Publications by authors named "Anne-Catherine Bachoud-Levi"

103 Publications

Improving efficacy of aphasia rehabilitation by using Core Assessment of Language Processing.

Ann Phys Rehabil Med 2022 Jan 11:101630. Epub 2022 Jan 11.

Département d'Etudes Cognitives, École normale supérieure, PSL University, 75005 Paris, France; Univ Paris Est Creteil, INSERM U955, Institut Mondor de Recherche Biomédicale, Equipe NeuroPsychologie Interventionnelle, F-94010 Creteil, France. Electronic address:

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http://dx.doi.org/10.1016/j.rehab.2022.101630DOI Listing
January 2022

An MDS Evidence-Based Review on Treatments for Huntington's Disease.

Mov Disord 2022 Jan 29;37(1):25-35. Epub 2021 Nov 29.

Instituto de Medicina Molecular João Lobo Antunes, Lisbon, Portugal.

Background: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments.

Objectives: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers.

Methods: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention.

Results: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments.

Conclusions: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28855DOI Listing
January 2022

The specific role of the striatum in interval timing: The Huntington's disease model.

Neuroimage Clin 2021 27;32:102865. Epub 2021 Oct 27.

Département d'Etudes Cognitives, Ecole Normale Supérieure, PSL University, Paris, France; Université Paris Est, Faculté de Médecine, Créteil, France; Inserm U955, Equipe E01 Neuropsychologie Interventionnelle, Créteil, France; AP-HP, Centre de référence Maladie de Huntington, Service de Neurologie, Hôpital Henri Mondor-Albert Chenevier, Créteil, France; NeurATRIS, Creteil, France.

Time processing over intervals of hundreds of milliseconds to minutes, also known as interval timing, is associated with the striatum. Huntington's disease patients (HD) with striatal degeneration have impaired interval timing, but the extent and specificity of these deficits remain unclear. Are they specific to the temporal domain, or do they extend to the spatial domain too? Do they extend to both the perception and production of interval timing? Do they appear before motor symptoms in Huntington's disease (Pre-HD)? We addressed these issues by assessing both temporal abilities (in the seconds range) and spatial abilities (in the cm range) in 20 Pre-HD, 25 HD patients, and 25 healthy Controls, in discrimination, bisection and production paradigms. In addition, all participants completed a questionnaire assessing temporal and spatial disorientation in daily life, and the gene carriers (i.e., HD and Pre-HD participants) underwent structural brain MRI. Overall, HD patients were more impaired in the temporal than in the spatial domain in the behavioral tasks, and expressed a greater disorientation in the temporal domain in the daily life questionnaire. In contrast, Pre-HD participants showed no sign of a specific temporal deficit. Furthermore, MRI analyses indicated that performances in the temporal discrimination task were associated with a larger striatal grey matter volume in the striatum in gene carriers. Altogether, behavioral, brain imaging and questionnaire data support the hypothesis that the striatum is a specific component of interval timing processes. Evaluations of temporal disorientation and interval timing processing could be used as clinical tools for HD patients.
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http://dx.doi.org/10.1016/j.nicl.2021.102865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8569718PMC
January 2022

Cognitive decline in Huntington's disease in the Digitalized Arithmetic Task (DAT).

PLoS One 2021 23;16(8):e0253064. Epub 2021 Aug 23.

Département d'Etudes Cognitives, École normale supérieure, PSL University, Paris, France.

Background: Efficient cognitive tasks sensitive to longitudinal deterioration in small cohorts of Huntington's disease (HD) patients are lacking in HD research. We thus developed and assessed the digitized arithmetic task (DAT), which combines inner language and executive functions in approximately 4 minutes.

Methods: We assessed the psychometric properties of DAT in three languages, across four European sites, in 77 early-stage HD patients (age: 52 ± 11 years; 27 females), and 57 controls (age: 50 ± 10, 31 females). Forty-eight HD patients and 34 controls were followed up to one year with 96 participants who underwent MRI brain imaging (HD patients = 46) at baseline and 50 participants (HD patients = 22) at one year. Linear mixed models and Pearson correlations were used to assess associations with clinical assessment.

Results: At baseline, HD patients were less accurate (p = 0.0002) with increased response time (p<0.0001) when compared to DAT in controls. Test-retest reliability in HD patients ranged from good to excellent for response time (range: 0.63-0.79) and from questionable to acceptable for accuracy (range: r = 0.52-0.69). Only DAT, the Mattis Dementia Rating Scale, the Symbol Digit Modalities Test, and Total Functional Capacity scores were able to detect a decline within a one-year follow-up in HD patients (all p< 0.05). In contrast with all the other cognitive tasks, DAT correlated with striatal atrophy over time (p = 0.037) but not with motor impairment.

Conclusions: DAT is fast, reliable, motor-free, applicable in several languages, and able to unmask cognitive decline correlated with striatal atrophy in small cohorts of HD patients. This likely makes it a useful endpoint in future trials for HD and other neurodegenerative diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253064PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382187PMC
November 2021

Learning spectro-temporal representations of complex sounds with parameterized neural networks.

J Acoust Soc Am 2021 07;150(1):353

Ecole des Hautes Etudes en Sciences Sociales, CNRS, Institut National de Recherche informatique et Automatique, Département d'Études Cognitives, Ecole Normale Supérieure-Paris Sciences et Lettres University, 29 Rue d'Ulm, 75005 Paris, France.

Deep learning models have become potential candidates for auditory neuroscience research, thanks to their recent successes in a variety of auditory tasks, yet these models often lack interpretability to fully understand the exact computations that have been performed. Here, we proposed a parametrized neural network layer, which computes specific spectro-temporal modulations based on Gabor filters [learnable spectro-temporal filters (STRFs)] and is fully interpretable. We evaluated this layer on speech activity detection, speaker verification, urban sound classification, and zebra finch call type classification. We found that models based on learnable STRFs are on par for all tasks with state-of-the-art and obtain the best performance for speech activity detection. As this layer remains a Gabor filter, it is fully interpretable. Thus, we used quantitative measures to describe distribution of the learned spectro-temporal modulations. Filters adapted to each task and focused mostly on low temporal and spectral modulations. The analyses show that the filters learned on human speech have similar spectro-temporal parameters as the ones measured directly in the human auditory cortex. Finally, we observed that the tasks organized in a meaningful way: the human vocalization tasks closer to each other and bird vocalizations far away from human vocalizations and urban sounds tasks.
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http://dx.doi.org/10.1121/10.0005482DOI Listing
July 2021

A case-study of language-specific executive disorder.

