Diagnostic accuracy of research criteria for prodromal frontotemporal dementia

Background: The Genetic Frontotemporal Initiative Staging Group has proposed clinical criteria for the diagnosis of prodromal frontotemporal dementia (FTD), termed mild cognitive and/or behavioral and/or motor impairment (MCBMI). The objective of the study was to validate the proposed research criteria for MCBMI-FTD in a cohort of genetically confirmed FTD cases against healthy controls. Methods: A total of 398 participants were enrolled, 117 of whom were carriers of an FTD pathogenic variant with mild clinical symptoms, while 281 were non-carrier family members (healthy controls (HC)). A subgroup of patients underwent blood neurofilament light (NfL) levels and anterior cingulate atrophy assessment. Results: The core clinical criteria correctly classified MCBMI vs HC with an AUC of 0.79 (p &lt; 0.001), while the addition of either blood NfL or anterior cingulate atrophy significantly increased the AUC to 0.84 and 0.82, respectively (p &lt; 0.001). The addition of both markers further increased the AUC to 0.90 (p &lt; 0.001). Conclusions: The proposed MCBMI criteria showed very good classification accuracy for identifying the prodromal stage of FTD.</p

Diagnostic accuracy of research criteria for prodromal frontotemporal dementia

Background: The Genetic Frontotemporal Initiative Staging Group has proposed clinical criteria for the diagnosis of prodromal frontotemporal dementia (FTD), termed mild cognitive and/or behavioral and/or motor impairment (MCBMI). The objective of the study was to validate the proposed research criteria for MCBMI-FTD in a cohort of genetically confirmed FTD cases against healthy controls. Methods: A total of 398 participants were enrolled, 117 of whom were carriers of an FTD pathogenic variant with mild clinical symptoms, while 281 were non-carrier family members (healthy controls (HC)). A subgroup of patients underwent blood neurofilament light (NfL) levels and anterior cingulate atrophy assessment. Results: The core clinical criteria correctly classified MCBMI vs HC with an AUC of 0.79 (p &lt; 0.001), while the addition of either blood NfL or anterior cingulate atrophy significantly increased the AUC to 0.84 and 0.82, respectively (p &lt; 0.001). The addition of both markers further increased the AUC to 0.90 (p &lt; 0.001). Conclusions: The proposed MCBMI criteria showed very good classification accuracy for identifying the prodromal stage of FTD.</p

Language impairment in the genetic forms of behavioural variant frontotemporal dementia

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

Monitoramento pós-mercado dos testes rápidos para COVID-19: enfrentamento da pandemia:

