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. 2023 Mar;270(3):1573-1586.
doi: 10.1007/s00415-022-11435-x. Epub 2022 Nov 29.

Loss of brainstem white matter predicts onset and motor neuron symptoms in C9orf72 expansion carriers: a GENFI study

Agnès Pérez-Millan #  1   2 , Sergi Borrego-Écija #  1 , John C van Swieten  3 , Lize Jiskoot  3   4 , Fermin Moreno  5   6 , Robert Laforce  7 , Caroline Graff  8   9 , Mario Masellis  10 , Maria Carmela Tartaglia  11 , James B Rowe  12 , Barbara Borroni  13 , Elizabeth Finger  14 , Matthis Synofzik  15   16 , Daniela Galimberti  17   18 , Rik Vandenberghe  19   20 , Alexandre de Mendonça  21 , Chris R Butler  22   23 , Alexander Gerhard  24   25 , Simon Ducharme  26   27 , Isabelle Le Ber  28   29 , Isabel Santana  30   31 , Florence Pasquier  32   33 , Johannes Levin  34   35 , Markus Otto  36 , Sandro Sorbi  37 , Pietro Tiraboschi  38 , Harro Seelaar  3 , Tobias Langheinrich  24 , Jonathan D Rohrer  4 , Roser Sala-Llonch #  2   39 , Raquel Sánchez-Valle #  40 ; Genetic FTD Initiative, GENFI
Collaborators, Affiliations
Free article

Loss of brainstem white matter predicts onset and motor neuron symptoms in C9orf72 expansion carriers: a GENFI study

Agnès Pérez-Millan et al. J Neurol. 2023 Mar.
Free article

Abstract

Background and objectives: The C9orf72 expansion is the most common genetic cause of frontotemporal dementia (FTD) and/or motor neuron disease (MND). Corticospinal degeneration has been described in post-mortem neuropathological studies in these patients, especially in those with MND. We used MRI to analyze white matter (WM) volumes in presymptomatic and symptomatic C9orf72 expansion carriers and investigated whether its measure may be helpful in predicting the onset of symptoms.

Methods: We studied 102 presymptomatic C9orf72 mutation carriers, 52 symptomatic carriers: 42 suffering from FTD and 11 from MND, and 75 non-carriers from the Genetic Frontotemporal dementia Initiative (GENFI). All subjects underwent T1-MRI acquisition. We used FreeSurfer to estimate the volume proportion of WM in the brainstem regions (midbrain, pons, and medulla oblongata). We calculated group differences with ANOVA tests and performed linear and non-linear regressions to assess group-by-age interactions.

Results: A reduced WM ratio was found in all brainstem subregions in symptomatic carriers compared to both noncarriers and pre-symptomatic carriers. Within symptomatic carriers, MND patients presented a lower ratio in pons and medulla oblongata compared with FTD patients. No differences were found between presymptomatic carriers and non-carriers. Clinical severity was negatively associated with the WM ratio. C9orf72 carriers presented greater age-related WM loss than non-carriers, with MND patients showing significantly more atrophy in pons and medulla oblongata.

Discussion: We find consistent brainstem WM loss in C9orf72 symptomatic carriers with differences related to the clinical phenotype supporting the use of brainstem measures as neuroimaging biomarkers for disease tracking.

Keywords: Brainstem; C9orf72; Frontotemporal dementia; GENFI.

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