Skip to main content
SpringerLink
Log in

Amyotrophic lateral sclerosis phenotypes significantly differ in terms of magnetic susceptibility properties of the precentral cortex

  • Neuro
  • Published:
European Radiology Aims and scope Submit manuscript

Abstract

Objectives

The aim of our study was to investigate whether the magnetic susceptibility varies according to the amyotrophic lateral sclerosis (ALS) phenotypes based on the predominance of upper motor neuron (UMN)/lower motor neuron (LMN) impairment.

Methods

We retrospectively collected imaging and clinical data of 47 ALS patients (12 with UMN predominance (UMN-ALS), 16 with LMN predominance (LMN-ALS), and 19 with no clinically defined predominance (Np-ALS)). We further enrolled 23 healthy controls (HC) and 15 ALS mimics (ALS-Mim). These participants underwent brain 3-T magnetic resonance imaging (3-T MRI) with T1-weighted and gradient-echo multi-echo sequences. Automatic segmentation and quantitative susceptibility mapping (QSM) were performed. The skewness of the susceptibility values in the precentral cortex (SuscSKEW) was automatically computed, compared among the groups, and correlated to the clinical variables.

Results

The Kruskal-Wallis test showed significant differences in terms of SuscSKEW among groups (χ2(3) = 24.2, p < 0.001), and pairwise tests showed that SuscSKEW was higher in UMN-ALS compared to those in LMN-ALS (p < 0.001), HC (p < 0.001), Np-ALS (p = 0.012), and ALS-Mim (p < 0.001). SuscSKEW was highly correlated with the Penn UMN score (Spearman’s rho 0.612, p < 0.001).

Conclusion

This study demonstrates that the clinical ALS phenotypes based on UMN/LMN sign predominance significantly differ in terms of magnetic susceptibility properties of the precentral cortex. Combined MRI-histopathology investigations are strongly encouraged to confirm whether this evidence is due to iron overload in UMN-ALS, unlike in LMN-ALS.

Key Points

• Magnetic susceptibility in the precentral cortex reflects the prevalence of UMN/LMN impairment in the clinical ALS phenotypes.

• The degree of UMN/LMN impairment might be well described by the automatically derived measure of SuscSKEW in the precentral cortex.

• Increased SuscSKEW in the precentral cortex is more relevant in UMN-ALS patients compared to those in Np-ALS and LMN-ALS patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

ALS:

Amyotrophic lateral sclerosis

ALSFRS-R:

Revised Amyotrophic Lateral Sclerosis Functional Rating Scale

ALS-Mim:

ALS mimics and chameleons

C-ALS:

“Classic” ALS

GRE:

Gradient-echo

HC:

Healthy controls

LMN:

Lower motor neuron

LMN-ALS:

ALS patients with LMN predominance

Np-ALS:

ALS patients with no clinically defined predominance

PLS:

Primary lateral sclerosis

PMA:

Progressive muscular atrophy

QSM:

Quantitative susceptibility mapping

SuscSKEW:

Skewness of the susceptibility value distribution in the precentral cortex

UMN:

Upper motor neuron

UMN-ALS:

ALS patients with UMN predominance

References

  1. Ludolph A, Drory V, Hardiman O et al (2015) A revision of the El Escorial criteria - 2015. Amyotroph Lateral Scler Frontotemporal Degener 16:291–292. https://doi.org/10.3109/21678421.2015.1049183

    Article  PubMed  Google Scholar 

  2. Al-Chalabi A, Hardiman O, Kiernan MC, Chiò A, Rix-Brooks B, van den Berg LH (2016) Amyotrophic lateral sclerosis: moving towards a new classification system. Lancet Neurol 15:1182–1194

  3. Costagli M, Donatelli G, Biagi L et al (2016) Magnetic susceptibility in the deep layers of the primary motor cortex in amyotrophic lateral sclerosis. Neuroimage Clin 12:965–969. https://doi.org/10.1016/j.nicl.2016.04.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kwan JY, Jeong SY, Van Gelderen P et al (2012) Iron accumulation in deep cortical layers accounts for MRI signal abnormalities in ALS: correlating 7 tesla MRI and pathology. PLoS One 7:e35241. https://doi.org/10.1371/journal.pone.0035241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Adachi Y, Sato N, Saito Y et al (2015) Usefulness of SWI for the detection of iron in the motor cortex in amyotrophic lateral sclerosis. J Neuroimaging 25:443–451

