TY - JOUR
T1 - Loss of brainstem white matter predicts onset and motor neuron symptoms in C9orf72 expansion carriers
T2 - a GENFI study
AU - Pérez-Millan, Agnès
AU - Borrego-Écija, Sergi
AU - van Swieten, John C.
AU - Jiskoot, Lize
AU - Moreno, Fermin
AU - Laforce, Robert
AU - Graff, Caroline
AU - Masellis, Mario
AU - Tartaglia, Maria Carmela
AU - Rowe, James B.
AU - Borroni, Barbara
AU - Genetic Frontotemporal Initiative (GENFI)
AU - Finger, Elizabeth
AU - Synofzik, Matthis
AU - Galimberti, Daniela
AU - Vandenberghe, Rik
AU - de Mendonça, Alexandre
AU - Butler, Chris R.
AU - Gerhard, Alexander
AU - Ducharme, Simon
AU - Le Ber, Isabelle
AU - Santana, Isabel
AU - Pasquier, Florence
AU - Levin, Johannes
AU - Otto, Markus
AU - Sorbi, Sandro
AU - Tiraboschi, Pietro
AU - Seelaar, Harro
AU - Langheinrich, Tobias
AU - Rohrer, Jonathan D.
AU - Sala-Llonch, Roser
AU - Sánchez-Valle, Raquel
AU - Rollin, Adeline
AU - Camuzat, Agnès
AU - Esteve, Aitana Sogorb
AU - Gabilondo, Alazne
AU - Lladó, Albert
AU - Benussi, Alberto
AU - Brice, Alexis
AU - Gorostidi, Ana
AU - Verdelho, Ana
AU - Arighi, Andrea
AU - Antonell, Anna
AU - Bertrand, Anne
AU - Engel, Annerose
AU - Vogels, Annick
AU - Bouzigues, Arabella
AU - Poos, Jackie
AU - M. Papma, Janne
AU - Giannini, Lucia
AU - van Minkelen, Rick
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85166393434
U2 - 10.1007/s00415-022-11435-x
DO - 10.1007/s00415-022-11435-x
M3 - Article
C2 - 36443488
AN - SCOPUS:85166393434
SN - 0340-5354
VL - 270
SP - 1573
EP - 1586
JO - Journal of Neurology
JF - Journal of Neurology
IS - 3
ER -