Search

(1) Background: Motor neuron diseases (MNDs) are fatal neurodegenerative diseases. Biomarkers could help in defining patients’ prognosis and stratification. Beyond neurofilaments, chitinases are a promising family of possible biomarker, which correlate with neuroinflammatory status. We evaluated plasmatic levels of CHI3L1 in MNDs, MND mimics and healthy controls (HCs); (2) Methods: We used Sandwich ELISA to quantify CHI3L1 in plasma samples from 44 MNDs, 7 HSP, 9 MND mimics and 19 HCs. We collect also ALSFRSr scale, MRC scale, spirometry, mutational status, progression rate (PR), blood sampling, neuropsychological evaluation; (3) Results: Plasma levels of CHI3L1 resulted to be different among groups (p= 0.005). Particularly, MND mimics showed higher CHI3L1 levels compared to MNDs and HCs. CHI3LI levels did not differ among PMA, PLS and ALS and we do not find correlation among CHI3L1 levels and clinical scores, spirometry parameters, PR, and neuropsychological features. Of note, red blood cells count and haemoglobin correlated with CHI3L1 levels (respectively, p

(1) Background: Motor neuron diseases (MNDs) are fatal neurodegenerative diseases. Biomarkers could help with defining patients’ prognoses and stratifications. Besides neurofilaments, chitinases are a promising family of possible biomarkers which correlate with neuroinflammatory status. We evaluated the plasmatic levels of CHI3L1 in MNDs, MND mimics, and healthy controls (HCs). (2) Methods: We used a sandwich ELISA to quantify the CHI3L1 in plasma samples from 44 MND patients, 7 hereditary spastic paraplegia (HSP) patients, 9 MND mimics, and 19 HCs. We also collected a ALSFRSr scale, MRC scale, spirometry, mutational status, progression rate (PR), blood sampling, and neuropsychological evaluation. (3) Results: The plasma levels of the CHI3L1 were different among groups (p = 0.005). Particularly, the MND mimics showed higher CHI3L1 levels compared with the MND patients and HCs. The CHI3L1 levels did not differ among PMA, PLS, and ALS, and we did not find a correlation among the CHI3L1 levels and clinical scores, spirometry parameters, PR, and neuropsychological features. Of note, the red blood cell count and haemoglobin was correlated with the CHI3L1 levels (respectively, p < 0.001, r = 0.63; p = 0.022, and r = 0.52). (4) Conclusions: The CHI3L1 plasma levels were increased in the MND mimics cohort compared with MNDs group. The increase of CHI3L1 in neuroinflammatory processes could explain our findings. We confirmed that the CHI3L1 plasma levels did not allow for differentiation between ALS and HCs, nor were they correlated with neuropsychological impairment.

Amyotrophic lateral sclerosis (ALS) is known to represent a collection of overlapping syndromes. Various classification systems based on empirical observations have been proposed, but it is unclear to what extent they reflect ALS population substructures. We aimed to use machine-learning techniques to identify the number and nature of ALS subtypes to obtain a better understanding of this heterogeneity, enhance our understanding of the disease, and improve clinical care.In this retrospective study, we applied unsupervised Uniform Manifold Approximation and Projection [UMAP]) modelling, semi-supervised (neural network UMAP) modelling, and supervised (ensemble learning based on LightGBM) modelling to a population-based discovery cohort of patients who were diagnosed with ALS while living in the Piedmont and Valle d'Aosta regions of Italy, for whom detailed clinical data, such as age at symptom onset, were available. We excluded patients with missing Revised ALS Functional Rating Scale (ALSFRS-R) feature values from the unsupervised and semi-supervised steps. We replicated our findings in an independent population-based cohort of patients who were diagnosed with ALS while living in the Emilia Romagna region of Italy.Between Jan 1, 1995, and Dec 31, 2015, 2858 patients were entered in the discovery cohort. After excluding 497 (17%) patients with missing ALSFRS-R feature values, data for 42 clinical features across 2361 (83%) patients were available for the unsupervised and semi-supervised analysis. We found that semi-supervised machine learning produced the optimum clustering of the patients with ALS. These clusters roughly corresponded to the six clinical subtypes defined by the Chiò classification system (ie, bulbar, respiratory, flail arm, classical, pyramidal, and flail leg ALS). Between Jan 1, 2009, and March 1, 2018, 1097 patients were entered in the replication cohort. After excluding 108 (10%) patients with missing ALSFRS-R feature values, data for 42 clinical features across 989 patients were available for the unsupervised and semi-supervised analysis. All 1097 patients were included in the supervised analysis. The same clusters were identified in the replication cohort. By contrast, other ALS classification schemes, such as the El Escorial categories, Milano-Torino clinical staging, and King's clinical stages, did not adequately label the clusters. Supervised learning identified 11 clinical parameters that predicted ALS clinical subtypes with high accuracy (area under the curve 0·982 [95% CI 0·980-0·983]).Our data-driven study provides insight into the ALS population substructure and confirms that the Chiò classification system successfully identifies ALS subtypes. Additional validation is required to determine the accuracy and clinical use of these algorithms in assigning clinical subtypes. Nevertheless, our algorithms offer a broad insight into the clinical heterogeneity of ALS and help to determine the actual subtypes of disease that exist within this fatal neurodegenerative syndrome. The systematic identification of ALS subtypes will improve clinical care and clinical trial design.US National Institute on Aging, US National Institutes of Health, Italian Ministry of Health, European Commission, University of Torino Rita Levi Montalcini Department of Neurosciences, Emilia Romagna Regional Health Authority, and Italian Ministry of Education, University, and Research.For the Italian and German translations of the abstract see Supplementary Materials section.

