Longitudinal Brain Atrophy Rates in Presymptomatic Carriers of Genetic Frontotemporal Dementia

Jackie M. Poos, Leonie D.M. Grandpierre, Emma L. van der Ende, Jessica L. Panman, Janne M. Papma, Harro Seelaar, Esther van den Berg, Ronald van't Klooster, Esther Bron, Rebecca Steketee, Meike W. Vernooij, Yolande A.L. Pijnenburg, Serge A.R.B. Rombouts, John van Swieten, Lize C. Jiskoot*

*Corresponding author for this work

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Abstract

Background and Objectives It is important to identify at what age brain atrophy rates in genetic frontotemporal dementia (FTD) start to accelerate and deviate from normal aging effects to find the optimal starting point for treatment. We investigated longitudinal brain atrophy rates in the presymptomatic stage of genetic FTD using normative brain volumetry software. Methods Presymptomatic GRN, MAPT, and C9orf72 pathogenic variant carriers underwent longitudinal volumetric T1-weighted magnetic resonance imaging of the brain as part of a prospective cohort study. Images were automatically analyzed with Quantib® ND, which consisted of volume measurements (CSF and sum of gray and white matter) of lobes, cerebellum, and hippocampus. All volumes were compared with reference centile curves based on a large population-derived sample of nondemented individuals (n = 4,951). Mixed-effects models were fitted to analyze atrophy rates of the different gene groups as a function of age. Results Thirty-four GRN, 8 MAPT, and 14 C9orf72 pathogenic variant carriers were included (mean age = 52.1, standard deviation = 7.2; 66% female). The mean follow-up duration of the study was 64 ± 33 months (median = 52; range 13-108). GRN pathogenic variant carriers showed a faster decline than the reference centile curves for all brain areas, though relative volumes remained between the 5th and 75th percentiles between the ages of 45 and 70 years. In MAPT pathogenic variant carriers, frontal lobe volume was already at the 5th percentile at age 45 years and showed a further decline between the ages 50 and 60 years. Temporal lobe volume started in the 50th percentile at age 45 years but showed fastest decline over time compared with other brain structures. Frontal, temporal, parietal, and cerebellar volume already started below the 5th percentile compared with the reference centile curves at age 45 years for C9orf72 pathogenic variant carriers, but there was minimal decline over time until the age of 60 years. Discussion We provide evidence for longitudinal brain atrophy in the presymptomatic stage of genetic FTD. The affected brain areas and the age after which atrophy rates start to accelerate and diverge from normal aging slopes differed between gene groups. These results highlight the value of normative volumetry software for disease tracking and staging biomarkers in genetic FTD. These techniques could help in identifying the optimal time window for starting treatment and monitoring treatment response.

Original languageEnglish
Pages (from-to)E2661-E2671
JournalNeurology
Volume99
Issue number24
DOIs
Publication statusPublished - 13 Dec 2022

Bibliographical note

Funding Information:
This work was supported by the Dioraphte Foundation (grant numbers 09-02-00); the Association for Frontotemporal Dementias Research Grant 2009; The Netherlands Organization for Scientific Research (NWO) grant HCMI (grant number 056-13-018); ZonMw Memorabel (Deltaplan Dementie, [project numbers 733 050 103 and 733 050 813]; JPND PreFrontAls consortium project number 733051042; and Alzheimer Nederland and the Bluefield project.

Funding Information:
The Article Processing Charge was funded by Erasmus Open Access Fund.

Publisher Copyright:
Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

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