Poos, Jackie M; MacDougall, Amy; van den Berg, Esther; Jiskoot, Lize C; Papma, Janne M; van der Ende, Emma L; Seelaar, Harro; ... Genetic FTD Initiative (GENFI); + view all Poos, Jackie M; MacDougall, Amy; van den Berg, Esther; Jiskoot, Lize C; Papma, Janne M; van der Ende, Emma L; Seelaar, Harro; Russell, Lucy L; Peakman, Georgia; Convery, Rhian; Pijnenburg, Yolande AL; Moreno, Fermin; Sanchez-Valle, Raquel; Borroni, Barbara; Laforce, Robert; DorÃ, Marie-Claire; Masellis, Mario; Tartaglia, Maria Carmela; Graff, Caroline; Galimberti, Daniela; Rowe, James; Finger, Elizabeth; Synofzik, Matthis; Vandenberghe, Rik; Mendonça, Alexandre; Tiraboschi, Pietro; Santana, Isabel; Ducharme, Simon; Butler, Christopher; Gerhard, Alexander; Levin, Johannes; Danek, Adrian; Otto, Markus; Le Ber, Isabelle; Pasquier, Florence; van Swieten, John; Rohrer, Jonathan D; Genetic FTD Initiative (GENFI); - view fewer (2022) Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort. Neurology 10.1212/WNL.0000000000200384. (In press).

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Abstract

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 firstly, cognitive decline in a large cohort of genetic FTD pathogenic variant carriers, and secondly, 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 eight cognitive domains, as part of the Genetic FTD Initiative (GENFI), a prospective multicenter cohort study. Pathogenic variant carriers were stratified according to disease stage using the global CDR® plus NACC FTLD score (0, 0.5 and ≥1). Linear mixed-effects models were used to investigate differences between genetic groups and disease stages, as well as the three-way interaction between time, genetic group and disease stage. RESULTS: 207 C9orf72, 206 GRN, 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, 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 endpoints for measuring treatment effects as well as characterizing the best time window for starting treatment.

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