Amyotrophic Lateral Sclerosis (ALS) is a specific disease that causes the death of neurons controlling voluntary muscles. The death affects Upper Motor Neurons (UMN) and Lower Motor Neurons (LMN). In this paper, we aim to identify UMN, LMN ALS patients and healthy subjects by studying their Electromyography (EMG) signals. More specifically, the Right Anterior Tibialis (RAT) muscle, responsible of dorsiflexing and inverting the foot during walking is studied. The solution is mainly composed of two blocks: features extraction and classification. A large feature vector, combining statistics, time, frequency and time-frequency domains features is extracted and their relevance is checked. Then, many classification techniques are tested in order to identify the most powerful ones. Finally, a dimensionality reduction, using both Principal Component Analysis and Sequential Forward Selection technique is carried out in order to select the most relevant features. Simulation results achieved 97% of overall accuracy for healthy/LMN/UMN separation and more than 99% for healthy/ALS and LMN/UMN classification.

The aetiology of Amyotrophic Lateral Sclerosis (ALS), a fatal and incurable disease caused by motor neuron degeneration, is still poorly understood. The discovery of genetic forms of ALS helped to shed light on the mechanisms underlying this pathology, but also showed how complex these mechanisms are. Excitotoxicity is one of the processes strongly suspected to play a role in motor neuron degeneration in ALS. This process consists in neuron damage due to excessive intake of calcium ions (Ca2+) by the cell. This study aims to find a relationship between the proteins coded by the most relevant genes associated with ALS and excitotoxicity. In detail, the profile of eight proteins (TDP-43, C9ORF72, p62/SQSTM1, matrin3, VCP, FUS, SOD1 and profilin-1), was analysed in three different cell types induced to raise their cytoplasmic amount of Ca2+. Intracellular Ca2+ accumulation causes a significant decrease in the levels of TDP-43, C9ORF72, matrin3, VCP, FUS, SOD1 and profilin-1 and an increase in p62/SQSTM1. These events are associated to the proteolytic action of two proteases, calpains and caspases, as well as to the activation of autophagy, a process responsible for the degradation and recycling of cytoplasmic components. Interestingly, Ca2+ appears to both favour and hinder autophagy. The discovery of when Ca2+ levels become toxic for the cell, as well as understanding why the physiological processes of calpain proteolysis and autophagy become pathological, may elucidate the mechanisms responsible for ALS and help discover new therapeutic targets.

We report a case of childhood-onset ALS with a FUS gene mutation presenting cognitive impairment and a rapid clinical progression. The patient, an 11-year-old girl, presented with right distal upper limb weakness and mild intellectual disability at the Griffith Mental Development Scales. The disease rapidly worsened and the patient became tetraplegic and bed-ridden 2 years after symptom onset. A c.1509_1510delAG mutation in exon 14 of the FUS gene was detected, resulting in a predicted truncated protein, p.G504Wfs*12, lacking the nuclear localization signal. The levels of FUS mRNA in the proband were not significantly different compared to controls. Western immunoblot analysis showed that one antibody (500-526) detected in the proband ~50% of the amount of FUS protein compared to controls, while 3 other antibodies (2-27, 400-450 and FUS C-terminal), which recognize both wild type and the mutated FUS, detected 60% to 75% of the amount of the protein. These findings indicate that p.G504Wfs*12 FUS is more prone to undergo post-translational modification respect to wild type FUS.

Aggregation and cytoplasmic mislocalization of TDP-43 are pathological hallmarks of amyotrophic lateral sclerosis and frontotemporal dementia spectrum. However, the molecular mechanism by which TDP-43 aggregates form and cause neurodegeneration remains poorly understood. Cyclophilin A, also known as peptidyl-prolyl cis-trans isomerase A (PPIA), is a foldase and molecular chaperone. We previously found that PPIA interacts with TDP-43 and governs some of its functions, and its deficiency accelerates disease in a mouse model of amyotrophic lateral sclerosis. Here we characterized PPIA knock-out mice throughout their lifespan and found that they develop a neurodegenerative disease with key behavioural features of frontotemporal dementia, marked TDP-43 pathology and late-onset motor dysfunction. In the mouse brain, deficient PPIA induces mislocalization and aggregation of the GTP-binding nuclear protein Ran, a PPIA interactor and a master regulator of nucleocytoplasmic transport, also for TDP-43. Moreover, in absence of PPIA, TDP-43 autoregulation is perturbed and TDP-43 and proteins involved in synaptic function are downregulated, leading to impairment of synaptic plasticity. Finally, we found that PPIA was downregulated in several patients with amyotrophic lateral sclerosis and amyotrophic lateral sclerosis-frontotemporal dementia, and identified a PPIA loss-of-function mutation in a patient with sporadic amyotrophic lateral sclerosis . The mutant PPIA has low stability, altered structure and impaired interaction with TDP-43. These findings strongly implicate that defective PPIA function causes TDP-43 mislocalization and dysfunction and should be considered in future therapeutic approaches., Pasetto et al. show that PPIA helps protect against TDP-43-mediated neurodegeneration. They identify a PPIA loss-of-function mutation in a patient with sporadic ALS, and reveal reduced PPIA levels in several other ALS and ALS-FTD patients. PPIA knock-out mice develop a neurodegenerative disease with a clear ALS-FTD phenotype.

