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Research paper
Neurite density is reduced in the presymptomatic phase of C9orf72 disease
  1. Junhao Wen1,2,
  2. Hui Zhang3,
  3. Daniel C Alexander3,
  4. Stanley Durrleman1,2,
  5. Alexandre Routier1,4,
  6. Daisy Rinaldi5,6,
  7. Marion Houot7,
  8. Philippe Couratier8,9,
  9. Didier Hannequin10,11,
  10. Florence Pasquier12,13,
  11. Jiaying Zhang3,
  12. Olivier Colliot1,6,14,
  13. Isabelle Le Ber5,6,15,
  14. Anne Bertrand1,6,16
  15. for the Predict to Prevent Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis (PREV-DEMALS) Study Group
    1. 1 Inria Paris, Aramis Project-Team, Paris, France
    2. 2 Sorbonne Université, Inserm, CNRS, Institut du Cerveau et la Moelle (ICM), Paris, France
    3. 3 Department of Computer Science and Centre for Medical Image Computing, University College London, London, UK
    4. 4 Sorbonne Université, Inserm, CNRS, Institut du Cerveau et la Moelle (ICM), FrontLab, Paris, France
    5. 5 AP-HP, Hôpital Pitié-Salpêtrière, Centre de Référence des Démences Rares ou Précoces, Paris, France
    6. 6 Sorbonne Université, Inserm, CNRS, Institut du Cerveau et la Moelle (ICM), AP-HP, Paris, France
    7. 7 AP-HP, Hôpital Pitié-Salpêtrière, Institute of Memory and Alzheimer’s Disease (IM2A), Centre of Excellence of Neurodegenerative Disease (CoEN), Department of Neurology, ICM, CIC Neurosciences, Paris, France
    8. 8 Department of Neurology, Centre de Compétences Démences Rares, Centre Hospitalier Universitaire de Limoges, Limoges, France
    9. 9 Limoges University, UMR1094, Limoges, France
    10. 10 Centre National de Référence pour les Malades Alzheimer Jeunes, Centre Hospitalier Universitaire de Rouen, INSERM 1245, Rouen, France
    11. 11 Department of Neurology, Centre Hospitalier Universitaire de Rouen, Rouen, France
    12. 12 Centre National de Référence pour les Malades Alzheimer Jeunes, Centre Hospitalier Universitaire de Lille, Paris, France
    13. 13 Université de Lille, INSERM U1171, Labex DistALZ, CoEN LiCEND, Lille, France
    14. 14 AP-HP, Departments of Neuroradiology and Neurology, Pitié-Salpêtrière Hospital, Paris, France
    15. 15 AP-HP, Department of Neurology, Hôpital Pitié-Salpêtrière, Institute of Memory and Alzheimer’s Disease (IM2A), Centre of excellence of neurodegenerative disease (CoEN), Paris, France
    16. 16 AP-HP,Department of Radiology, Saint-Antoine Hospital, Paris, France
    1. Correspondence to Dr Isabelle Le Ber, Institut du Cerveau et la Moelle (ICM), Pitié-Salpêtrière Hospital, Paris 75651, France; isabelle.leber{at}upmc.fr

    Abstract

    Objective To assess the added value of neurite orientation dispersion and density imaging (NODDI) compared with conventional diffusion tensor imaging (DTI) and anatomical MRI to detect changes in presymptomatic carriers of chromosome 9 open reading frame 72 (C9orf72) mutation.

    Methods The PREV-DEMALS (Predict to Prevent Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis) study is a prospective, multicentre, observational study of first-degree relatives of individuals carrying the C9orf72 mutation. Sixty-seven participants (38 presymptomatic C9orf72 mutation carriers (C9+) and 29 non-carriers (C9−)) were included in the present cross-sectional study. Each participant underwent one single-shell, multishell diffusion MRI and three-dimensional T1-weighted MRI. Volumetric measures, DTI and NODDI metrics were calculated within regions of interest. Differences in white matter integrity, grey matter volume and free water fraction between C9+ and C9− individuals were assessed using linear mixed-effects models.

    Results Compared with C9−, C9+ demonstrated white matter abnormalities in 10 tracts with neurite density index and only 5 tracts with DTI metrics. Effect size was significantly higher for the neurite density index than for DTI metrics in two tracts. No tract had a significantly higher effect size for DTI than for NODDI. For grey matter cortical analysis, free water fraction was increased in 13 regions in C9+, whereas 11 regions displayed volumetric atrophy.

    Conclusions NODDI provides higher sensitivity and greater tissue specificity compared with conventional DTI for identifying white matter abnormalities in the presymptomatic C9orf72 carriers. Our results encourage the use of neurite density as a biomarker of the preclinical phase.

    Trial registration number NCT02590276.