    Article  PubMed  Google Scholar 

  6. Contarino VE, Conte G, Morelli C et al (2020) Toward a marker of upper motor neuron impairment in amyotrophic lateral sclerosis: a fully automatic investigation of the magnetic susceptibility in the precentral cortex. Eur J Radiol 124:108815. https://doi.org/10.1016/j.ejrad.2020.108815

    Article  PubMed  Google Scholar 

  7. Schweitzer AD, Liu T, Gupta A et al (2015) Quantitative susceptibility mapping of the motor cortex in amyotrophic lateral sclerosis and primary lateral sclerosis. AJR Am J Roentgenol 204:1086–1092. https://doi.org/10.2214/AJR.14.13459

    Article  PubMed  PubMed Central  Google Scholar 

  8. de Carvalho M, Dengler R, Eisen A et al (2008) Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol 119:497–503. https://doi.org/10.1016/j.clinph.2007.09.143

    Article  PubMed  Google Scholar 

  9. Huynh W, Simon NG, Grosskreutz J, Turner MR, Vucic S, Kiernan MC (2016) Assessment of the upper motor neuron in amyotrophic lateral sclerosis. Clin Neurophysiol 127:2643–2660. https://doi.org/10.1016/j.clinph.2016.04.025

  10. Vázquez-Costa JF, Mazón M, Carreres-Polo J et al (2018) Brain signal intensity changes as biomarkers in amyotrophic lateral sclerosis. Acta Neurol Scand 137:262–271. https://doi.org/10.1111/ane.12863

    Article  CAS  PubMed  Google Scholar 

  11. Cedarbaum JM, Stambler N, Malta E et al (1999) The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. J Neurol Sci 169:13–21. https://doi.org/10.1016/S0022-510X(99)00210-5

    Article  CAS  PubMed  Google Scholar 

  12. Turner MR, Talbot K (2013) Mimics and chameleons in motor neurone disease. Pract Neurol 13:153–164. https://doi.org/10.1136/practneurol-2013-000557

    Article  PubMed  PubMed Central  Google Scholar 

  13. Liu C, Li W, Tong KA, Yeom KW, Kuzminski S (2015) Susceptibility-weighted imaging and quantitative susceptibility mapping in the brain. J Magn Reson Imaging 42:23–41. https://doi.org/10.1002/jmri.24768

  14. Fischl B (2012) FreeSurfer. Neuroimage 62:774–781. https://doi.org/10.1016/j.neuroimage.2012.01.021

    Article  PubMed  Google Scholar 

  15. Quade D (1967) Rank analysis of covariance. J Am Stat Assoc 62:1187–1200

    Article  Google Scholar 

  16. Geser F, Stein B, Partain M et al (2011) Motor neuron disease clinically limited to the lower motor neuron is a diffuse TDP-43 proteinopathy. Acta Neuropathol 121:509–517. https://doi.org/10.1007/s00401-011-0797-z

    Article  PubMed  PubMed Central  Google Scholar 

  17. Carrí MT, Ferri A, Cozzolino M, Calabrese L, Rotilio G (2003) Neurodegeneration in amyotrophic lateral sclerosis: the role of oxidative stress and altered homeostasis of metals. Brain Res Bull 61:365–374. https://doi.org/10.1016/s0361-9230(03)00179-5

  18. Wang Y, Spincemaille P, Liu Z et al (2017) Clinical quantitative susceptibility mapping (QSM): biometal imaging and its emerging roles in patient care. J Magn Reson Imaging 46:951–971. https://doi.org/10.1002/jmri.25693

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sheykhansari S, Kozielski K, Bill J et al (2018) Redox metals homeostasis in multiple sclerosis and amyotrophic lateral sclerosis: a review. Cell Death Dis 9:348. https://doi.org/10.1038/s41419-018-0379-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ince PG, Evans J, Knopp M et al (2003) Corticospinal tract degeneration in the progressive muscular atrophy variant of ALS. Neurology 60:1252–1258. https://doi.org/10.1212/01.wnl.0000058901.75728.4e

    Article  CAS  PubMed  Google Scholar 

  21. Brownell B, Oppenheimer DR, Hughes JT (1970) The central nervous system in motor neurone disease. J Neurol Neurosurg Psychiatry 33:338–357. https://doi.org/10.1136/jnnp.33.3.338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nishihira Y, Tan C-F, Hoshi Y et al (2009) Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology. Acta Neuropathol 117:45–53. https://doi.org/10.1007/s00401-008-0443-6