Objective: To investigate the impact of a novel heterozygous FUS mutation in the acceptor splice site of intron 14 (c.1542 ��� 1 g > t) on protein expression in Peripheral Blood Mononuclear Cells (PBMC) from a familial ALS patient. Methods: PBMC were isolated for mRNA analysis (cDNA synthesis, sequencing and one-step RT-PCR), Western Immunoblot (WI), and Immunofluorescence (IF). Results: cDNA analysis revealed the skipping of exon 15 and a premature stop codon at c.228. RT-PCR showed reduced FUS mRNA by more than half compared to a healthy control (HC) and an ALS patient without genetic mutations (wtALS). In WI FUS band intensity in the proband was 30���50% compared to HC and wtALS. An antibody expected to detect only the wild-type protein did not reveal any reduction of FUS band intensity compared to the other antibodies. IF showed no difference among HC, wtALS, and the proband. Discussion: The reduction of FUS mRNA and protein in PBMC suggests the absence of the truncated protein, probably due to nonsense-mediated decay, leading to loss of function.

The research has been carried out in order to understand if mental preparation (motor imagery) influences (increases) force level control, by viewing the achieved force level in accordance with the one required by the task. To do it, thirty six young healthy subjects performed isometric forearm contractions at 3 force levels (low, medium, high) of their maximal voluntary contraction. Half of the subjects have mentally prepared their motion (motor imagery) before to perform the exercise and the other half have performed the exercise without motor imagery (control group). The work is composed of three parts. The first one was devoted to force signal processing: baseline rectification, denoising and features extraction. The second part was devoted to unsupervised classification which aims re-organizing the realized force levels to three real separated classes. The third part aimed to provide results of force level self-control and regulation. We mainly show that mental preparation increase the performance the force level respect.

Aggregation and cytoplasmic mislocalization of TDP-43 are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum. However, the molecular mechanism by which TDP-43 aggregates form and cause neurodegeneration remains poorly understood. Cyclophilin A, also known as peptidyl-prolyl cis-trans isomerase A (PPIA), is a foldase and molecular chaperone. We previously found that PPIA interacts with TDP-43 and governs some of its functions, and its deficiency accelerates disease in a mouse model of ALS. Here we characterized PPIA knock-out mice throughout their lifespan and found that they develop a neurodegenerative disease with key behavioural features of FTD, marked TDP-43 pathology and late-onset motor dysfunction. In the mouse brain, deficient PPIA induces aggregation of the GTP-binding nuclear protein Ran, a PPIA substrate required for TDP-43 nucleocytoplasmic trafficking. Moreover, in absence of PPIA, TDP-43 autoregulation is perturbed and TDP-43 and proteins involved in synaptic function are downregulated, leading to impairment of synaptic plasticity. Finally, we found that PPIA was downregulated in several ALS and ALS-FTD patients and identified a PPIA loss-of-function mutation in a sporadic ALS patient. The mutant PPIA has low stability, altered structure and impaired interaction with TDP-43. These findings strongly implicate that defective PPIA function causes TDP-43 mislocalization and dysfunction and should be considered in future therapeutic approaches.

In this study, we employed a visuo-motor imagery task of alertness as a mental training to examine temporal processing of motor responses within healthy young adults. Participants were divided into two groups (group 1; n = 20 who performed the mental training before the real physical task and a control group who performed the physical task without mental training). We vary the time interval between the imperative stimulus and the preceding one (fore-period) in which temporal preparation and arousal increase briefly. Our behavioural results provide clear evidence that mental training reinforces both temporal preparation and arousal, by shortening reaction time (RT), especially for the shortest fore-periods (FP) within exogenous "FP 250 ms" (p = 0.008) and endogenous alertness "FP 650 ms" (p = 0.001). We investigated how the brain controls such small temporal changes. We focus our neural hypothesis on three brain regions: anterior insula, dorsolateral prefrontal cortex, and anterior cingulate cortex and three putative circuits: one top-down (from dorsolateral prefrontal cortex to anterior cingulate cortex) and two bottom-up (from anterior insula to dorsolateral prefrontal cortex and anterior cingulate cortex). In fMRI, effective connectivity is strengthened during exogenous alertness between anterior insula and dorsolateral prefrontal cortex (p = 0.001), between anterior insula and cingulate cortex (p = 0.01), and during endogenous alertness between dorsolateral prefrontal cortex and anterior cingulate cortex (p = 0.05). We suggest that attentional reinforcement induced by an intensive and short session of mental training induces a temporal deployment of attention and allow optimizing the time pressure by maintaining a high state of arousal and ameliorating temporal preparation.

