Publications (73)303.33 Total impact
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Article: C9ORF72 Repeat Expansions in the Frontotemporal Dementias Spectrum of Diseases: A Flowchart for Genetic Testing.
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ABSTRACT: Frontotemporal dementia (FTD) refers to a disease spectrum including the behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72 expansions were much more frequent in the large subgroup of patients with familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more frequent than in familial pure ALS, according to estimated frequencies in the literature (23-50%). The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative. Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72. Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9-56.1) than in MAPT patients (46.8, 95%CI: 43.0-50.6; p = 0.00001) and the same as in PGRN patients (59.6 years; 95%CI: 57.6-61.7; p = 0.4). ALS was more frequent in C9ORF72 than in MAPT and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT mutations, whereas hallucinations were indicative of PGRN mutations; prioritization of genetic testing is thus possible. Penetrance was age- and gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52% of females. This can also guide genetic testing and counseling. A flowchart for genetic testing is thus proposed.Journal of Alzheimer's disease: JAD 12/2012; · 3.74 Impact Factor -
Dataset: Pradat et al. Amyotr Lat Scler 2010
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Dataset: C9ORF72 Repeat Expansions in the Frontotemporal Dementias Spectrum of Diseases: A Flow-chart for Genetic Testing
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ABSTRACT: Frontotemporal dementia (FTD) refers to a disease spectrum including the behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72 expansions were much more frequent in the large subgroup of patients with familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more frequent than in familial pure ALS, according to estimated frequencies in the literature (23–50%). The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative. Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72. Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9–56.1) than in MAPT patients (46.8, 95%CI: 43.0–50.6; p = 0.00001) and the same as in PGRN patients (59.6 years; 95%CI: 57.6–61.7; p = 0.4). ALS was more frequent in C9ORF72 than in MAPT and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT mutations, whereas hallucinations were indicative of PGRN mutations; prioritization of genetic testing is thus possible. Penetrance was age- and gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52% of females. This can also guide genetic testing and counseling. A flowchart for genetic testing is thus proposed. -
Article: Prospective evaluation of behavioral scales in the behavioral variant of frontotemporal dementia.
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ABSTRACT: Background: The Neuropsychiatric Inventory (NPI) and the Frontal Behavioral Inventory (FBI) are widely used in patients with the behavioral variant of frontotemporal dementia (bvFTD). Yet, few data are available on the long-term relevance of these scales. Material and Methods: Based on a bvFTD population that participated in the Memantine Clinical Trial (NCT00200538), we studied the evolution and correlation between scores obtained on behavioral scales (NPI and FBI), cognitive scales [Mini-Mental State Examination (MMSE) and Mattis Dementia Rating Scale (MDRS)] and a burden scale [Zarit Burden Inventory (ZBI)]. The assessments were performed at 1 year in 41 patients and at 2 years in 23 patients who agreed to participate in this open-label study. Results: The 2-year scores obtained on the FBI were significantly higher than the scores at inclusion while those obtained on the NPI did not change. There were significant correlations between the FBI, and the MDRS and MMSE, especially regarding the negative items. The ZBI correlated with behavioral scales at all stages for positive items. Conclusions: This study based on a large population shows that the FBI is a better tool than the NPI for the long-term assessment of bvFTD patients. Moreover, the FBI allows a distinction to be made between behavioral disturbances that involve cognitive functions from those which have an important impact on caregiver burden.Dementia and Geriatric Cognitive Disorders 08/2012; 34(2):75-82. · 2.14 Impact Factor -
Article: Predicting Survival of Patients with Amyotrophic Lateral Sclerosis at Presentation: A 15-Year Experience.
