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Ann Neurol. 2019 Aug;86(2):158-167. doi: 10.1002/ana.25520. Epub 2019 Jun 27.

Presymptomatic spinal cord pathology in c9orf72 mutation carriers: A longitudinal neuroimaging study.

Author information

1
Department of Neurology, SLA Reference Center, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France.
2
Laboratory of Biomedical Imaging, National Center for Scientific Research, National Institute of Health and Medical Research, Sorbonne University, Paris, France.
3
Computational Neuroimaging Group, Academic Unit of Neurology, Trinity College Dublin, Dublin, Ireland.
4
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY.
5
Brain and Spinal Cord Institute, Sorbonne University, National Institute of Health and Medical Research U1127, National Center for Scientific Research Mixed Unit of Research 7225, Pitié-Salpêtrière Hospital, Paris, France.
6
Reference Center for Rare or Early Dementia, Pitié-Salpêtrière Hospital, Paris, France.
7
Department of Neurology, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Sorbonne University, National Center for Scientific Research Mixed Unit of Research 7622, National Institute of Health and Medical Research Accademic Research Unit 1156, Biology Institute Paris-Seine, Paris, France.
8
NeuroPoly Laboratory, Institute of Biomedical Engineering, Polytechnique Montreal, Montreal, Quebec, Canada.
9
Functional Neuroimaging Unit, Research Center of the University Institute of Geriatrics of Montreal, University of Montreal, Montreal, Quebec, Canada.
10
Aramis Project Team, Inria Research Center of Paris, Paris, France.
11
Center for Image Acquisition and Processing, Brain and Spinal Cord Institute, Paris, France.
12
Institute of Memory and Alzheimer's Disease, Center of Excellence of Neurodegenerative Disease, Department of Neurology, SLA Reference Center, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France.
13
Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute, Ulster University, Clinical-Translational Research and Innovation Center, Altnagelvin Hospital, Londonderry, United Kingdom.

Abstract

OBJECTIVE:

C9orf72 hexanucleotide repeats expansions account for almost half of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases. Recent imaging studies in asymptomatic C9orf72 carriers have demonstrated cerebral white (WM) and gray matter (GM) degeneration before the age of 40 years. The objective of this study was to characterize cervical spinal cord (SC) changes in asymptomatic C9orf72 hexanucleotide carriers.

METHODS:

Seventy-two asymptomatic individuals were enrolled in a prospective study of first-degree relatives of ALS and FTD patients carrying the c9orf72 hexanucleotide expansion. Forty of them carried the pathogenic mutation (C9+ ). Each subject underwent quantitative cervical cord imaging. Structural GM and WM metrics and diffusivity parameters were evaluated at baseline and 18 months later. Data were analyzed in C9+ and C9- subgroups, and C9+ subjects were further stratified by age.

RESULTS:

At baseline, significant WM atrophy was detected at each cervical vertebral level in C9+ subjects older than 40 years without associated changes in GM and diffusion tensor imaging parameters. At 18-month follow-up, WM atrophy was accompanied by significant corticospinal tract (CST) fractional anisotropy (FA) reductions. Intriguingly, asymptomatic C9+ subjects older than 40 years with family history of ALS (as opposed to FTD) also exhibited significant CST FA reduction at baseline.

INTERPRETATION:

Cervical SC imaging detects WM atrophy exclusively in C9+ subjects older than 40 years, and progressive CST FA reductions can be identified on 18-month follow-up. Cervical SC magnetic resonance imaging readily captures presymptomatic pathological changes and disease propagation in c9orf72-associated conditions. ANN NEUROL 2019;86:158-167.

PMID:
31177556
DOI:
10.1002/ana.25520

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