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1. Non-local diffusion-based biomarkers in patients with cocaine use disorder

Author

Alfonso Estudillo-Romero, Raffaella Migliaccio, Bénédicte Batrancourt, Pierre Jannin, and John S.H. Baxter

Subjects
Cocaine use disorder, Diffusion tensor imaging, Voxel-based diktiometry, Sparse principal components analysis, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Cocaine use disorder (CUD) is widely known to result in neurological reconfiguration which can be observed via local diffusivity characteristics of the brain. These changes can be highly correlated while simultaneously variable across patients with different comorbidities or histories of substance use. This implies that more complex neuroimage analysis tools may be necessary to better detect specific biomarkers that vary across these dimensions. We investigated white and gray matter integrity using voxel-based diktiometry (VBD) on whole brain diffusion tensor images (DTI) across a database of CUD patients and healthy controls using a purely data-driven approach. These VBD maps reveal significant cortical and subcortical differences that are indicative of these neural modifications including the insula, cerebellum, ventricles, thalamo-cortical radiations, and corpus callosum bundles. In order to disambiguate these results and investigate the heterogeneity of CUD, the VBD maps have been decomposed into five decorrelated biomarkers: one in the region surrounding the left insula, one implicating the corpus callosum, two concentrated in the left cerebellum, and the last concerning a proximal region of the interhemispheric fissure which serve as potential biomarkers playing a role in CUD. These decorrelated biomarkers have themselves been correlated with consumption patterns and psychiatric and borderline personality disorder scores on the CUD patient group. This preliminary approach to using machine learning techniques to both detect and disambiguate complex non-linear patterns shows promise for better understanding complex and heterogeneous disorders such as CUD.

Published
2024
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2. Differential Patterns of Domain-Specific Cognitive Complaints and Awareness Across the Alzheimer’s Disease Spectrum

Author

Federica Cacciamani, Valérie Godefroy, Simona M. Brambati, Raffaella Migliaccio, Stéphane Epelbaum, and Maxime Montembeault

Subjects
awareness, metacognition, anosognosia, Alzheimer’s disease, language, executive function, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Background: Characterizing self- and informant-reported cognitive complaints, as well as awareness of cognitive decline (ACD), is useful for an early diagnosis of Alzheimer’s disease (AD). However, complaints and ACD related to cognitive functions other than memory are poorly studied. Furthermore, it remains unclear which source of information is the most useful to distinguish various groups on the AD spectrum.Methods: Self- and informant-reported complaints were measured with the Everyday Cognition questionnaire (ECog-Subject and ECog-StudyPartner) in four domains (memory, language, visuospatial, and executive). ACD was measured as the subject-informant discrepancy in the four ECog scores. We compared the ECog and ACD scores across cognitive domains between four groups: 71 amyloid-positive individuals with amnestic AD, 191 amnestic mild cognitive impairment (MCI), or 118 cognitively normal (CN), and 211 amyloid-negative CN controls, selected from the ADNI database. Receiver operating characteristic curves analysis was performed to evaluate the accuracy of the ECog and ACD scores in discriminating clinical groups.Results: Self- and informant-reported complaints were generally distributed as follows: memory, language, executive, and visuospatial (from the most severe to the least severe). Both groups of CN participants presented on average more memory and language complaints than their informant. MCI participants showed good agreement with their informants. AD participants presented anosognosia in all domains, but especially for the executive domain. The four ECog-StudyPartner sub-scores allowed excellent discrimination between groups in almost all classifications and performed significantly better than the other two classifiers considered. The ACD was excellent in distinguishing the participants with AD from the two groups of CN participants. The ECog-Subject was the least accurate in discriminating groups in four of the six classifications performed.Conclusion: In research, the study of complaint and anosognosia should not be reduced solely to the memory domain. In clinical practice, non-amnestic complaints could also be linked to Alzheimer’s disease. The presence of an informant also seems necessary given its accuracy as a source of information.

Published
2022
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3. An ecological approach to identify distinct neural correlates of disinhibition in frontotemporal dementia

Author

Delphine Tanguy, Bénédicte Batrancourt, Alfonso Estudillo-Romero, John S.H. Baxter, Isabelle Le Ber, Arabella Bouzigues, Valérie Godefroy, Aurélie Funkiewiez, Céline Chamayou, Emmanuelle Volle, Dario Saracino, Armelle Rametti-Lacroux, Xavier Morandi, Pierre Jannin, Richard Levy, and Raffaella Migliaccio

Subjects
Compulsivity, Diffusion tensor imaging, Semi-ecological situation, Social disinhibition, Voxel-based morphometry, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

Disinhibition is a core symptom of many neurodegenerative diseases, particularly frontotemporal dementia, and is a major cause of stress for caregivers. While a distinction between behavioural and cognitive disinhibition is common, an operational definition of behavioural disinhibition is still missing. Furthermore, conventional assessment of behavioural disinhibition, based on questionnaires completed by the caregivers, often lacks ecological validity. Therefore, their neuroanatomical correlates are non-univocal.In the present work, we used an original behavioural approach in a semi-ecological situation to assess two specific dimensions of behavioural disinhibition: compulsivity and social disinhibition. First, we investigated disinhibition profile in patients compared to controls. Then, to validate our approach, compulsivity and social disinhibition scores were correlated with classic cognitive tests measuring disinhibition (Hayling Test) and social cognition (mini-Social cognition & Emotional Assessment). Finally, we disentangled the anatomical networks underlying these two subtypes of behavioural disinhibition, taking in account the grey (voxel-based morphometry) and white matter (diffusion tensor imaging tractography). We included 17 behavioural variant frontotemporal dementia patients and 18 healthy controls.We identified patients as more compulsive and socially disinhibited than controls. We found that behavioural metrics in the semi-ecological task were related to cognitive performance: compulsivity correlated with the Hayling test and both compulsivity and social disinhibition were associated with the emotion recognition test. Based on voxel-based morphometry and tractography, compulsivity correlated with atrophy in the bilateral orbitofrontal cortex, the right temporal region and subcortical structures, as well as with alterations of the bilateral cingulum and uncinate fasciculus, the right inferior longitudinal fasciculus and the right arcuate fasciculus. Thus, the network of regions related to compulsivity matched the “semantic appraisal” network. Social disinhibition was associated with bilateral frontal atrophy and impairments in the forceps minor, the bilateral cingulum and the left uncinate fasciculus, regions corresponding to the frontal component of the “salience” network.Summarizing, this study validates our semi-ecological approach, through the identification of two subtypes of behavioural disinhibition, and highlights different neural networks underlying compulsivity and social disinhibition. Taken together, these findings are promising for clinical practice by providing a better characterisation of inhibition disorders, promoting their detection and consequently a more adapted management of patients.

Published
2022
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4. Testing the therapeutic effects of transcranial direct current stimulation (tDCS) in semantic dementia: a double blind, sham controlled, randomized clinical trial

Author

Clara Sanches, Richard Levy, Sarah Benisty, Lisette Volpe-Gillot, Marie-Odile Habert, Aurelie Kas, Sébastian Ströer, Nadya Pyatigorskaya, Anna Kaglik, Angelina Bourbon, Bruno Dubois, Raffaella Migliaccio, Antoni Valero-Cabré, and Marc Teichmann

Subjects
Non-invasive brain stimulation, Transcranial direct current stimulation, Semantic dementia, Primary progressive aphasia, Language impairments, Neurodegenerative diseases, Medicine (General), R5-920
Abstract

Abstract Background Semantic dementia is a neurodegenerative disease that primarily affects the left anterior temporal lobe, resulting in a gradual loss of conceptual knowledge. There is currently no validated treatment. Transcranial stimulation has provided evidence for long-lasting language effects presumably linked to stimulation-induced neuroplasticity in post-stroke aphasia. However, studies evaluating its effects in neurodegenerative diseases such as semantic dementia are still rare and evidence from double-blind, prospective, therapeutic trials is required. Objective The primary objective of the present clinical trial (STIM-SD) is to evaluate the therapeutic efficacy of a multiday transcranial direct current stimulation (tDCS) regime on language impairment in patients with semantic dementia. The study also explores the time course of potential tDCS-driven improvements and uses imaging biomarkers that could reflect stimulation-induced neuroplasticity. Methods This is a double-blind, sham-controlled, randomized study using transcranial Direct Current Stimulation (tDCS) applied daily for 10 days, and language/semantic and imaging assessments at four time points: baseline, 3 days, 2 weeks and 4 months after 10 stimulation sessions. Language/semantic assessments will be carried out at these same 4 time points. Fluorodeoxyglucose positron emission tomography (FDG-PET), resting-state functional magnetic resonance imaging (rs-fMRI), T1-weighted images and white matter diffusion tensor imaging (DTI) will be applied at baseline and at the 2-week time point. According to the principle of inter-hemispheric inhibition between left (language-related) and right homotopic regions we will use two stimulation modalities - left-anodal and right-cathodal tDCS over the anterior temporal lobes. Accordingly, the patient population (n = 60) will be subdivided into three subgroups: left-anodal tDCS (n = 20), right-cathodal tDCS (n = 20) and sham tDCS (n = 20). The stimulation will be sustained for 20 min at an intensity of 1.59 mA. It will be delivered through 25cm2-round stimulation electrodes (current density of 0.06 mA/cm2) placed over the left and right anterior temporal lobes for anodal and cathodal stimulation, respectively. A group of healthy participants (n = 20) matched by age, gender and education will also be recruited and tested to provide normative values for the language/semantic tasks and imaging measures. Discussion The aim of this study is to assess the efficacy of tDCS for language/semantic disorders in semantic dementia. A potential treatment would be easily applicable, inexpensive, and renewable when therapeutic effects disappear due to disease progression. Trial registration ClinicalTrials.gov NCT03481933. Registered on March 2018.

Published
2019
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5. Past, Present, and Future of Non-invasive Brain Stimulation Approaches to Treat Cognitive Impairment in Neurodegenerative Diseases: Time for a Comprehensive Critical Review

Author

Clara Sanches, Chloé Stengel, Juliette Godard, Justine Mertz, Marc Teichmann, Raffaella Migliaccio, and Antoni Valero-Cabré

Subjects
neurodegenerative diseases, cognitive decline, non-invasive brain stimulation (NIBS), Transcranial Magnetic Stimulation (TMS), transcranial Direct Current Stimulation (tDCS), brain networks, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Low birth rates and increasing life expectancy experienced by developed societies have placed an unprecedented pressure on governments and the health system to deal effectively with the human, social and financial burden associated to aging-related diseases. At present, ∼24 million people worldwide suffer from cognitive neurodegenerative diseases, a prevalence that doubles every five years. Pharmacological therapies and cognitive training/rehabilitation have generated temporary hope and, occasionally, proof of mild relief. Nonetheless, these approaches are yet to demonstrate a meaningful therapeutic impact and changes in prognosis. We here review evidence gathered for nearly a decade on non-invasive brain stimulation (NIBS), a less known therapeutic strategy aiming to limit cognitive decline associated with neurodegenerative conditions. Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation, two of the most popular NIBS technologies, use electrical fields generated non-invasively in the brain to long-lastingly enhance the excitability/activity of key brain regions contributing to relevant cognitive processes. The current comprehensive critical review presents proof-of-concept evidence and meaningful cognitive outcomes of NIBS in eight of the most prevalent neurodegenerative pathologies affecting cognition: Alzheimer’s Disease, Parkinson’s Disease, Dementia with Lewy Bodies, Primary Progressive Aphasias (PPA), behavioral variant of Frontotemporal Dementia, Corticobasal Syndrome, Progressive Supranuclear Palsy, and Posterior Cortical Atrophy. We analyzed a total of 70 internationally published studies: 33 focusing on Alzheimer’s disease, 19 on PPA and 18 on the remaining neurodegenerative pathologies. The therapeutic benefit and clinical significance of NIBS remains inconclusive, in particular given the lack of a sufficient number of double-blind placebo-controlled randomized clinical trials using multiday stimulation regimes, the heterogeneity of the protocols, and adequate behavioral and neuroimaging response biomarkers, able to show lasting effects and an impact on prognosis. The field remains promising but, to make further progress, research efforts need to take in account the latest evidence of the anatomical and neurophysiological features underlying cognitive deficits in these patient populations. Moreover, as the development of in vivo biomarkers are ongoing, allowing for an early diagnosis of these neuro-cognitive conditions, one could consider a scenario in which NIBS treatment will be personalized and made part of a cognitive rehabilitation program, or useful as a potential adjunct to drug therapies since the earliest stages of suh diseases. Research should also integrate novel knowledge on the mechanisms and constraints guiding the impact of electrical and magnetic fields on cerebral tissues and brain activity, and incorporate the principles of information-based neurostimulation.