Purpose This study aimed to investigate the effects of partial sleep deprivation (PSD) on physical performance and psychophysiological responses during 12-minute self-paced running exercise. Methods Twenty runners (20.8±1.1 years, 70.6±4.9 kg, 175.1±3.9 cm) performed, in a randomized order, two running self-paced field exercises after a normal sleep night (CONT, bedtime from 22:30 h to 06:30 h) and one night of PSD (bedtime from 00:30 h to 04:30 h). Core temperature and motivation were recorded before exercise. Speed, covered distance, heart rate (HR), rating of perceived exertion (RPE) and respiratory parameters (i.e., minute ventilation (VE), oxygen uptake (VO2) and carbon dioxide production (VCO2)) were assessed during exercise. Blood lactate concentration [La] was assessed 2 min after exercise. Simple reaction time (SRT), mood and barrage test (BT) were assessed before and after exercise. Results Higher RPE (p=0.01, d=0.90) and lower physical performance (i.e., p=0.001, d=0.59 for running speed and p=0.01, d=0.7 and Δ (%)=-6% for covered distance), following PSD, were obtained compared to CONT. Similarly, PSD attenuated core temperature (p=0.01, d=0.84), HR (p=0.006, ɳp2=0.45), VE (p=0.001, ɳp2=0.73), VO2 (p=0.001, ɳp2=0.96), BT (p Conclusion The decrease of running performance and the increase of physical discomfort after PSD could be the origin of the lower cardio-respiratory responses to the 12-minute self-paced exercise. Effective strategies should be introduced to overcome the deterioration of physical performance and physiological responses after PSD.

BACKGROUND Gait impairment is poorly characterized in amyotrophic lateral sclerosis (ALS), despite increasing evidence of extrapyramidal and cerebellar dysfunction. Gait impairment adds to the considerable motor disability of ALS patients and requires targeted multidisciplinary interventions. PURPOSE To assess gait imagery-specific networks and functional adaptation in ALS. STUDY TYPE Prospective. POPULATION Seventeen ALS patients with lower motor neuron predominant (LMNp) disability, 14 patients with upper motor neurons predominant (UMNp) disease, and 14 healthy controls were included. FIELD STRENGTH/SEQUENCES 3T / gradient echo echo planar (GE-EPI). ASSESSMENT Subjects performed a dual motor imagery task: normal and precision gait. The Movement Imagery Questionnaire - Revised Second Version (MIQ-rs) was used to appraise movement imagery in each participant. Study group-specific activation patterns were evaluated during motor imagery of gait. Additional generalized psychophysiological interaction analyses were carried out using the supplementary motor area, caudate, cerebellum, and superior parietal lobule as seed regions. STATISTICAL TESTS Repeated-measures analysis of variance (ANOVA) was used to compare time imagery and MIQ-rs scores between groups. Size effects were also reported as partial eta squared (η2). One-way ANOVA was performed to explore differences in terms of connexions during motor imagery tasks. RESULTS A significant increase in imagery time in UMNp patients compared to controls (P

D’enormes progres ont ete realises pour comprendre comment en matiere davantage financier les individus prennent des decisions. En revanche, peu de travaux dans la litterature demontrent comment les patients decident ou font des choix en matiere de traitement medicamenteux. Cette etude vise a examiner d’un point de vue neurologique et cognitif chez des sujets sains comment ils ponderent les benefices (reduction de la progression de la maladie) et les risques (effets secondaires des medicaments) lorsqu’ils decident de prendre (ou refuse) un traitement medicamenteux hypothetique. Nous cherchons a identifier, au niveau cerebral, les processus et les circuits neuronaux impliques dans la prise de decision medicamenteuse. Quatorze sujets, en bonne sante, ont participe a cette etude menee en IRMf ; ils ont effectue dans le scanner une tâche de « probability discounting » dont l’efficacite du traitement et les effets secondaires du medicament variaient chacun de 1 % a 99,9 %. Les reponses comportementales et de la conductance cutanee etaient mesurees. Sur le plan fonctionnel, le cortex orbitofrontal (OFC), le striatum ventral (VS), l’amygdale et l’insula etaient selectionnes pour comparer les changements d’activite et de connectivite effective pour des effets secondaires « leger » a « severe » du medicament. Les resultats comportementaux ont montre que les participants devaluaient les avantages du traitement lorsqu’ils etaient confrontes a un risque eleve d’effets secondaires du medicament. Les valeurs de conductance cutanee etaient significativement plus elevees lorsque les participants devaient prendre la decision de prendre un medicament avec des effets secondaires severes. Sur le plan cerebral, les regions OFC et VS, activees dans la condition legere, etaient associees a une probabilite elevee de prise du medicament. Aussi, ces regions demontraient une connectivite effective plus elevee lorsque les participants evaluaient (positivement) les benefices du traitement medicamenteux. En revanche, l’OFC, l’insula et l’amygdale, actives dans la condition severe, etaient associees a la probabilite de refuser le traitement. Ces regions ont montre une connectivite effective renforcee lorsque les participants etaient confrontes aux effets secondaires severes. Il s’agit de la premiere etude qui examine les bases neurales et comportementales de la prise de decision medicamenteuse.

