Related Experiment Video
Updated: Sep 25, 2025

Abbiategrasso Brain Bank Protocol for Collecting, Processing and Characterizing Aging Brains
Published on: June 3, 2020
Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort
Jackie M Poos1, Amy MacDougall1, Esther van den Berg1
1From the Department of Neurology (J.M. Poos, E.v.d.B., L.C.J., J.M. Papma, E.L.v.d.E., H.S., J.v.S.), Erasmus MC University Medical Center, Rotterdam, the Netherlands; Dementia Research Centre (J.M. Poos, L.C.J., L.L.R., G.P., R.C., J.D.R.), Department of Neurodegenerative Disease, UCL Institute of Neurology; Department of Medical Statistics (A.M.), London School of Hygiene and Tropical Medicine, UK; Department of Neurology (Y.A.L.P.), Alzheimer Center, Amsterdam University Medical Center, Amsterdam Neuroscience, the Netherlands; Cognitive Disorders Unit (F.M.), Department of Neurology, Donostia University Hospital, San Sebastian, Gipuzkoa; Alzheimer's Disease and Other Cognitive Disorders Unit (R.S.-V.), Neurology Service, Hospital Clínic, Institut d'Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Spain; Centre for Neurodegenerative Disorders (B.B.), Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Italy; Clinique Interdisciplinaire de Mémoire (R.L., M.-C.D.), Département des Sciences Neurologiques, Université Laval, Québec; Sunnybrook Health Sciences Centre (M.M.), Sunnybrook Research Institute and Tanz Centre for Research in Neurodegenerative Diseases (M.C.T.), University of Toronto, Ontario, Canada; Department of Geriatric Medicine (C.G.), Karolinska University Hospital-Huddinge, Stockholm, Sweden; Centro Dino Ferrari (D.G.), University of Milan; Fondazione IRCCS Ca' Granda (D.G.), Ospedale Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; Department of Clinical Neurosciences (J.B.R.), University of Cambridge, UK; Department of Clinical Neurological Sciences (E.F.), University of Western Ontario, London, Canada; Department of Neurodegenerative Diseases (M.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (M.S.), Tübingen, Germany; Laboratory for Cognitive Neurology (R.V.), Department of Neurosciences, KU Leuven, Belgium; Faculty of Medicine (A.M.), University of Lisbon, Portugal; Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologica Carlo Besta (P.T.), Milan, Italy; Faculty of Medicine (I.S.), University of Coimbra, Portugal; Department of Psychiatry (S.D.), McGill University Health Centre, McGill University, Montreal, Québec, Canada; Department of Clinical Neurology (C.B.), University of Oxford; Divison of Neuroscience & Experimental Psychology (A.G.), Faculty of Medicine, Biology and Health, University of Manchester, UK; Departments of Geriatric Medicine and Nuclear Medicine (A.G.), Essen University Hospital, Germany; Department of Neurology (J.L., A.D.), Ludwig-Maximilians-University, Munich; German Center for Neurodegenerative Diseases (DZNE) (J.L.), Munich; Munich Cluster for Systems Neurology (SyNergy) (J.L.); Department of Neurology (M.O.), University of Ulm, Germany; Sorbonne Université (I.L.B.), Paris Brain Institute-Institut du Cerveau-ICM, Inserm U1127, CNRS UMR 7225, AP-HP-Hôpital Pitié-Salpêtrière; Centre de Référence des Démences Rares ou Précoces (I.L.B.), IM2A, Département de Neurologie, AP-HP-Hôpital Pitié-Salpêtrière; Univ Lille (F.P.); Inserm 1172 (F.P.); and CHU (F.P.), CNR-MAJ, Labex Distalz, LiCEND, Lille, France.
Background And Objectives:
Disease-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).
Methods:
C9orf72, 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.
Results:
A 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.
Discussion:
We 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.
More Related Videos
09:38Generalized Psychophysiological Interaction PPI Analysis of Memory Related Connectivity in Individuals at Genetic Risk for Alzheimer's Disease
Published on: November 14, 2017
06:23The 4 Mountains Test: A Short Test of Spatial Memory with High Sensitivity for the Diagnosis of Pre-dementia Alzheimer's Disease
Published on: October 13, 2016
Related Concept Videos
Longitudinal Research
Longitudinal Studies
Alzheimer's Disease: Overview
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ...
Cognitive Development During Adulthood