Published
2021
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6. Frontotemporal dementia subtypes based on behavioral inhibition deficits

Author

Valérie Godefroy, Delphine Tanguy, Arabella Bouzigues, Idil Sezer, Johan Ferrand‐Verdejo, Carole Azuar, David Bendetowicz, Guilhem Carle, Armelle Rametti‐Lacroux, Stéphanie Bombois, Emmanuel Cognat, Pierre Jannin, Xavier Morandi, Isabelle Le Ber, Richard Levy, Bénédicte Batrancourt, and Raffaella Migliaccio

Subjects
compulsivity, disinhibition, ecological design, frontotemporal dementia, gray matter atrophy, subtypes, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Introduction We aimed to investigate phenotypic heterogeneity in the behavioral variant of frontotemporal dementia (bvFTD) through assessment of inhibition deficits. Methods We assessed occurrences of 16 behavioral inhibition deficits from video recordings of 15 bvFTD patients (early stage) and 15 healthy controls (HC) in an ecological setting. We extracted dimensions of inhibition deficit and analyzed their correlations with cognitive and clinical measures. Using these dimensions, we isolated patient clusters whose atrophy patterns were explored. Results After identifying two patterns of inhibition deficit (compulsive automatic behaviors and socially unconventional behaviors), we isolated three behavioral clusters with distinct atrophy patterns. BvFTD‐G0 (N = 3), an outlier group, showed severe behavioral disturbances and more severe ventromedial prefrontal cortex/orbitofrontal cortex atrophy. Compared to bvFTD‐G1 (N = 6), bvFTD‐G2 (N = 6) presented higher anxiety and depression along with less diffuse atrophy especially in midline regions. Discussion Identifying clinico‐anatomical profiles through behavior observation could help to stratify bvFTD patients for adapted treatments.

Published
2021
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7. Atrophy, metabolism and cognition in the posterior cortical atrophy spectrum based on Alzheimer's disease cerebrospinal fluid biomarkers

Author

Maxime Montembeault, Simona M. Brambati, Foudil Lamari, Agnès Michon, Dalila Samri, Stéphane Epelbaum, Lucette Lacomblez, Stéphane Lehéricy, Marie-Odile Habert, Bruno Dubois, Aurélie Kas, and Raffaella Migliaccio

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

Introduction: In vivo clinical, anatomical and metabolic differences between posterior cortical atrophy (PCA) patients presenting with different Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers profiles are still unknown. Methods: Twenty-seven PCA patients underwent CSF examination and were classified as 1) PCA with a typical CSF AD profile (PCA-tAD; abnormal amyloid and T-tau/P-tau biomarkers, n = 13); 2) PCA with an atypical AD CSF profile (PCA-aAD; abnormal amyloid biomarker only, n = 9); and 3) PCA not associated with AD (PCA-nonAD; normal biomarkers, n = 5). All patients underwent clinical and cognitive assessment, structural MRI, and a subset of them underwent brain 18F-FDG PET. Results: All patients' groups showed a common pattern of posterior GM atrophy and hypometabolism typical of PCA, as well as equivalent demographics and clinical/cognitive profiles. PCA-tAD patients showed a group-specific pattern of hypometabolism in the left fusiform gyrus and inferior temporal gyrus. PCA-aAD did not present a group-specific atrophy pattern. Finally, group-specific gray matter atrophy in the right dorsolateral prefrontal cortex, left caudate nucleus and right medial temporal regions and hypometabolism in the right supplementary motor area and paracentral lobule were observed in PCA-nonAD patients. Conclusion: Our findings suggest that both PCA-tAD and PCA-aAD patients are on the AD continuum, in agreement with the recently suggested A/T/N model. Furthermore, in PCA, the underlying pathology has an impact at least on the anatomo-functional presentation. Brain damage observed in PCA-tAD and PCA-aAD was mostly consistent with the well-described presentation of the disease, although it was more widespread in PCA-tAD group, especially in the left temporal lobe. Additional fronto-temporal (especially dorsolateral prefrontal) damage seems to be a clue to underlying non-AD pathology in PCA, which warrants the need for longitudinal follow-ups to investigate frontal symptoms in these patients. Keywords: Posterior cortical atrophy, Alzheimer's disease, Cerebrospinal fluid, Biomarkers, Gray matter atrophy, Brain metabolism, Neuropsychology, Atypical dementia, 18F-FDG PET, Voxel-based morphometry

Published
2018
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8. Functional brain connectome in posterior cortical atrophy

Author

Raffaella Migliaccio, Federica Agosta, Silvia Basaia, Camilla Cividini, Marie-Odile Habert, Aurélie Kas, Maxime Montembeault, and Massimo Filippi

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

This study investigated the functional brain connectome architecture in patients with Posterior Cortical Atrophy (PCA). Eighteen PCA patients and 29 age- and sex- matched healthy controls were consecutively recruited in a specialized referral center. Participants underwent neurologic examination, cerebrospinal fluid (CSF) examination for Alzheimer's disease (AD) biomarkers, cognitive assessment, and brain MRI. For a smaller subset of participants, FDG-PET examination was available. We assessed topological brain network properties and regional functional connectivity as well as intra- and inter-hemispheric connectivity, using graph analysis and connectomics. Supplementary analyses were performed to explore the association between the CSF AD profile and the connectome status, and taking into account hypometabolic, atrophic, and spared regions (nodes). PCA patients showed diffuse functional connectome alterations at both global and regional level, as well as a connectivity breakdown between the posterior brain nodes. They had a widespread loss of both intra- and inter-hemispheric connections, exceeding the structural damage, and including the frontal connections. In PCA, connectome alterations were identified in all the brain nodes irrespectively of their structural and metabolic classification and were associated with a connectivity breakdown between damaged and spared areas. Taken together, these findings suggest the potentially high sensitivity of graph-analysis and connectomic in capturing the progression and maybe early signs of neurodegeneration in PCA patients. Keywords: Posterior cortical atrophy (PCA), Human connectome, Functional connectivity, Graph analysis

Published
2020
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9. Exploration Deficits Under Ecological Conditions as a Marker of Apathy in Frontotemporal Dementia

Author

Bénédicte Batrancourt, Karen Lecouturier, Johan Ferrand-Verdejo, Vincent Guillemot, Carole Azuar, David Bendetowicz, Raffaella Migliaccio, Armelle Rametti-Lacroux, Bruno Dubois, and Richard Levy

Subjects
apathy, disinhibition, motivation, frontotemporal lobar degeneration, behavior, neurodegenerative diseases, Neurology. Diseases of the nervous system, RC346-429
Abstract

Apathy is one of the six clinical criteria for the behavioral variant of frontotemporal dementia (bvFTD), and it is almost universal in this disease. Although its consequences in everyday life are debilitating, its underlying mechanisms are poorly known, its assessment is biased by subjectivity and its care management is very limited. In this context, we have developed “ECOCAPTURE,” a method aimed at providing quantifiable and objective signature(s) of apathy in order to assess it and identify its precise underlying mechanisms. ECOCAPTURE consists of the observation and recording of the patient's behavior when the participant is being submitted to a multiple-phase scenario reproducing a brief real-life situation. It is performed in a functional exploration platform transformed into a fully furnished waiting room equipped with a video and sensor-based data acquisition system. This multimodal method allowed video-based behavior analyses according to predefined behavioral categories (exploration behavior, sustained activities or inactivity) and actigraphy analyses from a 3D accelerometer. The data obtained were also correlated with behavioral/cognitive tests and scales assessing global cognitive efficiency, apathy, cognitive disinhibition, frontal syndrome, depression and anxiety. Here, bvFTD patients (n = 14) were compared to healthy participants (n = 14) during the very first minutes of the scenario, when the participants discovered the room and were encouraged to explore it. We showed that, in the context of facing a new environment, healthy participants first explored it and then engaged in sustained activities. By contrast, bvFTD patients were mostly inactive and eventually explored this new place, but in a more irregular and less efficient mode than normal subjects. This exploration deficit was correlated with apathy, disinhibition and cognitive and behavioral dysexecutive syndromes. These findings led us to discuss the presumed underlying mechanisms responsible for the exploration deficit (an inability to self-initiate actions, to integrate reward valuation and to inhibit involuntary behavior). Altogether, these results pave the way for simple and objective assessment of behavioral changes that represents a critical step for the evaluation of disease progression and efficacy of treatment in bvFTD.

Published
2019
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10. Clinical, Anatomical, and Pathological Features in the Three Variants of Primary Progressive Aphasia: A Review

Author

Maxime Montembeault, Simona M. Brambati, Maria Luisa Gorno-Tempini, and Raffaella Migliaccio

Subjects
primary progressive aphasia, nonfluent/agrammatic variant, semantic variant, logopenic variant, language, brain connectivity, Neurology. Diseases of the nervous system, RC346-429
Abstract

Primary progressive aphasias (PPA) are neurodegenerative diseases clinically characterized by an early and relatively isolated language impairment. Three main clinical variants, namely the nonfluent/agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA) have been described, each with specific linguistic/cognitive deficits, corresponding anatomical and most probable pathological features. Since the discovery and the development of diagnostic criteria for the PPA variants by the experts in the field, significant progress has been made in the understanding of these diseases. This review aims to provide an overview of the literature on each of the PPA variant in terms of their clinical, anatomical and pathological features, with a specific focus on recent findings. In terms of clinical advancements, recent studies have allowed a better characterization and differentiation of PPA patients based on both their linguistic and non-linguistic profiles. In terms of neuroimaging, techniques such as diffusion imaging and resting-state fMRI have allowed a deeper understanding of the impact of PPA on structural and functional connectivity alterations beyond the well-defined pattern of regional gray matter atrophy. Finally, in terms of pathology, despite significant advances, clinico-pathological correspondence in PPA remains far from absolute. Nonetheless, the improved characterization of PPA has the potential to have a positive impact on the management of patients. Improved reliability of diagnoses and the development of reliable in vivo biomarkers for underlying neuropathology will also be increasingly important in the future as trials for etiology-specific treatments become available.