International audience; In this study, we used fMRI to identify brain regions associated with concentration (sustained attention) during a motor preparation task. In comparison with a non-concentration task, increased activities were observed (P < 0.05, FWEcorrected P values) in cerebellar lobules VI and VII, motor cortex, pre-supplementary motor area (pre-SMA), thalamus, red nucleus (RN), and caudate nucleus (CN). Moreover, analysis of effective connectivity inter-areal (psychophysiological interactions) showed that during preparation, concentration-related brain activity increase was dependent on Cerebellothalamo-pre-SMA-RN and Pre-SMA-CN-thalamo-M1 loops. We postulate that, while pre-SMA common to both loops is specifically involved in the movement preparation and readiness for voluntary movement through the striatum, the cerebellar lobule VI in conjunction with RN, likely through a cerebellar-rubro-olivary-cerebellar loop, might be implicated in concentration-related optimization of upcoming motor performances.

D’enormes progres ont ete realises pour comprendre comment en matiere d’avantage financier les individus prennent des decisions. En revanche, peu de travaux dans la litterature demontrent comment les patients decident ou font des choix en matiere de traitements medicamenteux. Cette etude vise a examiner d’un point de vue neurologique et cognitif chez des sujets sains comment ils ponderent les benefices (reduction de la progression de la maladie) et les risques (effets secondaires des medicaments) lorsqu’ils decident de prendre (ou refusent) un traitement medicamenteux hypothetique. Nous cherchons a identifier, au niveau cerebral, les processus et les circuits neuronaux impliques dans la prise de decision medicamenteuse. Quatorze sujets, en bonne sante, ont participe a cette etude menee en IRMf ; ils ont effectue dans le scanner une tâche de « probability discounting » dont l’efficacite du traitement et les effets secondaires du medicament variaient chacun de 1 % a 99,9 %. Les reponses comportementales et de la conductance cutanee etaient mesurees. Sur le plan fonctionnel, le cortex orbitofrontal (OFC), le striatum ventral (VS), l’amygdale et l’insula etaient selectionnes pour comparer les changements d’activite et de connectivite effective pour des effets secondaires “legers” a “severes” du medicament. Les resultats comportementaux ont montre que les participants devaluaient les avantages du traitement lorsqu’ils etaient confrontes a un risque eleve d’effets secondaires du medicament. Les valeurs de conductance cutanee etaient significativement plus elevees lorsque les participants devaient prendre la decision de prendre un medicament avec des effets secondaires severes. Sur le plan cerebral, les regions OFC et VS, activees dans la condition leger, etaient associees a une probabilite elevee de prise du medicament. Aussi, ces regions demontraient une connectivite effective plus elevee lorsque les participants evaluaient (positivement) les benefices du traitement medicamenteux. En revanche, l’OFC, l’insula et l’amygdale, actives dans la condition severe, etaient associees a la probabilite de refuser le traitement. Ces regions ont montre une connectivite effective renforcee lorsque les participants etaient confrontes aux effets secondaires severes. Il s’agit de la premiere etude qui examine les bases neurales et comportementales de la prise de decision medicamenteuse.

Objectif Cette etude se proposait de determiner l’effet de la privation partielle du sommeil et de la fatigue mentale sur les reponses physiques et psychophysiologiques chez des coureurs de demi-fond. Methodes Quatorze coureurs de demi-fond volontaires (22 ± 1 ans, 73 ± 6 kg, 177 ± 4 cm) ont participe au protocole. Ils ont realise une epreuve de course a pied de 12 min contre la montre apres trois differentes sessions experimentales randomisees, La session S1 consistait en une nuit controle. La session S2 correspondait en une nuit controle suivie d’une tache cognitive intense et prolongee (30 minutes de test Stroop). La session S3 consistait en une privation partielle du sommeil suivie de la meme tache cognitive. La vitesse de course, les parametres cardiorespiratoires (frequence cardiaque [FC], debit ventilatoire [VE] et consommation d’oxygene [VO2]) ont ete moyennes chaque minute durant l’epreuve de course a pied. Le temps de reaction simple a ete evalue avant chaque session experimentale. Resultats FC, VE, VO2 et la vitesse de course diminuaient en S3 en comparaison avec S1 et S2 (p Conclusion La fatigue cumulee induite par une privation partielle du sommeil et une tache cognitive prolongee cause une alteration des parametres psychophysiologiques et une baisse de la performance. Une association de privation partielle du sommeil et une tache cognitive prolongee est a eviter avant chaque competition.

