Enhancing the interpretability of spinal cord atrophy in multiple sclerosis by reducing interindividual variability due to anatomical differences

Daan J. de Jong; Tom A. Fuchs; Mar Barrantes-Cepas; Julia R. Jelgerhuis; Samanta Noteboom; Martijn D. Steenwijk; Hugo Vrenken; Frederik Barkhof; Joep Killestein; Menno M. Schoonheim; Eva M.M. Strijbis

doi:10.1016/j.msard.2026.107079

Enhancing the interpretability of spinal cord atrophy in multiple sclerosis by reducing interindividual variability due to anatomical differences

Daan J. de Jong^*
, Tom A. Fuchs
, Mar Barrantes-Cepas
, Julia R. Jelgerhuis
, Samanta Noteboom
, Martijn D. Steenwijk
, Hugo Vrenken
, Frederik Barkhof
, Joep Killestein
, Menno M. Schoonheim
, Eva M.M. Strijbis

^*Corresponding author for this work

Vrije Universiteit Amsterdam
SUNY Buffalo
MS Center Amsterdam
Vrije Universiteit Amsterdam, Department of Radiology and Nuclear Medicine
University College London
Vrije Universiteit Amsterdam, Neurology

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background: Mean upper cervical cord area (MUCCA) is clinically relevant for measuring spinal cord atrophy in multiple sclerosis (MS), but anatomical variation may confound measurements. Interpretability of MUCCA may be improved by ensuring measurements reflect MS pathology rather than anatomical variability. To achieve this, several strategies are employed, but it is unclear which performs best. This study evaluated height, estimated total intracranial volume (eTIV), and cervical spinal canal area (SCaA) for MUCCA-normalisation. Methods: 272 persons with MS (pwMS; age 48.47±11.00y, 70.2% female) and 69 healthy controls (HC; age 46.42±9.14y, 59.4% female) were included. eTIV, and MUCCA and SCaA at C2/C3 were determined on 3D-T1w brain MRI. Factors were associated to MUCCA and remaining anatomical dependency was determined using linear regression. Sensitivity analyses were performed. Findings were validated in pwMS. Results: eTIV and SCaA were similar between HC and PwMS (p>0.05). MUCCA (PwMS: 62.12±10.40 mm2, HC: 68.00±9.89mm2, p<0.001) and height (PwMS: 173.35±9.20 cm, HC: 177.22±10.47cm, p=0.022) were lower in pwMS. In HCs, eTIV (std.β=0.326), height (std.β=0.312) and SCaA (std.β=0.322) were similarly related to MUCCA and resulted in similar reduction of variance due to anatomical dependency (R²=25%->10%) but multivariable normalisation (eTIV+SCaA) performed best (R²=0%). All factors were similarly robust in HC. In MS, SCaA was susceptible to disease-related variability and normalisation altered clinical relations. Only height was applicable for proportional normalisation. Conclusion: eTIV, height and SCaA were valid normalisation factors of MUCCA. Multivariable normalisation (eTIV+SCaA) performed reduced anatomical dependency best but masked clinical-anatomical relations. Proportional normalisation using height allows for individual clinical assessment of spinal cord atrophy.

Original language	English
Article number	107079
Journal	MULTIPLE SCLEROSIS AND RELATED DISORDERS
Volume	108
DOIs	https://doi.org/10.1016/j.msard.2026.107079
Publication status	Published - Apr 2026

Keywords

Biological variation
Image analysis
Magnetic Resonance Imaging
Multiple sclerosis
Spinal canal
Spinal cord

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de Jong, D. J., Fuchs, T. A., Barrantes-Cepas, M., Jelgerhuis, J. R., Noteboom, S., Steenwijk, M. D., Vrenken, H., Barkhof, F., Killestein, J., Schoonheim, M. M., & Strijbis, E. M. M. (2026). Enhancing the interpretability of spinal cord atrophy in multiple sclerosis by reducing interindividual variability due to anatomical differences. MULTIPLE SCLEROSIS AND RELATED DISORDERS, 108, Article 107079. https://doi.org/10.1016/j.msard.2026.107079

@article{84507bdffb3c4933a621bf959ed068eb,

title = "Enhancing the interpretability of spinal cord atrophy in multiple sclerosis by reducing interindividual variability due to anatomical differences",

abstract = "Background: Mean upper cervical cord area (MUCCA) is clinically relevant for measuring spinal cord atrophy in multiple sclerosis (MS), but anatomical variation may confound measurements. Interpretability of MUCCA may be improved by ensuring measurements reflect MS pathology rather than anatomical variability. To achieve this, several strategies are employed, but it is unclear which performs best. This study evaluated height, estimated total intracranial volume (eTIV), and cervical spinal canal area (SCaA) for MUCCA-normalisation. Methods: 272 persons with MS (pwMS; age 48.47±11.00y, 70.2\% female) and 69 healthy controls (HC; age 46.42±9.14y, 59.4\% female) were included. eTIV, and MUCCA and SCaA at C2/C3 were determined on 3D-T1w brain MRI. Factors were associated to MUCCA and remaining anatomical dependency was determined using linear regression. Sensitivity analyses were performed. Findings were validated in pwMS. Results: eTIV and SCaA were similar between HC and PwMS (p>0.05). MUCCA (PwMS: 62.12±10.40 mm2, HC: 68.00±9.89mm2, p<0.001) and height (PwMS: 173.35±9.20 cm, HC: 177.22±10.47cm, p=0.022) were lower in pwMS. In HCs, eTIV (std.β=0.326), height (std.β=0.312) and SCaA (std.β=0.322) were similarly related to MUCCA and resulted in similar reduction of variance due to anatomical dependency (R2=25\%->10\%) but multivariable normalisation (eTIV+SCaA) performed best (R2=0\%). All factors were similarly robust in HC. In MS, SCaA was susceptible to disease-related variability and normalisation altered clinical relations. Only height was applicable for proportional normalisation. Conclusion: eTIV, height and SCaA were valid normalisation factors of MUCCA. Multivariable normalisation (eTIV+SCaA) performed reduced anatomical dependency best but masked clinical-anatomical relations. Proportional normalisation using height allows for individual clinical assessment of spinal cord atrophy.",