Cogn Neuropsychol 2021 Feb-Mar;38(2):125-137. Epub 2021 Jun 22.

Univ Paris Est Creteil, INSERM U955, Institut Mondor de Recherche Biomédicale, Equipe NeuroPsychologie Interventionnelle, Créteil, France.

Executive control is recruited for language processing, particularly in complex linguistic tasks. Although the issue of the existence of an executive control specific to language is still an open issue, there is much evidence that executively-demanding language tasks rely on domain-general rather than language-specific executive resources. Here, we addressed this issue by assessing verbal and non-verbal executive capacities in LG, an aphasic patient after a stroke. First, we showed that LG's performance was spared in all non-verbal tasks regardless of the executive demands. Second, by contrasting conditions of high and low executive demand in verbal tasks, we showed that LG was only impaired in verbal task with high executive demand. The performance dissociation between low and high executive demand conditions in the verbal domain, not observed in the non-verbal domain, shows that verbal executive control partly dissociates from non-verbal executive control. This language-specific executive disorder suggests that some executive processes might be language-specific.
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http://dx.doi.org/10.1080/02643294.2021.1941828DOI Listing
September 2021

Striatum and language processing: Where do we stand?

Cognition 2021 08 29;213:104785. Epub 2021 May 29.

Département d'Etudes Cognitives, École normale supérieure, PSL University, 75005 Paris, France; Inserm U955, Institut Mondor de Recherche Biomédicale, Equipe E01 NeuroPsychologie Interventionnelle, 94000 Créteil, France; Université Paris-Est Créteil, Faculté de médecine, 94000 Créteil, France; Assistance Publique-Hôpitaux de Paris, National Reference Center for Huntington's Disease, Neurology Department, Henri Mondor-Albert Chenevier Hospital, Créteil, France. Electronic address:

More than a century ago, Broca (1861), Wernicke (1874) and Lichteim (1885) laid the foundations for the first anatomo-functional model of language, secondarily enriched by Geschwind (1967), leading to the Broca-Wernicke-Lichteim-Geschwind model. This model included the frontal, parietal, and temporal cortices as well as a subcortical structure, which could be the striatum, whose nature and role have remained unclear. Although the emergence of language deficits in patients with striatal injury has challenged the cortical language models developed over the past 30 years, the integration of the striatum into language processing models remains rare. The main argument for not including the striatum in language processing is that the disorders observed in patients with striatal dysfunction may result from the striatal role in cognitive functions beyond language, and not from the impairment of language itself. Indeed, unraveling the role of the striatum and the frontal cortex, linked by the fronto-striatal pathway, is a challenge. Here, we first reviewed the studies that explored the link between striatal functions and the different levels of language (phonetics, phonology, morphology, syntax, and lexico-semantics). We then looked at the language models, which included the striatum, and found that none of them captured the diversity of experimental data in this area. Finally, we propose an integrative anatomo-functional model of language processing combining traditional language processing levels and some "executive" functions, known to improve the efficiency and fluidity of language: control, working memory, and attention. We argue that within this integrative model, the striatum is a central node of a verbal executive network that regulates, monitors, and controls the allocations of limited cognitive resources (verbal working memory and verbal attention), whatever the language level. This model combines data from neurology, psycholinguistics, and cognitive science.
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http://dx.doi.org/10.1016/j.cognition.2021.104785DOI Listing
August 2021

Mild encephalopathy with reversible splenial lesion: Description of nine cases and review of the literature.

Seizure 2021 May 3;88:83-86. Epub 2021 Apr 3.

Department of Neurology, Henri Mondor Hospital, Public Hospitals of Paris Organisation, Paris, France. Electronic address:

Mild encephalopathy/encephalitis with reversible splenial lesion (MERS) is a transient clinico-radiological syndrome characterized by non-specific encephalopathy and specific magnetic resonance imaging (MRI) pattern. MRI shows an ovoid lesion in the mid-splenium of the corpus callosum (SCC), with signal-intensity anomaly similar to stroke but vanishing within few weeks. Although there are a lot of child MERS cases descriptions, there are just a few adult-onset reported. Our goal is to provide a better clinical and radiological description of this entity. We reported nine adult-onset cases of MERS managed in our stroke unit between 2017 and 2019. The study of our adult series suggests that epilepsy and the context of an infection are very common in MERS. Adult cases show frequent focal neurological deficits and few encephalopathies compared to children. The measurement of very low ADC values in SCC lesion is a new radiological feature of MERS that should be systematically assessed in suspected cases to differentiate this complex syndrome from SCC strokes.
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http://dx.doi.org/10.1016/j.seizure.2021.03.032DOI Listing
May 2021

Objectively characterizing Huntington's disease using a novel upper limb dexterity test.

J Neurol 2021 Jul 8;268(7):2550-2559. Epub 2021 Feb 8.

Centre for Trials Research, Cardiff University, 4th Floor, Neuadd Meirionnydd, Heath Park, Cardiff, CF14 4YS, United Kingdom.

Background: The Clinch Token Transfer Test (C3t) is a bi-manual coin transfer task that incorporates cognitive tasks to add complexity. This study explored the concurrent and convergent validity of the C3t as a simple, objective assessment of impairment that is reflective of disease severity in Huntington's, that is not reliant on clinical expertise for administration.