International audience; Introduction Extrapyramidal deficits are poorly characterised in amyotrophic lateral sclerosis (ALS) despite their contribu-tion 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

We report an apparently sporadic amyotrophic lateral sclerosis patient carrying a heterozygous novel frameshift SOD1 mutation (p.Ser108LeufsTer15), predicted to cause a premature protein truncation. RT-PCR analysis of SOD1 mRNA and SDS-PAGE/Western blot analysis of PBMC demonstrated that mRNA from the mutant allele is expressed at levels similar to those of the wild-type allele, but the truncated protein is undetectable also in the insoluble fraction and after proteasome inhibition. Accordingly, the dismutation activity in erythrocytes is halved. Thus, the pathogenic mechanism associated with this mutation might be based on an insufficient activity of SOD1 that would make motor neurons more vulnerable to oxidative injury. However, it cannot be excluded that p.Ser108LeufsTer15 SOD1 is present in the nervous tissue and, being less charged and hence having less repulsive forces than the wild-type protein, may trigger toxic mechanisms as a consequence of its propensity to aggregate.

International audience; BACKGROUND: The aim of the present study was to examine the effects of verbal encouragement on isometric force and associated electromyographic (EMG) parameters during a handgrip task.METHODS: Twenty-three participants (12 women and 11 men) performed maximal voluntary isometric handgrip contractions following three conditions: 1) verbal encouragement (VE) condition: participants executed isometric contractions while being verbally encouraged; 2) non-verbal encouragement (nVE) condition: the same starting and stopping signal but without encouragement; 3) non-concentration and non-motivation (nCM) condition: self-initiated contractions without concentration and motivation. Start and stop of the contraction were self-initiated. The maximal voluntary force (MVF) and the maximal rate of force development (MRFD) were measured. Integrated EMG corresponding to MVF (iEMGMVF) and to MRFD (iEMGMRFD) were collected from flexor digitorum superficialis (FDS) and extensor digitorum communis (EDC) muscles.RESULTS: MVF was higher during VE compared with nVE (+11.7%; P

International audience; Great progress has been made in understanding how people make financial decisions. However, there is little research on how people make health and treatment choices. Our study aimed to examine how participants weigh benefits (reduction in disease progression) and probability of risk (medications' side effects) when making hypothetical treatment decisions, and to identify the neural networks implicated in this process. Fourteen healthy participants were recruited to perform a treatment decision probability discounting task using MRI. Behavioral responses and skin conductance responses (SCRs) were measured. A whole brain analysis were performed to compare activity changes between "mild" and "severe" medications' side effects conditions. Then, orbitofrontal cortex (OFC), ventral striatum (VS), amygdala and insula were chosen for effective connectivity analysis. Behavioral data showed that participants are more likely to refuse medication when side effects are high and efficacy is low. SCRs values were significantly higher when people made medication decisions in the severe compared to mild condition. Functionally, OFC and VS were activated in the mild condition and were associated with increased likehood of choosing to take medication (higher area under the curve "AUC" side effects/efficacy). These regions also demonstrated an increased effective connectivity when participants valued treatment benefits. By contrast, the OFC, insula and amygdala were activated in the severe condition and were associated with and increased likelihood to refuse treatment. These regions showed enhanced effective connectivity when participants were confronted with increased side effects everity. This is the first study to examine the behavioral and neural bases of medical decision making.

International audience; Abstract : Background: The thumb plays a critical role for manual tasks during the activities of daily life and the incidence of neurological or musculoskeletal disorders affecting the voluntary movements of the thumb is high in the elderly. There is currently no tool to assess repetitive motor sequencing of the thumb during ageing.Objectives: To report a novel procedure (the Click Test) assessing the effects of ageing on fast motor sequencing of the thumb.Methods : Healthy subjects (n = 252; mean age +/- SD: 49.76 +/- 19.97 years; range: 19-89 years; F/M: 151/101) were asked to perform fast repeated flexion/extension movements of the thumb using a mechanical counter.Results: Motor performances (assessed by the number of clicks during 3 time periods: 15, 30 and 45 sec), significantly decreased as a function of age for both the dominant (age effect; p< 0.0001 for 15, 30 and 45 sec) and the non-dominant hand (p

International audience

Cortisol is an important hormone in the protective stress response system, the Hypothalamus-Pituitary-Adrenal (HPA axis). It becomes especially salient in immune suppression\ud syndromes such as multiple sclerosis and Cushing’s disease. Fatigue is a common symptom and mental and motor tasks are difficult and labored. The role of cortisol is mental and motor tasks and the recruitment of key brain regions in completion of these tasks is explored together with functional magnetic resonance imaging in healthy participants. Cortisol levels were found to be higher and had greater reduction in levels during mental versus motor tasks. Recruitment of brain stem and hypothalamus regions, important in cortisol activity, was affected differently. At low cortisol levels, mental task participants had less activity in the regions than their physical task counterparts. When cortisol levels were higher, widerspread recruitment of these brain regions was seen in the mental task participants, and for the physical task participants, the spread was at comparative low levels of cortisol. It is concluded that cortisol is implicated in these brain regions supporting the Thompson Cortisol Hypothesis and that brain region recruitment is likely to be dependent upon factors including cortisol levels as well as perception of stress in the task. It is suggested that mental tasks are perceived more stressful than physical but demand higher cortisol levels to promote wider spread brain region activity. Implication for neurological disease includes the use of cortisol in the proposed development of a potential new diagnostic biomarker for early detection of neurological sequelae.

