Abstract
Original language | English |
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Pages (from-to) | E281-E295 |
Journal | Neurology |
Volume | 99 |
Issue number | 3 |
DOIs | |
Publication status | Published - 19 Jul 2022 |
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In: Neurology, Vol. 99, No. 3, 19.07.2022, p. E281-E295.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort
AU - Poos, Jackie M.
AU - Macdougall, Amy
AU - van den Berg, Esther
AU - Jiskoot, Lize C.
AU - Papma, Janne M.
AU - van der Ende, Emma L.
AU - Seelaar, Harro
AU - Russell, Lucy L.
AU - Peakman, Georgia
AU - Convery, Rhian
AU - Pijnenburg, Yolande A. L.
AU - Moreno, Fermin
AU - Sanchez-Valle, Raquel
AU - Borroni, Barbara
AU - Laforce, Robert
AU - Dore, Marie-Claire
AU - Masellis, Mario
AU - Tartaglia, Maria Carmela
AU - Graff, Caroline
AU - Galimberti, Daniela
AU - Rowe, James B.
AU - Finger, Elizabeth
AU - Synofzik, Matthis
AU - Vandenberghe, Rik
AU - Mendonca, Alexandre
AU - Tiraboschi, Pietro
AU - Santana, Isabel
AU - Ducharme, Simon
AU - Butler, Christopher
AU - Gerhard, Alexander
AU - Levin, Johannes
AU - Danek, Adrian
AU - Otto, Markus
AU - le Ber, Isabelle
AU - Pasquier, Florence
AU - van Swieten, John
AU - Rohrer, Jonathan D.
N1 - Funding Information: The Article Processing Charge was funded by the authors. Funding Information: Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases (project ID 739510). J.D. Rohrer is supported by the Miriam Marks Brain Research UK Senior Fellowship, MRC Clinician Scientist Fellowship (MR/M008525/1), and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH) and both the MRC UK GENFI grant (MR/M023664/1) and the JPND GENFI-PROX grant (2019-02248). J.M. Poos, L. Jiskoot, E. van der Ende, J.M. Papma, H. Seelaar, and J. van Swieten's contributions to this work were supported by the Bluefield Project, the Dioraphte Foundation (grant 09-02-00), 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 numbers 733 050 103 and 733 050 813), and JPND PreFrontAls consortium (project number 733051042). J.M. Poos was supported by a Fellowship award from Alzheimer Nederland (WE.15-2019.02). J.M. Papma received additional funding outside this submitted work from ZonMw and Alzheimer Nederland. F. Moreno's contributions to this work were supported by the Tau Consortium. R. Sanchez-Valle's contributions to this work were supported by the ISCIII grant (PI20/00448). B. Borroni received funding outside this submitted work in the past 36 months from the JPND consortium, the Italian Ministry of Health, and the Alzheimer's Drug Discovery Foundation (ADDF). M. Masellis' contribution to this work was funded by the Canadian Institutes of Health Research; in addition, he received funding outside the submitted work in the past 36 months from the Ontario Brain Institute, ADDF, Brain Canada, Weston Brain Institute, Roche, Washington University, Axovant, and Alector. M.C. Tartaglia has received funding from the NIH. C. Graff's contribution to this work was supported by (1) cofunding from the Swedish Research council and JPND grant GENFI-PROX (2019-02248), (2) cofunding from the Swedish Research Council and JPND grant PrefrontALS (2015-02926), (3) the Swedish Research Council (2018-02754), (4) the Schörling Foundation and Swedish FTD Initiative, (5) the Swedish Alzheimer Foundation, (6) the Swedish Brain Foundation, (7) the Region Stockholm ALF project, (8) Karolinska Institutet Doctoral and StratNeuro grants, and (9) the Swedish Dementia Foundation. J. Rowe's contribution to this work was supported by the National Institute for Health Research and the Medical Research Council (BRC-1215-20014) and the Medical Research Council (SUAG/051 G101400); he received additional funding outside the submitted work in the past 36 months from the Wellcome Trust (103838), Parkinsons UK, Alzheimer Research UK, PSP Association, Evelyn Trust, Janssen, Lilly, and AstraZeneca. E. Finger's contribution to this work was supported by the Canadian Institutes for Health Research; in addition, she received funding in the past 36 months from the Physician's Services Incorporated Foundation. M. Synofzik's contribution to this work was supported by the JPND GENFI-PROX grant via DLR/DFG 01ED2008B. R. Vandenberghe received funding outside this submitted work in the past 36 months from a clinical trial agreement with AbbVie, Roche, Alector, UCB, Johnson & Johnson, the Flemish Research Foundation, and Bijzonder Onderzoeksfonds KU Leuven. A. Mendonça received funding outside the submitted work for FMUL: BEYOND BETA-AMYLOID: Deciphering Early Pathogenic Changes in Alzheimer's Disease, FCT (2018-2022), and RADAR-AD: Remote Assessment of Disease And Relapse: Alzheimer's Disease (2020-2022). S. Ducharme received funding from the Canadian Institutes of Health Research: Neurosciences, Mental Health and Addiction, the FRQS Junior 2 Clinician Scientist Award, the Ministère de l'Économie et de l'Innovation (Brouillette Operational Grant), and JPND. C. Butler's contributions to this work were supported by the Medical Research Council. In addition, he received funding in the past 36 months from the Alzheimer's Association. A. Gerhard's contributions to this work were supported by the Medical Research Council UK. J. Levin's contributions to this work were supported 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). A. Danek received funding from Advocacy for Neuroacanthocytosis Patients. M. Otto received funding outside the submitted work in the past 36 months from BMBF, Boehringer Ingelheim, Alector, and Axon. I. Le Ber has received funding in the past 36 months from JPND. Publisher Copyright: © American Academy of Neurology.