Methods: One-hundred-and-five participants presenting with pre-manifest (n = 16) or manifest (TFC-Stage-1 n = 39; TFC-Stage-2 n = 43; TFC-Stage-3 n = 7) Huntington's disease completed the Unified Huntington's Disease Rating Scale and the C3t at baseline. Of these, thirty-three were followed up after 12 months. Regression was used to estimate baseline individual and composite clinical scores (including cognitive, motor, and functional ability) using baseline C3t scores. Correlations between C3t and clinical scores were assessed using Spearman's R and visually inspected in relation to disease severity using scatterplots. Effect size over 12 months provided an indication of longitudinal behaviour of the C3t in relation to clinical measures.

Results: Baseline C3t scores predicted baseline clinical scores to within 9-13% accuracy, being associated with individual and composite clinical scores. Changes in C3t scores over 12 months were small ([Formula: see text] ≤ 0.15) and mirrored the change in clinical scores.

Conclusion: The C3t demonstrates promise as a simple, easy to administer, objective outcome measure capable of predicting impairment that is reflective of Huntington's disease severity and offers a viable solution to support remote clinical monitoring. It may also offer utility as a screening tool for recruitment to clinical trials given preliminary indications of association with the prognostic index normed for Huntington's disease.
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http://dx.doi.org/10.1007/s00415-020-10375-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868671PMC
July 2021

The European Reference Network for Rare Neurological Diseases.

Front Neurol 2020 14;11:616569. Epub 2021 Jan 14.

Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

While rare diseases (RDs) are by definition of low prevalence, the total number of patients suffering from an RD is high, and the majority of them have neurologic manifestations, involving central, peripheral nerve, and muscle. In 2017, 24 European Reference Networks (ERNs), each focusing on a specific group of rare or low-prevalence complex diseases, were formed to improve the care for patients with an RD. One major aim is to have "the knowledge travel instead of the patient," which has been put into practice by the implementation of the Clinical Patient Management System (CPMS) that enables clinicians to perform pan-European virtual consultations. The European Reference Network for Rare Neurological Diseases (ERN-RND) provides an infrastructure for knowledge sharing and care coordination for patients affected by a rare neurological disease (RND) involving the most common central nervous system pathological conditions. It covers the following disease groups: (i) Cerebellar Ataxias and Hereditary Spastic Paraplegias; (ii) Huntington's disease and Other Choreas; (iii) Frontotemporal dementia; (iv) Dystonia, (non-epileptic) paroxysmal disorders, and Neurodegeneration with Brain Iron Accumulation; (v) Leukoencephalopathies; and (vi) Atypical Parkinsonian Syndromes. At the moment, it unites 32 expert centers and 10 affiliated partners in 21 European countries, as well as patient representatives, but will soon cover nearly all countries of the European Union as a result of the ongoing expansion process. Disease expert groups developed and consented on diagnostic flowcharts and disease scales to assess the different aspects of RNDs. ERN-RND has started to discuss diagnostically unclear patients in the CPMS, is one of four ERNs that serve as foundation of Solve-RD, and has established an RND training and education program. The network will facilitate trial readiness through the establishment of an ERN-RND registry with a minimal data of all patients seen at the ERN-RND centers, thus providing a unique overview of existing genotype-based cohorts. The overall aim of the ERNs is to improve access for patients with RDs to quality diagnosis, care, and treatment. Based on this objective, ERNs are monitored by the European Commission on a regular basis to provide transparency and reassurance to the RD community and the general public.
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http://dx.doi.org/10.3389/fneur.2020.616569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840612PMC
January 2021

Cell therapy in Huntington's disease: Taking stock of past studies to move the field forward.

Stem Cells 2021 02 25;39(2):144-155. Epub 2020 Nov 25.

Centre for Trials Research, Cardiff University, Cardiff, UK.

Huntington's disease (HD) is a rare inherited neurodegenerative disease that manifests mostly in adulthood with progressive cognitive, behavioral, and motor dysfunction. Neuronal loss occurs predominantly in the striatum but also extends to other brain regions, notably the cortex. Most patients die around 20 years after motor onset, although there is variability in the rate of progression and some phenotypic heterogeneity. The most advanced experimental therapies currently are huntingtin-lowering strategies, some of which are in stage 3 clinical trials. However, even if these approaches are successful, it is unlikely that they will be applicable to all patients or will completely halt continued loss of neural cells in all cases. On the other hand, cellular therapies have the potential to restore atrophied tissues and may therefore provide an important complementary therapeutic avenue. Pilot studies of fetal cell grafts in the 2000s reported the most dramatic clinical improvements yet achieved for this disease, but subsequent studies have so far failed to identify methodology to reliably reproduce these results. Moving forward, a major challenge will be to generate suitable donor cells from (nonfetal) cell sources, but in parallel there are a host of procedural and trial design issues that will be important for improving reliability of transplants and so urgently need attention. Here, we consider findings that have emerged from clinical transplant studies in HD to date, in particular new findings emerging from the recent multicenter intracerebral transplant HD study, and consider how these data may be used to inform future cell therapy trials.
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http://dx.doi.org/10.1002/stem.3300DOI Listing
February 2021

Approximating dementia prevalence in population-based surveys of aging worldwide: An unsupervised machine learning approach.

Alzheimers Dement (N Y) 2020 27;6(1):e12074. Epub 2020 Aug 27.

UCSF Global Brain Health Institute San Francisco California USA.

Introduction: Ability to determine dementia prevalence in low- and middle-income countries (LMIC) remains challenging because of frequent lack of data and large discrepancies in dementia case ascertainment.

Methods: High likelihood of dementia was determined with hierarchical clustering after principal component analysis applied in 10 population surveys of aging: HRS (USA, 2014), SHARE (Europe and Israel, 2015), MHAS (Mexico, 2015), ELSI (Brazil, 2016), CHARLS (China, 2015), IFLS (Indonesia, 2014-2015), LASI (India, 2016), SAGE-Ghana (2007), SAGE-South Africa (2007), SAGE-Russia (2007-2010). We approximated dementia prevalence using weighting methods.

