Journal Article

DZNE-2023-00682

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Presymptomatic grey matter alterations in ALS kindreds: a computational neuroimaging study of asymptomatic C9orf72 and SOD1 mutation carriers.

Bede, P.Extern* ; Lulé, D.Extern* ; Müller, H.-P.Extern* ; Tan, E. L.Extern* ; Dorst, J.Extern* ; Ludolph, A. C.DZNE* ; Kassubek, J. (Last author)DZNE*

2023
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00415-023-11764-5

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.

Keyword(s): Humans (MeSH) ; Amyotrophic Lateral Sclerosis: diagnostic imaging (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Bayes Theorem (MeSH) ; C9orf72 Protein: genetics (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Gray Matter: diagnostic imaging (MeSH) ; Magnetic Resonance Imaging (MeSH) ; Mutation (MeSH) ; Neuroimaging (MeSH) ; Prospective Studies (MeSH) ; Superoxide Dismutase-1: genetics (MeSH) ; C9orf72 Protein ; Amyotrophic lateral sclerosis ; Asymptomatic ; Biomarker ; C9orf72 ; Frontotemporal dementia ; Magnetic resonance imaging (MRI) ; Pharmaceutical trials ; Presymptomatic ; SOD1 ; C9orf72 protein, human ; SOD1 protein, human ; Superoxide Dismutase-1

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Contributing Institute(s):

1. Clinical Study Center Ulm (Clinical Study Center Ulm)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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