Classification of operator’s workload based on physiological response

People spend most of their lives at work, during which time they are exposed to mechanical and environmental conditions that can harm their health. This risk can occur in an hour- long or over long periods, even when performed at a light to moderate intensity due to cumulative fatigue. Several measures have been proposed in order to prevent or reduce fatigue-inducing repetitive work. However, these measures are essentially subjective or only measure fatigue locally. Wearables are an attractive solution to measure work-related fatigue globally and at any time. The purpose of this study is to quantify biosignals information for the determination of fatigue while performing repetitive work. Electrocardiogram (ECG), electromyography (EMG), respiratory inductance plethysmography (RIP) and Accelerometer (ACC) signals were collected from 25 healthy participants. The participants were instructed to perform a repetitive task after induced fatigue. Their biosignals were processed, and different families of features were extracted. These features were used to fit a classifier in order to evaluate fatigue. Self-Similarity Matrix (SSM) was used to select and segment the data in Baseline and Fatigue. Autocorrelation of inertial measures, respiratory synchrony, and the root mean square of the cardiovascular load features achieved 88% of accuracy. It was possible to verify that the ACC’s features lead to the best classification results, followed by the RIP, EMG and finally the ECG’s features. Multimodal data allows global classification of when a person is working after expe- riencing fatigue. Motor information contributes significantly to this classification due to compensations that occur while performing the repetitive task. More studies should be done to develop an index characterising the fatigue state.As pessoas passam a maior parte da sua vida a trabalhar. A exposição a condições mecânicas e ambientais no trabalho pode ser prejudicial à sua saúde. Este risco pode ocorrer devido à fadiga cumulativa. Lesões podem surgir tanto em curtos como em longos períodos, mesmo quando a tarefa tem uma intensidade leve a moderada. Várias medidas foram propostas para prevenir ou reduzir o trabalho repetitivo que induz fadiga, no entanto, estas medidas são essencialmente subjetivas ou apenas medem a fadiga localmente. Os wearables são uma solução interessante para medir a fadiga relacionada ao trabalho a nível global e em qualquer momento. O objetivo deste estudo foi quantificar informações de biosinais para a determinação da fadiga durante a realização de trabalhos repetitivos. Os sinais de eletrocardiograma (ECG), eletromiografia (EMG), pletismografia de indutância respiratória (RIP) e acelerómetro (ACC) foram recolhidos de 25 participantes saudáveis. Os participantes realizaram uma tarefa repetitiva onde fadiga foi provocada. Os biosinais foram processados, e diferentes famílias de métricas foram extraídas. Estas métricas foram usadas para classificar a fadiga. Recorreu-se a Matrizes de Auto-Similaridade (SSM) para selecionar e segmentar os dados em fadiga e não fadiga. A autocorrelação das medidas inerciais, a sincronia respiratória e o quadrado médio da raiz da carga cardiovascular alcançaram 88% de precisão. Foi possível verificar que as features do ACC tiveram os melhores resultados de classificação, seguindo-se do RIP, EMG e, por último, de ECG. Os dados multimodais permitiram a classificação global de quando uma pessoa está a trabalhar, após sentir fadiga. A informação motora contribui, significativamente, para esta classificação devido às compensações que ocorrem durante a realização da tarefa repetitiva. Futuro trabalho deve ser feito com fim a determinar um índice que possa caracterizar o estado de fadiga

Functional network resilience to pathology in presymptomatic genetic frontotemporal dementia