Results: Estimated numbers of dementia cases were: China, 40.2 million; India, 18.0 million; Russia, 5.2 million; Europe and Israel, 5.0 million; United States, 4.4 million; Brazil, 2.2 million; Mexico, 1.6 million; Indonesia, 1.3 million; South Africa, 1.0 million; Ghana, 319,000.

Discussion: Our estimations were similar to prior ones in high-income countries but much higher in LMIC. Extrapolating these results globally, we suggest that almost 130 million people worldwide were living with dementia in 2015.
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http://dx.doi.org/10.1002/trc2.12074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453145PMC
August 2020

Posterior reversible encephalopathy syndrome associated with SARS-CoV-2 infection.

J Neurol Neurosurg Psychiatry 2020 Jul 27. Epub 2020 Jul 27.

Neurology, Henri Mondor University Hospitals, APHP, Créteil, France.

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http://dx.doi.org/10.1136/jnnp-2020-323923DOI Listing
July 2020

Human Fetal Cell Therapy in Huntington's Disease: A Randomized, Multicenter, Phase II Trial.

Mov Disord 2020 08 15;35(8):1323-1335. Epub 2020 Jul 15.

Assistance Publique-Hôpitaux de Paris, National Reference Center for Huntington's Disease, Neurology Department, Henri Mondor-Albert Chenevier Hospital, Créteil, France.

Background: Huntington's disease is a rare, severe, inherited neurodegenerative disease in which we assessed the safety and efficacy of grafting human fetal ganglionic eminence intrastriatally.

Methods: Patients at the early stage of the disease were enrolled in the Multicentric Intracerebral Grafting in Huntington's Disease trial, a delayed-start phase II randomized study. After a run-in period of 12 months, patients were randomized at month 12 to either the treatment group (transplanted at month 13-month 14) or the control group and secondarily treated 20 months later (month 33-month 34). The primary outcome was total motor score compared between both groups 20 months postrandomization (month 32). Secondary outcomes included clinical, imaging, and electrophysiological findings and a comparison of pregraft and postgraft total motor score slopes during the entire study period (month 0-month 52) regardless of the time of transplant.

Results: Of 54 randomized patients, 45 were transplanted; 26 immediately (treatment) and 19 delayed (control). Mean total motor score at month 32 did not differ between groups (treated controls difference in means adjusted for M12: +2.9 [95% confidence interval, -2.8 to 8.6]; P = 0.31). Its rate of decline after transplantation was similar to that before transplantation. A total of 27 severe adverse events were recorded in the randomized patients, 10 of which were related to the transplant procedure. Improvement of procedures during the trial significantly decreased the frequency of surgical events.We found antihuman leucocytes antigen antibodies in 40% of the patients.

Conclusion: No clinical benefit was found in this trial. This may have been related to graft rejection. Ectopia and high track number negatively influence the graft outcome. Procedural adjustments substantially improved surgical safety. (ClinicalTrials.gov NCT00190450.) © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28201DOI Listing
August 2020

Long before Huntington's disease: what matters most?

Lancet Neurol 2020 06 26;19(6):473-475. Epub 2020 May 26.

Assistance Publique-Hôpitaux de Paris, National Reference Center for Huntington's Disease, Neurology Department, Henri Mondor-Albert Chenevier Hospital, 94000 Créteil, France; Equipe Neuropsychologie Interventionnelle, Département d'Etudes Cognitives, École Normale Supérieure, PSL Research University, Institut Mondor de Recherche Biomédicale, Université Paris-Est, INSERM, Paris and Créteil, France; Faculté de Santé, Université Paris Est, Créteil, France. Electronic address:

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http://dx.doi.org/10.1016/S1474-4422(20)30156-3DOI Listing
June 2020

Neocortical morphometry in Huntington's disease: Indication of the coexistence of abnormal neurodevelopmental and neurodegenerative processes.

Neuroimage Clin 2020 13;26:102211. Epub 2020 Feb 13.

Functional Magnetic Resonance Imaging of the Brain (FMRIB) Centre, Wellcome Centre for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom. Electronic address:

Huntington's disease (HD) is an inherited, autosomal dominant disorder that is characteristically thought of as a degenerative disorder. Despite cellular and molecular grounds suggesting HD could also impact normal development, there has been scarce systems-level data obtained from in vivo human studies supporting this hypothesis. Sulcus-specific morphometry analysis may help disentangle the contribution of coexisting neurodegenerative and neurodevelopmental processes, but such an approach has never been used in HD. Here, we investigated cortical sulcal depth, related to degenerative process, as well as cortical sulcal length, related to developmental process, in early-stage HD and age-matched healthy controls. This morphometric analysis revealed significant differences in the HD participants compared with the healthy controls bilaterally in the central and intra-parietal sulcus, but also in the left intermediate frontal sulcus and calcarine fissure. As the primary visual cortex is not connected to the striatum, the latter result adds to the increasing in vivo evidence for primary cortical degeneration in HD. Those sulcal measures that differed between HD and healthy populations were mainly atrophy-related, showing shallower sulci in HD. Conversely, the sulcal morphometry also revealed a crucial difference in the imprint of the Sylvian fissure that could not be related to loss of grey matter volume: an absence of asymmetry in the length of this fissure in HD. Strong asymmetry in that cortical region is typically observed in healthy development. As the formation of the Sylvian fissure appears early in utero, and marked asymmetry is specifically found in this area of the neocortex in newborns, this novel finding likely indicates the foetal timing of a disease-specific, genetic interplay with neurodevelopment.
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http://dx.doi.org/10.1016/j.nicl.2020.102211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044794PMC
March 2021

Acute Hippocampal Encephalopathy in Heavy Cannabis Users: About 2 Cases.

Am J Med 2020 07 24;133(7):e360-e364. Epub 2019 Dec 24.

Assistance Publique-Hôpitaux de Paris, CHU Henri Mondor, service de Neurologie, Créteil, France; INSERM U955 Equipe E01, Institut Mondor de recherche biomédicale, Neuropsychologie Interventionnelle, Créteil, France; Département d'Etudes Cognitives, Ecole Normale Supérieure, PSL University, Paris, France; Université Paris Est, Faculté de Médecine, Créteil, France; Global Brain Health Institute, UCSF, San Francisco, California, USA. Electronic address:

Background: Cannabis use is increasing worldwide despite the various health effects of this substance.

