TY - JOUR
T1 - Early cognitive, structural, and microstructural changes in presymptomatic C9orf72 carriers younger than 40 years
AU - Predict to Prevent Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis (PREV-DEMALS) Study Group
AU - Bertrand, Anne
AU - Wen, Junhao
AU - Rinaldi, Daisy
AU - Houot, Marion
AU - Sayah, Sabrina
AU - Camuzat, Agnès
AU - Fournier, Clémence
AU - Fontanella, Sabrina
AU - Routier, Alexandre
AU - Couratier, Philippe
AU - Pasquier, Florence
AU - Habert, Marie Odile
AU - Hannequin, Didier
AU - Martinaud, Olivier
AU - Caroppo, Paola
AU - Levy, Richard
AU - Dubois, Bruno
AU - Brice, Alexis
AU - Durrleman, Stanley
AU - Colliot, Olivier
AU - Le Ber, Isabelle
PY - 2018/2/1
Y1 - 2018/2/1
N2 - 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.
AB - 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.
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U2 - 10.1001/jamaneurol.2017.4266
DO - 10.1001/jamaneurol.2017.4266
M3 - Article
AN - SCOPUS:85041947894
VL - 75
SP - 236
EP - 245
JO - JAMA Neurology
JF - JAMA Neurology
SN - 2168-6149
IS - 2
ER -