Published
2018
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11. Social Cognition Dysfunctions in Neurodegenerative Diseases: Neuroanatomical Correlates and Clinical Implications

Author

Foteini Christidi, Raffaella Migliaccio, Hernando Santamaría-García, Gabriella Santangelo, and Francesca Trojsi

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Social cognitive function, involved in the perception, processing, and interpretation of social information, has been shown to be crucial for successful communication and interpersonal relationships, thereby significantly impacting mental health, well-being, and quality of life. In this regard, assessment of social cognition, mainly focusing on four key domains, such as theory of mind (ToM), emotional empathy, and social perception and behavior, has been increasingly evaluated in clinical settings, given the potential implications of impairments of these skills for therapeutic decision-making. With regard to neurodegenerative diseases (NDs), most disorders, characterized by variable disease phenotypes and progression, although similar for the unfavorable prognosis, are associated to impairments of social cognitive function, with consequent negative effects on patients’ management. Specifically, in some NDs these deficits may represent core diagnostic criteria, such as for behavioral variant frontotemporal dementia (bvFTD), or may emerge during the disease course as critical aspects, such as for Parkinson’s and Alzheimer’s diseases. On this background, we aimed to revise the most updated evidence on the neurobiological hypotheses derived from network-based approaches, clinical manifestations, and assessment tools of social cognitive dysfunctions in NDs, also prospecting potential benefits on patients’ well-being, quality of life, and outcome derived from potential therapeutic perspectives of these deficits.

Published
2018
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13. COGEVIS: A New Scale to Evaluate Cognition in Patients with Visual Deficiency

Author

Claire Meyniel, Dalila Samri, Farah Stefano, Joel Crevoisier, Florence Bonté, Raffaella Migliaccio, Laure Delaby, Anne Bertrand, Marie Odile Habert, Bruno Dubois, Bahram Bodaghi, and Stéphane Epelbaum

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

We evaluated the cognitive status of visually impaired patients referred to low vision rehabilitation (LVR) based on a standard cognitive battery and a new evaluation tool, named the COGEVIS, which can be used to assess patients with severe visual deficits. We studied patients aged 60 and above, referred to the LVR Hospital in Paris. Neurological and cognitive evaluations were performed in an expert memory center. Thirty-eight individuals, 17 women and 21 men with a mean age of 70.3 ± 1.3 years and a mean visual acuity of 0.12 ± 0.02, were recruited over a one-year period. Sixty-three percent of participants had normal cognitive status. Cognitive impairment was diagnosed in 37.5% of participants. The COGEVIS score cutoff point to screen for cognitive impairment was 24 (maximum score of 30) with a sensitivity of 66.7% and a specificity of 95%. Evaluation following 4 months of visual rehabilitation showed an improvement of Instrumental Activities of Daily Living (p=0.004), National Eye Institute Visual Functioning Questionnaire (p=0.035), and Montgomery–Åsberg Depression Rating Scale (p=0.037). This study introduces a new short test to screen for cognitive impairment in visually impaired patients.

Published
2018
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14. The Brain Network of Naming: A Lesson from Primary Progressive Aphasia.

Author

Raffaella Migliaccio, Claire Boutet, Romain Valabregue, Sophie Ferrieux, Marie Nogues, Stéphane Lehéricy, Didier Dormont, Richard Levy, Bruno Dubois, and Marc Teichmann

Subjects
Medicine, Science
Abstract

OBJECTIVE:Word finding depends on the processing of semantic and lexical information, and it involves an intermediate level for mapping semantic-to-lexical information which also subserves lexical-to-semantic mapping during word comprehension. However, the brain regions implementing these components are still controversial and have not been clarified via a comprehensive lesion model encompassing the whole range of language-related cortices. Primary progressive aphasia (PPA), for which anomia is thought to be the most common sign, provides such a model, but the exploration of cortical areas impacting naming in its three main variants and the underlying processing mechanisms is still lacking. METHODS:We addressed this double issue, related to language structure and PPA, with thirty patients (11 semantic, 12 logopenic, 7 agrammatic variant) using a picture-naming task and voxel-based morphometry for anatomo-functional correlation. First, we analyzed correlations for each of the three variants to identify the regions impacting naming in PPA and to disentangle the core regions of word finding. We then combined the three variants and correlation analyses for naming (semantic-to-lexical mapping) and single-word comprehension (lexical-to-semantic mapping), predicting an overlap zone corresponding to a bidirectional lexical-semantic hub. RESULTS AND CONCLUSIONS:Our results showed that superior portions of the left temporal pole and left posterior temporal cortices impact semantic and lexical naming mechanisms in semantic and logopenic PPA, respectively. In agrammatic PPA naming deficits were rare, and did not correlate with any cortical region. Combined analyses revealed a cortical overlap zone in superior/middle mid-temporal cortices, distinct from the two former regions, impacting bidirectional binding of lexical and semantic information. Altogether, our findings indicate that lexical/semantic word processing depends on an anterior-posterior axis within lateral-temporal cortices, including an anatomically intermediate hub dedicated to lexical-semantic integration. Within this axis our data reveal the underpinnings of anomia in the PPA variants, which is of relevance for both diagnosis and future therapy strategies.

Published
2016
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16. Primary progressive aphasias associated with C9orf72 expansions: Another side of the story

Author

idier Hannequin, Eino Solje, Sabrina Sayah, Emmanuel Gerardin, Marie Sarazin, Florence Pasquier, Marion Houot, Assi-Hervé Oya, Martine Vercelletto, Julien Lagarde, Marie Noguès-Lassiaille, Marie Chupin, Vincent Deramecourt, Sophie Auriacombe, Agnès Camuzat, Marc Teichmann, Jérémie Pariente, Sophie Ferrieux, Lucette Lacomblez, Mathieu Chastan, Jacques Monteil, Yaohua Chen, Marie-Paule Boncoeur, Lorenzo Cipriano, Anne Bissery, Simona Bottani, David Wallon, Christine Delmaire, Carole Roué-Jagot, Benjamin Le Toullec, Bernard-François Michel, Grégory Petyt, Olivier Martinaud, Philippe Couratier, Dario Saracino, Adeline Rollin-Sillaire, Daisy Rinaldi, Mira Didic, Serge Belliard, Amandine Géraudie, Géraldine Lautrette, Frédérique Etcharry-Bouyx, Xavier Delbeuck, Richard Levy, Frédéric Blanc, Mathieu Ceccaldi, Christel Thauvin-Robinet, Marie-Odile Habert, Eve Benchetrit, Maïté Formaglio, Alexis Brice, Isabelle Le Ber, Charles Duyckaerts, Véronique Golfier, Raffaella Migliaccio, Marie-Anne Mackowiak, Catherine Thomas-Antérion, Anne Bertrand, Olivier Colliot, François Sellal, Claire Boutoleau-Bretonnière, Anne M. Remes, Hugo Bertin, Aurélie Funkiewiez, and Stéphanie Bombois

Subjects
medicine.medical_specialty, C9orf72 Protein, Apraxias, Cognitive Neuroscience, Inferior frontal gyrus, Experimental and Cognitive Psychology, Frontotemporal lobar degeneration, respiratory system, Audiology, medicine.disease, Magnetic Resonance Imaging, Apraxia, Primary progressive aphasia, Aphasia, Primary Progressive, Neuropsychology and Physiological Psychology, Atrophy, C9orf72, medicine, Humans, Speech, Orbitofrontal cortex, Psychology, Language, Frontotemporal dementia
Abstract

C9orf72 repeat expansions are rarely associated with primary progressive aphasias (PPA). In-depth characterization of the linguistic deficits, and the underlying patterns of grey-matter atrophy in PPA associated with the C9orf72 expansions (PPA-C9orf72) are currently lacking. In this study, we comprehensively analyzed a unique series of 16 patients affected by PPA-C9orf72. Eleven patients were issued from two independent French and Finnish cohorts, and five were identified by means of literature review. Voxel-based morphometry (VBM) studies were performed on three of them. This study depicts the spectrum of C9orf72–related aphasic phenotypes, and illustrates their linguistic presentation. The non-fluent/agrammatic variant was the most frequent phenotype in our series (9/16 patients, 56%), with apraxia of speech being the main defining feature. Left frontal lobe atrophy was present in these subjects, peaking in inferior frontal gyrus. Three patients (19%) showed the semantic variant, with progression of atrophy in temporo-polar regions, later involving orbitofrontal cortex. Anterior temporal lobe dysfunction was also particularly relevant in two patients (12.5%) with mixed forms of PPA. Lastly, two patients (12.5%) had unclassifiable PPA with predominating word-finding difficulties. No PPA-C9orf72 patients in our series fulfilled the criteria of the logopenic variant. Importantly, this study underlines the role of C9orf72 mutation in the disruption of the most anterior parts of the language network, including prefrontal and temporo-polar areas. It provides guidelines for C9orf72 testing in PPA patients, with important clinical impact as gene-specific therapies are upcoming.

Published
2021
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17. Evidence for functional connectivity pattern changes in Frontotemporal dementia patients using connectome gradient mapping

Author

Arabella Bouzigues, Lucy L Russell, Valérie Godefroy, Vincent Le Du, Dario Saracino, Isabelle Le Ber, Bénédicte Batrancourt, Richard Levy, Daniel Margulies, Jonathan D. Rohrer, and Raffaella Migliaccio

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022
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19. Disentangling Clinical Profiles of Apathy in Behavioral Variant Frontotemporal Dementia

Author

Valérie Godefroy, Bénédicte Batrancourt, Sylvain Charron, Arabella Bouzigues, Idil Sezer, David Bendetowicz, Guilhem Carle, Armelle Rametti-Lacroux, Stéphanie Bombois, Emmanuel Cognat, Raffaella Migliaccio, and Richard Levy

Subjects
Psychiatry and Mental health, Clinical Psychology, Cognition, General Neuroscience, Frontotemporal Dementia, Humans, General Medicine, Geriatrics and Gerontology, Atrophy, Neuropsychological Tests, Magnetic Resonance Imaging, Frontal Lobe
Abstract

Background: Apathy is highly frequent in behavioral variant frontotemporal dementia (bvFTD). It is presumed to involve different pathophysiological mechanisms and neuroanatomical regions. Objective: We explored the hypothesis that subgroups showing distinct profiles of apathy and distinct patterns of atrophy within frontal lobes could be disentangled in bvFTD. Methods: Using data-driven clustering applied to 20 bvFTD patients, we isolated subgroups according to their profiles on the three subscales of the Dimensional Apathy Scale (DAS). We explored their apathy profiles and atrophy patterns. Apathy profiles were characterized through both subjective measures of apathy by questionnaires and measures including objective behavioral metrics. Atrophy patterns were obtained by voxel-based morphometry, contrasting each bvFTD subgroup with healthy controls (N = 16). Results: By clustering based on DAS dimensions, we disentangled three subgroups of bvFTD patients, with distinct apathy profiles and atrophy patterns. One subgroup, which presented the smallest pattern of atrophy (including orbitofrontal cortex) with a right asymmetry, was characterized by high self-reported emotional and initiation apathy and by a self-initiation deficit reversible by external guidance. In other subgroups showing more diffuse bilateral atrophies extending to lateral prefrontal cortex, apathy was not reversible by external guidance and more difficulty to focus on goal-management was observed, especially in the subgroup with the largest atrophy and highest levels of executive apathy. Conclusion: Distinct clinical profiles of apathy, corresponding to distinct anatomical subtypes of bvFTD, were identified. These findings have implications for clinicians in a perspective of precision medicine as they could contribute to personalize treatments of apathy.

