Presymptomatic grey matter alterations in ALS kindreds: a computational neuroimaging study of asymptomatic C9orf72 and SOD1 mutation carriers

Abstract

Background 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. Methods 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. Results 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. Discussion 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.

Progressive Cerebrocerebellar Uncoupling in Sporadic and Genetic Forms of Amyotrophic Lateral Sclerosis

“…With the advent of antisense oligonucleotide therapies, there is an ever-growing interest in presymptomatic processes in ALS. 30 Early subcortical changes have been consistently described in C9orf72 cohorts, often decades before predicted symptom onset, 31 and there is some data to suggest presymptomatic cerebellar disease burden also. Selective thalamic degeneration is also well described in ALS, 32 but it is typically linked to the concomitant degeneration of the frontal cortex, whereas here, we also capture thalamocerebellar structural disconnection at baseline.…”

Structural and microstructural neuroimaging signature of C9orf72-associated ALS: A multiparametric MRI study

“…In this context, lower volumes of the thalamus have been reported in ALS patients with C9orf72 mutations, as well as in patients with ALS-FTD and FTD ( Agosta et al, 2017 , Bocchetta et al, 2018 , Nigri et al, 2023 , Schönecker et al, 2018 , van der Burgh et al, 2020 , Westeneng et al, 2016 ). Alterations in subcortical gray matter of the thalamus and the hippocampus were recently reported to occur in presymptomatic C9orf72 gene carriers and to precede changes in cortical gray matter ( Bede et al, 2023 ).…”

Update on recent advances in amyotrophic lateral sclerosis

“…On the other hand, another study has suggested that the flail arm syndrome, a phenotypical variant of ALS, may show a similar degree of CST involvement as to that seem in patients with a ‘classical’ ALS presentation [ 133 ]. Subtle structural brain alterations have been shown to occur even in the earliest phases of the disease, as presymptomatic carriers of a C9orf72 expansion demonstrated significant, selective thalamic and focal hippocampal volume reductions [ 207 , 312 ].…”