Early Cognitive, Structural, and Microstructural Changes in Presymptomatic C9orf72 Carriers Younger Than 40 Years

Abstract

Importance: Presymptomatic carriers of chromosome 9 open reading frame 72 (C9orf72) mutation, the most frequent genetic cause of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, represent the optimal target population for the development of disease-modifying drugs. Preclinical biomarkers are needed to monitor the effect of therapeutic interventions in this population.

Objectives: To assess the occurrence of cognitive, structural, and microstructural changes in presymptomatic C9orf72 carriers.

Design, setting, and participants: The PREV-DEMALS study is a prospective, multicenter, observational study of first-degree relatives of individuals carrying the C9orf72 mutation. Eighty-four participants entered the study between October 2015 and April 2017; 80 (95%) were included in cross-sectional analyses of baseline data. All participants underwent neuropsychological testing and magnetic resonance imaging; 63 (79%) underwent diffusion tensor magnetic resonance imaging. Gray matter volumes and diffusion tensor imaging metrics were calculated within regions of interest. Anatomical and microstructural differences between individuals who carried the C9orf72 mutation (C9+) and those who did not carry the C9orf72 mutation (C9-) were assessed using linear mixed-effects models. Data were analyzed from October 2015 to April 2017.

Main outcomes and measures: Differences in neuropsychological scores, gray matter volume, and white matter integrity between C9+ and C9- individuals.

Results: Of the 80 included participants, there were 41 C9+ individuals (24 [59%] female; mean [SD] age, 39.8 [11.1] years) and 39 C9- individuals (24 [62%] female; mean [SD] age, 45.2 [13.9] years). Compared with C9- individuals, C9+ individuals had lower mean (SD) praxis scores (163.4 [6.1] vs 165.3 [5.9]; P = .01) and intransitive gesture scores (34.9 [1.6] vs 35.7 [1.5]; P = .004), atrophy in 8 cortical regions of interest and in the right thalamus, and white matter alterations in 8 tracts. When restricting the analyses to participants younger than 40 years, compared with C9- individuals, C9+ individuals had lower praxis scores and intransitive gesture scores, atrophy in 4 cortical regions of interest and in the right thalamus, and white matter alterations in 2 tracts.

Conclusions and relevance: Cognitive, structural, and microstructural alterations are detectable in young C9+ individuals. Early and subtle praxis alterations, underpinned by focal atrophy of the left supramarginal gyrus, may represent an early and nonevolving phenotype related to neurodevelopmental effects of C9orf72 mutation. White matter alterations reflect the future phenotype of frontotemporal lobar degeneration/amyotrophic lateral sclerosis, while atrophy appears more diffuse. Our results contribute to a better understanding of the preclinical phase of C9orf72 disease and of the respective contribution of magnetic resonance biomarkers.

Trial registration: clinicaltrials.gov Identifier: NCT02590276.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Couratier has received consultant fees from Boehringer Ingelheim and funding for his institution from Cytokinetics. Dr Habert has received payments for lectures from Piramal and Eli Lilly. Dr Dubois has received consultant fees from Eli Lilly, Cytox, and Boehringer Ingelheim, and he has received funding for his institution from Merck, Pfizer, and Roche. Drs Durrleman and Colliot are funded by the European Union Horizon 2020 research and innovation program under grant 666992 (EuroPOND) and 720270 (HBP SGA1). Dr Durrleman is funded by the European Research Council under grant 678304. Dr Colliot is supported by a Contrat d’Interface Local from the Assistance Publique–Hôpitaux de Paris. No other disclosures were reported.

Figures

Figure 1.. Early Cognitive Changes in C9orf72 Mutation Carriers

Compared with individuals who did not carry the C9orf72 mutation (C9−), those who carried the C9orf72 mutation (C9+) showed significantly lower mean (SD) praxis scores (163.4 [6.1] vs 165.3 [5.9]; P = .01 [Mann-Whitney test]) (A), significantly lower mean (SD) intransitive gesture subscores (34.9 [1.6] vs 35.7 [1.5]; P = .004 [Mann-Whitney test]) (B), and significantly lower mean (SD) free cued and recall scores (46.4 [1.5] vs 47.1 [1.5]; P = .005 [Mann-Whitney test]) (C). Praxis score was significantly correlated with age in C9+ individuals (r = –0.387; P = .01) and C9− individuals (r = –0.508; P = .001) (Spearman correlation coefficient; correlation assessed after removal of the 2 outliers with a score of 133). Other scores did not correlate with age. The box indicates the interquartile range; error bars, the fifth to 95th percentiles. Outliers are presented as individual data points. The exact age of individuals is not provided to prevent individuals from identifying their mutation status. aStatistically significant at P < .01.

Figure 2.. Cortical Atrophy in C9orf72 Mutation Carriers

Color-coded representation of P values corresponding to the association of C9orf72 mutation with the volume of cortical regions of interest before (A) and after (B) correction for multiple comparisons. C, Graphs of normalized cortical volumes as a function of age in individuals who carried the C9orf72 mutation (C9+) and individuals who did not carry the C9orf72 mutation (C9−). The exact age is not provided to prevent individuals from identifying their mutation status.

Figure 3.. Alterations of White Matter in C9orf72 Mutation Carriers

Color-coded representation of P values corresponding to the association of C9orf72 mutation with the diffusion tensor magnetic resonance imaging scalars of white matter regions of interest, both before (left 3) and after (right 3) correction for multiple comparisons.

Figure 4.. Subcortical Atrophy in C9orf72 Mutation Carriers

Color-coded representation of P values corresponding to the association of C9orf72 mutation with the volume of subcortical structures before (A) and after (B) correction for multiple comparisons. C, Graph of normalized thalamic volumes in the left thalamus as a function of age in individuals who carried the C9orf72 mutation (C9+) and individuals who did not carry the C9orf72 mutation (C9−). D, Graph of normalized thalamic volumes in the right thalamus as a function of age in C9+ and C9− individuals. The exact age is not provided to prevent individuals from identifying their mutation status.