Published
2022

20. The temporal lobe in typical and atypical Alzheimer disease

Author

Raffaella, Migliaccio and Federica, Cacciamani

Subjects
Memory Disorders, Amyloid beta-Peptides, Alzheimer Disease, Brain, Humans, Plaque, Amyloid, Temporal Lobe, Aged
Abstract

Alzheimer disease (AD) is defined neuropathologically by abnormal extra-cellular β-amyloid plaques combined with intraneuronal tau aggregation. Patients sharing the same neuropathological features but presenting different clinical manifestations and evolutions have led to the notion of AD spectrum. This spectrum encompasses typical and atypical forms of AD. For all of them, specific parts of the temporal lobes, as well as their structural and functional connections with other brain regions, are affected. In typical amnestic late-onset Alzheimer's disease (65 years old; LOAD), tau pathology gradually spreads to the brain from the medial temporal lobe (MTL). MTL is an inhomogeneous structure consisting of several subregions densely connected to each other and to other cortical and subcortical brain regions. These regions play a crucial role in the storage of information in episodic memory. In less common early-onset AD (65 years old; EOAD), a large proportion of patients presents atypical clinical manifestations, in which memory impairment is not inaugural and predominant. Instead, these patients have predominant and/or isolated deficits in language, visuospatial, motor, or executive/behavioral functions. In atypical variants, brain damage is mainly centered on the posterior regions, with relative sparing of the MTL. However, the temporal lobe also appears to be variably and specifically damaged in some subtypes of EOAD. For example, the left superior temporal gyrus is the core of brain damage in the language variant, as well as the ventral regions of the temporal lobe play an important role in the clinic of the visual variant.

Published
2022

22. A temporal classification method based on behavior time series data in patients with behavioral variant of frontotemporal dementia and apathy

Author

Caroline Peltier, François-Xavier Lejeune, Lars G.T. Jorgensen, Armelle Rametti-Lacroux, Delphine Tanguy, Valérie Godefroy, David Bendetowicz, Guilhem Carle, Emmanuel Cognat, Stéphanie Bombois, Raffaella Migliaccio, Richard Levy, Frédéric Marin, Bénédicte Batrancourt, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Plateforme Chemosens [Dijon], Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Dijon, PROBE Infrasctructure de Recherche (PROBE), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biomécanique et Bioingénierie (BMBI), Université de Technologie de Compiègne (UTC)-Centre National de la Recherche Scientifique (CNRS), and BATRANCOURT, Bénédicte

Subjects
Time Factors, Testing session under ecological settings, Time series behavior, General Neuroscience, Apathy, Behavioral variant of frontotemporal dementia, R package, Temporal classification method, [SCCO] Cognitive science, Neuropsychological Tests, Human ethology, Key features of apathetic behaviors, Neuropsychological profiles, ECOCAPTURE kinetics, [SCCO]Cognitive science, Behavioral study encoding time, Behavioral kinetics, Ethological approach, Subject's behavior, Frontotemporal Dementia, Open-source software (OSS), Measuring behavior, Humans
Abstract

International audience; Background Apathy is a common behavioral syndrome that occurs across neurological and psychiatric disorders. An influential theoretical framework defined apathy as the quantitative reduction of self-generated voluntary and purposeful behaviors. There is evidence in the literature of the multidimensional nature of apathy with cognitive, behavioral, and emotional dimensions. To date, apathy has been assessed using various scales and questionnaires. Alternative objective and ecological measurements of apathy are needed. New method We used the ECOCAPTURE protocol and an ethological approach to investigate behavior in bvFTD patients under ecological conditions (a waiting room) while they freely explored a novel environment. Data were collected by behavioral coding from 7-minute video using an ethogram and transformed into behavior time series data. We present an approach considering behavioral kinetics to assess behavior. We aimed to construct a new behavior analysis method, called ECOCAPTURE kinetics, using temporal classification for behavior time series data analysis. To develop our classifier, we retained a nonelastic Euclidian metric, combined with a convolutional approach. Results We applied the ECOCAPTURE kinetics method to a cohort of 20 bvFTD patients and 18 healthy controls. We showed that bvFTD patients can be classified according to their behavioral kinetics into three groups. Each subgroup was characterized by specific behavior disorders and neuropsychological profile. Comparison with Existing Method(s) The ECOCAPTURE kinetics method is different from those of the classical approach of measuring behavior, producing time budgets, frequency of behavior occurrences, or kinematic diagrams. Conclusions This approach can be extended to any behavioral study encoding time.

Published
2022
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23. Cognitive and behavioural inhibition deficits in neurodegenerative dementias

Author

Raffaella Migliaccio, Delphine Tanguy, Arabella Bouzigues, Idil Sezer, Bénédicte Batrancourt, Isabelle Le Ber, Bruno Dubois, Valérie Godefroy, Richard Levy, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Raffaella Migliaccio is supported by 'France Alzheimer' and 'Philippe Chatrier' Foundations, and by 'Rosita Gomez association'. Delphine Tanguy is supported by École Normale Supérieure Paris-Saclay. Arabella Bouzigues is supported by 'Fondation Vaincre Alzheimer'. Raffaella Migliaccio, Richard Levy, Valérie Godefroy and Bénédicte Batrancourt are supported by 'Fondation pour la Recherche Medicale'., Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Jonchère, Laurent

Subjects
Cognitive Neuroscience, [SDV.NEU.PC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Experimental and Cognitive Psychology, Disease, Neuropsychological Tests, Disinhibition, Impulsivity, 050105 experimental psychology, Article, Progressive supranuclear palsy, Inhibition assessment, 03 medical and health sciences, Cognition, 0302 clinical medicine, Alzheimer Disease, Behavioural variant of frontotemporal dementia (bvFTD), medicine, Humans, 0501 psychology and cognitive sciences, Non pharmacological, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, 05 social sciences, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, medicine.disease, Inhibition, Psychological, Neuropsychology and Physiological Psychology, Cognitive inhibition, Frontotemporal Dementia, Alzheimer's disease (AD), Brain correlates, Supranuclear Palsy, Progressive, medicine.symptom, Psychology, Neuroscience, [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

International audience; Disinhibition, mainly caused by damage in frontotemporal brain regions, is one of the major causes of caregiver distress in neurodegenerative dementias. Behavioural inhibition deficits are usually described as a loss of social conduct and impulsivity, whereas cognitive inhibition deficits refer to impairments in the suppression of prepotent verbal responses and resistance to distractor interference. In this review, we aim to discuss inhibition deficits in neurodegenerative dementias through behavioural, cognitive, neuroanatomical and neurophysiological exploration. We also discuss impulsivity and compulsivity behaviours as related to disinhibition. We will therefore describe different tests available to assess both behavioural and cognitive disinhibition and summarise different manifestations of disinhibition across several neurodegenerative diseases (behavioural variant of frontotemporal dementia, Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, Huntington's disease). Finally, we will present the latest findings about structural, metabolic, functional, neurophysiological and also neuropathological correlates of inhibition impairments. We will briefly conclude by mentioning some of the latest pharmacological and non pharmacological treatment options available for disinhibition. Within this framework, we aim to highlight i) the current interests and limits of tests and questionnaires available to assess behavioural and cognitive inhibition in clinical practice and in clinical research; ii) the interpretation of impulsivity and compulsivity within the spectrum of inhibition deficits; and iii) the brain regions and networks involved in such behaviours.

Published
2020
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24. Dementia and COVID-19 Lockdown: More Than a Double Blow for Patients and Caregivers

Author

Raffaella Migliaccio and Arabella Bouzigues

Subjects
2019-20 coronavirus outbreak, Medical staff, Coronavirus disease 2019 (COVID-19), business.industry, General Neuroscience, COVID-19, Flexibility (personality), Caregiver, medicine.disease, lockdown, Clinical Practice, Psychiatry and Mental health, Clinical Psychology, Nursing, Pandemic, Commentary, medicine, collateral damage, Dementia, Geriatrics and Gerontology, business, dementia, Dementia research
Abstract

In dementia research and in clinical practice, the COVID-19 pandemic represents an important challenge, not only for neurological staff and researchers, but above all for patients and their caregivers. It is important that the medical staff demonstrate flexibility, open-mindedness, and humanity when following patients and caregivers. It seems inevitable that caregivers will pay the highest price during this crisis.

Published
2020
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25. Brain Metabolic Profile in Presymptomatic GRN Carriers Throughout a 5-Year Follow-up

Author

Dario, Saracino, Leila, Sellami, Hugo, Boniface, Marion, Houot, Mélanie, Pélégrini-Issac, Aurélie, Funkiewiez, Daisy, Rinaldi, Maxime, Locatelli, Carole, Azuar, Valérie, Causse-Lemercier, Alice, Jaillard, Florence, Pasquier, Mathieu, Chastan, David, Wallon, Anne, Hitzel, Jeremie, Pariente, Amandine, Pallardy, Claire, Boutoleau-Bretonnière, Eric, Guedj, Mira, Didic, Raffaella, Migliaccio, Aurélie, Kas, Marie-Odile, Habert, Isabelle, Le Ber, Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de médecine nucléaire [Marseille], Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Européen de Recherche en Imagerie médicale (CERIMED), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-École Centrale de Marseille (ECM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Centre National de la Recherche Scientifique (CNRS), Imagerie MOléculaire pour applications THéranostiques personnalisées (IMOTHEP), Institut FRESNEL (FRESNEL), and Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
Neurology (clinical), [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background and ObjectivesGRNvariants are a frequent cause of familial frontotemporal dementia (FTD). Monitoring disease progression in asymptomatic carriers of genetic variants is a major challenge in delivering preventative therapies before clinical onset. This study aimed to assess the usefulness of fluorodeoxyglucose (FDG)–PET in identifying metabolic changes in presymptomaticGRNcarriers (PS-GRN+) and to trace their longitudinal progression.MethodsParticipants were longitudinally evaluated over 5 years in a prospective cohort study focused onGRNdisease (Predict-PGRN). They underwent cognitive/behavioral assessment, plasma neurofilament measurement, brain MRI, and FDG-PET. Voxel-wise comparisons of structural and metabolic imaging data between 2 groups were performed for each time point. Longitudinal PET changes were evaluated with voxel-wise comparisons and the metabolic percent annual changes method. The association of regional brain metabolism with plasma neurofilament and cognitive changes was analyzed.ResultsAmong the 80 individuals enrolled in the study, 58 (27 PS-GRN+ and 31 noncarriers) were included in the analyses. Cross-sectional comparisons between PS-GRN+ and controls found a significant hypometabolism in the left superior temporal sulcus (STS) region (encompassing the middle and superior temporal gyri), approximately 15 years before the expected disease onset, without significant cortical atrophy. The longitudinal metabolic decline over the following 5 years peaked around the right STS in carriers (p< 0.001), without significantly greater volume loss compared with that in controls. Their estimated annualized metabolic decrease (−1.37%) was higher than that in controls (−0.21%,p= 0.004). Lower glucose uptake was associated with higher neurofilament increase (p= 0.003) and lower frontal cognitive scores (p= 0.014) in PS-GRN+.DiscussionThis study detected brain metabolic changes in the STS region, preceding structural and cognitive alterations, thus contributing to the characterization of the pathochronology of preclinicalGRNdisease. Owing to the STS involvement in the perception of facially communicated cues, it is likely that its dysfunction contributes to social cognition deficits characterizing FTD. Overall, our study highlights brain metabolic changes as an early disease-tracking biomarker and proposes annualized percent decrease as a metric to monitor therapeutic response in forthcoming trials.

Published
2022
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26. Avoiding Over-Reliance on Multi-Domain Interventions for Dementia Prevention

Author

Timothy Daly, Ignacio Mastroleo, and Raffaella Migliaccio

Subjects
Psychiatry and Mental health, Clinical Psychology, Alzheimer Disease, Risk Factors, General Neuroscience, Humans, General Medicine, Geriatrics and Gerontology, Risk Reduction Behavior
Abstract

Given the unknown therapeutic value of targeting Alzheimer’s disease pathology and the discovery of robust risk factors for dementia, non-pharmacological risk reduction (RR) is increasingly offered as an alternative to targeting Alzheimer’s disease pathology. While RR will surely be a useful tool to make public health gains, we propose solutions to three possible issues with over-reliance on multi-domain interventions to achieve RR: limited individual impact, an exclusive focus on later life, and overlooking social determinants of dementia. We argue in favor of a broader debate within the research community and greater society about how different therapeutic avenues should be explored.