Introduction: In December 2019, the  first group of patients with symptoms of atypical pneumonia was discovered in Wuhan, China. On January 7, 2020, the etiologic agent was identified; it was a new betacoronavirus, genetically similar to SARS-CoV-1, consisting of a simple RNA strand, an enveloped virus of 50-200nm in diameter, which was called SARS-CoV-2. Soon after, the disease was named COVID-19. On January 30, WHO declared a Public Health Emergency of International Importance due to the spread of the coronavirus. Tests for serological detection of IgM and IgG antibodies are those that provide an estimate of the immune response to SARS-CoV-2, highlighting the Rapid Diagnostic Tests (RDT), simple and accessible with a result within 5-30 minutes, based on sensitization of antigens/antibodies conjugated to colloidal gold capturing specific proteins present in the infected serum, plasma or blood. Objective: This work aims to show the analysis carried out with RDT for COVID-19 diagnosis in compliance with the current legislation from 02.04 to 18.08.2020. Method: In March of 2020, 25 serum/plasma samples were donated, without any identification. These samples were the remaining samples of tests performed on individuals with a confirmed diagnosis of SARS-CoV-2 infection by the RT-PCR technique from health services (National Institute of Infectious Diseases Evandro Chagas – INI and State Institute of the Brain Paulo Niemeyer – IEC) located in the metropolitan region of the state of Rio de Janeiro. The samples obtained in order to become a serological panel were stored at -20ºC until the moment of use. Simultaneously, a panel of samples with confirmed reactivity for IgM and IgG antibodies from COVID-19 was being made, throughout the pandemic and the samples used were evaluated against three Rapid Tests, of different antigenic compositions or different brands; two ELISA tests for IgM and IgG; two chemiluminescence tests and when applicable, a molecular test. In order to assess the specificity of the products sent, surplus donation plasma samples were selected, known to be negative for HIV, HTLV, hepatitis b and c, chagas and syphilis, collected between 2013 and 2014, in the southern regions of the country, period in which SARS-CoV-2 was nonexistent in the world. In addition to True Positive (VP) and True Negative (VN) samples, interfering serum or plasma samples with reactivity for HIV, HCV, HTLV, HBsAg, chagas disease, syphilis and dengue were also included in the evaluation. Results:  Out of 178 TR lots, 74.1%, 132 lots were from China and 25.9%, 46 TR lots were from Brazil; Germany; South Korea; Canada; USA; Singapore; Ireland and Switzerland. The analytical result showed that 57.0%, 101 TR lots obtained a Satisfactory result and 43%, 77 lots had Unsatisfactory results, when compared to the Sensitivity and Specificity values declared by the manufacturer, in the Instructions for Use. Conclusions:The results obtained show the need for constant monitoring of TRs for COVID-19 with the primary purpose of guaranteeing the quality of products sold in the country, one of the National Health Surveillance System pillars of action.  Introdução: Em dezembro de 2019, foi descoberto na cidade de Wuhan, China, um primeiro grupo de pacientes com sintomas de uma pneumonia atípica. Em 7 de janeiro de 2020, o seu agente etiológico foi identificado: tratava-se de um novo betacoronavírus, geneticamente similar ao SARS-CoV-1, constituído defita simples de RNA, vírus envelopado de 50-200 nm de diâmetro designado como SARS-CoV-2, e a doença foi denominada COVID-19. Em 30 de janeiro, a Organização Mundial da Saúde declarou Emergência de Saúde Pública de Importância Internacional em razão da disseminação desse novo vírus. Os testes para detecção sorológica de anticorpos IgM e IgG fornecem uma estimativa da resposta imune ao SARS-CoV-2, com destaque para os Testes Rápidos (TR) que são simples e acessíveis fornecendo resultados em 5-30 min. Esses testes são sensibilizados com antígenos/anticorpos conjugados ao ouro coloidal, capturando proteínas específicas presentes no soro, plasma ou sangue de pacientes infectados. Objetivo: Demonstrar a análise efetuada nos TR para diagnóstico da COVID-19, em atendimento a legislação vigente, no período de 2 de abril a 18 de agosto de 2020. Método: Durante o mês de março de 2020, foram cedidas 25 amostras de soro/plasma, sem qualquer identificação, excedentes dos testes efetuados em indivíduos com diagnóstico confirmado de infecção pelo SARS-CoV-2 pela técnica de RT-PCR provenientes de serviços de saúde (InstitutoNacional de Infectologia Evandro Chagas – INI e Instituto Estadual do Cérebro Paulo Niemeyer – IEC) localizados na região metropolitana do estado do Rio de Janeiro. As amostras obtidas para a confecção de painel sorológico foram armazenadas a -20ºC até o momento do uso. Concomitantemente, um painel de amostras com reatividade confirmada para anticorpos IgM e IgG da COVID-19 foi sendo confeccionado ao longo da pandemia e as amostras utilizadas foram avaliadas frente a três TR, de diferentes composições antigênicas ou diferentes marcas; dois testes ELISA para IgM e IgG; dois testes de quimioluminescência e quando aplicável, um teste molecular. Para avaliação da especificidade dos produtos encaminhados, foram selecionadas amostras de plasma excedentes de doação, sabidamente negativas para HIV, HTLV, hepatite B e C, doença de chagas e sífilis coletadas nos anos de 2013 e 2014, na Região Sul do país, período no qual o SARS-CoV-2 era inexistente. Além de amostras Verdadeiro Positivas (VP) e Verdadeiro Negativas (VN), ainda foram incluídas na avaliação amostras de soro ou plasma interferentes com reatividade para HIV, HCV, HTLV, HBsAg, doença de chagas, sífilis e dengue. Resultados:  Dos 178 lotes de TR, 74,1% foram provenientes da China e 25,9%, do Brasil, da Alemanha, da Coreia do Sul, do Canadá, dos EUA, da Cingapura,da Irlanda e da Suíça. O resultado analítico demonstrou que 57,0% dos TR obtiveram resultados satisfatórios e 43,0%, resultados insatisfatórios, quando comparados aos valores de sensibilidade e especificidade declarados pelo fabricante na instrução de uso. Conclusões: Há necessidade de constante monitoramento dos TR para COVID-19, com finalidade precípua de garantir a qualidade dos produtos comercializados no país, um dos pilares das ações do Sistema Nacional de Vigilância Sanitária

The inner fluctuations of the brain in presymptomatic Frontotemporal Dementia: The chronnectome fingerprint.