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    Footnotes

    • Deceased Anne Bertrand died on 2 March 2018

    • Collaborators The PrevDemAls study group includes: Eve Benchetrit, BSc (Hôpital Pitié-Salpêtrière, Paris, acquisition of data), Hugo Bertin, BSc (Hôpital de la Salpêtrière, Paris, acquisition of data), Anne Bertrand, MD (Hôpital Pitié-Salpêtrière, Paris, acquisition of data), Anne Bissery, MD (Hôpital Pitié-Salpêtrière, Paris, acquisition of data), Stéphanie Bombois, MD (CHU Roger Salengro, Lille, acquisition of data), Marie-Paule Boncoeur, MD (CHU Limoges, acquisition of data), Pascaline Cassagnaud, MD (CHU Roger Salengro, Lille, acquisition of data), Mathieu Chastan, MD (CHU Charles Nicolle, Rouen, acquisition of data), Yaohua Chen, MD (CHU Roger Salengro, Lille, acquisition of data), Marie Chupin, PhD (CATI, ICM, Paris, acquisition of data), Olivier Colliot, PhD (ICM, Paris, acquisition of data), Philippe Couratier, MD (CHU Limoges, acquisition of data), Xavier Delbeucq, PhD (CHU Roger Salengro, Lille, acquisition of data), Vincent Deramecourt, MD (CHU Roger Salengro, Lille, acquisition of data), Christine Delmaire, (CHU Roger Salengro, Lille, acquisition of data), Emmanuel Gerardin, (CHU Charles Nicolle, Rouen, acquisition of data), Claude Hossein-Foucher, (CHU Roger Salengro, Lille, acquisition of data), Bruno Dubois, (Hôpital Pitié-Salpêtrière, Paris, acquisition of data), Marie-Odile Habert, (Hôpital Pitié-Salpêtrière, Paris, acquisition of data), Didier Hannequin, (CHU Charles Nicolle, Rouen, acquisition of data), Géraldine Lautrette, (CHU Limoges, acquisition of data), Thibaud Lebouvier, (CHU Roger Salengro, Lille, acquisition of data), Isabelle Le Ber, PhD (Hôpital Pitié-Salpêtrière Salpêtrière, Paris, acquisition of data), Stéphane Lehéricy, (Hôpital Pitié-Salpêtrière Salpêtrière, Paris, acquisition of data), Benjamin Le Toullec, PhD (ICM, Paris, acquisition of data), Richard Levy, (Hôpital Pitié-Salpêtrière Salpêtrière, Paris, acquisition of data), Olivier Martinaud, (CHU Charles Nicolle, Rouen, acquisition of data), Kelly Martineau, PhD (CATI, ICM, Paris, acquisition of data), Marie-Anne Mackowiak, (CHU Roger Salengro, Lille, acquisition of data), Jacques Monteil, (CHU Limoges, acquisition of data), Florence Pasquier, (CHU Roger Salengro, Lille, acquisition of data), Grégory Petyt, (CHU Roger Salengro, Lille, acquisition of data), Pierre-François Pradat, (Hôpital Pitié-Salpêtrière, Paris, acquisition of data), Assi-Hervé Oya (BSc, Hôpital Pitié-Salpêtrière, Paris, acquisition of data), Daisy Rinaldi, PhD (Hôpital Pitié-Salpêtrière, Paris, acquisition of data), Adeline Rollin-Sillaire, (CHU Roger Salengro, Lille, acquisition of data), François Salachas, (Hôpital Pitié-Salpêtrière, Paris, acquisition of data), Sabrina Sayah, PhD (Hôpital Pitié-Salpêtrière, Paris, acquisition of data), David Wallon, MD, (CHU Rouen, acquisition of data).

    • Contributors JW had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. JW, OC, AB, ILB, HZ, SD, AR: study concept and design. JW, HZ, DCA, SD, AR, DR, MH, PC, DH, FP, JZ, OC, ILB, AB: acquisitions, analysis or interpretation of data. JW, OC, ILB, AB: drafting of the manuscript. JW, OC, ILB, AB: critical revision of the manuscript for important intellectual content. JW: statistical analysis. OC, ILB: obtained funding. OC, AB, ILB: administrative, technical or material support. OC, AB, HZ, DCA, ILB: study supervision.

    • Funding This study was funded by Assistance Publique-Hôpitaux de Paris (Clinical Research and Development Department), grant ANR/DGOS PRTS 2015-2019 PrevDemAls (to ILB) and by 'Investissements d’avenir' ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-Investissements-Avenir-Institut-Hospitalo-Universitaire-06). EPSRC Grants EP/L022680/1 EP/M020533/1 and EP/N018702/1 support DCA and HZ’s work on this topic. OC is supported by a 'Contrat d’Interface Local' from Assistance Publique-Hôpitaux de Paris (AP-HP). The study was conducted with the support of the Centre d’Investigation Clinique (CIC 1422) and the Centre pour l’Acquisition et le Traitement des Images (CATI) platform, at IHU-A-ICM, Paris, France. China Scholarship Council supports JW’s work on this topic. This study has been registered on the website http://clinicaltrials.gov/ under trial registration number NCT02590276. The funding sources had no role in design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.

    • Competing interests Competing financial interests unrelated to the present article: OC and SD are funded by European Union’s Horizon 2020 research and innovation programme under grant agreement no 666992 (EuroPOND) and no 720270 (HBP SGA1). SD is funded by the European Research Council (ERC) under grant agreement no 678304. PC received consultant fees from Boehringer Ingelheim and funding for his institution from Cytokinetics.

    • Patient consent Not required.

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

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

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