Published
2022

28. Functional connectivity correlates of reduced goal-directed behaviors in behavioural variant frontotemporal dementia

Author

Valérie Godefroy, Bénédicte Batrancourt, Sylvain Charron, Arabella Bouzigues, David Bendetowicz, Guilhem Carle, Armelle Rametti-Lacroux, Stéphanie Bombois, Emmanuel Cognat, Raffaella Migliaccio, Richard Levy, Martinez Rico, Clara, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144))

Subjects
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Histology, Resting-state functional connectivity, General Neuroscience, Apathy, fMRI, Brain, Ecological design, Magnetic Resonance Imaging, Cognition, Goal-directed behavior, Frontotemporal Dementia, Parietal Lobe, Humans, Anatomy, Goals, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

INTRODUCTION: We explored the resting state functional connectivity correlates of apathy assessed as a multidimensional construct, using behavioral metrics, in behavioral variant frontotemporal dementia (bvFTD).METHODS: We recorded the behavior of 20 bvFTD patients and 16 healthy controls (HC) in a close-to-real-life situation including a free phase (FP – in which actions were self-initiated) and a guided phase (GP – in which initiation of actions was facilitated by external guidance). We investigated the activity time and walking episode features as quantifiers of apathy. We used the means ((FP+GP)/2) and the differences (FP-GP) calculated for these metrics as well as measures by questionnaires to extract apathy dimensions by factor analysis. We assessed two types of connectivity measures (local low-frequency signal power and distant seed-based functional connectivity) and explored their relationship with extracted apathy dimensions. RESULTS: Apathy in bvFTD was associated with lower time spent in activity combined with walking episodes of higher frequency, lower acceleration and higher duration. Using these behavioral metrics and apathy measures by questionnaires, we disentangled two dimensions: the global reduction of goal-directed behaviors and the specific deficit of selfinitiation. Global apathy was associated with lower resting state activity within prefrontal cortex and lower connectivity of salience network hubs while the decrease in self-initiation was related to increased connectivity of parietal default-mode network hubs. DISCUSSION: Through a new dimensional approach of apathy, we dissociated the functional connectivity correlates of global apathy and self-initiation deficit. This contributes to better understand the role of functional networks in the production of goal-directed behaviors.

Published
2022
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30. Right-Side Spatial Neglect and White Matter Disconnection after Left-Hemisphere Strokes

Author

Monica N. Toba, Raffaella Migliaccio, Alexia Potet, Pascale Pradat-Diehl, Paolo Bartolomeo, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Médecine Physique et de Réadaptation [CHU Pitié-Salpêtrière] (MPR), GRC 24 : Handicap Moteur et Cognitif et Réadaptation (HaMCRe ), Sorbonne Université (SU), and DESSAIVRE, Louise

Subjects
Histology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, General Neuroscience, White matter, Disconnection, Neuropsychological Tests, Functional Laterality, Perceptual Disorders, Stroke, Diffusion Tensor Imaging, Right neglect, Humans, Attention, Nerve Net, Anatomy, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Spatial neglect usually concerns left-sided events after right-hemisphere damage. Its anatomical correlates are debated, with evidence suggesting an important role for fronto-parietal white matter disconnections in the right hemisphere. Here, we describe the less frequent occurrence of neglect for right-sided events, observed in three right-handed patients after a focal stroke in the left hemisphere. Patients were tested 1 month and 3 months after stroke. They performed a standardized paper-and-pencil neglect battery and underwent brain MRI with both structural and diffusion tensor (DT) sequences, in order to assess both grey matter and white matter tracts metrics. Lesions were manually reconstructed for each patient. Patients presented signs of mild right-sided neglect during visual search and line bisection. One patient also showed pathological performance in everyday life. Structural MRI demonstrated left parietal strokes in two patients, in the region extending from the postcentral gyrus to the temporo-parietal junction. One of these two patients also had had a previous occipital stroke. The remaining patient had a left frontal stroke, affecting the precentral, the postcentral gyri and the basal ganglia. DT MRI tractography showed disconnections in the fronto-parietal regions, concerning principally the superior longitudinal fasciculus (SLF). These results suggest an important role for left SLF disconnection in right-side neglect, which complements analogous evidence for right SLF disconnection in left-side neglect.

Published
2022
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31. Multi-atlas Multilayer Brain Networks, a new multimodal approach to neurodegenerative disease

Author

Vincent Le Du, Charley Presigny, Arabella Bouzigues, Valerie Godefroy, Benedicte Batrancourt, Richard Levy, Fabrizio De Vico Fallani, Raffaella Migliaccio, FRONTLAB: Fonctions et dysfonctions de systèmes frontaux [ICM Paris] (FRONTlab), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM)

Subjects
bvFTD, Coreness, Multilayer, Brain, Network, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Atlas
Abstract

International audience; Multilayer networks (MNs) constitute an elegant and insightful multidimensional or multimodal framework. Bimodal MNs made from brain functional and structural networks extracted from neuroimaging modalities commonly lay the ground for truly emergent multimodal analysis. Thus far, they are computed using the same atlas for both layers. However, different atlases are required for specific imaging modalities. Depending on which atlas is chosen for a specific modality, this can lead to information from the other modalities being compromised. In this paper, we propose a new way to build such networks using specific atlases suited to each modality. The new technique is based on the computation of spatial overlaps between regions from different parcellations used for each available modality. We generalized the multiplex core-periphery method used to distinguish core and peripheral brain regions to apply it to such MNs, and to evaluate the approach and compare it to previous versions. We applied this new method in behavioral variant frontotemporal dementia (bvFTD) patients and healthy controls. First, we chose two specific atlases, the AAL2 and Schaefer100-Yeo17, for our DWI and fMRI data respectively. Subsequently, we computed richness and coreness for each subject. Finally, we benchmarked our results to evaluate the technique. We obtained higher peaks of significance and Fishers Criterion than with the previous method in the conditions that replicates previous findings. This highlights the potential of our multi-atlas MNs as well as their usefulness in MN analysis.

Published
2021
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32. Reduction of behavioural inhibition disorders in behavioural variant frontotemporal dementia patients observed under semi‐ecological conditions

Author

Delphine Tanguy, Bénédicte Batrancourt, Arabella Bouzigues, Valérie Godefroy, David Bendetowicz, Armelle Rametti‐Lacroux, Stéphanie Bombois, Emmanuel Cognat, Isabelle Le Ber, Xavier Morandi, Pierre Jannin, Richard Levy, and Raffaella Migliaccio

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2021
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33. An ecological approach to identify distinct neural correlates of disinhibition in frontotemporal dementia

Author

Delphine Tanguy, Bénédicte Batrancourt, Alfonso Estudillo-Romero, John S.H. Baxter, Isabelle Le Ber, Arabella Bouzigues, Valérie Godefroy, Aurélie Funkiewiez, Céline Chamayou, Emmanuelle Volle, Dario Saracino, Armelle Rametti-Lacroux, Xavier Morandi, Pierre Jannin, Richard Levy, Raffaella Migliaccio, Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This study was funded by the program 'Investissements d’avenir' ANR-10-IAIHU-0006, the 'Fondation pour la recherche médicale', FRM DEQ20150331725, frm.org, and by ENEDIS, enedis.fr., Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Jonchère, Laurent

Subjects
[SDV.IB] Life Sciences [q-bio]/Bioengineering, Semi-ecological situation, Cognitive Neuroscience, Compulsivity, Voxel-based morphometry, Neuropsychological Tests, Social disinhibition, Frontal Lobe, Diffusion Tensor Imaging, Neurology, Frontotemporal Dementia, Humans, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Radiology, Nuclear Medicine and imaging, Neurology (clinical), Atrophy
Abstract

International audience; Disinhibition is a core symptom of many neurodegenerative diseases, particularly frontotemporal dementia, and is a major cause of stress for caregivers. While a distinction between behavioural and cognitive disinhibition is common, an operational definition of behavioural disinhibition is still missing. Furthermore, conventional assessment of behavioural disinhibition, based on questionnaires completed by the caregivers, often lacks ecological validity. Therefore, their neuroanatomical correlates are non-univocal. In the present work, we used an original behavioural approach in a semi-ecological situation to assess two specific dimensions of behavioural disinhibition: compulsivity and social disinhibition. First, we investigated disinhibition profile in patients compared to controls. Then, to validate our approach, compulsivity and social disinhibition scores were correlated with classic cognitive tests measuring disinhibition (Hayling Test) and social cognition (mini-Social cognition and Emotional Assessment). Finally, we disentangled the anatomical networks underlying these two subtypes of behavioural disinhibition, taking in account the grey (voxel-based morphometry) and white matter (diffusion tensor imaging tractography). We included 17 behavioural variant frontotemporal dementia patients and 18 healthy controls. We identified patients as more compulsive and socially disinhibited than controls. We found that behavioural metrics in the semi-ecological task were related to cognitive performance: compulsivity correlated with the Hayling test and both compulsivity and social disinhibition were associated with the emotion recognition test. Based on voxel-based morphometry and tractography, compulsivity correlated with atrophy in the bilateral orbitofrontal cortex, the right temporal region and subcortical structures, as well as with alterations of the bilateral cingulum and uncinate fasciculus, the right inferior longitudinal fasciculus and the right arcuate fasciculus. Thus, the network of regions related to compulsivity matched the "semantic appraisal" network. Social disinhibition was associated with bilateral frontal atrophy and impairments in the forceps minor, the bilateral cingulum and the left uncinate fasciculus, regions corresponding to the frontal component of the "salience" network. Summarizing, this study validates our semi-ecological approach, through the identification of two subtypes of behavioural disinhibition, and highlights different neural networks underlying compulsivity and social disinhibition. Taken together, these findings are promising for clinical practice by providing a better characterisation of inhibition disorders, promoting their detection and consequently a more adapted management of patients.

