthly bee venom injections or equivalent volumes of saline (treatment/placebo group: n = 20/20). The primary objective of this study was to assess a potential symptomatic effect of s.c. bee venom injections (100 μg) compared to placebo 11 months after initiation of therapy on United Parkinson’s Disease Rating Scale (UPDRS) III scores in the « off » condition pre-and post-injection at a 60 minute interval. Secondary objectives included the evolution of UPDRS III scores over the study period and [123I]-FP-CIT scans to evaluate disease progression. Finally, safety was assessed by monitoring specific IgE against bee venom and skin tests when necessary. After an 11 month period of monthly administration, bee venom did not significantly decrease UPDRS III scores in the « off » condition. Also, UPDRS III scores over the study course, and nuclear imaging, did not differ significantly between treatment groups. Four patients were excluded during the trial due to positive skin tests but no systemic allergic reaction was recorded. After an initial increase, specific IgE against bee venom decreased in all patients completing the trial. This study did not evidence any clear symptomatic or disease-modifying effects of monthly bee venom injections over an 11 month period compared to placebo using a standard bee venom allergy desensitization protocol in Parkinson disease patients. However, bee venom administration appeared safe in non-allergic subjects. Thus, we suggest that higher administration frequency and possibly higher individual doses of bee venom may reveal its potency in treating Parkinson disease.

Trial Registration: ClinicalTrials.gov NCT01341431.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158235PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942057PMC
July 2017

Semantic and nonfluent aphasic variants, secondarily associated with amyotrophic lateral sclerosis, are predominant frontotemporal lobar degeneration phenotypes in TBK1 carriers.

Alzheimers Dement (Amst) 2015 Dec 30;1(4):481-6. Epub 2015 Oct 30.

Institut du Cerveau et de la Moelle épinière (ICM), CNRS UMR 7225, INSERM U 1127, Sorbonne Universités, Université Pierre et Marie, Univ Paris 06, UPMC-P6 UMR S 1127 - Hôpital Pitié-Salpêtrière, Paris, France; APHP, Département des Maladies du Système Nerveux, Hôpital de la Salpêtrière, Paris, France; Centre de Référence des Démences Rares, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.

Introduction: TBK1 mutations represent a rare novel genetic cause of amyotrophic lateral sclerosis (ALS) without or with dementia. The full spectrum of TBK1 phenotypes has not been completely defined so far.

Methods: We describe the clinical and neuroimaging characteristics of loss-of-function mutation carriers initially presenting with frontotemporal lobar degeneration (FTLD) phenotypes.

Results: Two carriers initially presented semantic variant of FTLD (svFTLD); two other developed nonfluent variant of FTLD (nfvFTLD) and corticobasal syndrome (CBS), associated with severe anterior temporal and opercular atrophy. All secondarily developed ALS.

Discussion: This study enlarges the phenotypic spectrum of TBK1 mutations, including svFTLD and nfvFTLD/CBS, not reported so far. Aphasic presentations seem to be more evocative of TBK1 genotype than behavioral variant of FTLD, and TBK1 should be analyzed in patients with isolated FTLD at onset, particularly in rare aphasic cases secondarily associated with ALS.
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http://dx.doi.org/10.1016/j.dadm.2015.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879495PMC
December 2015

Executive functioning and risk-taking behavior in Parkinson's disease patients with impulse control disorders.

J Neural Transm (Vienna) 2016 06 16;123(6):573-81. Epub 2016 Apr 16.

Département des Maladies du Système Nerveux, Sorbonne Universités, UPMC Univ Paris 06, and INSERM UMRS_1127 and CIC_1422, and CNRS UMR_7225, and AP-HP, and ICM, Hôpital Pitié-Salpêtrière, 75013, Paris, France.