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ABSTRACT: Objective: To describe the clinical features at first evaluation that best predict survival of the amyotrophic lateral sclerosis (ALS) population from the Salpêtrière Hospital between 1995 and 2009. Methods: Data are collected and entered into a clinical database from all patients seen at the Paris ALS Center. Variables analyzed were demographic and baseline information, strength testing (manual muscle testing; 1995-2009), the revised ALS Functional Rating Scale (ALSFRS-R; 2002-2009) and survival status. The χ(2) test and ANOVA assessed differences in variables by region and across time period. Univariate and multivariate Cox proportional hazards models determined which variables best predicted survival. Flexible modeling of continuous predictors (splines) assessed trends in survival for different variables. Results: 3,885 patients with ALS were seen in 1995-2009, of whom 2,037 had ALSFRS-R scores. Age, weight, strength, and site of onset varied by region of residence. The proportion of patients living outside Paris, the time to first visit, patient age, and motor function differed across time periods. In Cox models, site of onset, time to first visit greater than 18 months, strength and the year of visit after 2006 predicted survival (all p values <0.0001). Compared to patients first seen between 1999 and 2002, the hazard ratio of death was 1.04 (95% CI = 0.95-1.14) for 2003-2006, and 0.76 (95% CI = 0.66-0.87) after 2006, while adjusting for other predictors of survival. The use of noninvasive ventilation increased during 2004-2008 from 16 to 51% of patients. Conclusions: Older age, bulbar onset, shorter delay to first visit and poor motor function at first visit predicted shorter survival rates in this large center-based sample from France, showing marked consistency across time and region of residence. Survival improved after 2006, concurrent with increasing rates of noninvasive ventilation use. Clinicopathologic correlation could better define subgroups, but identification of etiologies may be needed to elucidate individual forms of ALS with unique survival patterns.Neurodegenerative Diseases 08/2012; · 3.06 Impact Factor -
Article: Stressful events and severity of memory complaints in cognitively normal adults aged from 25 to 85 years.
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ABSTRACT: The relationships between subjective cognitive difficulties and stressful events (SE) have rarely been examined. Broadbent et al. (1982) suggested that such difficulties disclose a high sensitivity to stress, independently of depression and personality. Objective: To explore the relationships between the severity of memory complaints and SE occurred during the previous year. Methods: 260 cognitively normal subjects, aged from 25 to 85 years were examined in a Memory clinic through one year. The severity of memory complaints was globally assessed by asking the participants to qualify the intensity of their subjective difficulties as major or minor, and quantitatively, by using a 8-item subjective memory scale. SE were assessed by asking the subjects whether they experienced one or more events that had negative effects on their physic or mental well-being in the domains of health, family, social environment and financial position during the last 12 months. Affective status was assessed by the Zung's depression (ZD) and anxiety (ZA) scales, and by a Wellbeing questionnaire, QBE. Cognition was assessed using a semi-computerized battery exploring memory and several cognitive abilities. Results: SE were reported in 156 subjects (60%). No differences were found between subjects with or without SE according to age, genre, familial status and activity, as well as cognitive performance. Subjects with SE reported more severe complaints and higher scores on ZD and ZA scales, and lower scores on the QBE. Severity of memory complaints was mainly correlated to QBE in subjects with SE and to ZA scale in subjects without. Subjects with age < 50 years reported more SE than subjects aged ≥ 50 years. No difference was found between the two age groups according to the type of SE in the domain of health, family, and finances, but higher SE were reported in younger subjects in the domain of social environment. The main correlates of the severity of memory complaints were depression in younger subjects with or without SE, and anxiety in absence of SE and QBE in presence of SE in older subjects. However, the affective scores explained only a weak part of the variance of the severity of memory complaints. Conclusion: SE do not seem to play a direct role in the severity of memory complaints, but they increase the affective disturbances. We suggest that anxiety and various factors such as decrease in self-esteem and modification of self-identity result in a psychological vulnerability which contribute to memory complaints.Geriatrie et psychologie neuropsychiatrie du vieillissement 06/2012; 10(2):187-196. -
Article: Resting state FDG-PET functional connectivity as an early biomarker of Alzheimer's disease using conjoint univariate and independent component analyses.
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ABSTRACT: Imaging cerebral glucose metabolism with positron emission tomography (PET) in Alzheimer's disease (AD) has allowed for improved characterisation of this pathology. Such patterns are typically analysed using either univariate or multivariate statistical techniques. In this work we combined voxel-based group analysis and independent component analysis to extract differential characteristic patterns from PET data of glucose metabolism in a large cohort of normal elderly controls and patients with AD. The patterns were used in conjunction with a support vector machine to discriminate between subjects with mild cognitive impairment (MCI) at risk or not of converting to AD. The method was applied to baseline fluoro-deoxyglucose (FDG)-PET images of subjects from the ADNI database. Our approach achieved improved early detection and differentiation of typical versus pathological metabolic patterns in the MCI population, reaching 80% accuracy (85% sensitivity and 75% specificity) when using selected regions. The method has the potential to assist in the advance diagnosis of Alzheimer's disease, and to identify early in the development of the disease those individuals at high risk of rapid cognitive decline who could be candidates for new therapeutic approaches.NeuroImage 04/2012; 63(2):936-46. · 5.89 Impact Factor -
Article: Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS-related genes.