Published
2021
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34. A future for PET imaging in Alzheimer’s disease

Author

Raffaella Migliaccio, Bertrand Tavitian, and Aurélie Kas

Subjects
medicine.medical_specialty, Alzheimer Disease, business.industry, Positron-Emission Tomography, Brain, Humans, Medicine, Radiology, Nuclear Medicine and imaging, General Medicine, Disease, Radiology, Pet imaging, business
Published
2019
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35. Testing the therapeutic effects of transcranial direct current stimulation (tDCS) in semantic dementia: a double blind, sham controlled, randomized clinical trial

Author

Bruno Dubois, Angelina Bourbon, Raffaella Migliaccio, Lisette Volpe-Gillot, Marc Teichmann, Sébastian Ströer, Clara Sanches, Richard Levy, Antoni Valero-Cabré, Sarah Benisty, Aurélie Kas, Nadya Pyatigorskaya, Marie-Odile Habert, Anna Kaglik, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Service de médecine nucléaire [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], CATI Multicenter Neuroimaging Platform (CATI), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Neuroradiologie [CHU Pitié-Salpêtrière], Centre de Neuro-Imagerie de Recherche (CENIR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Open University of Catalonia [Barcelona], Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Espace Interprofessionnel Mémoire Autonomie Gestes. Intégration Nutrition Equilibre [Hôpital Léopold Bellan, Paris] (IMAGINE), Hôpital Léopold Bellan [Paris] (HLB), Service de Médecine nucléaire [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Unité de Recherche Clinique des hôpitaux Pitié-Salpêtrière – Charles Foix [CHU Pitié Salpêtrière] (URC PSL-CFX), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Direction de la Recherche Clinique et de l'Innovation [AP-HP] (DRCI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Universitat Oberta de Catalunya (UOC), Sorbonne Université, Boston University School of Medicine, Gestionnaire, Hal Sorbonne Université, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupe Hospitalier Paris Saint Joseph, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP]

Subjects
Neurology, medicine.medical_treatment, Medicine (miscellaneous), Transcranial direct current stimulation, law.invention, Primary progressive aphasia, Executive Function, Study Protocol, 0302 clinical medicine, Randomized controlled trial, law, Medicine, Pharmacology (medical), lcsh:R5-920, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Transcranial direct-current stimulation, medicine.diagnostic_test, 05 social sciences, Neurodegenerative diseases, Semantic dementia, Electroencephalography, Magnetic Resonance Imaging, Semantics, 3. Good health, Research Design, Frontotemporal Dementia, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.IB]Life Sciences [q-bio]/Bioengineering, medicine.symptom, lcsh:Medicine (General), medicine.medical_specialty, 050105 experimental psychology, 03 medical and health sciences, Language impairments, Physical medicine and rehabilitation, Double-Blind Method, Aphasia, Humans, 0501 psychology and cognitive sciences, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Non-invasive brain stimulation, [SDV.IB] Life Sciences [q-bio]/Bioengineering, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, medicine.disease, Clinical trial, Positron-Emission Tomography, business, Functional magnetic resonance imaging, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background Semantic dementia is a neurodegenerative disease that primarily affects the left anterior temporal lobe, resulting in a gradual loss of conceptual knowledge. There is currently no validated treatment. Transcranial stimulation has provided evidence for long-lasting language effects presumably linked to stimulation-induced neuroplasticity in post-stroke aphasia. However, studies evaluating its effects in neurodegenerative diseases such as semantic dementia are still rare and evidence from double-blind, prospective, therapeutic trials is required. Objective The primary objective of the present clinical trial (STIM-SD) is to evaluate the therapeutic efficacy of a multiday transcranial direct current stimulation (tDCS) regime on language impairment in patients with semantic dementia. The study also explores the time course of potential tDCS-driven improvements and uses imaging biomarkers that could reflect stimulation-induced neuroplasticity. Methods This is a double-blind, sham-controlled, randomized study using transcranial Direct Current Stimulation (tDCS) applied daily for 10 days, and language/semantic and imaging assessments at four time points: baseline, 3 days, 2 weeks and 4 months after 10 stimulation sessions. Language/semantic assessments will be carried out at these same 4 time points. Fluorodeoxyglucose positron emission tomography (FDG-PET), resting-state functional magnetic resonance imaging (rs-fMRI), T1-weighted images and white matter diffusion tensor imaging (DTI) will be applied at baseline and at the 2-week time point. According to the principle of inter-hemispheric inhibition between left (language-related) and right homotopic regions we will use two stimulation modalities - left-anodal and right-cathodal tDCS over the anterior temporal lobes. Accordingly, the patient population (n = 60) will be subdivided into three subgroups: left-anodal tDCS (n = 20), right-cathodal tDCS (n = 20) and sham tDCS (n = 20). The stimulation will be sustained for 20 min at an intensity of 1.59 mA. It will be delivered through 25cm2-round stimulation electrodes (current density of 0.06 mA/cm2) placed over the left and right anterior temporal lobes for anodal and cathodal stimulation, respectively. A group of healthy participants (n = 20) matched by age, gender and education will also be recruited and tested to provide normative values for the language/semantic tasks and imaging measures. Discussion The aim of this study is to assess the efficacy of tDCS for language/semantic disorders in semantic dementia. A potential treatment would be easily applicable, inexpensive, and renewable when therapeutic effects disappear due to disease progression. Trial registration ClinicalTrials.gov NCT03481933. Registered on March 2018.

Published
2019
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36. ECOCAPTURE@HOME: Protocol for the Remote Assessment of Apathy and Its Everyday-Life Consequences

Author

Valérie Godefroy, Raffaella Migliaccio, Bénédicte Batrancourt, Richard Levy, Arabella Bouzigues, Armelle Rametti-Lacroux, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), CHU Pitié-Salpêtrière [AP-HP], and HAL-SU, Gestionnaire

Subjects
[SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Health, Toxicology and Mutagenesis, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Apathy, sensors, 03 medical and health sciences, Study Protocol, patient-caregiver dyads, 0302 clinical medicine, Quality of life (healthcare), Alzheimer Disease, Surveys and Questionnaires, Ecological psychology, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Dementia, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030212 general & internal medicine, Everyday life, remote monitoring, [SDV.IB] Life Sciences [q-bio]/Bioengineering, Protocol (science), blood volume pulse, Public Health, Environmental and Occupational Health, acceleration, medicine.disease, electrodermal activity, 3. Good health, Observational Studies as Topic, Caregivers, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Quality of Life, Medicine, Observational study, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.IB]Life Sciences [q-bio]/Bioengineering, fronto-temporal dementia, medicine.symptom, Alzheimer's disease, Psychology, 030217 neurology & neurosurgery, Clinical psychology
Abstract

International audience; Apathy, a common neuropsychiatric symptom associated with dementia, has a strong impact on patients’ and caregivers’ quality of life. However, it is still poorly understood and hard to define. The main objective of the ECOCAPTURE programme is to define a behavioural signature of apathy using an ecological approach. Within this program, ECOCAPTURE@HOME is an observational study which aims to validate a method based on new technologies for the remote monitoring of apathy in real life. For this study, we plan to recruit 60 couples: 20 patient-caregiver dyads in which patients suffer from behavioral variant Fronto-Temporal Dementia, 20 patient-caregiver dyads in which patients suffer from Alzheimer Disease and 20 healthy control couples. These dyads will be followed for 28 consecutive days via multi-sensor bracelets collecting passive data (acceleration, electrodermal activity, blood volume pulse). Active data will also be collected by questionnaires on a smartphone application. Using a pool of metrics extracted from these passive and active data, we will validate a measurement model for three behavioural markers of apathy (i.e., daytime activity, quality of sleep, and emotional arousal). The final purpose is to facilitate the follow-up and precise diagnosis of apathy, towards a personalised treatment of this condition within everyday life.

Published
2021
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37. Plasma NfL levels and longitudinal change rates in

Author

Dario, Saracino, Karim, Dorgham, Agnès, Camuzat, Daisy, Rinaldi, Armelle, Rametti-Lacroux, Marion, Houot, Fabienne, Clot, Philippe, Martin-Hardy, Ludmila, Jornea, Carole, Azuar, Raffaella, Migliaccio, Florence, Pasquier, Philippe, Couratier, Sophie, Auriacombe, Mathilde, Sauvée, Claire, Boutoleau-Bretonnière, Jérémie, Pariente, Mira, Didic, Didier, Hannequin, David, Wallon, Olivier, Colliot, Bruno, Dubois, Alexis, Brice, Richard, Levy, and Sylvie, Forlani

Subjects
Adult, Aged, 80 and over, Male, C9orf72 Protein, Amyotrophic Lateral Sclerosis, Middle Aged, Progranulins, Neurofilament Proteins, Frontotemporal Dementia, Disease Progression, Humans, Female, Neurogenetics, Aged
Abstract

Objective Neurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages. Methods We analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical–genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index. Results pNfL levels increased with age in controls, from ~5 to~18 pg/mL (p

Published
2021

38. Quantitative Assessment of Motor Neglect

Author

François Cotton, Gilles Rode, Paolo Bartolomeo, Monica N. Toba, L Spinazzola, Marco Rabuffetti, Francesca Baglio, Raffaella Migliaccio, Norbert Nighoghossian, Chiara Pagliari, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Picardie Jules Verne (UPJV), Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Fondazione Don Carlo Gnocchi, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital Henry Gabrielle [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), FRONTLAB: Fonctions et dysfonctions de systèmes frontaux [ICM Paris] (FRONTlab), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], ANR-16-CE37-0005,BRANDY,Étude intracérébrale et MEG de la dynamique des réseaux cérébraux de l'attention chez des sujets sains et chez des patients cérébro-lésés(2016), Gestionnaire, Hal Sorbonne Université, Étude intracérébrale et MEG de la dynamique des réseaux cérébraux de l'attention chez des sujets sains et chez des patients cérébro-lésés - - BRANDY2016 - ANR-16-CE37-0005 - AAPG2016 - VALID, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), FRONTlab - Systèmes frontaux : fonctions et dysfonctions (FRONTlab), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP]

Subjects
Adult, Male, medicine.medical_specialty, media_common.quotation_subject, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Hemiplegia, motor disorders, 050105 experimental psychology, Neglect, Upper Extremity, hypokinesia, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Hypokinesia, Quantitative assessment, medicine, Humans, 0501 psychology and cognitive sciences, Motor activity, Motor asymmetry, Stroke, media_common, Aged, Advanced and Specialized Nursing, Aged, 80 and over, Rehabilitation, business.industry, 05 social sciences, Stroke Rehabilitation, Objective method, Actigraphy, Middle Aged, medicine.disease, stroke, attention, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Upper limb, Female, Neurology (clinical), medicine.symptom, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery, actigraphy
Abstract

Background and Purpose: We used differential actigraphy as a novel, objective method to quantify motor neglect (a clinical condition whereby patients mimic hemiplegia even in the absence of sensorimotor deficits), whose diagnosis is at present highly subjective, based on the clinical observation of patients’ spontaneous motor behavior. Methods: Patients wear wristwatch-like accelerometers, which record spontaneous motor activity of their upper limbs during 24 hours. Asymmetries of motor behavior are then automatically computed offline. On the basis of normal participants’ performance, we calculated cutoff scores of left/right motor asymmetry. Results: Differential actigraphy showed contralesional motor neglect in 9 of 35 patients with unilateral strokes, consistent with clinical assessment. An additional patient with clinical signs of motor neglect obtained a borderline asymmetry score. Lesion location in a subgroup of 25 patients was highly variable, suggesting that motor neglect is a heterogenous condition. Conclusions: Differential actigraphy provides an ecological measure of spontaneous motor behavior, and can assess upper limb motricity in an objective and quantitative manner. It thus offers a convenient, cost-effective, and relatively automatized procedure for following-up motor behavior in neurological patients and to assess the effects of rehabilitation.