Impulse control disorders (ICD) are common in Parkinson's disease (PD) and are associated with dopaminergic medication. The purpose of this study was to investigate executive function and risk-taking behavior in PD patients with ICD. 17 PD patients with ICD (ICD-PD) were compared to 20 PD patients without ICD (CTRL-PD) using neuropsychological and experimental tasks. Executive functions were assessed using standard executive testing (Conner's Performance Test, Modified Wisconsin Card Sorting Test, Trail Making Test and phonological verbal fluency). Subjects were also submitted to an experimental gambling task consisted of three decks of money cards: neutral deck (equal opportunity for gains as losses), winning deck (small amount of money with a positive balance) and loser deck (high amount of money with a negative balance), evaluating risk-taking behavior (number of cards picked in each deck) and valuation of the reward (subjective appreciation of the value of each deck). There was no significant difference in executive functioning between groups. Both groups selected more cards in the losing deck (high amount of money) as compared to the neutral deck (Mann-Whitney test, ICD-PD, p = 0.02; CTRL-PD, p = 0.003) and to the winning deck (Mann-Whitney test, ICD-PD p = 0.0001; CTRL-PD p = 0.003), suggesting an increased risk-taking behavior. Interestingly, we found that ICD-PD patients estimated the value of decks differently from CTRL-PD patients, taking into account mainly the positive reinforced value of the decks (Mann-Whitney test, p = 0.04). This study showed that executive pattern and risk-taking behavior are similar between ICD-PD and CTRL-PD patients. However, ICD-PD patients showed a specific deficit of the subjective estimation of the reward. Links between this deficit and metacognitive skills are discussed.
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http://dx.doi.org/10.1007/s00702-016-1549-yDOI Listing
June 2016

Functional Connectivity of Ventral and Dorsal Visual Streams in Posterior Cortical Atrophy.

J Alzheimers Dis 2016 ;51(4):1119-30

INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, and Université Pierre et Marie Curie-Paris 6, UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM), F-75013 Paris, France.

Background: Posterior cortical atrophy (PCA) induces progressive dysfunction of ventral and dorsal visual networks. Little is known, however, about corresponding changes in functional connectivity (FC).

Objectives: To investigate FC changes in the visual networks, their relationship with cortical atrophy, and the association with Alzheimer's disease (AD) pathology.

Methods: Ten PCA patients and 28 age-matched controls participated in the study. Using resting state fMRI, we measured FC in ventral and dorsal cortical visual networks, defined on the basis of a priori knowledge of long-range white matter connections. To assess the relationships with AD, we determined AD biomarkers in cerebrospinal fluid and FC in the default mode network (DMN), which is vulnerable to AD pathology. Voxel-based morphometry analysis assessed the pattern of grey matter (GM) atrophy.

Results: PCA patients showed GM atrophy in bilateral occipital and inferior parietal regions. PCA patients had lower FC levels in a ventral network than controls, but higher FC in inferior components of the dorsal network. In particular, the increased connectivity correlated with greater GM atrophy in occipital regions. All PCA patients had positive cerebrospinal fluid biomarkers for AD; however, FC in global DMN did not differ from controls.

Conclusions: FC in PCA reflects brain structure in a non-univocal way. Hyperconnectivity of dorsal networks may indicate aberrant communication in response to posterior brain atrophy or processes of neural resilience during the initial stage of brain dysfunction. The lack of difference from controls in global DMN FC highlights the atypical nature of PCA with respect to typical AD.
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http://dx.doi.org/10.3233/JAD-150934DOI Listing
December 2016

Methotrexate and temozolomide versus methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: an intergroup ANOCEF-GOELAMS randomised phase 2 trial.

Lancet Haematol 2015 Jun 3;2(6):e251-9. Epub 2015 Jun 3.

APHP, Sorbonne Universités UPMC Universités Paris VI, IHU, ICM, INCa-LOC Network, Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. Electronic address:

Background: No standard chemotherapy regimen exists for primary CNS lymphoma, reflecting an absence of randomised studies. We prospectively tested two promising methotrexate-based regimens, one more intensive and a milder regimen, for primary CNS lymphoma in the elderly population, who account for most patients.