PY - 2022/7/19
Y1 - 2022/7/19
N2 - Background and ObjectivesDisease-modifying therapeutic trials for genetic frontotemporal dementia (FTD) are underway, but sensitive cognitive outcome measures are lacking. The aim of this study was to identify such cognitive tests in early stage FTD by investigating cognitive decline in a large cohort of genetic FTD pathogenic variant carriers and by investigating whether gene-specific differences are moderated by disease stage (asymptomatic, prodromal, and symptomatic).MethodsC9orf72, GRN, and MAPT pathogenic variant carriers as well as controls underwent a yearly neuropsychological assessment covering 8 cognitive domains as part of the Genetic FTD Initiative, a prospective multicenter cohort study. Pathogenic variant carriers were stratified according to disease stage using the global Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center (NACC) FTLD score (0, 0.5, or ≥1). Linear mixed-effects models were used to investigate differences between genetic groups and disease stages as well as the 3-way interaction between time, genetic group, and disease stage.ResultsA total of 207 C9orf72, 206 GRN, and 86 MAPT pathogenic variant carriers and 255 controls were included. C9orf72 pathogenic variant carriers performed lower on attention, executive function, and verbal fluency from CDR plus NACC FTLD 0 onwards, with relatively minimal decline over time regardless of the CDR plus NACC FTLD score (i.e., disease progression). The cognitive profile in MAPT pathogenic variant carriers was characterized by lower memory performance at CDR plus NACC FTLD 0.5, with decline over time in language from the CDR plus NACC FTLD 0.5 stage onwards, and executive dysfunction rapidly developing at CDR plus NACC FTLD ≥1. GRN pathogenic variant carriers declined on verbal fluency and visuoconstruction in the CDR plus NACC FTLD 0.5 stage, with progressive decline in other cognitive domains starting at CDR plus NACC FTLD ≥1.DiscussionWe confirmed cognitive decline in the asymptomatic and prodromal stage of genetic FTD. Specifically, tests for attention, executive function, language, and memory showed clear differences between genetic groups and controls at baseline, but the speed of change over time differed depending on genetic group and disease stage. This confirms the value of neuropsychological assessment in tracking clinical onset and progression and could inform clinical trials in selecting sensitive end points for measuring treatment effects as well as characterizing the best time window for starting treatment.
AB - Background and ObjectivesDisease-modifying therapeutic trials for genetic frontotemporal dementia (FTD) are underway, but sensitive cognitive outcome measures are lacking. The aim of this study was to identify such cognitive tests in early stage FTD by investigating cognitive decline in a large cohort of genetic FTD pathogenic variant carriers and by investigating whether gene-specific differences are moderated by disease stage (asymptomatic, prodromal, and symptomatic).MethodsC9orf72, GRN, and MAPT pathogenic variant carriers as well as controls underwent a yearly neuropsychological assessment covering 8 cognitive domains as part of the Genetic FTD Initiative, a prospective multicenter cohort study. Pathogenic variant carriers were stratified according to disease stage using the global Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center (NACC) FTLD score (0, 0.5, or ≥1). Linear mixed-effects models were used to investigate differences between genetic groups and disease stages as well as the 3-way interaction between time, genetic group, and disease stage.ResultsA total of 207 C9orf72, 206 GRN, and 86 MAPT pathogenic variant carriers and 255 controls were included. C9orf72 pathogenic variant carriers performed lower on attention, executive function, and verbal fluency from CDR plus NACC FTLD 0 onwards, with relatively minimal decline over time regardless of the CDR plus NACC FTLD score (i.e., disease progression). The cognitive profile in MAPT pathogenic variant carriers was characterized by lower memory performance at CDR plus NACC FTLD 0.5, with decline over time in language from the CDR plus NACC FTLD 0.5 stage onwards, and executive dysfunction rapidly developing at CDR plus NACC FTLD ≥1. GRN pathogenic variant carriers declined on verbal fluency and visuoconstruction in the CDR plus NACC FTLD 0.5 stage, with progressive decline in other cognitive domains starting at CDR plus NACC FTLD ≥1.DiscussionWe confirmed cognitive decline in the asymptomatic and prodromal stage of genetic FTD. Specifically, tests for attention, executive function, language, and memory showed clear differences between genetic groups and controls at baseline, but the speed of change over time differed depending on genetic group and disease stage. This confirms the value of neuropsychological assessment in tracking clinical onset and progression and could inform clinical trials in selecting sensitive end points for measuring treatment effects as well as characterizing the best time window for starting treatment.
UR - http://www.scopus.com/inward/record.url?scp=85134841354&partnerID=8YFLogxK
U2 - https://doi.org/10.1212/WNL.0000000000200384
DO - https://doi.org/10.1212/WNL.0000000000200384
M3 - Article
C2 - 35483895
SN - 0028-3878
VL - 99
SP - E281-E295
JO - Neurology
JF - Neurology
IS - 3
ER -