Published
2021
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39. Frontotemporal dementia subtypes based on behavioral inhibition deficits

Author

Richard Levy, Arabella Bouzigues, Valérie Godefroy, Stéphanie Bombois, Johan Ferrand-Verdejo, Delphine Tanguy, Idil Sezer, Bénédicte Batrancourt, Emmanuel Cognat, Raffaella Migliaccio, David Bendetowicz, Armelle Rametti-Lacroux, Guilhem Carle, Pierre Jannin, Isabelle Le Ber, Xavier Morandi, Carole Azuar, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gestionnaire, Hal Sorbonne Université, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio], Ventromedial prefrontal cortex, disinhibition, frontotemporal dementia, 03 medical and health sciences, 0302 clinical medicine, Atrophy, compulsivity, medicine, RC346-429, 030304 developmental biology, 0303 health sciences, business.industry, Genetic heterogeneity, subtypes, RC952-954.6, Cognition, medicine.disease, [SDV] Life Sciences [q-bio], gray matter atrophy, Psychiatry and Mental health, ecological design, medicine.anatomical_structure, Disinhibition, Geriatrics, Anxiety, Orbitofrontal cortex, Cognitive & Behavioral Assessment, Neurology (clinical), Neurology. Diseases of the nervous system, medicine.symptom, business, Neuroscience, 030217 neurology & neurosurgery, Frontotemporal dementia, Research Article
Abstract

International audience; Introduction: We aimed to investigate phenotypic heterogeneity in the behavioral variant of frontotemporal dementia (bvFTD) through assessment of inhibition deficits.Methods: We assessed occurrences of 16 behavioral inhibition deficits from video recordings of 15 bvFTD patients (early stage) and 15 healthy controls (HC) in an ecological setting. We extracted dimensions of inhibition deficit and analyzed their correlations with cognitive and clinical measures. Using these dimensions, we isolated patient clusters whose atrophy patterns were explored.Results: After identifying two patterns of inhibition deficit (compulsive automatic behaviors and socially unconventional behaviors), we isolated three behavioral clusters with distinct atrophy patterns. BvFTD-G0 (N = 3), an outlier group, showed severe behavioral disturbances and more severe ventromedial prefrontal cortex/orbitofrontal cortex atrophy. Compared to bvFTD-G1 (N = 6), bvFTD-G2 (N = 6) presented higher anxiety and depression along with less diffuse atrophy especially in midline regions.Discussion: Identifying clinico-anatomical profiles through behavior observation could help to stratify bvFTD patients for adapted treatments.

Published
2021
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40. Primary Progressive Aphasia Associated With GRN Mutations: New Insights Into the Nonamyloid Logopenic Variant

Author

Bruno Dubois, Audrey Gabelle, François Sellal, Jérémie Pariente, Marie Sarazin, Agnès Camuzat, Raffaella Migliaccio, Frédérique Etcharry-Bouyx, Amandine Geraudie, Sophie Ferrieux, Simona Bottani, Carole Roué-Jagot, Mira Didic, Florence Pasquier, Leila Sellami, Alexis Brice, Olivier Colliot, Fabienne Clot, Marc Teichmann, Didier Hannequin, Christel Thauvin-Robinet, Claire Boutoleau-Bretonnière, Julien Lagarde, Cinzia Coppola, David Wallon, Richard Levy, Marie Noguès-Lassiaille, Dario Saracino, Aurélie Funkiewiez, Maria Luisa Gorno-Tempini, Olivier Martinaud, Isabelle Le Ber, Marion Houot, Stéphane Epelbaum, Sophie Auriacombe, Alexandre Morin, Vincent Deramecourt, Ftd-Als, Philippe Couratier, Daisy Rinaldi, Saracino, Dario, Ferrieux, Sophie, Noguès-Lassiaille, Marie, Houot, Marion, Funkiewiez, Aurélie, Sellami, Leila, Deramecourt, Vincent, Pasquier, Florence, Couratier, Philippe, Pariente, Jérémie, Géraudie, Amandine, Epelbaum, Stéphane, Wallon, David, Hannequin, Didier, Martinaud, Olivier, Clot, Fabienne, Camuzat, Agnè, Bottani, Simona, Rinaldi, Daisy, Auriacombe, Sophie, Sarazin, Marie, Didic, Mira, Boutoleau-Bretonnière, Claire, Thauvin-Robinet, Christel, Lagarde, Julien, Roué-Jagot, Carole, Sellal, Françoi, Gabelle, Audrey, Etcharry-Bouyx, Frédérique, Morin, Alexandre, Coppola, Cinzia, Levy, Richard, Dubois, Bruno, Brice, Alexi, Colliot, Olivier, Luisa Gorno-Tempini, Maria, Teichmann, Marc, Migliaccio, Raffaella, Le Ber, Isabelle, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Lille, CHU Limoges, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropsychologie et imagerie de la mémoire humaine (NIMH), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Charles Foix [AP-HP], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), GHU AP-HP Centre Université de Paris, Hôpitaux Civils de Colmar, Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), University of the Study of Campania Luigi Vanvitelli, University of California [San Francisco] (UC San Francisco), University of California (UC), The research leading to these results received funding from the Investissements davenir ANR-11-INBS-0011. This work was funded by the Programme Hospitalier de Recherche Clinique (PHRC) FTLD-exome (to ILB, promotion by Assistance Publique Hôpitaux de Paris), PHRC Predict-PGRN (to ILB, promotion by Assistance Publique Hôpitaux de Paris)., ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Admin, Oskar, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of California [San Francisco] (UCSF), University of California, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Normandie Université (NU)-Normandie Université (NU)-École Pratique des Hautes Études (EPHE)

Subjects
Oncology, medicine.medical_specialty, Apraxia, 050105 experimental psychology, Primary progressive aphasia, 03 medical and health sciences, Dementia aphasia, 0302 clinical medicine, Atrophy, Gyrus, Aphasia, Agrammatism, Internal medicine, medicine, 0501 psychology and cognitive sciences, Prospective cohort study, business.industry, 05 social sciences, respiratory system, medicine.disease, medicine.anatomical_structure, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

ObjectiveTo determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with GRN (progranulin) mutations and to study their neuroanatomic correlates.MethodsPatients with PPA carrying GRN mutations (PPA-GRN) were selected among a national prospective research cohort of 1,696 patients with frontotemporal dementia, including 235 patients with PPA. All patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and gray matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls and patients with sporadic PPA.ResultsAmong the 235 patients with PPA, 45 (19%) carried GRN mutations, and we studied 32 of these. We showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (n = 13, 41%), followed by nonfluent/agrammatic (nfvPPA; n = 9, 28%) and mixed forms (n = 8, 25%). Semantic variant was rather rare (n = 2, 6%). Patients with lvPPA, qualified as nonamyloid lvPPA, presented canonical logopenic deficit. Seven of 13 had a pure form; 6 showed subtle additional linguistic deficits not fitting criteria for mixed PPA and hence were labeled as logopenic-spectrum variant. GM atrophy involved primarily left posterior temporal gyrus, mirroring neuroanatomic changes of amyloid-positive-lvPPA. Patients with nfvPPA presented agrammatism (89%) rather than apraxia of speech (11%).ConclusionsThis study shows that the most frequent PPA variant associated with GRN mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. GRN testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming GRN gene–specific therapies.

Published
2021
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41. Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications

Author

Fabienne Clot, Florence Pasquier, Didier Hannequin, Olivier Colliot, Armelle Rametti-Lacroux, Sophie Auriacombe, Raffaella Migliaccio, Ludmila Jornea, Marion Houot, Agnès Camuzat, Carole Azuar, Alexis Brice, Mathilde Sauvée, Philippe Martin-Hardy, Richard Levy, Philippe Couratier, Isabelle Le Ber, Jérémie Pariente, Claire Boutoleau-Bretonnière, Karim Dorgham, Dario Saracino, Bruno Dubois, Mira Didic, Daisy Rinaldi, Prev-Demals, David Wallon, Predict-PGRN study groups, Ftd-Als, Sylvie Forlani, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Lille 2 - Faculté de Médecine, CHU Limoges, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU), CIC - Nantes, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Institut de Neurosciences des Systèmes (INS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Hôpital de la Timone [CHU - APHM] (TIMONE), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), The research leading to these results received funding from the ’Investissements d’avenir’ ANR-11- INBS-0011. This work was partially funded by the Programme Hospitalier de Recherche Clinique (PHRC) Predict- PGRN (to ILB, promotion by Assistance Publique–Hôpitaux de Paris), the PHRC FTLD- exome (to ILB, promotion by Assistance Publique–Hôpitaux de Paris), by the ANR- PRTS PREV- DEMALS project (to ILB, grant number ANR-14- CE15-0016-07, promotion by Assistance Publique–Hôpitaux de Paris) and the Fondation Vaincre Alzheimer (to ILB, grant number FR-17035)., ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Faculté de Médecine Henri Warembourg - Université de Lille, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Saracino, Dario, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées

Subjects
Oncology, 0303 health sciences, medicine.medical_specialty, business.industry, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Disease progression, Youden's J statistic, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, Therapeutic trial, 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, C9orf72, Internal medicine, Medicine, Biomarker (medicine), Surgery, Neurology (clinical), Amyotrophic lateral sclerosis, business, Trial registration, 030217 neurology & neurosurgery, 030304 developmental biology, Frontotemporal dementia
Abstract

ObjectiveNeurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages.MethodsWe analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical–genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index.ResultspNfL levels increased with age in controls, from ~5 to~18 pg/mL (pGRN patients had higher levels than C9orf72 (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72 patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades.ConclusionsThis study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression.Trial registration numbersNCT02590276 and NCT04014673.

Published
2021
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42. Identification of subtypes for the behavioral variant of frontotemporal dementia based on the assessment of disinhibition and compulsion

Author

Isabelle Le Ber, Arabella Bouzigues, Valérie Godefroy, Carole Azuar, Raffaella Migliaccio, Armelle Rametti-Lacroux, Idil Sezer, Delphine Tanguy, Richard Levy, Guilhem Carle, David Bendetowicz, and Bénédicte Batrancourt

Subjects
Epidemiology, Behavioral neurology, business.industry, Health Policy, Neuropsychiatry, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Disinhibition, medicine, Identification (biology), Neurology (clinical), Geriatrics and Gerontology, medicine.symptom, business, Frontotemporal dementia, Clinical psychology
Published
2020
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43. Primary Progressive Aphasia Associated With

Author

Dario, Saracino, Sophie, Ferrieux, Marie, Noguès-Lassiaille, Marion, Houot, Aurélie, Funkiewiez, Leila, Sellami, Vincent, Deramecourt, Florence, Pasquier, Philippe, Couratier, Jérémie, Pariente, Amandine, Géraudie, Stéphane, Epelbaum, David, Wallon, Didier, Hannequin, Olivier, Martinaud, Fabienne, Clot, Agnès, Camuzat, Simona, Bottani, Daisy, Rinaldi, Sophie, Auriacombe, Marie, Sarazin, Mira, Didic, Claire, Boutoleau-Bretonnière, Christel, Thauvin-Robinet, Julien, Lagarde, Carole, Roué-Jagot, François, Sellal, Audrey, Gabelle, Frédérique, Etcharry-Bouyx, Alexandre, Morin, Cinzia, Coppola, Richard, Levy, Bruno, Dubois, Alexis, Brice, Olivier, Colliot, Maria Luisa, Gorno-Tempini, Marc, Teichmann, Raffaella, Migliaccio, Isabelle, Le Ber, and Martine, Vercelletto

Subjects
Male, Tomography, Emission-Computed, Single-Photon, Language Tests, Middle Aged, Neuropsychological Tests, Magnetic Resonance Imaging, Cohort Studies, Aphasia, Primary Progressive, Cross-Sectional Studies, Progranulins, Gene Frequency, Frontotemporal Dementia, Mutation, Humans, Speech, Female, Prospective Studies, Atrophy, Biomarkers, Aged
Abstract

To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated withPatients with PPA carryingAmong the 235 patients with PPA, 45 (19%) carriedThis study shows that the most frequent PPA variant associated with

Published
2020

44. Parietal Involvement in the Semantic Variant of Primary Progressive Aphasia with Alzheimer’s Disease Cerebrospinal Fluid Profile

Author

Géraldine Bera, Marie-Odile Habert, Sophie Ferrieux, Hugo Bertin, Bruno Dubois, Thibaut Michelin, Foudil Lamari, Aurélie Kas, Marc Teichmann, Raffaella Migliaccio, and Marie Nogues

Subjects
Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Perfusion scanning, Disease, Primary progressive aphasia, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Alzheimer Disease, Parietal Lobe, Humans, Medicine, Aged, Tomography, Emission-Computed, Single-Photon, business.industry, General Neuroscience, Parietal lobe, General Medicine, Middle Aged, medicine.disease, Semantics, Psychiatry and Mental health, Clinical Psychology, Aphasia, Primary Progressive, 030104 developmental biology, Posterior cingulate, Biomarker (medicine), Female, Geriatrics and Gerontology, business, Perfusion, Biomarkers, 030217 neurology & neurosurgery
Abstract

Semantic variant of primary progressive aphasia (svPPA) is typically associated with non-Alzheimer's disease (AD) pathology. However, some anatomopathological studies have found AD lesions in those patients. We compared brain perfusion SPECT of 18 svPPA patients with cerebrospinal fluid (CSF) biomarkers indicative of non-AD pathology (svPPA-nonAD) and three svPPA patients with CSF biomarkers indicative of underlying AD (svPPA-AD). All svPPA patients had severe left temporopolar hypoperfusion. SvPPA-nonAD had additional anterior cingulate and mediofrontal hypoperfusion, whereas svPPA-AD had greater left parietal and posterior cingulate involvement. Parietal damage in svPPA constitutes a biomarker for underlying Alzheimer pathology thus refining the classification of this PPA variant.