Cortisol is an important hormone in the protective stress response system, the Hypothalamus-Pituitary-Adrenal (HPA-axis). It becomes especially salient in immune suppression syndromes such as multiple sclerosis and Cushing's disease. Fatigue is a common symptom and mental and motor tasks are difficult and labored. The role of cortisol is mental and motor tasks and the recruitment of key brain regions in completion of these tasks is explored together with functional magnetic resonance imaging in healthy participants. Cortisol levels were found to be higher and had greater reduction in levels during mental versus motor tasks. Recruitment of brain-stem and hypothalamus regions, important in cortisol activity, was affected differently. At low cortisol levels, mental task participants had less activity in the regions than their physical task counterparts. When cortisol levels were higher, wider spread recruitment of these brain regions was seen in the mental task participants, and for the physical task participants, the spread was at comparative low levels of cortisol. It is concluded that cortisol is implicated in these brain regions supporting the Thompson Cortisol Hypothesis and that brain region recruitment is likely to be dependent upon factors including cortisol levels as well as perception of stress in the task. It is suggested that mental tasks are perceived more stressful than physical but demand higher cortisol levels to promote wider spread brain region activity. Implication for neurological disease includes the use of cortisol in the proposed development of a potential new diagnostic biomarker for early detection of neurological sequelae.

TDP-43, encoded by TARDBP, is a ubiquitously expressed, primarily nuclear protein. In recent years, TDP-43 has been identified as the major pathological protein in ALS due to its mislocalisation in the cytoplasm of motor neurons of patients with and without TARDBP mutations and expression in forms that do not match its predicted molecular weight. In this study, the TDP-43 profile was investigated using western immunoblot analysis in whole lysates, nuclei and cytoplasm of circulating lymphomonocytes from 16 ALS patients, 4 with (ALS/TDP+) and 12 without (ALS/TDP-) TARDBP mutations in the protein C-terminal domain, and thirteen age-matched, healthy donors (controls). Three disease-unaffected first-degree relatives of an ALS/TDP+ patient were also included: one carried the parent mutation (Rel/TDP+) whereas the other two did not (Rel/TDP-). In all ALS patients, relatives and controls, TDP-43 retained the predicted molecular weight in whole cell lysates and nuclei, but in the cytoplasm its molecular weight was slightly smaller than expected. In quantitative terms, TDP-43 was expressed at approximately the same levels in whole cell lysates of ALS patients, relatives and controls. In contrast, TDP-43 accumulated in the cytoplasm with concomitant nuclear depletion in all ALS/TDP+ patients, in about 50% of ALS/TDP- patients and in the Rel/TDP+ subject compared to the controls. In the remaining ALS/TDP- patients and in the two Rel/TDP- subjects, TDP-43 matched the control levels in both subcellular compartments. Were these findings further confirmed, circulating lymphomonocytes could be informative of TDP-43 mislocalisation in nervous tissue and used as a biomarker for future disease risk.

Stimulation of naive CD4(+) T cells through engagement of the T-cell receptor (TCR) and the CD28 co-receptor initiates cell proliferation which critically depends on interleukin (IL)-2 secretion and subsequent autocrine signalling via the IL-2 receptor. However, several studies indicate that in CD28-costimulated T cells additional IL-2-independent signals are also required for cell proliferation. In this study, using a neutralizing anti-human IL-2 antibody and two selective, structurally unrelated, cell-permeable I-κB kinase (IKK) inhibitors, BMS-345541 and PS-1145, we show that in human naive CD4(+) T cells stimulated through a short engagement of the TCR and the CD28 co-receptor, IKK controls the expression of the cell cycle regulatory proteins cyclin D3, cyclin E and cyclin-dependent kinase 2 (CDK2) and the stability of the F-box protein S-phase kinase-associated protein 2 (SKP2) and its co-factor CDC28 protein kinase regulatory subunit 1B (CKS1B), through IL-2-independent mechanisms.

