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J Neurol Neurosurg Psychiatry. 2019 Apr;90(4):387-394. doi: 10.1136/jnnp-2018-318994. Epub 2018 Oct 24.

Neurite density is reduced in the presymptomatic phase of C9orf72 disease.

Author information

1
Inria Paris, Aramis Project-Team, Paris, France.
2
Sorbonne Université, Inserm, CNRS, Institut du Cerveau et la Moelle (ICM), Paris, France.
3
Department of Computer Science and Centre for Medical Image Computing, University College London, London, UK.
4
Sorbonne Université, Inserm, CNRS, Institut du Cerveau et la Moelle (ICM), FrontLab, Paris, France.
5
AP-HP, Hôpital Pitié-Salpêtrière, Centre de Référence des Démences Rares ou Précoces, Paris, France.
6
Sorbonne Université, Inserm, CNRS, Institut du Cerveau et la Moelle (ICM), AP-HP, Paris, France.
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
Department of Neurology, Centre de Compétences Démences Rares, Centre Hospitalier Universitaire de Limoges, Limoges, France.
9
Limoges University, UMR1094, Limoges, France.
10
Centre National de Référence pour les Malades Alzheimer Jeunes, Centre Hospitalier Universitaire de Rouen, INSERM 1245, Rouen, France.
11
Department of Neurology, Centre Hospitalier Universitaire de Rouen, Rouen, France.
12
Centre National de Référence pour les Malades Alzheimer Jeunes, Centre Hospitalier Universitaire de Lille, Paris, France.
13
Université de Lille, INSERM U1171, Labex DistALZ, CoEN LiCEND, Lille, France.
14
AP-HP, Departments of Neuroradiology and Neurology, Pitié-Salpêtrière Hospital, Paris, France.
15
AP-HP, Hôpital Pitié-Salpêtrière, Centre de Référence des Démences Rares ou Précoces, Paris, France isabelle.leber@upmc.fr.
16
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.
17
AP-HP,Department of Radiology, Saint-Antoine Hospital, Paris, France.

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.

PMID:
30355607
DOI:
10.1136/jnnp-2018-318994

Conflict of interest statement

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.

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