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Cognitive inhibition impairments in presymptomatic C9orf72 carriers
  1. Maxime Montembeault1,2,3,4,
  2. Sabrina Sayah1,
  3. Daisy Rinaldi1,5,
  4. Benjamin Le Toullec1,5,
  5. Anne Bertrand2,6,7,
  6. Aurélie Funkiewiez5,8,
  7. Dario Saracino1,5,7,
  8. Agnès Camuzat1,
  9. Philippe Couratier9,10,
  10. Marianne Chouly9,10,
  11. Didier Hannequin11,12,
  12. Carole Aubier-Girard11,12,
  13. Florence Pasquier13,
  14. Xavier Delbeuck13,
  15. Olivier Colliot1,7,
  16. Bénédicte Batrancourt1,2,3,
  17. Carole Azuar1,3,5,
  18. Richard Lévy1,2,3,5,
  19. Bruno Dubois1,2,5,
  20. Isabelle Le Ber1,2,3,5,
  21. Raffaella Migliaccio1,2,3,5
  22. PrevDemAls study group
    1. 1 Inserm U1127, Institut du Cerveau, Hôpital Pitié-Salpêtrière, Paris, France
    2. 2 Sorbonne University, Paris, France
    3. 3 FrontLab, Paris, France
    4. 4 Department of Neurology, University of California San Francisco, Memory and Aging Center, San Francisco, California, USA
    5. 5 Reference Centre for Rare of Early Onset Dementias, Hôpital Pitié-Salpêtrière, Assistance Publique–Hôpitaux de Paris, Paris, France
    6. 6 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 Épinière, FrontLAB, Hôpital Pitié-Salpêtrière, Assistance Publique–Hôpitaux de Paris, Paris, France
    7. 7 Aramis Project Team, Inria Research Center of Paris, Paris, France
    8. 8 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
    9. 9 Centre de Référence SLA et autres maladies du motoneurone, Centre Hospitalier Universitaire de Limoges, Limoges, France
    10. 10 Centre de Compétence Démences Rares, Centre Hospitalier Universitaire de Limoges, Limoges, France
    11. 11 Centre National de Référence pour les Malades Alzheimer Jeunes, Centre Hospitalier Universitaire de Rouen, INSERM 1245, Rouen, France
    12. 12 Department of Neurology, Centre Hospitalier Universitaire de Rouen, Rouen, France
    13. 13 Université de Lille, INSERM U1171, Centre de la mémoire (CMRR), Centre national de référence pour les malades Alzheimer jeunes (CNRMAJ), CHU Lille, Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease (DistAlz), Lille, France
    1. Correspondence to Dr Raffaella Migliaccio, INSERM U1127, FrontLab, Institut du Cerveau, Hôpital Pitié-Salpêtrière, Paris 75013, France; lara.migliaccio{at}


    Objective To investigate cognitive inhibition in presymptomatic C9orf72 mutation carriers (C9+) and its associated neuroanatomical correlates.

    Methods Thirty-eight presymptomatic C9orf72 mutation carriers (C9+, mean age 38.2±8.0 years) and 22 C9− controls from the PREV-DEMALS cohort were included in this study. They underwent a cognitive inhibition assessment with the Hayling Sentence Completion Test (HSCT; time to completion (part B−part A); error score in part B) as well as a 3D MRI.

    Results C9+ individuals younger than 40 years had higher error scores (part B) but equivalent HSCT time to completion (part B−part A) compared to C9− individuals. C9+ individuals older than 40 years had both higher error scores and longer time to completion. HSCT time to completion significantly predicted the proximity to estimated clinical conversion from presymptomatic to symptomatic phase in C9+ individuals (based on the average age at onset of affected relatives in the family). Anatomically, we found that HSCT time to completion was associated with the integrity of the cerebellum.

    Conclusion The HSCT represents a good marker of cognitive inhibition impairments in C9+ and of proximity to clinical conversion. This study also highlights the key role of the cerebellum in cognitive inhibition.

    • C9orf72 mutation
    • cognitive inhibition
    • hayling sentence completion test
    • voxel-based morphometry
    • cerebellum

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    • ILB and RM contributed equally.

    • Contributors Study supervision: ILB, RM. Study conception and design: MM, RM, ILB. Data acquisition: SS, DS, DR, BLT, ILB, AF, AC, PC, MC, DH, CA-G, FP, XD. Analysis and interpretation of data: MM, RM, ILB, SS, BB, OC, AB. Drafting the manuscript: MM, RM, ILB. Obtaining funding: ILB, OC, AB. All authors critically revised the manuscript for its intellectual content.

    • Funding This study was funded by grant ANR/DGOS PRTS 2015-2019 PREV-DEMALS from the Assistance Publique–Hôpitaux de Paris (Dr Le Ber) and by grant ANR-10-IAIHU-06 from the Agence Nationale de la Recherche. The study was conducted with the support of the Centre d’Investigation Clinique and the Centre pour l’Acquisition et le Traitement des Images platform. Raffaella Migliaccio is supported by France Alzheimer and Philippe Chatrier Foundations, and by Rosita Gomez association. Raffaella Migliaccio, Richard Levy and Bénédicte Batrancourt are supported by Fondation pour la Recherche Medicale. Maxime Montembeault is supported by postdoctoral fellowships from the Canadian Institutes of Health Research (CIHR) and Fonds de Recherche du Québec en Santé (FRQS).

    • Competing interests None declared.

    • Patient consent for publication Obtained.

    • Ethics approval This study was approved by the Comité de Protection des Personnes Ile de France VI of the Hôpital Pitié-Salpetrière.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available on reasonable request (