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ABSTRACT: Expanded GGGGCC hexanucleotide repeats in the promoter of the C9ORF72 gene have recently been identified in frontotemporal dementia (FTD), Amyotrophic Lateral Sclerosis (ALS) and ALS-FTD and appear as the most common genetic cause of familial (FALS) and sporadic (SALS) forms of ALS. We searched for the C9ORF72 repeat expansion in 950 French ALS patients (225 FALS and 725 SALS) and 580 control subjects and performed genotype-phenotype correlations. The repeat expansion was present in 46% of FALS, 8% of SALS and 0% of controls. Phenotype comparisons were made between FALS patients with expanded C9ORF72 repeats and patients carrying another ALS-related gene (SOD1, TARDBP, FUS) or a yet unidentified genetic defect. SALS patients with and without C9ORF72 repeat expansions were also compared. The C9ORF72 group presented more frequent bulbar onset both in FALS (p<0.0001 vs SOD1, p=0.002 vs TARDBP, p=0.011 vs FUS, p=0.0153 vs other FALS) and SALS (p=0.047). FALS patients with C9ORF72 expansions had more frequent association with FTD than the other FALS patients (p<0.0001 vs SOD1, p=0.04 vs TARDBP, p=0.004 vs FUS, p=0.03 vs other FALS). C9ORF72-linked FALS patients presented an older age of onset than SOD1 (p=0.0139) or FUS mutation (p<0.0001) carriers. Disease duration was shorter for C9ORF72 expansion carriers than for SOD1 (p<0.0001) and TARDBP (p=0.0242) carriers, other FALS (p<0.0001) and C9ORF72-negative SALS (p=0.0006). Our results confirm the major role of expanded repeats in C9ORF72 as causative for ALS and provide evidence for specific phenotypic aspects compared to patients with other ALS-related genes.Journal of Medical Genetics 04/2012; 49(4):258-63. · 6.36 Impact Factor -
Article: [Apathy in frontotemporal dementia and Alzheimer's disease: are there distinct profiles?].
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ABSTRACT: To find out if distinct clinical profiles of apathy can be distinguished in frontotemporal dementia (FTD) and Alzheimer's disease (AD). Subjects: 13 outpatients with the frontal variant of DFT, 36 with AD and 29 control subjects. The scores of the Apathy evaluation scale, AES (Marin), filled in by close relatives, were compared to a) cognitives measures, including global ratings (Mini mental state, Dementia rating scale), and specific assessments for memory (Selective reminding test), inhibition (Stroop test) and planification (6 elements); b) affective measures for depression (Montgomery and Asberg, and Hamilton depression rating scales), emotional disturbances (Abrams and Taylor scale, ATS; Depression mood scale, DMS), assessment of valence and intensity of affective reactions by the International affective picture system, IAPS), dimensions of personality (NEO PI-R, Defensive style questionnaire, DSQ); c) functional assessment: Self-maintenance physical scale (ADL) and Instrumental activities of daily living (Lawton), Social activities scale (Katz and Lyerly), and Disability assessment for dementia, DAD. Apathy was also assessed by the Neuropsychiatric Inventory (NPI) and a new tool, the Goal-directed activities scale (GDAS), which allows a quantitative assessment of 32 goal-directed activities and a qualitative evaluation of 4 causal attributions: E = related to external factors; M = disease related; C = affective disturbance related; and D = lack of motivation. A close relationship was found between AES scores and global cognitive deficits in FTD and AD, but only in AD for the memory and executive tests. No relationship was found with the depression scales or dimensions of personality. A significant relationship was found both in FDT and AD with blunted affect as assessed by ATS, but not with direct assessment by the DMS or reactions to the IAPS. Functional activities were closely related to AES scores in all evaluations, except for ADL score in FTD. Causal attributions were mainly related to lack of motivation in FTD (60% of cases according to the patients, and 85% according to the spouses), and both to affective disturbances (respectively in 36 and 48% of cases) and lack of motivation (33% and 45%) in AD. No distinct cognitive or emotional profiles of apathy could be found in FTD and AD. Apathy was constant, more severe, and mainly related to lack of motivation in FTD, less constant, less severe in AD, and related both to affective disturbances and lack of motivation.Geriatrie et psychologie neuropsychiatrie du vieillissement 03/2012; 10(1):107-15. -
Article: Improving survival in a large French ALS center cohort.
