Spinal Cord Gray Matter Atrophy in Amyotrophic Lateral Sclerosis

Paquin, M.-Ê.; Mendili, Mohamed Mounir El; Gros, Charley; Dupont, Sara M.; Cohen‐Adad, Julien; Pradat, Pierre‐François

doi:10.3174/ajnr.a5427

Cited by 44 publications

(60 citation statements)

References 29 publications

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“…35 The precise molecular mechanisms underlying C9orf72-associated degeneration remains largely unknown, even if putative cell-to-cell propagation of the DPRs and TDP-43 inclusions has been proposed. 36 Despite the detection sensitivity of novel spinal imaging techniques in ALS, [24][25][26][37][38][39] the lack of imaging findings in younger mutation carriers may be due to technological limitations and does not necessarily represent lack of pathology. Presymptomatic imaging in C9orf72 has dual academic and clinical relevance.…”

Section: Discussionmentioning

confidence: 99%

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

Querin

Bede

Mendili

et al. 2019

Annals of Neurology

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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. View this article online at wileyonlinelibrary.com.Additional supporting information can be found in the online version of this article.

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Section: Discussionmentioning

confidence: 99%

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

Querin

Bede

Mendili

et al. 2019

Annals of Neurology

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“…Progressive death of motor neurons in ALS leads to observable changes in the brain and spinal cord as highlighted by El Mendili et al 2019 [40]. Longitudinal studies have established a connection between cervical spinal cord atrophy and functional decline in ALS patients [41][42][43]. Additionally, reviews on the utility of various imaging techniques for visualizing changes in CNS have discussed a potential use in the diagnosis and tracking of ALS [33,44,45].…”

Section: Mri Based Als Biomarkers Investigated In Previous Studiesmentioning

confidence: 99%

Non-invasive MRI quantification of cerebrospinal fluid dynamics in amyotrophic lateral sclerosis patients

Sass

Khani

Romm

et al. 2020

Fluids Barriers CNS

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Background: Developing novel therapeutic agents to treat amyotrophic lateral sclerosis (ALS) has been difficult due to multifactorial pathophysiologic processes at work. Intrathecal drug administration shows promise due to close proximity of cerebrospinal fluid (CSF) to affected tissues. Development of effective intrathecal pharmaceuticals will rely on accurate models of how drugs are dispersed in the CSF. Therefore, a method to quantify these dynamics and a characterization of differences across disease states is needed. Methods: Complete intrathecal 3D CSF geometry and CSF flow velocities at six axial locations in the spinal canal were collected by T2-weighted and phase-contrast MRI, respectively. Scans were completed for eight people with ALS and ten healthy controls. Manual segmentation of the spinal subarachnoid space was performed and coupled with an interpolated model of CSF flow within the spinal canal. Geometric and hydrodynamic parameters were then generated at 1 mm slice intervals along the entire spine. Temporal analysis of the waveform spectral content and feature points was also completed. Results: Comparison of ALS and control groups revealed a reduction in CSF flow magnitude and increased flow propagation velocities in the ALS cohort. Other differences in spectral harmonic content and geometric comparisons may support an overall decrease in intrathecal compliance in the ALS group. Notably, there was a high degree of variability between cases, with one ALS patient displaying nearly zero CSF flow along the entire spinal canal. Conclusion: While our sample size limits statistical confidence about the differences observed in this study, it was possible to measure and quantify inter-individual and cohort variability in a non-invasive manner. Our study also shows the potential for MRI based measurements of CSF geometry and flow to provide information about the hydrodynamic environment of the spinal subarachnoid space. These dynamics may be studied further to understand the behavior of CSF solute transport in healthy and diseased states.

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“…The points of the first intervertebral disk until the second intervertebral disk revealed more significant differences with p < 0.001. Height in cm 172 [10] 174 [9] t(140) = −0.7, p = 0.5 c…”

Section: Samplementioning

confidence: 99%

The upper cervical spinal cord in ALS assessed by cross-sectional and longitudinal 3T MRI

Wimmer

Schreiber

Hensiek

et al. 2020

Sci Rep

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the upper cervical spinal cord is measured in a large longitudinal amyotrophic lateral sclerosis (ALS) cohort to evaluate its role as a biomarker. Specifically, the cervical spinal cord´s cross-sectional area (CSA) in plane of the segments C1-C3 was measured semi-automatically with T1-weighted 3T MRI sequences in 158 ALS patients and 86 controls. Six-month longitudinal follow-up MRI scans were analyzed in 103 patients. Compared to controls, in ALS there was a significant mean spinal cord atrophy (63.8 mm² vs. 60.8 mm², p = 0.001) which showed a trend towards worsening over time (mean spinal cord CSA decrease from 61.4 mm² to 60.6 mm² after 6 months, p = 0.06). Findings were most pronounced in the caudal segments of the upper cervical spinal cord and in limb-onset ALS. Baseline CSA was related to the revised ALS functional rating scale, disease duration, precentral gyrus thickness and total brain gray matter volume. In conclusion, spinal cord atrophy as assessed in brain MRIs in ALS patients mirrors the extent of overall neurodegeneration and parallels disease severity. Spinal cord involvement is a well-known and prominent feature of amyotrophic lateral sclerosis (ALS), that reflects both anterior horn cell ("amyotrophy") and pyramidal tract degeneration/sclerosis of the lateral columns ("lateral sclerosis")-which has been highlighted since Charcot's pathology studies in 1865 1. Autopsy studies correspondingly reveal mild to marked loss of motor neurons in around 80% of the ALS patients which can affect the anterior horn of the entire spinal cord from the level of C2 to the level of its caudal sacral segments 2. Anterior horn cell loss is furthermore closely associated with large myelinated fiber degeneration of the pyramidal tract 2-4. In-vivo studies applying magnetic resonance imaging (MRI) correspondingly display a reduction of the spinal cord cross-sectional area (CSA) in ALS, i.e. showing spinal cord atrophy together with pyramidal tract integrity loss in diffusion tensor imaging (DTI) 5-7. Controversies remain, however, on the relationship of in-vivo MRI spinal cord atrophy to clinical features and biomarkers in ALS. While some studies reported an association between CSA reduction and worse motor performance or longer disease duration 8,9 , others failed to find such a clinical correlation 10,11. Conflicting or negative results might stem from small sample sizes in that most studies included less than 30 patients 8,9,12. Additionally, only a few ALS studies thus far took advantage of the capability of spinal cord in-vivo MRI to monitor CSA evolution over time 5,12,13. In consideration of these uncertainties, we conducted a retrospective analysis of the upper cervical spinal cord within brain MRIs that were acquired during a large cross-sectional (N = 158) and longitudinal (N = 103) multicenter study to understand how in-vivo spinal cord atrophy relates to clinical features, other biomarkers, and, how it evolves over time in ALS.

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Spinal Cord Gray Matter Atrophy in Amyotrophic Lateral Sclerosis

Cited by 44 publications

References 29 publications

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

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

Non-invasive MRI quantification of cerebrospinal fluid dynamics in amyotrophic lateral sclerosis patients

The upper cervical spinal cord in ALS assessed by cross-sectional and longitudinal 3T MRI

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