Introduction De nombreuses etudes montrent les benefices de la pratique de l’activite physique (AP) chez les patients atteints de sclerose en plaques (SEP). Mais l’adhesion des patients a l’AP est difficile a obtenir, et surtout, a maintenir. L’objectif de cette etude est d’evaluer deux types de soutiens visant a aider le patient a initier et a perenniser sa pratique. Materiels et methodes Quarante-cinq patients seront repartis aleatoirement dans 3 groupes : une intervention basee sur l’implementation d’intention [1] , une intervention basee sur la pleine conscience [2] et un groupe controle. Ces deux 1ers groupes beneficient d’un soutien internet et d’un soutien telephonique hebdomadaire. Les participants beneficient du meme programme d’AP, de 2 heures par semaines sur 2 mois. Des mesures d’actimetries sont effectuees avant et apres le programme sur une duree de 7 jours, puis, a 3 et a 6 mois apres le programme. Des questionnaires mesurant les changements de comportement au regard de la motivation a l’AP et des questionnaires mesurant l’impact des interventions complementaires, permettront de determiner l’efficacite des soutiens proposes. Enfin, des scores d’evaluations moteurs et psychologiques seront effectues. Resultats preliminaires Douze patients ont termine le programme a 3 mois. Ces resultats ne permettent actuellement pas de constater de differences significatives entre les groupes pour l’actimetrie, mais montrent une amelioration significative (p Conclusion Ces resultats preliminaires confirment l’efficacite de la pratique de l’AP sur les tests moteurs. Ils devront etre completes par un nombre de patients plus important pour observer des resultats sur l’actimetrie et sur l’impact des interventions sur la pratique de l’AP chez les patients.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder consisting of progressive loss of motor neurons. TDP‐43 has been identified as a component of ubiquitin‐immunoreactive inclusions of motor neurons in ALS. We focused on the diffuse cytoplasmic TDP‐43 immunoreactivity in ALS neurons, and quantitatively assessed it in comparison with skein/round TDP‐43 and ubiquitin immunostaining in motor neurons of 30 sporadic ALS cases. The percentage of spinal motor neurons with cytoplasmic TDP‐43 immunoreactivity was higher than that of ubiquitin‐immunoreactive ones. The percentage of TDP‐43‐positive motor neurons was independent of neuron counts in anterior horns, while the percentage of ubiquitinated neurons was inversely correlated. Aiming to define the cytosolic localization of TDP‐43, the immunoblot analysis of spinal cord and frontal cortex showed that full‐length TDP‐43, the 45 kDa form and ubiquitinated TDP‐43 are found in the soluble inclusion‐free fraction. The present data suggest that delocalization, accumulation and ubiquitination of TDP‐43 in the cytoplasm of motor neurons are early dysfunctions in the cascade of the events leading to motor neuron degeneration in ALS, preceding the formation of insoluble inclusion bodies. Being cytoplasmic accumulation an ongoing event during the course of the illness, a therapeutic approach to this incurable disease can be envisaged.

Functional neuroimaging first allowed researchers to describe the functional segregation of regionally activated areas during a variety of experimental tasks. More recently, functional integration studies have described how these functionally specialized areas (i.e. areas whose activity is temporally modified) interact within a highly distributed neural network. When applied to the field of functional magnetic resonance imaging (fMRI), structural equation modeling (SEM) uses theoretical and/or empirical hypotheses to estimate the effects (path coefficients) of an experimental task within a putative network. Structural equation modeling represents a linear technique for multivariate analysis of fMRI data and has been developed to simultaneously examine ratios of multiple causality in an experimental design; the method attempts to explain a covariance structure within an anatomical (constrained) model. This method, when combined with the concept of effective connectivity, can provide information on the strength and direction of the functional interactions which take place between identified nodes of a putative network. After having provided a brief reminder of the principle of the blood oxygen level-dependent (BOLD) contrast effect, the physiological bases of brain activity and the concepts of functional integration and effective connectivity, we specify the various steps in the SEM analysis and the use of fMRI data to explore putative networks of interconnected active areas.

International audience

Damage caused by tree root growth to archaeological monuments buried underground, over the course of centuries, has been frequently reported in the city of Rome. The Domus Aurea, Nero's Imperial residence, now lies under the Horti Traianei (Trajan's Park) on the Oppian hill. These gardens, planted at the beginning of the last century, are located only 3–4m above the surviving archaeological structures. In some cases roots have damaged the underlying vaults, sometimes creating serious structural problems. Results of the study show that a variety of species with strong root systems growing for many metres laterally, and to depths of several metres, are present. Identification of the plants responsible for the damage has been achieved through a study of the anatomy of their wood. A real and potential assessment of the risk posed by tree roots to the archaeological structures has been attempted. The data collected will contribute to evaluating the risk to monuments under similar conditions and will al...

Rationale and Objectives: Using magnetic resonance imaging (MRI), we investigated cerebral blood and cerebrospinal fluid (CSF) flows in patients with communicating hydrocephalus (CH) and in healthy volunteers to determine the contribution of CSF flow to brain pressure regulation in CH patients. Methods: Cine phase-contrast MRI data from 16 healthy volunteers and 12 patients with CH characterized by hyperdynamic aqueductal CSF flow were analyzed using in-house image-processing software that automatically measured flow curves. Amplitude and temporal CSF and blood flow parameters were compared in the 2 groups. Results: Jugular peak flow occurred significantly earlier (P 0.01) in the CH patients than in the healthy volunteers. Cervical CSF oscillations were not significantly different between the 2 groups. Conclusion: Venous vessel compression and/or changes in intracranial subarachnoid CSF flow produce an increase in ventricular CSF flush that compensates for vascular brain expansion in patients with CH.

Patterns of leukoaraiosis were analyzed on both T2-weighted fast fluid-attenuated inversion-recovery and 3D T1-weighted sequences in 23 community-dwelling older subjects with mild cognitive impairment. Mobility assessment had allowed their classification into higher and lower mobility groups (P