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ABSTRACT: The aim of this work was to determine whether survival changed during 2002-2009 at a French amyotrophic lateral sclerosis (ALS) center. We included all patients with ALS who were seen consecutively at the center from January 2002-May 2009. Participants were followed from date of first visit through death, date of censoring, or December 31, 2009, whichever occurred first. Cox proportional hazard models computed hazard ratios (HR; 95% confidence interval CI) of death, and flexible modeling of continuous predictors (splines) assessed trends in survival. We analyzed a total of 2,037 ALS patients, of whom 1,471 died before the end of follow-up. Median survival was 2.83 years from onset and 1.65 years from first visit. Compared to patients first seen before 2004, the HR of death was 0.97 (95% CI = 0.85-1.11, p = 0.6721) for patients first seen in 2004-2005, 0.96 (95% CI = 0.83-1.10, p = 0.5125) for 2006-2007, and 0.56 (95% CI = 0.46-0.69, p < 0.0001) after 2007, while adjusting for other survival predictors. Spline analysis confirmed that survival remained stable during 2002-2006, then markedly improved. The proportion of patients receiving non-invasive ventilation (NIV) increased from 16 (2004) to 51% (2008). At this large ALS center, survival improved after 2006. Because more aggressive use of NIV was the principal therapeutic adaptation, our data suggest that better survival resulted from improved respiratory care.Journal of Neurology 01/2012; 259(9):1788-92. · 3.47 Impact Factor -
Article: Mutations in UBQLN2 are rare in French amyotrophic lateral sclerosis.
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ABSTRACT: Mutations in UBQLN2 encoding ubiquilin-2 have recently been identified in families with dominant X-linked juvenile and adult-onset amyotrophic lateral sclerosis (ALS) and ALS/dementia. Ubiquilin-2 is a component of the ubiquitin inclusions detected in degenerating neurons in ALS patients. All the previously reported UBQLN2 mutations were localized in 1 of the 12 PXX domains of ubiquilin-2 protein. We sequenced UBQLN2 in 130 French patients with familial ALS (FALS) and absence of male-to-male transmission and the PXX domain in 240 more patients with sporadic ALS (SALS). We identified, at the heterozygote state, the c.1500_1508delCATAGGCCC, p.Gly502_Ile504del, in 1 affected woman. This deletion presumably leads to the in-frame deletion of 1 PXX repeat in the protein. This variant did not segregate with the disease in the corresponding family and was also detected in 1/380 control subject. Our results suggest that UBQLN2 gene mutations are rare in French ALS.Neurobiology of aging 12/2011; 33(4):839.e1-3. · 5.94 Impact Factor -
Article: Abnormal TDP-43 and FUS proteins in muscles of sporadic IBM: similarities in a TARDBP-linked ALS patient.
Journal of neurology, neurosurgery, and psychiatry 12/2011; 82(12):1414-6. · 4.87 Impact Factor -
Article: Muscle gene expression is a marker of amyotrophic lateral sclerosis severity.
