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@ARTICLE{Bede:258909,
author = {Bede, Peter and Lulé, Dorothée and Müller, Hans-Peter
and Tan, Ee Ling and Dorst, Johannes and Ludolph, Albert C
and Kassubek, Jan},
title = {{P}resymptomatic grey matter alterations in {ALS} kindreds:
a computational neuroimaging study of asymptomatic {C}9orf72
and {SOD}1 mutation carriers.},
journal = {Journal of neurology},
volume = {270},
number = {9},
issn = {0367-004x},
address = {Heidelberg},
publisher = {Springer},
reportid = {DZNE-2023-00682},
pages = {4235-4247},
year = {2023},
abstract = {The characterisation of presymptomatic disease-burden
patterns in asymptomatic mutation carriers has a dual
academic and clinical relevance. The understanding of
disease propagation mechanisms is of considerable conceptual
interests, and defining the optimal time of pharmacological
intervention is essential for improved clinical trial
outcomes.In a prospective, multimodal neuroimaging study, 22
asymptomatic C9orf72 GGGGCC hexanucleotide repeat carriers,
13 asymptomatic subjects with SOD1, and 54 'gene-negative'
ALS kindreds were enrolled. Cortical and subcortical grey
matter alterations were systematically appraised using
volumetric, morphometric, vertex, and cortical thickness
analyses. Using a Bayesian approach, the thalamus and
amygdala were further parcellated into specific nuclei and
the hippocampus was segmented into anatomically defined
subfields.Asymptomatic GGGGCC hexanucleotide repeat carriers
in C9orf72 exhibited early subcortical changes with the
preferential involvement of the pulvinar and mediodorsal
regions of the thalamus, as well as the lateral aspect of
the hippocampus. Volumetric approaches, morphometric
methods, and vertex analyses were anatomically consistent in
capturing focal subcortical changes in asymptomatic C9orf72
hexanucleotide repeat expansion carriers. SOD1 mutation
carriers did not exhibit significant subcortical grey matter
alterations. In our study, none of the two asymptomatic
cohorts exhibited cortical grey matter alterations on either
cortical thickness or morphometric analyses.The
presymptomatic radiological signature of C9orf72 is
associated with selective thalamic and focal hippocampal
degeneration which may be readily detectable before cortical
grey matter changes ensue. Our findings confirm selective
subcortical grey matter involvement early in the course of
C9orf72-associated neurodegeneration.},
keywords = {Humans / Amyotrophic Lateral Sclerosis: diagnostic imaging
/ Amyotrophic Lateral Sclerosis: genetics / Bayes Theorem /
C9orf72 Protein: genetics / Frontotemporal Dementia:
genetics / Gray Matter: diagnostic imaging / Magnetic
Resonance Imaging / Mutation / Neuroimaging / Prospective
Studies / Superoxide Dismutase-1: genetics / C9orf72 Protein
(NLM Chemicals) / Amyotrophic lateral sclerosis (Other) /
Asymptomatic (Other) / Biomarker (Other) / C9orf72 (Other) /
Frontotemporal dementia (Other) / Magnetic resonance imaging
(MRI) (Other) / Pharmaceutical trials (Other) /
Presymptomatic (Other) / SOD1 (Other) / C9orf72 protein,
human (NLM Chemicals) / SOD1 protein, human (NLM Chemicals)
/ Superoxide Dismutase-1 (NLM Chemicals)},
cin = {Clinical Study Center Ulm},
ddc = {610},
cid = {I:(DE-2719)5000077},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pmc = {pmc:PMC10421803},
pubmed = {pmid:37178170},
doi = {10.1007/s00415-023-11764-5},
url = {https://pub.dzne.de/record/258909},
}