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

Abstract

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.

Pilot Study on Quantitative Cervical Cord and Muscular MRI in Spinal Muscular Atrophy: Promising Biomarkers of Disease Evolution and Treatment?

“…Quantitative MRI (qMRI) of the cervical SC has been widely used to investigate cord pathology in several neurodegenerative disorders such as MS ( 21 , 22 ) and ALS ( 23 , 24 ). Through the acquisition of images with high contrast between white matter (WM) and gray matter (GM), SC MRI enables tissue segmentation and measurement of the cross-sectional area (CSA) of the SC, total GM, and ventral horns (VHs), thus making it possible to quantify total SC and GM atrophy ( 25 ).…”

Selective atrophy of the cervical enlargement in whole spinal cord MRI of amyotrophic lateral sclerosis

“…Despite this, there is sparse evidence about regional distribution patterns and in vivo changes of atrophy and other mechanistic alterations affecting the spinal cord in human ALS. Two recent 3T studies reported cervical cord atrophy in ALS participants, but these studies evaluated limited portions of the cervical spinal cord ( Grolez et al, 2018 , Wimmer et al, 2020 ). The Grolez et al study ( Grolez et al, 2018 ) evaluated a short segment of the cord between vertebral levels C3 and C5 in 40 ALS participants and observed correlations of spinal cord volume reduction with slow vital capacity decline from baseline.…”

“…The Grolez et al study ( Grolez et al, 2018 ) evaluated a short segment of the cord between vertebral levels C3 and C5 in 40 ALS participants and observed correlations of spinal cord volume reduction with slow vital capacity decline from baseline. Another recent multi-center study ( ) similarly examined only the rostral cervical cord (C1–C3) and observed a 5% decrease in cord CSA at these levels in ALS compared to HCs at baseline (60.8 mm 2 vs. 63.8 mm 2 ) ( Wimmer et al, 2020 ).…”

Analysis of brain and spinal MRI measures in a common domain to investigate directional neurodegeneration in motor neuron disease

“…Differing patterns in sporadic and SOD1 MND/ALS patients have also been reported, with intracranial corticospinal tract FA reduction and cervical cord atrophy predominating, respectively [50]. Longitudinal studies focussed on either brain or cervical cord in isolation have shown progression of intracranial grey [20] and white matter tissue damage [34,[51][52][53] in some, but not all [17,54], studies, with only modest cervical cord atrophy evident even in quite large cohorts (mean 0.8 mm 2 over 6 months in 103 patients, not reaching statistical significance) [40]. Results of studies of asymptomatic gene carriers, which represent an ideal model of the earliest stages of MND/ALS, have reported early detectable changes both at cortical [8] and cord levels [50,55].…”

“…MRI is often performed routinely at diagnosis of MND/ ALS primarily to exclude mimics, but also provides established group-level markers of tissue damage. Primary motor cortical thinning on T1-weighted MRI [17][18][19][20][21][22][23][24], decreased fractional anisotropy (FA) within corticospinal tracts on diffusion tensor imaging [14,[25][26][27][28][29][30][31][32][33][34][35] and reduced crosssectional area of the cervical spinal cord [36][37][38][39][40] have been consistently reported. The aim of this study was to determine whether analysis of these metrics in a common domain could demonstrate group-level gradients of tissue damage to support either a dying-forward or dying-back hypothesis.…”