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset degenerative disease characterized by the loss of upper and lower motor neurons leading to progressive muscle atrophy and paralysis. The lack of molecular markers of the progression of disease is detrimental to clinical practice and therapeutic trials. This study was designed to identify gene expression changes in skeletal muscle that could reliably define the degree of disease severity. Gene expression profiles were obtained from the deltoid muscles of ALS patients and healthy subjects. Changes in differentially expressed genes were compared to the status of deltoid muscle disability, as determined by manual muscle testing, electrophysiology and the degree of myofiber atrophy. Functionally related genes were grouped by annotation analysis, and deltoid muscle injury was predicted using binary tree classifiers. Two sets of 25 and 70 transcripts appeared differentially regulated exclusively in early and advanced states of deltoid muscle impairment, respectively. The expression of another set of 198 transcripts correlated with a composite score of muscle injury combining manual muscle testing and histological examination. From the totality of these expression changes, 155 transcripts distinguished advanced from early deltoid muscle impairment with 80% sensitivity and 100% specificity. Nine of these transcripts, known also to be regulated in ALS mouse and surgically denervated muscle, predicted the advanced disease status with 100% sensitivity and specificity. We provide robust gene expression changes that can be of practical use when monitoring ALS status and the effects of disease-modifying drugs.Neurodegenerative Diseases 09/2011; 9(1):38-52. · 3.06 Impact Factor -
Article: Association of long ATXN2 CAG repeat sizes with increased risk of amyotrophic lateral sclerosis.
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ABSTRACT: To analyze the ataxin 2 (ATXN2) CAG repeat size in a cohort of patients with amyotrophic lateral sclerosis (ALS) and healthy controls. Large (CAG)(n) alleles of the ATXN2 gene (27-33 repeats) were recently reported to be associated with an increased risk of ALS. Case-control study. France and Quebec, Canada. A total of 556 case patients with ALS and 471 healthy controls; both groups of participants are of French or French-Canadian origin. We observed a significant association between ATXN2 high-length alleles (≥29 CAG repeats) and ALS in French and French-Canadian ALS populations. Furthermore, we identified spinocerebellar ataxia type 2-pathogenic polyglutamine expansions (≥32 CAG repeats) in both familial and sporadic ALS cases. Altogether, our findings support ATXN2 high-length repeats as a risk factor for ALS and further indicate a genetic link between spinocerebellar ataxia type 2 and ALS.Archives of neurology 06/2011; 68(6):739-42. · 6.31 Impact Factor -
Article: A proof-of-concept, randomized, placebo-controlled, multiple cross-overs (n-of-1) study of naftazone in Parkinson's disease.
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ABSTRACT: To explore for the first time the tolerability and efficacy of naftazone in patients with Parkinson's disease (PD). Proof-of-concept, randomized, double-blind, placebo-controlled, multiple-cross-over n-of-1 study in patients with PD with wearing-off and dyskinesias. Naftazone was titrated up to 120 mg/day during an initial single-blind dose-finding phase. Seven patients entered the placebo-controlled phase (four consecutive 28-day cross-overs). Three outcome measures were used to collect preliminary indices of efficacy: (i) 48-h ON-OFF diaries; (ii) Unified PD Rating Scale (UPDRS) part III while ON; (iii) seven-point Likert scale to assess "patients' discomfort caused by dyskinesias" (Q1) and 'disability during OFF-periods' (Q2). A 'responder' analysis (proportion of patients with mean treatment effect [naftazone minus placebo] favoring naftazone over the 4 cross-over periods) was used. Treatment effects were derived from mixed-effects anova. On diaries, 5/7 patients responded to naftazone for 'ON-time with troublesome dyskinesia' (reduced time, treatment effect: -49 [95% CI: -93/-4] min, P = 0.03), 6/7 regarding 'ON-time without troublesome dyskinesia' (increased time, treatment effect: 35 [-19/88], P = 0.2). No trend was observed for 'OFF' time. There were 7/7 'responders' regarding UPDRSIII (reduced score, treatment effect: -2.1[-4.5/0.2], P = 0.08). The 7-point scales did not show clear trends in favor of naftazone (3/7 responders for Q1 and 4/7 for Q2). Four of the seven patients reported adverse events after randomization, mostly related to the CNS (mild: 2, severe: 2). These pilot findings are consistent with preclinical data in primates and support the hypothesis that naftazone may have antiparkinsonian and antidyskinetic effects in humans that deserve further clinical investigation.Fundamental and Clinical Pharmacology 05/2011; 26(4):557-64. · 1.80 Impact Factor -
Article: The range and clinical impact of cognitive impairment in French patients with ALS: a cross-sectional study of neuropsychological test performance.