Methods: In this open-label, randomised phase 2 trial, done in 13 French institutions, we enrolled immunocompetent patients who had neuroimaging and histologically confirmed newly diagnosed primary CNS lymphoma, were aged 60 years and older, and had a Karnofsky performance scale score of 40 or more. Participants were stratified by Karnofsky performance scale score (<60 vs ≥60) and treating institution and randomly assigned (1:1) to receive methotrexate (3·5 g/m(2)) with temozolomide (150 mg/m(2)) or methotrexate (3·5 g/m(2)), procarbazine (100 mg/m(2)), vincristine (1·4 mg/m(2)), and cytarabine (3 mg/m(2)). Neither regimen included radiotherapy; both included prophylactic G-CSF and corticosteroids. The primary endpoint was 1-year progression-free survival. Analysis was intent to treat, in a non-comparative phase 2 trial design. This study is registered with ClinicalTrials.gov, number NCT00503594.

Findings: Between July 16, 2007, and March 25, 2010, 98 patients were enrolled, of whom 95 were randomly assigned and analysed; 48 to methotrexate with temozolomide and 47 to methotrexate, procarbazine, vincristine, and cytarabine. 1-year progression-free survival was 36% (95% CI 22-50) in the methotrexate, procarbazine, vincristine, and cytarabine group and 36% (22-50) in the methotrexate with temozolomide group; median progression-free survival was 9·5 months (95% CI 5·3-13·8) versus 6·1 months (3·8-11·9), respectively. Objective responses were noted in 82% (95% CI 68-92) of patients in the methotrexate, procarbazine, vincristine, and cytarabine group versus 71% (55-84) of patients in the methotrexate with temozolomide group. Median overall survival was 31 months (95% CI 12·2-35·8) in the methotrexate, procarbazine, vincristine, and cytarabine group and 14 months (8·1-28·4) in the methotrexate with temozolomide group. No differences were noted in toxic effects between the two groups. The most common grades 3 and 4 toxicities in both groups were liver dysfunction (21 [4%] in the the methotrexate and temozolomide group and 18 [38%] in the methotrexate, procarbazine, vincristine, and cytarabine group), lymphopenia (14 [29%] and 14 [30%]), and infection (six [13%] and seven [15%]). To date, 33 (69%) patients in the methotrexate and temozolomide group have died, versus 31 (55%) in the methotrexate, procarbazine, vincristine and cytarabine group. Quality-of-life evaluation (QLQ-C30 and BN20) showed improvements in most domains (p=0·01-0·0001) compared with baseline in both groups. Prospective neuropsychological testing showed no evidence of late neurotoxicity.

Interpretation: In this study of two different methotrexate-based combination regimens in elderly patients, the efficacy endpoints tended to favour the methotrexate, procarbazine, vincristine, and cytarabine group. Both regimens were associated with similar, moderate toxicity, but quality of life improved with time, suggesting pursuing treatment in these poor prognosis patients is worthwhile. New alternatives are needed to improve response duration in this population.

Funding: Schering-Plough/Merck and French Government.
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http://dx.doi.org/10.1016/S2352-3026(15)00074-5DOI Listing
June 2015

TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts.

Neurobiol Aging 2015 Nov 14;36(11):3116.e5-3116.e8. Epub 2015 Aug 14.

Institut du Cerveau et de la Moelle épinière (ICM), INSERM U1127, CNRS UMR 7225, Sorbonne Universités, Université Pierre et Marie Curie, Univ Paris 06, UPMC-P6 UMR S 1127 Hôpital de la Pitié-Salpêtrière, Paris, France; Département des Maladies du Système Nerveux, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France; Département de Génétique et Cytogénétique, Unité Fonctionnelle de Génétique Clinique, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France. Electronic address:

TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4%-4% of ALS. Considering the strong genetic overlap existing between frontotemporal dementia (FTD) and ALS, we have evaluated the frequencies of TBK1 mutations in a cohort of French FTD and of ALS patients. We identified 5 LoF mutations, in 4 FTD-ALS and 1 ALS patients. We also identified 5 heterozygous missense variants, predicted to be deleterious, in 1 isolated FTD, 1 FTD-ALS, and 3 ALS cases. Our results demonstrate that TBK1 loss-of-function mutations are more frequent in patients with FTD-ALS (10.8%) than in isolated ALS. TBK1 should thus also be sequenced, after exclusion of C9orf72 mutation, in patients presenting FTD, particularly in cases secondarily associated with ALS.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.08.009DOI Listing
November 2015

Endplate denervation correlates with Nogo-A muscle expression in amyotrophic lateral sclerosis patients.