Published
2018
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45. Functional brain connectome in posterior cortical atrophy

Author

Federica Agosta, Massimo Filippi, Aurélie Kas, Silvia Basaia, Maxime Montembeault, Camilla Cividini, Marie-Odile Habert, Raffaella Migliaccio, Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de médecine nucléaire [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], University of California [San Francisco] (UCSF), University of California, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Médecine nucléaire [CHU Pitié-Salpétrière], University of California [San Francisco] (UC San Francisco), University of California (UC), Gestionnaire, Hal Sorbonne Université, Migliaccio, R., Agosta, F., Basaia, S., Cividini, C., Habert, M. -O., Kas, A., Montembeault, M., Filippi, M., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
Male, [SDV]Life Sciences [q-bio], lcsh:RC346-429, Functional connectivity, 0302 clinical medicine, Cerebrospinal fluid, Medicine, Cerebral Cortex, Brain Diseases, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, 05 social sciences, Neurodegeneration, Neurodegenerative Diseases, Regular Article, Human Connectome, Middle Aged, Magnetic Resonance Imaging, [SDV] Life Sciences [q-bio], Human connectome, Neurology, Graph analysi, Connectome, lcsh:R858-859.7, Female, Connectomics, Cognitive Neuroscience, Posterior cortical atrophy (PCA), Graph analysis, lcsh:Computer applications to medicine. Medical informatics, 050105 experimental psychology, 03 medical and health sciences, Functional brain, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, lcsh:Neurology. Diseases of the nervous system, Aged, business.industry, Posterior cortical atrophy, medicine.disease, Neurology (clinical), Atrophy, Nerve Net, business, Neuroscience, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Highlights • PCA patients present widespread loss of both intra- and inter-hemispheric connections. • Functional connectivity alterations were also observed in frontal connections. • They exceeded structural and metabolic brain damage. • Graph-analysis and connectomic have a high sensitivity in capturing the disease progression in PCA patients., This study investigated the functional brain connectome architecture in patients with Posterior Cortical Atrophy (PCA). Eighteen PCA patients and 29 age- and sex- matched healthy controls were consecutively recruited in a specialized referral center. Participants underwent neurologic examination, cerebrospinal fluid (CSF) examination for Alzheimer's disease (AD) biomarkers, cognitive assessment, and brain MRI. For a smaller subset of participants, FDG-PET examination was available. We assessed topological brain network properties and regional functional connectivity as well as intra- and inter-hemispheric connectivity, using graph analysis and connectomics. Supplementary analyses were performed to explore the association between the CSF AD profile and the connectome status, and taking into account hypometabolic, atrophic, and spared regions (nodes). PCA patients showed diffuse functional connectome alterations at both global and regional level, as well as a connectivity breakdown between the posterior brain nodes. They had a widespread loss of both intra- and inter-hemispheric connections, exceeding the structural damage, and including the frontal connections. In PCA, connectome alterations were identified in all the brain nodes irrespectively of their structural and metabolic classification and were associated with a connectivity breakdown between damaged and spared areas. Taken together, these findings suggest the potentially high sensitivity of graph-analysis and connectomic in capturing the progression and maybe early signs of neurodegeneration in PCA patients.

Published
2020
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46. A dissociation between preserved abstract spatial knowledge and impaired navigation in a blind patient

Author

Tal Seidel Malkinson, Monica N. Toba, Hélène Migeot, C. Picq, Paolo Bartolomeo, Pascale Pradat-Diehl, Raffaella Migliaccio, Antonio Cerrato, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), FRONTlab - Systèmes frontaux : fonctions et dysfonctions (FRONTlab), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Service de Médecine Physique et de Réadaptation [CHU Pitié-Salpêtrière] (MPR), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Naples Federico II, CHU Amiens-Picardie, Université de Picardie Jules Verne (UPJV), Service de médecine physique et de réadaptation [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Dissociation (neuropsychology), business.industry, Cognitive Neuroscience, 05 social sciences, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Experimental and Cognitive Psychology, Spatial knowledge, Blindness, 050105 experimental psychology, 03 medical and health sciences, 0302 clinical medicine, Neuropsychology and Physiological Psychology, Text mining, Humans, 0501 psychology and cognitive sciences, business, Psychology, Visually Impaired Persons, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, Cognitive psychology
Abstract

International audience

Published
2020
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47. Behavioural and Cognitive Changes in Neurodegenerative Diseases and Brain Injury

Author

Gabriella Santangelo, Hernando Santamaría-García, Raffaella Migliaccio, Francesca Trojsi, Foteini Christidi, Trojsi, Francesca, Christidi, Foteini, Migliaccio, Raffaella, Santamaría-García, Hernando, and Santangelo, Gabriella

Subjects
0301 basic medicine, Article Subject, Neurosciences. Biological psychiatry. Neuropsychiatry, 03 medical and health sciences, Cognition, 0302 clinical medicine, Text mining, Brain Injurie, Cognitive Changes, Humans, Medicine, Nervous System Disease, business.industry, Neurodegenerative Diseases, General Medicine, Editorial, 030104 developmental biology, Neuropsychology and Physiological Psychology, Neurology, Brain Injuries, Neurology (clinical), Nervous System Diseases, business, Neuroscience, 030217 neurology & neurosurgery, RC321-571, Human
Published
2018
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48. Animacy distinctions and semantic dementia

Author

Raffaella Migliaccio, Clara Sanches, Antoni Valero-Cabré, Marc Teichmann, Anna Kaglik, and Elsa Mhanna

Subjects
medicine, Semantic dementia, Psychology, Animacy, medicine.disease, Cognitive psychology
Published
2019
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49. Cognitive inhibition impairments in presymptomatic

Author

Maxime, Montembeault, Sabrina, Sayah, Daisy, Rinaldi, Benjamin, Le Toullec, Anne, Bertrand, Aurélie, Funkiewiez, Dario, Saracino, Agnès, Camuzat, Philippe, Couratier, Marianne, Chouly, Didier, Hannequin, Carole, Aubier-Girard, Florence, Pasquier, Xavier, Delbeuck, Olivier, Colliot, Bénédicte, Batrancourt, Carole, Azuar, Richard, Lévy, Bruno, Dubois, Isabelle, Le Ber, Raffaella, Migliaccio, and David, Wallon

Subjects
Adult, Male, Heterozygote, Inhibition, Psychological, C9orf72 Protein, Brain, Humans, Cognitive Dysfunction, Female, Middle Aged, Neuropsychological Tests
Abstract

To investigate cognitive inhibition in presymptomaticThirty-eight presymptomaticC9+ individuals younger than 40 years had higher error scores (part B) but equivalent HSCT time to completion (part B-part A) compared to C9- individuals. C9+ individuals older than 40 years had both higher error scores and longer time to completion. HSCT time to completion significantly predicted the proximity to estimated clinical conversion from presymptomatic to symptomatic phase in C9+ individuals (based on the average age at onset of affected relatives in the family). Anatomically, we found that HSCT time to completion was associated with the integrity of the cerebellum.The HSCT represents a good marker of cognitive inhibition impairments in C9+ and of proximity to clinical conversion. This study also highlights the key role of the cerebellum in cognitive inhibition.

Published
2019

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

Author

Aurélie Kas, Paolo Bartolomeo, Vincent Perlbarg, Cecile Gallea, Stéphane Lehéricy, Laura Trotta, Dalila Samri, Bruno Dubois, Agnès Michon, Raffaella Migliaccio, Lucette Lacomblez, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neuroradiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Neuro-Imagerie de Recherche (CENIR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de médecine nucléaire [CHU Pitié-Salpétrière], Laboratoire d'Imagerie Biomédicale (LIB), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de neurosciences translationnelles de Paris (NeurATRIS - IHU-A-ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Service des Maladies du Système Nerveux [CHU Pitié-Salpêtrière], Service de pharmacologie médicale [CHU Pitié-Salpêtrière], Dpt of Psychology [Milan], Catholic University - Milano, HAL-UPMC, Gestionnaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Médecine nucléaire [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pôle des Maladies du Système Nerveux [CHU Pitié-Salpêtrière] (Pôle MSN), Service de Pharmacologie médicale [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Laboratoire d'Imagerie Biomédicale [Paris] (LIB)

Subjects
Male, Brain resilience, posterior cortical atrophy, Neuropsychological Tests, Grey matter, Visual system, 050105 experimental psychology, White matter, 03 medical and health sciences, 0302 clinical medicine, Atrophy, ventral stream, Alzheimer Disease, Image Processing, Computer-Assisted, medicine, Humans, Visual Pathways, 0501 psychology and cognitive sciences, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Default mode network, Aged, Cerebral Cortex, Resting state fMRI, General Neuroscience, functional connectivity, 05 social sciences, Posterior cortical atrophy, General Medicine, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Oxygen, Psychiatry and Mental health, Clinical Psychology, dorsal stream, medicine.anatomical_structure, Cerebral cortex, Case-Control Studies, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Geriatrics and Gerontology, Mental Status Schedule, Psychology, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; Abstract: Background:Posterior cortical atrophy (PCA) induces progressive dysfunction of ventral and dorsal visual networks. Little is known, however, about corresponding changes in functional connectivity (FC). Objectives:To investigate FC changes in the visual networks, their relationship with cortical atrophy, and the association with Alzheimer’s disease (AD) pathology. Methods:Ten PCA patients and 28 age-matched controls participated in the study. Using resting state fMRI, we measured FC in ventral and dorsal cortical visual networks, defined on the basis of a priori knowledge of long-range white matter connections. To assess the relationships with AD, we determined AD biomarkers in cerebrospinal fluid and FC in the default mode network (DMN), which is vulnerable to AD pathology. Voxel-based morphometry analysis assessed the pattern of grey matter (GM) atrophy. Results:PCA patients showed GM atrophy in bilateral occipital and inferior parietal regions. PCA patients had lower FC levels in a ventral network than controls, but higher FC in inferior components of the dorsal network. In particular, the increased connectivity correlated with greater GM atrophy in occipital regions. All PCA patients had positive cerebrospinal fluid biomarkers for AD; however, FC in global DMN did not differ from controls. Conclusions:FC in PCA reflects brain structure in a non-univocal way. Hyperconnectivity of dorsal networks may indicate aberrant communication in response to posterior brain atrophy or processes of neural resilience during the initial stage of brain dysfunction. The lack of difference from controls in global DMN FC highlights the atypical nature of PCA with respect to typical AD.

Published
2016
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