Methods: We report 2 cases of acute hippocampal encephalopathy in heavy cannabis users (>10 joints/d).

Results: In both male patients, acute encephalitis was suspected. Brain magnetic resonance imaging (MRI) diffusion-weighted sequences showed bilateral high signal abnormalities in hippocampal regions. Patients had renal dysfunction, rhabdomyolysis, and inflammatory syndrome. Investigations showed no evidence of infectious or autoimmune encephalitides. Repeated electroencephalograms revealed no epileptic activity. Clinical, biological, and magnetic resonance imaging acute abnormalities improved within weeks. New exposure to cannabis yielded a new episode of encephalopathy. In both patients, severe long-lasting episodic memory impairment associated with hippocampal atrophy were observed several months later.

Conclusions: Health professionals should be aware of this cannabis-related syndrome given its severe and long-lasting effects.
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http://dx.doi.org/10.1016/j.amjmed.2019.11.018DOI Listing
July 2020

International Guidelines for the Treatment of Huntington's Disease.

Front Neurol 2019 3;10:710. Epub 2019 Jul 3.

NeuroZentrumSiloah and Department of Neurology, Swiss HD Center, University of Bern, Bern, Switzerland.

The European Huntington's Disease Network (EHDN) commissioned an international task force to provide global evidence-based recommendations for everyday clinical practice for treatment of Huntington's disease (HD). The objectives of such guidelines are to standardize pharmacological, surgical and non-pharmacological treatment regimen and improve care and quality of life of patients. A formalized consensus method, adapted from the French Health Authority recommendations was used. First, national committees (French and English Experts) reviewed all studies published between 1965 and 2015 included dealing with HD symptoms classified in motor, cognitive, psychiatric, and somatic categories. Quality grades were attributed to these studies based on levels of scientific evidence. Provisional recommendations were formulated based on the strength and the accumulation of scientific evidence available. When evidence was not available, recommendations were framed based on professional agreement. A European Steering committee supervised the writing of the final recommendations through a consensus process involving two rounds of online questionnaire completion with international multidisciplinary HD health professionals. Patients' associations were invited to review the guidelines including the HD symptoms. Two hundred and nineteen statements were retained in the final guidelines. We suggest to use this adapted method associating evidence base-medicine and expert consensus to other rare diseases.
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http://dx.doi.org/10.3389/fneur.2019.00710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618900PMC
July 2019

Improving language evaluation in neurological disorders: The French Core Assessment of Language Processing (CALAP).

Psychol Assess 2019 May 10;31(5):622-630. Epub 2019 Jan 10.

Département d'Etudes Cognitives, Ecole normale supérieure, Paris Science Lettres University.

Aphasia is a devastating brain disorder, detrimental for medical care and social interaction. The early diagnosis of language disorders and accurate identification of patient-specific deficits are crucial for patients' care, as aphasia rehabilitation is more effective when focused on patient-specific language deficits. We developed the Core Assessment of Language Processing (CALAP), a new scale combining screening and detailed evaluation to rapidly diagnose and identify patient-specific language deficits. This scale is based on a model of language processing distinguishing between the comprehension, production, and repetition modalities, and their different components: phonology (set of speech-sounds), morphology (how the sounds combine to form words), lexicon (words), syntax (how words combine to form sentences), and concept (semantic knowledge). This scale was validated by 189 participants who underwent the CALAP, and patients not unequivocally classified as without aphasia by a speech-language pathologist underwent the Boston Diagnosis Aphasia Evaluation as the gold standard. CALAP-screening classified patients with and without aphasia with a sensitivity of 1 and a specificity of 0.72, in 3.14 ± 1.23 min. CALAP-detailed evaluation specifically assessed the language components in 8.25 ± 5.1 min. Psychometric properties including concurrent validity, internal validity, internal consistency and interrater reliability showed that the CALAP is a valid and reliable scale. The CALAP provides an aphasia diagnosis along with the identification of patient-specific impairment making it possible to improve clinical follow up and deficit-based rehabilitation. It is a short and easy-to-use scale that can be scored and interpreted by clinicians nonexpert in language, in patients with fatigue and concentration deficits. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/pas0000683DOI Listing
May 2019

The role of the striatum in linguistic selection: Evidence from Huntington's disease and computational modeling.

Cortex 2018 12 15;109:189-204. Epub 2018 Sep 15.

Département d'Etudes Cognitives, Ecole Normale Supérieure - PSL Research University, Paris, France; Equipe de NeuroPsychologie Interventionnelle, Institut National de la Santé et Recherche Médical (INSERM) U955, Equipe 01, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France; Centre de référence maladie de Huntington, Hôpital Henri Mondor, AP-HP, Créteil, France.

Though accumulating evidence indicates that the striatum is recruited during language processing, the specific function of this subcortical structure in language remains to be elucidated. To answer this question, we used Huntington's disease as a model of striatal lesion. We investigated the morphological deficit of 30 early Huntington's disease patients with a novel linguistic task that can be modeled within an explicit theory of linguistic computation. Behavioral results reflected an impairment in HD patients on the linguistic task. Computational model-based analysis compared the behavioral data to simulated data from two distinct lesion models, a selection deficit model and a grammatical deficit model. This analysis revealed that the impairment derives from an increased randomness in the process of selecting between grammatical alternatives, rather than from a disruption of grammatical knowledge per se. Voxel-based morphometry permitted to correlate this impairment to dorsal striatal degeneration. We thus show that the striatum holds a role in the selection of linguistic alternatives, just as in the selection of motor and cognitive programs.
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http://dx.doi.org/10.1016/j.cortex.2018.08.031DOI Listing
December 2018

Structural priming in sentence comprehension: A single prime is enough.

PLoS One 2018 2;13(4):e0194959. Epub 2018 Apr 2.

Département d'Etudes Cognitives, Ecole Normale Supérieure-PSL Research University, Paris, France.

