Differential early subcortical involvement in genetic FTD within the GENFI cohort

Martina Bocchetta,Juan Eugenio Iglesias,Rik Vandenberghe,Matthis Synofzik,Alexander Gerhard,Caroline Graff,James B Rowe,Markus Otto,David M Cash,John C Van Swieten,Jonathan D Rohrer,Florence Pasquier,Elizabeth Finger,Georgia Peakman,Daniela Galimberti,Adrian Danek,Mario Masellis,Rhian S Convery,Isabelle Le Ber,Maria Carmela Tartaglia,David L Thomas,Fabrizio Tagliavini,Harro Seelaar,Lize C Jiskoot,Johannes Levin,Isabel Santana,Lucy L Russell,Sandro Sorbi,Robert Laforce,Simon Ducharme,Alexandre De Mendonça,Barbara Borroni,Emily Todd ,Chris Butler ,Fermín Moreno ,Raquel Sánchez‐Valle ,Genetic Frontotemporal Dementia Initiative

doi:10.1016/j.nicl.2021.102646

Abstract

BackgroundStudies have previously shown evidence for presymptomatic cortical atrophy in genetic FTD. Whilst initial investigations have also identified early deep grey matter volume loss, little is known about the extent of subcortical involvement, particularly within subregions, and how this differs between genetic groups. Methods480 mutation carriers from the Genetic FTD Initiative (GENFI) were included (198 GRN, 202 C9orf72, 80 MAPT), together with 298 non-carrier cognitively normal controls. Cortical and subcortical volumes of interest were generated using automated parcellation methods on volumetric 3 T T1-weighted MRI scans. Mutation carriers were divided into three disease stages based on their global CDR® plus NACC FTLD score: asymptomatic (0), possibly or mildly symptomatic (0.5) and fully symptomatic (1 or more). ResultsIn all three groups, subcortical involvement was seen at the CDR 0.5 stage prior to phenoconversion, whereas in the C9orf72 and MAPT mutation carriers there was also involvement at the CDR 0 stage. In the C9orf72 expansion carriers the earliest volume changes were in thalamic subnuclei (particularly pulvinar and lateral geniculate, 9–10%) cerebellum (lobules VIIa-Crus II and VIIIb, 2–3%), hippocampus (particularly presubiculum and CA1, 2–3%), amygdala (all subregions, 2–6%) and hypothalamus (superior tuberal region, 1%). In MAPT mutation carriers changes were seen at CDR 0 in the hippocampus (subiculum, presubiculum and tail, 3–4%) and amygdala (accessory basal and superficial nuclei, 2–4%). GRN mutation carriers showed subcortical differences at CDR 0.5 in the presubiculum of the hippocampus (8%). ConclusionsC9orf72 expansion carriers show the earliest and most widespread changes including the thalamus, basal ganglia and medial temporal lobe. By investigating individual subregions, changes can also be seen at CDR 0 in MAPT mutation carriers within the limbic system. Our results suggest that subcortical brain volumes may be used as markers of neurodegeneration even prior to the onset of prodromal symptoms.

Highlights

Frontotemporal dementia (FTD) is a common cause of early onset dementia
Whilst initial investigations have identified early deep grey matter volume loss, little is known about the extent of subcortical involvement, within subregions, and how this differs between genetic groups
In the chromosome 9 open reading frame 72 (C9orf72) expansion carriers the earliest volume changes were in thalamic subnuclei cerebellum, hippocampus, amygdala and hypothalamus

Summary

Introduction

In about a third of the cases it is associated with an autosomal dominant inherited mutation in one of three genes: microtubuleassociated protein tau (MAPT), progranulin (GRN), and chromosome 9 open reading frame 72 (C9orf72) (Warren et al, 2013) For each of these genetic groups, there is evidence of a differential pattern of cortical at rophy (Chen and Kantarci, 2020), with changes occurring pre symptomatically, up to twenty years before estimated phenoconversion (Rohrer et al, 2015; Cash et al, 2018). Our results suggest that subcortical brain volumes may be used as markers of neurodegeneration even prior to the onset of prodromal symptoms

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Results

Conclusion