Ann Clin Transl Neurol 2015 Apr 16;2(4):362-72. Epub 2015 Feb 16.

Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France ; APHP, Hôpital Pitié-Salpêtrière, Centre de référence de pathologie neuromusculaire Paris-Est, Institut de Myologie Paris, France.

Objective: Data from mouse models of amyotrophic lateral sclerosis (ALS) suggest early morphological changes in neuromuscular junctions (NMJs), with loss of nerve-muscle contact. Overexpression of the neurite outgrowth inhibitor Nogo-A in muscle may play a role in this loss of endplate innervation.

Methods: We used confocal and electron microscopy to study the structure of the NMJs in muscle samples collected from nine ALS patients (five early-stage patients and four long-term survivors). We correlated the morphological results with clinical and electrophysiological data, and with Nogo-A muscle expression level.

Results: Surface electromyography assessment of neuromuscular transmission was abnormal in 3/9 ALS patients. The postsynaptic apparatus was morphologically altered for almost all NMJs (n = 430) analyzed using confocal microscopy. 19.7% of the NMJs were completely denervated (fragmented synaptic gutters and absence of nerve terminal profile). The terminal axonal arborization was usually sparsely branched and 56.8% of innervated NMJs showed a typical reinnervation pattern. Terminal Schwann cell (TSC) morphology was altered with extensive cytoplasmic processes. A marked intrusion of TSCs in the synaptic cleft was seen in some cases, strikingly reducing the synaptic surface available for neuromuscular transmission. Finally, high-level expression of Nogo-A in muscle was significantly associated with higher extent of NMJ denervation and negative functional outcome.

Interpretation: Our results support the hypothesis that morphological alterations of NMJs are present from early-stage disease and may significantly contribute to functional motor impairment in ALS patients. Muscle expression of Nogo-A is associated with NMJ denervation and thus constitutes a therapeutic target to slow disease progression.
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http://dx.doi.org/10.1002/acn3.179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402082PMC
April 2015

Plasma peptide biomarker discovery for amyotrophic lateral sclerosis by MALDI-TOF mass spectrometry profiling.

PLoS One 2013 5;8(11):e79733. Epub 2013 Nov 5.

Exploratory Unit, Sanofi, Toulouse, France.

The diagnostic of Amyotrophic lateral sclerosis (ALS) remains based on clinical and neurophysiological observations. The actual delay between the onset of the symptoms and diagnosis is about 1 year, preventing early inclusion of patients into clinical trials and early care of the disease. Therefore, finding biomarkers with high sensitivity and specificity remains urgent. In our study, we looked for peptide biomarkers in plasma samples using reverse phase magnetic beads (C18 and C8) and MALDI-TOF mass spectrometry analysis. From a set of ALS patients (n=30) and healthy age-matched controls (n=30), C18- or C8-SVM-based models for ALS diagnostic were constructed on the base of the minimum of the most discriminant peaks. These two SVM-based models end up in excellent separations between the 2 groups of patients (recognition capability overall classes > 97%) and classify blinded samples (10 ALS and 10 healthy age-matched controls) with very high sensitivities and specificities (>90%). Some of these discriminant peaks have been identified by Mass Spectrometry (MS) analyses and correspond to (or are fragments of) major plasma proteins, partly linked to the blood coagulation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0079733PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818176PMC
August 2014

Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression.

Brain 2013 Aug 3;136(Pt 8):2359-68. Epub 2013 Jul 3.

APHP, Hôpital Pitié-Salpêtrière, Département de Neurologie, Centre référent SLA, Paris Cedex 13, France.