Experiencing a syntactic structure affects how we process subsequent instances of that structure. This phenomenon, called structural priming, is observed both in language production and in language comprehension. However, while abstract syntactic structures can be primed independent of lexical overlap in sentence production, evidence for structural priming in comprehension is more elusive. In addition, when structural priming in comprehension is found, it can often be accounted for in terms of participants' explicit expectations. Participants may use the structural repetition over several sentences and build expectations, which create a priming effect. Here, we use a new experimental paradigm to investigate structural priming in sentence comprehension independent of lexical overlap and of participants' expectations. We use an outcome dependent variable instead of commonly used online measures, which allows us to more directly compare these effects with those found in sentence production studies. We test priming effects in syntactically homogeneous and heterogeneous conditions on a sentence-picture matching task that forces participants to fully parse the sentences. We observe that, while participants learn the structural regularity in the homogeneous condition, structural priming is also found in the heterogeneous condition, in which participants do not expect any particular structure. In fact, we find that a single prime is enough to trigger priming. Our results indicate that-like in sentence production-structural priming can be observed in sentence comprehension without lexical repetition and independent of participants' expectation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194959PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880384PMC
July 2018

Cortical thickness, stance control, and arithmetic skill: An exploratory study in premanifest Huntington disease.

Parkinsonism Relat Disord 2018 06 23;51:17-23. Epub 2018 Feb 23.

Genetics of Neurodegenerative and Metabolic Diseases, IRCCS-Foundation Neurological Institute Carlo Besta, Milan, Italy. Electronic address:

Background: Huntington disease (HD) is an inherited neurodegenerative disorder most commonly manifesting in adulthood. Identification of biomarkers tracking neurodegeneration before the onset of motor symptoms is important for future interventional studies. Our study aimed to contribute in the phenotypic characterization of the premanifest HD phase.

Methods: 28 premanifest subjects (preHD), 25 age-matched controls, and 12 manifest HD patients were enrolled for the study. The participants underwent a multimodal protocol including cognitive evaluations, arithmetic ability test, posturography, composite cerebellar functional test (CCFS), and brain 3T-MRI. PreHD were divided at the group median for predicted years to expected onset into "far-from-onset" (>15 years, PreHD-far), and "close-to-onset" (≤15 years, preHD-close). Basal ganglia volumes and cortical thickness were computed using FreeSurfer.

Results: PreHD-close showed significantly lower scores than controls in Symbol Digit Modalities Test (p = 0.017), Arithmetic subtraction task (p = 0.04), and MMSE (p < 0.006). At posturography, preHD-close showed increased sway velocity (<0.04) and distance (p < 0.02) compared to controls. PreHD-close had reduced striatum and globus pallidus volumes and left occipital cortical thinning compared to controls. Compared to PreHD far-from-onset, PreHD-close showed bilateral cortical thinning in occipital and parahippocampal regions, inversely correlating with burden score and prognostic index for HD. CCFS only differed between controls and manifest HD. PreHD far-from-onset did not show significant differences in comparison with controls.

Conclusions: We confirmed that quantitative brain MRI represents a valid biomarker of neurodegeneration in preHD. Posturography and Arithmentic tests seem promising tools for detecting early changes in premanifest HD, but need to be further confirmed in large cohorts.
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http://dx.doi.org/10.1016/j.parkreldis.2018.02.033DOI Listing
June 2018

Rating scales for cognition in Huntington's disease: Critique and recommendations.

Mov Disord 2018 02 26;33(2):187-195. Epub 2017 Dec 26.

National Center of Epidemiology and CIBERNED, Carlos III Institute of Health, Madrid, Spain.

Cognitive impairment is one of the main features of Huntington's disease and is present across the disease spectrum. As part of the International Parkinson's Disease and Movement Disorder Society-sponsored project to review all clinical rating scales used in Huntington's disease, a systematic review of the literature was performed to identify cognitive scales used in Huntington's disease and make recommendations for their use. A total of 17 cognitive scales were identified and evaluated. None of the scales met criteria for a "recommended" status. For assessing severity of cognitive dysfunction, the Montreal Cognitive Assessment was "recommended with caveats." The UHDRS Cognitive Assessment, the UHDRS-For Advanced Patients cognitive section, the Alzheimer's Disease Assessment Scale-Cognitive Subscale, the Frontal Assessment Battery, the Mattis Dementia Rating Scale, the Mini-Mental State Examination, and the Repeatable Battery for the Assessment of Neuropsychological Status were "suggested" for evaluating severity of cognitive impairment. The MoCA was "suggested" as a screening tool for cognitive impairment. The major challenge in the assessment of cognition in Huntington's disease is the lack of a formal definition of dementia and/or mild cognitive impairment in this disease. The committee concluded that there is a need to further validate currently available cognitive scales in Huntington's disease, but that it is premature to recommend the development of new scales. Recently developed Huntington's disease-specific scales, such as the Huntington's Disease-Cognitive Assessment Battery, hold promise but require the completion of more comprehensive clinimetric development. © 2017 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27227DOI Listing
February 2018

Cognitive dysfunction associated with aluminum hydroxide-induced macrophagic myofasciitis: A reappraisal of neuropsychological profile.

J Inorg Biochem 2018 04 6;181:132-138. Epub 2017 Oct 6.