© 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)The presymptomatic phase of neurodegenerative diseases are characterized by structural brain changes without significant clinical features. We set out to investigate the contribution of functional network resilience to preserved cognition in presymptomatic genetic frontotemporal dementia. We studied 172 people from families carrying genetic abnormalities in C9orf72, MAPT, or PGRN. Networks were extracted from functional MRI data and assessed using graph theoretical analysis. We found that despite loss of both brain volume and functional connections, there is maintenance of an efficient topological organization of the brain's functional network in the years leading up to the estimated age of frontotemporal dementia symptom onset. After this point, functional network efficiency declines markedly. Reduction in connectedness was most marked in highly connected hub regions. Measures of topological efficiency of the brain's functional network and organization predicted cognitive dysfunction in domains related to symptomatic frontotemporal dementia and connectivity correlated with brain volume loss in frontotemporal dementia. We propose that maintaining the efficient organization of the brain's functional network supports cognitive health even as atrophy and connectivity decline presymptomatically.This work was funded by the UK Medical Research Council, the Italian Ministry of Health, and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant [grant number CoEN015]. JBR was supported by the Wellcome Trust [grant number 103838]. JBR, RB, TR, and SJ were supported by the NIHR Cambridge Biomedical Research Centre and Medical Research Council [grant number G1100464]. The Dementia Research Centre at UCL is supported by Alzheimer's Research UK, Brain Research Trust, and The Wolfson Foundation, NIHR Queen Square Dementia Biomedical Research Unit, NIHR UCL/H Biomedical Research Centre and Dementia Platforms UK. JDR is supported by an MRC Clinician Scientist Fellowship [grant number MR/M008525/1] and has received funding from the NIHR Rare Disease Translational Research Collaboration [grant number BRC149/NS/MH]. MM is supported by the Canadian Institutes of Health Research, Department of Medicine at Sunnybrook Health Sciences Centre and the University of Toronto, and the Sunnybrook Research Institute. RL is supported by Réseau de médecine génétique appliquée, Fonds de recherche du Québec—Santé [grant number FRQS]. FT is supported by the Italian Ministry of Health. DG is supported by the Fondazione Monzino and Italian Ministry of Health, Ricerca Corrente. SS is supported by Cassa di Risparmio di Firenze [grant number CRF 2013/0199] and the Ministry of Health [grant number RF-2010-2319722]. JvS is supported by The Netherlands Organisation for Health Research and Development Memorable grant [grant number 733050103] and Netherlands Alzheimer Foundation Memorable grant [grant number 733050103].info:eu-repo/semantics/publishedVersio

Disease-related cortical thinning in presymptomatic granulin mutation carriers

© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an increased CTh loss associated with age and estimated proximity to symptoms onset in GRN carriers, even before the disease onset.The authors thank all the volunteers for their participation in this study. SBE is a recipient of the Rio-Hortega post-residency grant from the Instituto de Salud Carlos III, Spain. This study was partially funded by Fundació Marató de TV3, Spain (grant no. 20143810 to RSV). The GENFI study has been supported by the Medical Research Council UK, the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, as well as other individual funding to investigators. KM has received funding from an Alzheimer’s Society PhD studentship. JDR acknowledges support from the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Unit and the University College London Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre, the UK Dementia Research Institute, Alzheimer’s Research UK, the Brain Research Trust and the Wolfson Foundation. JCvS was supported by the Dioraphte Foundation grant 09-02-03-00, the Association for Frontotemporal Dementias Research Grant 2009, The Netherlands Organization for Scientific Research (NWO) grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield project. CG have received funding from JPND-Prefrontals VR Dnr 529-2014-7504, VR: 2015-02926, and 2018-02754, the Swedish FTD Initiative-Schörling Foundation, Alzheimer Foundation, Brain Foundation and Stockholm County Council ALF. DG has received support from the EU Joint Programme – Neurodegenerative Disease Research (JPND) and the Italian Ministry of Health (PreFrontALS) grant 733051042. JBR is funded by the Wellcome Trust (103838) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. MM has received funding from a Canadian Institutes of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. RV has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. EF has received funding from a CIHR grant #327387. JDR is an MRC Clinician Scientist (MR/M008525/1) and has received funding from the NIHR Rare Diseases Translational Research Collaboration (BRC149/NS/MH), the Bluefield Project and the Association for Frontotemporal Degeneration. MS was supported by a grant 779257 “Solve-RD” from the Horizon 2020 research and innovation programme.info:eu-repo/semantics/publishedVersio

Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Introduction: The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial frontotemporal dementia (FTD). Methods: We studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data-driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset. Results: There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviorally relevant structural and functional network differences. Structure-function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non-carriers, and increased with proximity to the expected onset of disease. Discussion: Our findings suggest that the maintenance of functional network connectivity enables carriers to maintain cognitive performance.K.A.T. is supported by the British Academy Postdoctoral Fellowship (PF160048) and the Guarantors of Brain (101149). J.B.R. is supported by the Wellcome Trust (103838), the Medical Research Council (SUAG/051 G101400), and the Cambridge NIHR Biomedical Research Centre. R. S.‐V. is supported by the Instituto de Salud Carlos III and the JPND network PreFrontAls (01ED1512/AC14/0013) and the Fundació Marató de TV3 (20143810). M.M and E.F are supported by the UK Medical Research Council, the Italian Ministry of Health, and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, and also a Canadian Institutes of Health Research operating grant (MOP 327387) and funding from the Weston Brain Institute. J.D.R., D.C., and K.M.M. are supported by the NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre, and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility. J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH), the MRC UK GENFI grant (MR/ M023664/1), and The Bluefield Project. F.T. is supported by the Italian Ministry of Health (Grant NET‐2011‐02346784). L.C.J. and J.V.S. are supported by the Association for Frontotemporal Dementias Research Grant 2009, ZonMw Memorabel project number 733050103 and 733050813, and the Bluefield project. R.G. is supported by Italian Ministry of Health, Ricerca Corrente. J.L. was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145; SyNergy ‐ ID 390857198). The Swedish contributors C.G., L.O., and C.A. were supported by grants from JPND Prefrontals Swedish Research Council (VR) 529‐2014‐7504, JPND GENFI‐PROX Swedish Research Council (VR) 2019‐02248, Swedish Research Council (VR) 2015‐ 02926, Swedish Research Council (VR) 2018‐02754, Swedish FTD Initiative‐Schorling Foundation, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Karolinska Institutet Doctoral Funding, and StratNeuro, Swedish Demensfonden, during the conduct of the study.info:eu-repo/semantics/publishedVersio

Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study

© The Author(s) 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background: Neuroinflammation is emerging as an important pathological process in frontotemporal dementia (FTD), but biomarkers are lacking. We aimed to determine the value of complement proteins, which are key components of innate immunity, as biomarkers in cerebrospinal fluid (CSF) and plasma of presymptomatic and symptomatic genetic FTD mutation carriers. Methods: We measured the complement proteins C1q and C3b in CSF by ELISAs in 224 presymptomatic and symptomatic GRN, C9orf72 or MAPT mutation carriers and non-carriers participating in the Genetic Frontotemporal Dementia Initiative (GENFI), a multicentre cohort study. Next, we used multiplex immunoassays to measure a panel of 14 complement proteins in plasma of 431 GENFI participants. We correlated complement protein levels with corresponding clinical and neuroimaging data, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Results: CSF C1q and C3b, as well as plasma C2 and C3, were elevated in symptomatic mutation carriers compared to presymptomatic carriers and non-carriers. In genetic subgroup analyses, these differences remained statistically significant for C9orf72 mutation carriers. In presymptomatic carriers, several complement proteins correlated negatively with grey matter volume of FTD-related regions and positively with NfL and GFAP. In symptomatic carriers, correlations were additionally observed with disease duration and with Mini Mental State Examination and Clinical Dementia Rating scale® plus NACC Frontotemporal lobar degeneration sum of boxes scores. Conclusions: Elevated levels of CSF C1q and C3b, as well as plasma C2 and C3, demonstrate the presence of complement activation in the symptomatic stage of genetic FTD. Intriguingly, correlations with several disease measures in presymptomatic carriers suggest that complement protein levels might increase before symptom onset. Although the overlap between groups precludes their use as diagnostic markers, further research is needed to determine their potential to monitor dysregulation of the complement system in FTD.This study was supported in the Netherlands by Memorabel grants from Deltaplan Dementie (ZonMw and Alzheimer Nederland; grant numbers 733050813, 733050103, 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), and the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1) and the JPND GENFI-PROX grant (2019-02248); JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); ASE supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK; IJS is supported by the Alzheimer’s Association; JBR is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to RSV); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 “Solve-RD” from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding, and StratNeuro. HZ is a Wallenberg Scholar.info:eu-repo/semantics/publishedVersio

Structural MRI predicts clinical progression in presymptomatic genetic frontotemporal dementia: findings from the GENetic Frontotemporal dementia Initiative (GENFI) cohort

Abstract Biomarkers that can predict disease progression in individuals with genetic frontotemporal dementia are urgently needed. We aimed to identify whether baseline MRI-based grey and white matter abnormalities are associated with different clinical progression profiles in presymptomatic mutation carriers in the GENetic Frontotemporal dementia Initiative. 387 mutation carriers were included (160 GRN, 160 C9orf72, 67 MAPT), together with 240 non-carrier cognitively normal controls. Cortical and subcortical grey matter volumes were generated using automated parcellation methods on volumetric 3 T T1-weighted MRI scans, while white matter characteristics were estimated using diffusion tensor imaging. Mutation carriers were divided into two disease stages based on their global CDR®+NACC-FTLD score: presymptomatic (0 or 0.5) and fully symptomatic (1 or greater). W-scores in each grey matter volumes and white matter diffusion measures were computed to quantify the degree of abnormality compared to controls for each presymptomatic carrier, adjusting for their age, sex, total intracranial volume, and scanner type. Presymptomatic carriers were classified as “normal” or “abnormal” based on whether their grey matter volume and white matter diffusion measure w-scores were above or below the cut point corresponding to the 10th percentile of the controls. We then compared the change in disease severity between baseline and one year later in both the “normal” and “abnormal” groups within each genetic subtype, as measured by the CDR®+NACC-FTLD sum-of-boxes score and revised Cambridge Behavioural Inventory total score. Overall, presymptomatic carriers with normal regional w-scores at baseline did not progress clinically as much as those with abnormal regional w-scores. Having abnormal grey or white matter measures at baseline was associated with a statistically significant increase in the CDR®+NACC-FTLD of up to 4 points in C9orf72 expansion carriers, and 5 points in the GRN group as well as a statistically significant increase in the revised Cambridge Behavioural Inventory of up to 11 points in MAPT, 10 points in GRN, and 8 points in C9orf72 mutation carriers. Baseline regional brain abnormalities on MRI in presymptomatic mutation carriers are associated with different profiles of clinical progression over time. These results may be helpful to inform stratification of participants in future trials