Frontotemporal Dementia (FTD) is preceded by a long period of subtle brain changes, occurring in the absence of overt cognitive symptoms, that need to be still fully characterized. Dynamic network analysis based on resting-state magnetic resonance imaging (rs-fMRI) is a potentially powerful tool for the study of preclinical FTD. In the present study, we employed a "chronnectome" approach (recurring, time-varying patterns of connectivity) to evaluate measures of dynamic connectivity in 472 at-risk FTD subjects from the Genetic Frontotemporal dementia research Initiative (GENFI) cohort. We considered 249 subjects with FTD-related pathogenetic mutations and 223 mutation non-carriers (HC). Dynamic connectivity was evaluated using independent component analysis and sliding-time window correlation to rs-fMRI data, and meta-state measures of global brain flexibility were extracted. Results show that presymptomatic FTD exhibits diminished dynamic fluidity, visiting less meta-states, shifting less often across them, and travelling through a narrowed meta-state distance, as compared to HC. Dynamic connectivity changes characterize preclinical FTD, arguing for the desynchronization of the inner fluctuations of the brain. These changes antedate clinical symptoms, and might represent an early signature of FTD to be used as a biomarker in clinical trials

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

Extending the phenotypic spectrum assessed by the CDR plus NACC FTLD in genetic frontotemporal dementia

INTRODUCTION: We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD). METHODS: Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD-NM scale. This was assessed in 522 mutation carriers and 310 mutation-negative controls from the Genetic Frontotemporal dementia Initiative (GENFI). RESULTS: The new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales. DISCUSSION: Adding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely. Highlights: The new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD-NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS). No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD-NM rating scale. Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains. A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales.</p

Altered plasma protein profiles in genetic FTD – a GENFI study

© The Author(s) 2023. 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: Plasma biomarkers reflecting the pathology of frontotemporal dementia would add significant value to clinical practice, to the design and implementation of treatment trials as well as our understanding of disease mechanisms. The aim of this study was to explore the levels of multiple plasma proteins in individuals from families with genetic frontotemporal dementia. Methods: Blood samples from 693 participants in the GENetic Frontotemporal Dementia Initiative study were analysed using a multiplexed antibody array targeting 158 proteins. Results: We found 13 elevated proteins in symptomatic mutation carriers, when comparing plasma levels from people diagnosed with genetic FTD to healthy non-mutation controls and 10 proteins that were elevated compared to presymptomatic mutation carriers. Conclusion: We identified plasma proteins with altered levels in symptomatic mutation carriers compared to non-carrier controls as well as to presymptomatic mutation carriers. Further investigations are needed to elucidate their potential as fluid biomarkers of the disease process.Open access funding provided by Karolinska Institute. C.G. received funding from EU Joint Programme—Neurodegenerative Disease Research -Prefrontals Vetenskapsrådet Dnr 529–2014-7504, Vetenskapsrådet 2015–02926, Vetenskapsrådet 2018–02754, the Swedish FTD Inititative-Schörling Foundation, Alzheimer Foundation, Brain Foundation, Dementia Foundation and Region Stockholm ALF-project. PN received funding from KTH Center for Applied Precision Medicine (KCAP) funded by the Erling-Persson Family Foundation, the Swedish FTD Inititative-Schörling Foundation and Åhlén foundation. D.G. received support from the EU Joint Programme—Neurodegenerative Disease Research and the Italian Ministry of Health (PreFrontALS) grant 733051042. E.F. has received funding from a Canadian Institute of Health Research grant #327387. F.M. received funding from the Tau Consortium and the Center for Networked Biomedical Research on Neurodegenerative Disease. J.B.R. has received funding from the Welcome 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). J.C.V.S. was supported by the Dioraphte Foundation grant 09–02-03–00, Association for Frontotemporal Dementias Research Grant 2009, Netherlands Organization for Scientific Research grant HCMI 056–13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield Project. J.D.R. is supported by the Bluefield Project and the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and a Miriam Marks Brain Research UK Senior Fellowship. M.M. has received funding from a Canadian Institute of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. M.O. has received funding from Germany’s Federal Ministry of Education and Research (BMBF). R.S-V. is supported by Alzheimer’s Research UK Clinical Research Training Fellowship (ARUK-CRF2017B-2) and has received funding from Fundació Marató de TV3, Spain (grant no. 20143810). R.V. has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. This work was also supported by the EU Joint Programme—Neurodegenerative Disease Research GENFI-PROX grant [2019–02248; to J.D.R., M.O., B.B., C.G., J.C.V.S. and M.S.info:eu-repo/semantics/publishedVersio