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ABSTRACT: Our objective was to assess the spectrum and clinical associations of cognitive impairment in French patients with ALS, and determine the effect of cognitive impairment on survival in this population. One hundred and thirty-one patients were enrolled in a cross-sectional cohort study of neuropsychological test performance. ANOVA and χ(2) tests assessed differences in clinical characteristics between impaired and unimpaired patients; multiple regression determined which features contributed most strongly to cognitive status, and Cox models compared survival. Fifty-three patients (40%) were categorized as cognitively impaired based on test performance. Thirteen (10%) patients had frontotemporal dementia (FTD) clinically; all scored in the moderate to severely impaired range on testing. Impaired patients had less education (p = 0.001), and severely impaired patients were more likely to have bulbar onset than unimpaired patients (p < 0.001). Severe cognitive impairment predicted shorter survival (p = 0.007), even when controlled for motor severity (p = 0.001). In summary, 10% of a consecutive series of French ALS patients had overt dementia and 40% were cognitively impaired by neuropsychological testing. We conclude that lower education level and possibly bulbar-onset ALS were associated with impairment. As in other causes of dementia, higher education attainment may protect against clinical cognitive deterioration in ALS. French patients with severe cognitive impairment have shorter survival time.Amyotrophic Lateral Sclerosis 05/2011; 12(5):372-8. · 3.40 Impact Factor -
Article: Neural correlates of cognitive impairment in posterior cortical atrophy.
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ABSTRACT: With the prospect of disease-modifying drugs that will target the physiopathological process of Alzheimer's disease, it is now crucial to increase the understanding of the atypical focal presentations of Alzheimer's disease, such as posterior cortical atrophy. This study aimed to (i) characterize the brain perfusion profile in posterior cortical atrophy using regions of interest and a voxel-based approach; (ii) study the influence of the disease duration on the clinical and imaging profiles; and (iii) explore the correlations between brain perfusion and cognitive deficits. Thirty-nine patients with posterior cortical atrophy underwent a specific battery of neuropsychological tests, mainly targeting visuospatial functions, and a brain perfusion scintigraphy with 99mTc-ethyl cysteinate dimer. The imaging analysis included a comparison with a group of 24 patients with Alzheimer's disease, matched for age, disease duration and Mini-Mental State Examination, and 24 healthy controls. The single-photon emission computed tomography profile in patients with posterior cortical atrophy was characterized by extensive and severe hypoperfusion in the occipital, parietal, posterior temporal cortices and in a smaller cortical area corresponding to the frontal eye fields (Brodmann areas 6/8). Compared with patients with Alzheimer's disease, the group with posterior cortical atrophy showed more severe occipitoparietal hypoperfusion and higher perfusion in the frontal, anterior cingulate and mesiotemporal regions. When considering the disease duration, the functional changes began and remained centred on the posterior lobes, even in the late stage. Correlation analyses of brain perfusion and neuropsychological scores in posterior cortical atrophy highlighted the prominent role of left inferior parietal damage in acalculia, Gerstmann's syndrome, left-right indistinction and limb apraxia, whereas damage to the bilateral dorsal occipitoparietal regions appeared to be involved in Bálint's syndrome. Our findings provide new insight into the natural history of functional changes according to disease duration and highlight the role of parietal and occipital cortices in the cognitive syndromes that characterize the posterior cortical atrophy.Brain 05/2011; 134(Pt 5):1464-78. · 9.46 Impact Factor -
Article: Fronto-temporal lobar degeneration: neuropathology in 60 cases.
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ABSTRACT: Sixty cases of frontotemporal lobar degeneration (FTLD) were collected over 22 years. Brain weight was negatively correlated with disease duration. The neuronal and/or glial inclusions were labeled by anti-TDP, anti-FUS or anti-TAU antibodies, respectively, in 40, 3 and 12 cases. In the FTLD-TDP group, mutation of the progranulin gene was found in four cases (FTD-GRN), with nuclear, cat eye inclusions and severe neuronal loss in CA1 and subiculum. The motor neurons were involved in 27 cases (fronto-temporal dementia with amyotrophic lateral sclerosis = FTD-ALS). Familial FTD-ALS cases lived longer than sporadic ones. In nine cases, there was no ALS, no GRN mutation (FTD-NAP). The cases in the FTD-ALS and FTD-NAP subgroups were of Sampathu type 2 (TDP-positive inclusions located mostly in cell bodies and short neurites) with the exception of five cases which belonged to type 1 (long TDP-positive neurites in the superficial layers of the cortex). All of the FTLD-FUS of this series cases were affected by neuronal intermediate filament inclusion disease (NIFID). They were young. The survival was short. In the FTLD-tau group, mutations P301P (previously not recognized as pathogenic), P301L and S305N were identified. Pick disease (n = 5) appeared as a homogeneous sporadic disorder. The current nomenclature allows the neuropathological classification of nearly all the cases of FTD. The prevalence of the different types of FTD is tightly linked to the recruitment. This series was enriched in motor neuron disease (explaining the overall predominance of type 2 TDP inclusions).Acta Neurovegetativa 05/2011; 118(5):753-64. · 2.73 Impact Factor -
Article: Identification of novel FUS mutations in sporadic cases of amyotrophic lateral sclerosis.