Language impairment in the genetic forms of behavioural variant frontotemporal dementia

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Background: Behavioural variant fronto-temporal dementia (bvFTD) is characterised by a progressive change in personality in association with atrophy of the frontal and temporal lobes. Whilst language impairment has been described in people with bvFTD, little is currently known about the extent or type of linguistic difficulties that occur, particularly in the genetic forms. Methods: Participants with genetic bvFTD along with healthy controls were recruited from the international multicentre Genetic FTD Initiative (GENFI). Linguistic symptoms were assessed using items from the Progressive Aphasia Severity Scale (PASS). Additionally, participants undertook the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency test. Participants underwent a 3T volumetric T1-weighted MRI, with language network regional brain volumes measured and compared between the genetic groups and controls. Results: 76% of the genetic bvFTD cohort had impairment in at least one language symptom: 83% C9orf72, 80% MAPT and 56% GRN mutation carriers. All three genetic groups had significantly impaired functional communication, decreased fluency, and impaired sentence comprehension. C9orf72 mutation carriers also had significantly impaired articulation and word retrieval as well as dysgraphia whilst the MAPT mutation group also had impaired word retrieval and single word comprehension. All three groups had difficulties with naming, semantic knowledge and verbal fluency. Atrophy in key left perisylvian language regions differed between the groups, with generalised involvement in the C9orf72 group and more focal temporal and insula involvement in the other groups. Correlates of language symptoms and test scores also differed between the groups. Conclusions: Language deficits exist in a substantial proportion of people with familial bvFTD across all three genetic groups. Significant atrophy is seen in the dominant perisylvian language areas and correlates with language impairments within each of the genetic groups. Improved understanding of the language phenotype in the main genetic bvFTD subtypes will be helpful in future studies, particularly in clinical trials where accurate stratification and monitoring of disease progression is required.info:eu-repo/semantics/publishedVersio

A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions.This study was supported in the Netherlands by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813,733050103 and 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); V.V. and S.K. have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 666992 (EuroPOND). E.B. was supported by the Hartstichting (PPP Allowance, 2018B011); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1); J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); I.J.S. is supported by the Alzheimer’s Association; J.B.R. is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to R.S.V.); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 ‘Solve-RD’ from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding and StratNeuro. H.Z. is a Wallenberg Scholar.info:eu-repo/semantics/publishedVersio

Anomia is present pre-symptomatically in frontotemporal dementia due to MAPT mutations

© The Author(s) 2022. Springer Nature Switzerland AG. Part of Springer Nature. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Introduction: A third of frontotemporal dementia (FTD) is caused by an autosomal-dominant genetic mutation in one of three genes: microtubule-associated protein tau (MAPT), chromosome 9 open reading frame 72 (C9orf72) and progranulin (GRN). Prior studies of prodromal FTD have identified impaired executive function and social cognition early in the disease but few have studied naming in detail. Methods: We investigated performance on the Boston Naming Test (BNT) in the GENetic Frontotemporal dementia Initiative cohort of 499 mutation carriers and 248 mutation-negative controls divided across three genetic groups: C9orf72, MAPT and GRN. Mutation carriers were further divided into 3 groups according to their global CDR plus NACC FTLD score: 0 (asymptomatic), 0.5 (prodromal) and 1 + (fully symptomatic). Groups were compared using a bootstrapped linear regression model, adjusting for age, sex, language and education. Finally, we identified neural correlates of anomia within carriers of each genetic group using a voxel-based morphometry analysis. Results: All symptomatic groups performed worse on the BNT than controls with the MAPT symptomatic group scoring the worst. Furthermore, MAPT asymptomatic and prodromal groups performed significantly worse than controls. Correlates of anomia in MAPT mutation carriers included bilateral anterior temporal lobe regions and the anterior insula. Similar bilateral anterior temporal lobe involvement was seen in C9orf72 mutation carriers as well as more widespread left frontal atrophy. In GRN mutation carriers, neural correlates were limited to the left hemisphere, and involved frontal, temporal, insula and striatal regions. Conclusion: This study suggests the development of early anomia in MAPT mutation carriers, likely to be associated with impaired semantic knowledge. Clinical trials focused on the prodromal period within individuals with MAPT mutations should use language tasks, such as the BNT for patient stratification and as outcome measures.he Dementia Research Centre is supported by Alzheimer's Research UK, Alzheimer's Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the NIHR UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. JDR is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project and the JPND GENFI-PROX grant (2019-02248). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. MB is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). MB’s work is also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. RC/CG are supported by a Frontotemporal Dementia Research Studentships in Memory of David Blechner funded through The National Brain Appeal (RCN 290173). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases—Project ID No 739510. This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198).info:eu-repo/semantics/publishedVersio