Amyotrophic lateral sclerosis is a typically rapidly progressive neurodegenerative disorder affecting motor neurons leading to progressive muscle paralysis and death, usually from respiratory failure, in 3-5 years. Some patients have slow disease progression and prolonged survival, but the underlying mechanisms remain poorly understood. Riluzole, the only approved treatment, only modestly prolongs survival and has no effect on muscle function. In the early phase of the disease, motor neuron loss is initially compensated for by collateral reinnervation, but over time this compensation fails, leading to progressive muscle wasting. The crucial role of muscle histone deacetylase 4 and its regulator microRNA-206 in compensatory reinnervation and disease progression was recently suggested in a mouse model of amyotrophic lateral sclerosis (transgenic mice carrying human mutations in the superoxide dismutase gene). Here, we sought to investigate whether the microRNA-206-histone deacetylase 4 pathway plays a role in muscle compensatory reinnervation in patients with amyotrophic lateral sclerosis and thus contributes to disease outcome differences. We studied muscle reinnervation using high-resolution confocal imaging of neuromuscular junctions in muscle samples obtained from 11 patients with amyotrophic lateral sclerosis, including five long-term survivors. We showed that the proportion of reinnervated neuromuscular junctions was significantly higher in long-term survivors than in patients with rapidly progressive disease. We analysed the expression of muscle candidate genes involved in the reinnervation process and showed that histone deacetylase 4 upregulation was significantly greater in patients with rapidly progressive disease and was negatively correlated with the extent of muscle reinnervation and functional outcome. Conversely, the proposed regulator of histone deacetylase 4, microRNA-206, was upregulated in both patient groups, but did not correlate with disease progression or reinnervation. We conclude that muscle expression of histone deacetylase 4 may be a key factor for muscle reinnervation and disease progression in patients with amyotrophic lateral sclerosis. Specific histone deacetylase 4 inhibitors may then constitute a therapeutic approach to enhancing motor performance and slowing disease progression in amyotrophic lateral sclerosis.
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http://dx.doi.org/10.1093/brain/awt164DOI Listing
August 2013

[Role of demotivation and affective disorders in apathy in patients with Parkinson's disease without dementia and depression].

Geriatr Psychol Neuropsychiatr Vieil 2013 Jun;11(2):197-207

Fédération des maladies du système nerveux, Groupe hospitalier Pitié-Salpêtrière, Paris, France.

Objective: to assess the role of demotivation and various affective factors in apathy in patients with Parkinson's disease (PD) without dementia and depression.

Subjects: 20 patients and 20 control subjects matched with age, education level, and genre.

Methods: apathy was assessed by the Apathy evaluation scale (AES) and by a specific scale including a quantitative evaluation of 32 intentional activities and a qualitative assessment of the causes of attribution of restricted activities by a semi-structured interview (GDAS). Four causal attributions were distinguished: E = related to external factors, M = disease symptoms related, C = affective disturbances with preservation of motivation, and D = demotivation. The results were compared to a battery of tests including cognitive evaluation (mini-mental state and Mattis dementia rating scale for global evaluation, selecting reminding test for memory; Stroop test for inhibition, and six element test for planification); affective evaluation (Montgomery & Asberg and Hamilton depression rating scales for depression, emotional disturbances by the Abrams and Taylor scale, the Depression mood scale, and the International picture system), premorbid personality (NEOPI-R), and defensive psychological mechanisms (DSQ-40); functional assessment by a combined scale including the Self-maintenance physical scale and the Instrumental activities of daily living (Lawton) and the Social activities scale (Katz & Lyerly), the Disability assessment scale, and the UPDRS.

Results: apathy was found in 25% of the patients according to the AES, but only in 15% according to the GDAS. Scores on cognitive and affective evaluation were higher in patients than in controls but only emotional blunting was correlated to apathy. Some results coud be interpreted in favor of a premorbid personality disorder in patients with PD, but were not correlated to apathy. Causal attribution was M in 38% of cases of reduced activities, D in 30%, E in 22%, and C in 10%.

Conclusion: emotional blunting was the main correlate of apathy in PD patients without dementia and depression. Demotivation was the causal mechanism in only 30% of the patients with apathy.
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http://dx.doi.org/10.1684/pnv.2013.0404DOI Listing
June 2013
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