INSERM/UPEC U955 Team 10 'Biology of Neuromuscular System', Faculty of Médecine, 94000 Créteil, France; Expert Center for Neuromuscular Diseases, Department of Pathology, Henri Mondor University Hospital, 94000 Créteil, France. Electronic address:

Patients with macrophagic myofasciitis (MMF) present with diffuse arthromyalgias, chronic fatigue, and cognitive disorder. Representative features of MMF-associated cognitive dysfunction include attentional dysfunction, dysexecutive syndrome, visual memory deficit and left ear extinction. Our study aims to reevaluate the neuropsychological profile of MMF. 105 unselected consecutive MMF patients were subjected to a neuropsychological battery of screen short term and long-term memory, executive functions, attentional abilities, instrumental functions and dichotic listening. From these results, patients were classified in four different groups: Subsymptomatic patients (n=41) with performance above pathological threshold (-1.65 SD) in all tests; Fronto-subcortical patients (n=31) who showed pathological results at executive functions and selective attention tests; Papezian patients (n=24) who showed pathological results in storage, recognition and consolidation functions for episodic verbal memory, in addition to fronto-subcortical dysfunction; and Extinction patients (n=9) who had a left ear extinction at dichotic listening test in association to fronto-subcortical and papezian dysfunction. In addition, inter-test analysis showed that patients with apparently normal cognitive functions (Subsymptomatic group) performed significantly worse to attention tests compared to others. In conclusion, our study shows that (i) most patients have specific cognitive deficits; (ii) all patients with cognitive deficit have impairment of executive functions and selective attention; (iii) patients without measurable cognitive deficits display significant weakness in attention; (iv) episodic memory impairment affects verbal, but not visual, memory; (v) none of the patients show an instrumental dysfunction.
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http://dx.doi.org/10.1016/j.jinorgbio.2017.09.019DOI Listing
April 2018

Association Between Motor Symptoms and Brain Metabolism in Early Huntington Disease.

JAMA Neurol 2017 09;74(9):1088-1096

Commissariat à l'Energie Atomique et aux Energies Alternatives, Département des Sciences du Vivant, Institut d'Imagerie Biomédicale, MIRCen, Fontenay-aux-Roses, France.

Importance: Brain hypometabolism is associated with the clinical consequences of the degenerative process, but little is known about regional hypermetabolism, sometimes observed in the brain of patients with clinically manifest Huntington disease (HD). Studying the role of regional hypermetabolism is needed to better understand its interaction with the motor symptoms of the disease.

Objective: To investigate the association between brain hypometabolism and hypermetabolism with motor scores of patients with early HD.

Design, Setting, And Participants: This study started in 2001, and analysis was completed in 2016. Sixty symptomatic patients with HD and 15 healthy age-matched control individuals underwent positron emission tomography to measure cerebral metabolism in this cross-sectional study. They also underwent the Unified Huntington's Disease Rating Scale motor test, and 2 subscores were extracted: (1) a hyperkinetic score, combining dystonia and chorea, and (2) a hypokinetic score, combining bradykinesia and rigidity.

Main Outcomes And Measures: Statistical parametric mapping software (SPM5) was used to identify all hypo- and hypermetabolic regions in patients with HD relative to control individuals. Correlation analyses (P < .001, uncorrected) between motor subscores and brain metabolic values were performed for regions with significant hypometabolism and hypermetabolism.

Results: Among 60 patients with HD, 22 were women (36.7%), and the mean (SD) age was 44.6 (7.6) years. Of the 15 control individuals, 7 were women (46.7%), and the mean (SD) age was 42.2 (7.3) years. In statistical parametric mapping, striatal hypometabolism was significantly correlated with the severity of all motor scores. Hypermetabolism was negatively correlated only with hypokinetic scores in the cuneus (z score = 3.95, P < .001), the lingual gyrus (z score = 4.31, P < .001), and the crus I/II of the cerebellum (z score = 3.77, P < .001), a region connected to associative cortical areas. More severe motor scores were associated with higher metabolic values in the inferior parietal lobule, anterior cingulate, inferior temporal lobule, the dentate nucleus, and the cerebellar lobules IV/V, VI, and VIII bilaterally corresponding to the motor regions of the cerebellum (z score = 3.96 and 3.42 in right and left sides, respectively; P < .001).

Conclusions And Relevance: Striatal hypometabolism is associated with clinical disease severity. Conversely, hypermetabolism is likely compensatory in regions where it is associated with decreasing motor scores. Hypermetabolism might be detrimental in other structures in which it is associated with more severe motor symptoms. In the cerebellum, both compensatory and detrimental contributions seem to occur. This study helps to better understand the motor clinical relevance of hypermetabolic brain regions in HD.
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http://dx.doi.org/10.1001/jamaneurol.2017.1200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710184PMC
September 2017

From open to large-scale randomized cell transplantation trials in Huntington's disease: Lessons from the multicentric intracerebral grafting in Huntington's disease trial (MIG-HD) and previous pilot studies.

Prog Brain Res 2017 23;230:227-261. Epub 2017 Feb 23.

Assistance Publique-Hôpitaux de Paris, Centre de Référence Maladie de Huntington, Service de Neurologie, Hôpital Henri Mondor-Albert Chenevier, Créteil, France; INSERM U955, Equipe 01 Neuropsychologie Interventionnelle, Créteil, France; Département d'Etudes Cognitives, Ecole Normale Supérieure, PSL* Research University, Paris, France; Université Paris Est, Faculté de Médecine, Créteil, France. Electronic address:

Fifty-one patients from open-label pilot trials have been transplanted in Huntington's disease (HD) using human fetal cells; clinical data and follow-up are available in 30 of them. These open-label studies were mostly designed for safety and feasibility. However, signs of long-term efficacy have been reported in 4 out of 30 patients, differences in tissue preparation, surgical procedure, patients characteristics, immunosuppression regimens, clinical, and imaging assessments, makes it difficult to define the optimal procedure for future trials. Forty-five patients have now been grafted in the multicentric intracerebral grafting trial in Huntington's in France (MIG-HD) and Belgium, and 22 in Germany in a randomized delayed start design. Whereas the 10 patients published from the German cohort showed no improvement, the results from the MIG-HD trial are still under analysis. However, the MIG-HD trial has already changed cell transplantation for HD by showing alloimmunization with graft rejection in one patient and HLA antibodies against the transplant in others. Moreover, MIG-HD has established a new surgical procedure to avoid subdural hematoma, the most frequent adverse effect in transplant in HD, and a surgical strategy to eradicate eventual choroid cysts. By reviewing all the published results, new avenues are provided for optimization for cell preparation, delivery methods, standardization of clinical assessment, and surgical procedure with blind video scoring, imaging, and electrophysiology. Future trials should capitalize on a new CAPIT-HD2 battery to determine efficacy with sufficiently long pre and postgraft follow-up, using patient stratification and randomization, control of alloimmunization, HLA monitoring, and standardization of the consent procedure.
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http://dx.doi.org/10.1016/bs.pbr.2016.12.011DOI Listing
May 2018

A randomized, double-blind, placebo-controlled trial evaluating cysteamine in Huntington's disease.