Examining empathy deficits across familial forms of frontotemporal dementia within the GENFI cohort

© 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).Background: Reduced empathy is a common symptom in frontotemporal dementia (FTD). Although empathy deficits have been extensively researched in sporadic cases, few studies have explored the differences in familial forms of FTD. Methods: Empathy was examined using a modified version of the Interpersonal Reactivity Index (mIRI) in 676 participants from the Genetic FTD Initiative: 216 mutation-negative controls, 192 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT mutation carriers. Using global scores from the CDR® plus NACC FTLD, mutation carriers were divided into three groups, asymptomatic (0), very mildly symptomatic/prodromal (.5), or fully symptomatic (1 or more). The mIRI Total score, as well as the subscores of Empathic Concern (EC) and Perspective Taking (PT) were assessed. Linear regression models with bootstrapping were used to assess empathy ratings across genetic groups, as well as across phenotypes in the symptomatic carriers. Neural correlates of empathy deficits were examined using a voxel-based morphometry (VBM) analysis. Results: All fully symptomatic groups scored lower on the mIRI Total, EC, and PT when compared to controls and their asymptomatic or prodromal counterparts (all p < .001). Prodromal C9orf72 expansion carriers also scored significantly lower than controls on the mIRI Total score (p = .046). In the phenotype analysis, all groups (behavioural variant FTD, primary progressive aphasia and FTD with amyotrophic lateral sclerosis) scored significantly lower than controls (all p < .007). VBM revealed an overlapping neural correlate of the mIRI Total score across genetic groups in the orbitofrontal lobe but with additional involvement in the temporal lobe, insula and basal ganglia in both the GRN and MAPT groups, and uniquely more posterior regions such as the parietal lobe and thalamus in the GRN group, and medial temporal structures in the MAPT group. Conclusions: Significant empathy deficits present in genetic FTD, particularly in symptomatic individuals and those with a bvFTD phenotype, while prodromal deficits are only seen using the mIRI in C9orf72 expansion carriers.This work was supported by the NIHR UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project and the JPND GENFI-PROX grant (2019-02248). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. RC/CG are supported by a Frontotemporal Dementia Research Studentships in Memory of David Blechner funded through The National Brain Appeal (RCN 290173). MB is supported by a Fellowship award from the Alzheimer's Society, UK (AS-JF-19a-004-517). MB's work is also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. JCVS was supported by the Dioraphte Foundation grant 09-02-03-00, the Association for Frontotemporal Dementias Research Grant 2009, The Netherlands Organisation for Scientific Research grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield project. FM received funding from the Tau Consortium and the Center for Networked Biomedical Research on Neurodegenerative Disease (CIBERNED). RS-V is supported by an Alzheimer’s Research UK Clinical Research Training Fellowship (ARUK-CRF2017B-2), and has received funding from Fundació Marató de TV3, Spain (grant no. 20143810). CG received funding from JPND-Prefrontals VR Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, the Swedish FTD Inititative-Schörling Foundation, Alzheimer Foundation, Brain Foundation and Stockholm County Council ALF. MM has received funding from a Canadian Institute of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. JBR has received funding from the Wellcome Trust (103838) and is supported by the Cambridge University Centre for Frontotemporal Dementia, the Medical Research Council (SUAG/051 G101400) and the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014). EF has received funding from a CIHR grant #327387. DG received support from the EU Joint Programme – Neurodegenerative Disease Research and the Italian Ministry of Health (PreFrontALS) grant 733051042. RV has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. MO has received funding from BMBF (FTLDc).info:eu-repo/semantics/publishedVersio