Anne Bertrand1,2,3,4, Junhao Wen2,5, Daisy Rinaldi1,6, Marion Houot7, Sabrina Sayah5, Agnès Camuzat5, Clémence Fournier5, Sabrina Fontanella2,5, Alexandre Routier2,5, Philippe Couratier8,9, Florence Pasquier10,11, Marie-Odile Habert12,13, Didier Hannequin14,15, Olivier Martinaud14,15, Paola Caroppo5,16, Richard Levy1,6,7, Bruno Dubois1,6,7, Alexis Brice1, Stanley Durrleman2,5, Olivier Colliot1,2,17, Isabelle Le Ber1,6,7. 1. Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Institut du Cerveau et la Moelle, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France. 2. Aramis Project Team, Inria Research Center of Paris, Paris, France. 3. Department of Neuroradiology, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France. 4. Department of Radiology, Hôpital Saint Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France. 5. Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Institut du Cerveau et la Moelle, Hôpital Pitié-Salpêtrière, Paris, France. 6. Centre de Référence des Démences Rares ou Précoces, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France. 7. Institute of Memory and Alzheimer's Disease, Centre of Excellence of Neurodegenerative Disease, Department of Neurology, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France. 8. Department of Neurology, Amyotrophic Lateral Sclerosis Center, Centre Hospitalier Universitaire de Limoges, Limoges, France. 9. Limoges University, Institut d'Epidémiologie Neurologique et Neurologie Tropicale, Centre National de la Recherche Scientifique, Fédération de Recherche 3503, Institut Génomique, Environnement, Immunité, Santé et Thérapeutiques, Limoges, France. 10. Neurology Department, National Reference Center for Young Onset Dementia, Centre Hospitalier Régional Universitaire de Lille, INSERM U1171, Lille, France. 11. Equipe d'accueil 1046, Maladie d'Alzheimer et Pathologies Vasculaires, Lille University, Lille, France. 12. Department of Nuclear Medicine, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France. 13. Laboratoire d'Imagerie Biomédicale, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, INSERM U1146, Centre National de la Recherche Scientifique, UMR 7371, Paris, France. 14. Centre National de Référence pour les Malades Alzheimer Jeunes, Centre Hospitalier Universitaire de Rouen, INSERM 1245, Rouen, France. 15. Department of Neurology, Centre Hospitalier Universitaire de Rouen, Rouen, France. 16. Division of Neurology V and Neuropathology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milano, Italy. 17. Centre pour l'Acquisition et le Traitement des Images, Institut du Cerveau et la Moelle, Paris, France.
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.
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.
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