Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort

Abstract

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.

Frontoparietal network integrity supports cognitive function despite atrophy and hypoperfusion in pre-symptomatic frontotemporal dementia: multimodal analysis of brain function, structure and perfusion

“…Although worse performance on some cognitive domains can be evident at the pre-symptomatic stage of FTD, in comparison with non-carrier controls [19, 21, 61], it is difficult to distinguish genetic mutation carriers from non-carriers simply based on performance on cognitive tasks. We found no significant difference in cognitive performance between genetic mutation carriers and non-carriers at the pre-symptomatic stage, confirming that genetic mutation carriers maintain similar overall cognition as non-carriers before symptom onset.…”

Defining the presymptomatic phase of frontotemporal dementia

“…Cognitive deficits are measurable using neuropsychological tasks in the prodromal stage and recent work has shown that the domains involved are relatively specific to the different genetic groups, e.g. early deficits of episodic memory and language are seen in prodromal MAPT mutation carriers [33,34], although executive function and social cognition deficits are commonly seen across the genetic groups [35]. Recently, a cognitive composite (the GENFI-Cog) unique to each genetic group has been developed for use in the prodromal period decreasing the sample size required for trials [36 ▪▪ ].…”

Changing perspectives on frontotemporal dementia: A review

“…The Genetic Frontotemporal Dementia Initiative (GENFI) is such an international enterprise. GENFI studies have demonstrated structural imaging and cognitive changes 5–10 years before the expected onset of symptoms (Rohrer et al, 2015), sensitivity of cognitive measures in tracking progression (Poos et al, 2022) and gene‐specific differences in cognitive profile (Poos et al, 2022). Research criteria for prodromal bvFTD have been proposed (Barker et al, 2022).…”