Mov Disord 2017 06 24;32(6):932-936. Epub 2017 Apr 24.

Centre Hospitalier Universitaire d'Angers, Département de Biochimie et Génétique et UMR CNRS 6214 - INSERM U1083 et Institut Mitovasc, Angers, France.

Background: Cysteamine has been demonstrated as potentially effective in numerous animal models of Huntington's disease.

Methods: Ninety-six patients with early-stage Huntington's disease were randomized to 1200 mg delayed-release cysteamine bitartrate or placebo daily for 18 months. The primary end point was the change from baseline in the UHDRS Total Motor Score. A linear mixed-effects model for repeated measures was used to assess treatment effect, expressed as the least-squares mean difference of cysteamine minus placebo, with negative values indicating less deterioration relative to placebo.

Results: At 18 months, the treatment effect was not statistically significant - least-squares mean difference, -1.5 ± 1.71 (P = 0.385) - although this did represent less mean deterioration from baseline for the treated group relative to placebo. Treatment with cysteamine was safe and well tolerated.

Conclusions: Efficacy of cysteamine was not demonstrated in this study population of patients with Huntington's disease. Post hoc analyses indicate the need for definitive future studies. © 2017 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27010DOI Listing
June 2017

Embodied emotion impairment in Huntington's Disease.

Cortex 2017 07 18;92:44-56. Epub 2017 Mar 18.

École Normale Supérieure, Institut d'Étude de la Cognition, Paris, France; Inserm U955-E01, Institut Mondor de Recherche Biomédicale, Créteil, France; Université Paris Est Créteil, Medical Faculty, Créteil, France; Assistance Publique-Hôpitaux de Paris, Huntington's Disease Reference Center, Groupe Henri-Mondor Albert-Chenevier, Créteil, France.

Theories of embodied cognition suggest that perceiving an emotion involves somatovisceral and motoric re-experiencing. Here we suggest taking such an embodied stance when looking at emotion processing deficits in patients with Huntington's Disease (HD), a neurodegenerative motor disorder. The literature on these patients' emotion recognition deficit has recently been enriched by some reports of impaired emotion expression. The goal of the study was to find out if expression deficits might be linked to a more motoric level of impairment. We used electromyography (EMG) to compare voluntary emotion expression from words to emotion imitation from static face images, and spontaneous emotion mimicry in 28 HD patients and 24 matched controls. For the latter two imitation conditions, an underlying emotion understanding is not imperative (even though performance might be helped by it). EMG measures were compared to emotion recognition and to the capacity to identify and describe emotions using alexithymia questionnaires. Alexithymia questionnaires tap into the more somato-visceral or interoceptive aspects of emotion perception. Furthermore, we correlated patients' expression and recognition scores to cerebral grey matter volume using voxel-based morphometry (VBM). EMG results replicated impaired voluntary emotion expression in HD. Critically, voluntary imitation and spontaneous mimicry were equally impaired and correlated with impaired recognition. By contrast, alexithymia scores were normal, suggesting that emotion representations on the level of internal experience might be spared. Recognition correlated with brain volume in the caudate as well as in areas previously associated with shared action representations, namely somatosensory, posterior parietal, posterior superior temporal sulcus (pSTS) and subcentral sulcus. Together, these findings indicate that in these patients emotion deficits might be tied to the "motoric level" of emotion expression. Such a double-sided recognition and expression impairment may have important consequences, interrupting empathy in nonverbal communication both ways (understanding and being understood), independently of intact internal experience of emotion.
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http://dx.doi.org/10.1016/j.cortex.2017.02.019DOI Listing
July 2017

Brain F-FDG PET Metabolic Abnormalities in Patients with Long-Lasting Macrophagic Myofascitis.

J Nucl Med 2017 03 20;58(3):492-498. Epub 2016 Oct 20.

INSERM U955-Team 10, Créteil, France.

The aim of this study was to characterize brain metabolic abnormalities in patients with macrophagic myofascitis (MMF) and the relationship with cognitive dysfunction through the use of PET with F-FDG. F-FDG PET brain imaging and a comprehensive battery of neuropsychological tests were performed in 100 consecutive MMF patients (age [mean ± SD], 45.9 ± 12 y; 74% women). Images were analyzed with statistical parametric mapping (SPM12). Through the use of analysis of covariance, all F-FDG PET brain images of MMF patients were compared with those of a reference population of 44 healthy subjects similar in age (45.4 ± 16 y; = 0.87) and sex (73% women; = 0.88). The neuropsychological assessment identified 4 categories of patients: those with no significant cognitive impairment ( = 42), those with frontal subcortical (FSC) dysfunction ( = 29), those with Papez circuit dysfunction ( = 22), and those with callosal disconnection ( = 7). In comparison with healthy subjects, the whole population of patients with MMF exhibited a spatial pattern of cerebral glucose hypometabolism ( < 0.001) involving the occipital lobes, temporal lobes, limbic system, cerebellum, and frontoparietal cortices, as shown by analysis of covariance. The subgroup of patients with FSC dysfunction exhibited a larger extent of involved areas (35,223 voxels vs. 13,680 voxels in the subgroup with Papez circuit dysfunction and 5,453 voxels in patients without cognitive impairment). Nonsignificant results were obtained for the last subgroup because of its small population size. Our study identified a peculiar spatial pattern of cerebral glucose hypometabolism that was most marked in MMF patients with FSC dysfunction. Further studies are needed to determine whether this pattern could represent a diagnostic biomarker of MMF in patients with chronic fatigue syndrome and cognitive dysfunction.
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http://dx.doi.org/10.2967/jnumed.114.151878DOI Listing
March 2017
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