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ABSTRACT: Mutations in the FUS gene have been recently associated with amyotrophic lateral sclerosis (ALS). While most of the variants have been identified in patients with a family history of the disease, a few mutations were also found in sporadic patients. Considering this, we wanted to evaluate the frequency of mutations in the coding region of the FUS gene in a sporadic ALS (SALS) cohort compared to a control population. We tested 475 SALS cases of European origin and 475 matched controls for coding variations in the 15 exons of the FUS gene. Rare novel variants were identified in a total of five SALS patients: one missense, one deletion, one frameshift, and one nonsense substitution. Two of the four variants are located in the carboxy terminal of the protein where the previously reported variants were mostly clustered. In conclusion, FUS gene mutations are rare in SALS, with four new FUS variants identified in five different SALS cases. These findings will help evaluate the proportion of FUS variations in the SALS population, and to better understand its contributing role to ALS pathology.Amyotrophic Lateral Sclerosis 03/2011; 12(2):113-7. · 3.40 Impact Factor -
Article: Disease severity and progression in progressive supranuclear palsy and multiple system atrophy: validation of the NNIPPS--Parkinson Plus Scale.
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ABSTRACT: The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS) study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n = 362) and Multiple System Atrophy (MSA, n = 398). To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study. Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n = 116), validity (n = 760), and responsiveness (n = 642). Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach α ≥ 0.70). Inter-rater reliability was high for the total score (Intra-class coefficient = 0.94) and 9 dimensions (Intra-class coefficient = 0.80-0.93), and moderate (Intra-class coefficient = 0.54-0.77) for 6. Correlations of the total score with other clinical measures of severity were good (rho ≥ 0.70). The total score was significantly and linearly related to survival (p<0.0001). Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM = 1.10), though higher in PSP (SRM = 1.25) than in MSA (SRM = 1.0), indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall severity and progression was similar. The NNIPPS-PPS has suitable validity, is reliable and sensitive, and therefore is appropriate for use in clinical studies with PSP or MSA. ClinicalTrials.gov NCT00211224.PLoS ONE 01/2011; 6(8):e22293. · 4.09 Impact Factor
Top co-authors
Top Journals
Institutions
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2007–2012
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INSERM, GIP CYCERON
Caen, Basse-Normandie, France
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2011
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Université du Québec à Montréal
Montréal, Quebec, Canada
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2007–2011
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Assistance Publique – Hôpitaux de Paris
- Département de Neurologie
Paris, Ile-de-France, France
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2010
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Université de Strasbourg
Strasbourg, Alsace, France -
Université de Versailles Saint-Quentin
Versailles, Ile-de-France, France -
Centre Hospitalier Universitaire de Nantes
Nantes, Pays de la Loire, France
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2007–2010
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Université Pierre et Marie Curie Paris 6
- Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière
Paris, Ile-de-France, France
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2002–2010
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Hôpital La Pitié Salpêtrière – Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix"
Paris, Ile-de-France, France
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2009
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Institut national de la santé et de la recherche médicale
Paris, Ile-de-France, France -
Columbia University
- Department of Neurology
New York City, NY, USA
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2008
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Centre hospitalier de l'Université de Montréal (CHUM)
Montréal, Quebec, Canada
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2006
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Université Paris Descartes
Paris, Ile-de-France, France -
Brigham and Women's Hospital
- Brigham and Women's Hospital and Harvard Medical School
Boston, MA, USA
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2005
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Institut Universitaire de France
Paris, Ile-de-France, France
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2004
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Université de Rennes 1
- Faculté de Médecine
Rennes, Brittany, France
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