TY  - JOUR
AU  - Bede, Peter
AU  - Lulé, Dorothée
AU  - Müller, Hans-Peter
AU  - Tan, Ee Ling
AU  - Dorst, Johannes
AU  - Ludolph, Albert C
AU  - Kassubek, Jan
TI  - Presymptomatic grey matter alterations in ALS kindreds: a computational neuroimaging study of asymptomatic C9orf72 and SOD1 mutation carriers.
JO  - Journal of neurology
VL  - 270
IS  - 9
SN  - 0367-004x
CY  - Heidelberg
PB  - Springer
M1  - DZNE-2023-00682
SP  - 4235-4247
PY  - 2023
AB  - 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.
KW  - Humans
KW  - Amyotrophic Lateral Sclerosis: diagnostic imaging
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Bayes Theorem
KW  - C9orf72 Protein: genetics
KW  - Frontotemporal Dementia: genetics
KW  - Gray Matter: diagnostic imaging
KW  - Magnetic Resonance Imaging
KW  - Mutation
KW  - Neuroimaging
KW  - Prospective Studies
KW  - Superoxide Dismutase-1: genetics
KW  - C9orf72 Protein (NLM Chemicals)
KW  - Amyotrophic lateral sclerosis (Other)
KW  - Asymptomatic (Other)
KW  - Biomarker (Other)
KW  - C9orf72 (Other)
KW  - Frontotemporal dementia (Other)
KW  - Magnetic resonance imaging (MRI) (Other)
KW  - Pharmaceutical trials (Other)
KW  - Presymptomatic (Other)
KW  - SOD1 (Other)
KW  - C9orf72 protein, human (NLM Chemicals)
KW  - SOD1 protein, human (NLM Chemicals)
KW  - Superoxide Dismutase-1 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC10421803
C6  - pmid:37178170
DO  - DOI:10.1007/s00415-023-11764-5
UR  - https://pub.dzne.de/record/258909
ER  -