Early Cognitive, Structural, and Microstructural Changes in Presymptomatic <i>C9orf72</i> Carriers Younger Than 40 Years
Authors: Anne Bertrand, Junhao Wen, Daisy Rinaldi, Marion Houot, Sabrina Sayah, Agnès Camuzat, Clémence Fournier, Sabrina Fontanella, Alexandre Routier, Philippe Couratier, Florence Pasquier, Marie-Odile Habert, Didier Hannequin, Olivier Martinaud, Paola Caroppo, Richard Levy, Bruno Dubois, Alexis Brice, Stanley Durrleman, Olivier Colliot, Isabelle Le Ber
Journal: JAMA Neurology (2018)

<h3>Importance</h3> Presymptomatic carriers of chromosome 9 open reading frame 72 (<i>C9orf72</i>) 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. <h3>Objectives</h3> To assess the occurrence of cognitive, structural, and microstructural changes in presymptomatic<i>C9orf72</i>carriers. <h3>Design, Setting, and Participants</h3> The PREV-DEMALS study is a prospective, multicenter, observational study of first-degree relatives of individuals carrying the<i>C9orf72</i>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<i>C9orf72 </i>mutation (<i>C9</i>+) and those who did not carry the<i>C9orf72</i>mutation (<i>C9</i>−) were assessed using linear mixed-effects models. Data were analyzed from October 2015 to April 2017. <h3>Main Outcomes and Measures</h3> Differences in neuropsychological scores, gray matter volume, and white matter integrity between<i>C9</i>+ and<i>C9</i>− individuals. <h3>Results</h3> Of the 80 included participants, there were 41<i>C9</i>+ individuals (24 [59%] female; mean [SD] age, 39.8 [11.1] years) and 39<i>C9</i>− individuals (24 [62%] female; mean [SD] age, 45.2 [13.9] years). Compared with<i>C9</i>− individuals,<i>C9</i>+ individuals had lower mean (SD) praxis scores (163.4 [6.1] vs 165.3 [5.9];<i>P</i> = .01) and intransitive gesture scores (34.9 [1.6] vs 35.7 [1.5];<i>P</i> = .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<i>C9</i>− individuals,<i>C9</i>+ 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. <h3>Conclusions and Relevance</h3> Cognitive, structural, and microstructural alterations are detectable in young<i>C9</i>+ 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<i>C9orf72</i>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<i>C9orf72</i>disease and of the respective contribution of magnetic resonance biomarkers. <h3>Trial Registration</h3> clinicaltrials.gov Identifier: NCT02590276