The value of magnetic resonance imaging as a biomarker for amyotrophic lateral sclerosis: a systematic review

Grolez et al. BMC Neurology (2016) 16:155 DOI 10.1186/s12883-016-0672-6 RESEARCH ARTICLE Open Access The value of magnetic resonance imaging as a biomarker for amyotrophic lateral sclerosis: a systematic review G. Grolez1,2 , C. Moreau1,2, V. Danel-Brunaud1,2, C. Delmaire2,3, R. Lopes2,3, P. F. Pradat4,5, M. M. El Mendili4, L. Defebvre1,2 and D. Devos1,2,6* Abstract Background: Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease that mainly affects the motor system. A number of potentially neuroprotective and neurorestorative disease-modifying drugs are currently in clinical development. At present, the evaluation of a drug’s clinical efficacy in ALS is based on the ALS Functional Rating Scale Revised, motor tests and survival. However, these endpoints are general, variable and late-stage measures of the ALS disease process and thus require the long-term assessment of large cohorts. Hence, there is a need for more sensitive radiological biomarkers. Various sequences for magnetic resonance imaging (MRI) of the brain and spinal cord have may have value as surrogate biomarkers for use in future clinical trials. Here, we review the MRI findings in ALS, their clinical correlations, and their limitations and potential role as biomarkers. Methods: The PubMed database was screened to identify studies using MRI in ALS. We included general MRI studies with a control group and an ALS group and longitudinal studies even if a control group was lacking. Results: A total of 116 studies were analysed with MRI data and clinical correlations. The most disease-sensitive MRI patterns are in motor regions but the brain is more broadly affected. Conclusion: Despite the existing MRI biomarkers, there is a need for large cohorts with long term MRI and clinical follow-up. MRI assessment could be improved by standardized MRI protocols with multicentre studies. Keywords: Amyotrophic lateral sclerosis, Magnetic resonance imaging, Morphometry, Diffusion tensor imaging, Magnetic resonance spectroscopy, Spinal cord, Biomarkers Abbreviations: AD, Axial diffusivity; ADC, Apparent diffusion coefficient; ALFF, Amplitude of low frequency fluctuations; ALS, Amyotrophic lateral sclerosis; ALSFRS, Amyotrophic lateral sclerosis functional rating scale; ALSFRSR, Amyotrophic lateral sclerosis functional rating scale revised; CAFS, Combined assessment of function and survival; Cho, Choline; Cr, Creatine; CSF, Cerebro spinal fluid; CST(s), Cortico-spinal tract(s); DTI, Diffusion tensor imaging; FA, Fractional anisotropy; fMRI, Functional magnetic resonance imaging; GABA, Gamma aminobutyric acid; Gln, Glutamine; Glu, Glutamate; Glx, Glutamine and glutamate; Ins, myo-inositol; MD, Mean diffusivity; MRI, Magnetic resonance imaging; MRS, Magnetic resonance spectroscopy; NAA, N-acetyl-aspartate; NiALS, Neurimaging symposium in amyotrophic lateral sclerosis; Pcr, Phosphocreatine; PD, Parkinson’s disease; PLIC, Posterior limb of internal capsule; QSM, Quantitative susceptibility mapping; RD, Radial diffusivity; SWI, Susceptibility weighted imaging; VBM, Voxel-based morphometry * Correspondence: 1 Department of Movement Disorders and Neurology, Lille University Hospital, Faculty of Medicine, University of Lille, Lille, France 2 INSERM U1171, Lille University Hospital, Faculty of Medicine, University of Lille, Lille, France Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Grolez et al. BMC Neurology (2016) 16:155 Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that mainly affects the motor system. At present, the only drug to have produced an increase in patient survival in a controlled clinical trial is riluzole [1]. The condition is always fatal; the median survival time after onset is 36 [2], although there are great individual variations [3]. Although ALS is a clinically recognizable condition (in terms of the pattern of progressive upper and lower motor neuron degeneration), the clinical presentation and progression are heterogeneous [4]. Moreover, there are now strong reasons for considering a broader aetiological and pathogenic spectrum [5]. This clinical heterogeneity is observed in other neurodegenerative diseases, such as Parkinson’s disease (PD). Nevertheless, it has been found that all PD patients display degeneration and iron overload of the substantia nigra, which might become a surrogate biomarker [6]. In ALS, iron overload in the motor cortex was confirmed [7] after being suspected in mouse models [8]. Ongoing drug trials in the field of neurodegenerative disease are mainly seeking to establish neuroprotection and neurorestoration. Since neuroprotection can never be unambiguously demonstrated in a given patient, the concept of disease-modifying drugs (with a slowing of the disease progression) has arisen. At present, the evaluation of a drug’s clinical efficacy in ALS is based on the ALS Functional Rating Scale Revised, motor tests, survival or a combination of these measures (such as the Combined Assessment of Function and Survival (CAFS)) [9, 10]. However, these endpoints are general, variable and late-stage measures of the ALS disease process and thus require the long-term assessment of large cohorts. These assessments are risky and expensive, which considerably limits the number of trials being conducted. A sensitive surrogate biomarker might help to (i) reduce the sample size in pilot studies, (ii) better define the sample size required in Phase III clinical trials (by comparison with clinical scales) and (iii) define endophenotypes for separate assessment in clinical trials. Biomarkers are typically divided into “wet biomarkers” and “dry biomarkers”. Wet biomarkers are biological substances that are measured in a body fluid (such as whole blood, serum, plasma, saliva or cerebrospinal fluid (CSF)). “Dry biomarkers” are based on functional scales, task performance, electrophysiology or imaging. Magnetic resonance imaging is a widely available and non-invasive technique, which makes it an appropriate candidate for biomarkers. Although early reports stated that ALS starts in the spinal cord, the initial site of neurodegeneration has not been unambiguously identified; disease may start in the spinal cord, in the motor cortex or at both sites simultaneously [11, 12]. The development of radiological Page 2 (...truncated)