    Article  CAS  PubMed  Google Scholar 

  23. Riku Y, Atsuta N, Yoshida M et al (2014) Differential motor neuron involvement in progressive muscular atrophy: a comparative study with amyotrophic lateral sclerosis. BMJ Open 4:e005213. https://doi.org/10.1136/bmjopen-2014-005213

    Article  PubMed  PubMed Central  Google Scholar 

  24. Spinelli EG, Agosta F, Ferraro PM et al (2016) Brain MR imaging in patients with lower motor neuron-predominant disease. Radiology 280:545–556. https://doi.org/10.1148/radiol.2016151846

    Article  PubMed  Google Scholar 

  25. Jeong SY, Rathore KI, Schulz K, Ponka P, Arosio P, David S (2009) Dysregulation of iron homeostasis in the CNS contributes to disease progression in a mouse model of amyotrophic lateral sclerosis. J Neurosci 29:610–619

  26. Golko-Perez S, Amit T, Bar-Am, Youdim MBH, Weinreb O (2017) A novel iron chelator-radical scavenger ameliorates motor dysfunction and improves life span and mitochondrial biogenesis in SOD1G93A ALS mice. Neurotox Res 31:230–244

  27. Moreau C, Danel V, Devedjian JC et al (2018) Could Conservative Iron Chelation Lead to Neuroprotection in Amyotrophic Lateral Sclerosis?© Caroline Moreau et al 2018; Published by Mary Ann Liebert, Inc. This Open Access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Antioxid Redox Signal 29:742–748

Download references

Funding

The authors state that this work has not received any funding.

Author information

Author notes

  1. Giorgio Conte and Valeria Elisa Contarino contributed equally to this work.

Authors and Affiliations

  1. Neuroradiology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, Milan, Italy

    Giorgio Conte, Valeria Elisa Contarino, Silvia Casale, Elisa Scola, Silvia Siggillino, Claudia Maria Cinnante, Luca Caschera, Francesco Maria Lo Russo & Fabio Maria Triulzi

  2. Department of Neurology-Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano IRCCS, piazzale Brescia 20, Milan, Italy

    Claudia Morelli, Francesca Trogu & Vincenzo Silani

  3. Neuroradiology Unit, ASST Santi Paolo e Carlo, San Carlo Borromeo Hospital, Via Pio II 3, Milan, Italy

    Sara Sbaraini

  4. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, via Festa del Perdono 7, Milan, Italy

    Francesca Trogu, Fabio Maria Triulzi & Vincenzo Silani

Authors
  1. Giorgio Conte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valeria Elisa Contarino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silvia Casale
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claudia Morelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sara Sbaraini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elisa Scola
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Francesca Trogu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Silvia Siggillino
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Claudia Maria Cinnante
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Luca Caschera
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Francesco Maria Lo Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Fabio Maria Triulzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Vincenzo Silani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Silvia Casale.

Ethics declarations

Guarantor

The scientific guarantor of this publication is Dr. Giorgio Conte, Ospedale Maggiore Policlinico, Neuroradiology Unit.

Conflict of interest

Prof. Vincenzo Silani receives or has received research supports from the Italian Ministry of Health (Grant RF-201302355764), Fondazione Italiana di Ricerca per la SLA-AriSLA (Grants Exomefals and Novals), Fondazione regionale per la Ricerca Biomedica Regione Lombardia (Project nr. 2015-0023), and E-RARE JTC 2018 (Project Repetomics).

All other authors declare no disclosures of possible conflict of interest and/or commercial involvement involving contents of this manuscript.

Statistics and biometry

One of the authors has significant statistical expertise.

Informed consent

Written informed consent was obtained from all subjects (patients) in this study.

Ethical approval

Institutional Review Board approval was obtained.

Study subjects or cohorts overlap

Some study subjects or cohorts have been previously reported in Contarino VE, Conte G, Morelli C, et al (2020) “Toward a marker of upper motor neuron impairment in amyotrophic lateral sclerosis: a fully automatic investigation of the magnetic susceptibility in the precentral cortex.” Eur J Radiol 124:108815. https://doi.org/10.1016/j.ejrad.2020.108815

Methodology

• retrospective

• observational

• performed at one institution

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(DOCX 404 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Conte, G., Contarino, V.E., Casale, S. et al. Amyotrophic lateral sclerosis phenotypes significantly differ in terms of magnetic susceptibility properties of the precentral cortex. Eur Radiol 31, 5272–5280 (2021). https://doi.org/10.1007/s00330-020-07547-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00330-020-07547-5

Keywords

Search

Navigation