keywords = "Biological variation, Image analysis, Magnetic Resonance Imaging, Multiple sclerosis, Spinal canal, Spinal cord",

author = "\{de Jong\}, \{Daan J.\} and Fuchs, \{Tom A.\} and Mar Barrantes-Cepas and Jelgerhuis, \{Julia R.\} and Samanta Noteboom and Steenwijk, \{Martijn D.\} and Hugo Vrenken and Frederik Barkhof and Joep Killestein and Schoonheim, \{Menno M.\} and Strijbis, \{Eva M.M.\}",

note = "Publisher Copyright: {\textcopyright} 2026 The Author(s)",

year = "2026",

month = apr,

doi = "10.1016/j.msard.2026.107079",

language = "English",

volume = "108",

journal = "MULTIPLE SCLEROSIS AND RELATED DISORDERS",

issn = "2211-0348",

publisher = "Elsevier",

}

de Jong, DJ, Fuchs, TA, Barrantes-Cepas, M, Jelgerhuis, JR, Noteboom, S, Steenwijk, MD , Vrenken, H , Barkhof, F , Killestein, J , Schoonheim, MM & Strijbis, EMM 2026, 'Enhancing the interpretability of spinal cord atrophy in multiple sclerosis by reducing interindividual variability due to anatomical differences', MULTIPLE SCLEROSIS AND RELATED DISORDERS, vol. 108, 107079. https://doi.org/10.1016/j.msard.2026.107079

TY - JOUR

T1 - Enhancing the interpretability of spinal cord atrophy in multiple sclerosis by reducing interindividual variability due to anatomical differences

AU - de Jong, Daan J.

AU - Fuchs, Tom A.

AU - Barrantes-Cepas, Mar

AU - Jelgerhuis, Julia R.

AU - Noteboom, Samanta

AU - Steenwijk, Martijn D.

AU - Vrenken, Hugo

AU - Barkhof, Frederik

AU - Killestein, Joep

AU - Schoonheim, Menno M.

AU - Strijbis, Eva M.M.

PY - 2026/4

Y1 - 2026/4

N2 - Background: Mean upper cervical cord area (MUCCA) is clinically relevant for measuring spinal cord atrophy in multiple sclerosis (MS), but anatomical variation may confound measurements. Interpretability of MUCCA may be improved by ensuring measurements reflect MS pathology rather than anatomical variability. To achieve this, several strategies are employed, but it is unclear which performs best. This study evaluated height, estimated total intracranial volume (eTIV), and cervical spinal canal area (SCaA) for MUCCA-normalisation. Methods: 272 persons with MS (pwMS; age 48.47±11.00y, 70.2% female) and 69 healthy controls (HC; age 46.42±9.14y, 59.4% female) were included. eTIV, and MUCCA and SCaA at C2/C3 were determined on 3D-T1w brain MRI. Factors were associated to MUCCA and remaining anatomical dependency was determined using linear regression. Sensitivity analyses were performed. Findings were validated in pwMS. Results: eTIV and SCaA were similar between HC and PwMS (p>0.05). MUCCA (PwMS: 62.12±10.40 mm2, HC: 68.00±9.89mm2, p<0.001) and height (PwMS: 173.35±9.20 cm, HC: 177.22±10.47cm, p=0.022) were lower in pwMS. In HCs, eTIV (std.β=0.326), height (std.β=0.312) and SCaA (std.β=0.322) were similarly related to MUCCA and resulted in similar reduction of variance due to anatomical dependency (R2=25%->10%) but multivariable normalisation (eTIV+SCaA) performed best (R2=0%). All factors were similarly robust in HC. In MS, SCaA was susceptible to disease-related variability and normalisation altered clinical relations. Only height was applicable for proportional normalisation. Conclusion: eTIV, height and SCaA were valid normalisation factors of MUCCA. Multivariable normalisation (eTIV+SCaA) performed reduced anatomical dependency best but masked clinical-anatomical relations. Proportional normalisation using height allows for individual clinical assessment of spinal cord atrophy.

AB - Background: Mean upper cervical cord area (MUCCA) is clinically relevant for measuring spinal cord atrophy in multiple sclerosis (MS), but anatomical variation may confound measurements. Interpretability of MUCCA may be improved by ensuring measurements reflect MS pathology rather than anatomical variability. To achieve this, several strategies are employed, but it is unclear which performs best. This study evaluated height, estimated total intracranial volume (eTIV), and cervical spinal canal area (SCaA) for MUCCA-normalisation. Methods: 272 persons with MS (pwMS; age 48.47±11.00y, 70.2% female) and 69 healthy controls (HC; age 46.42±9.14y, 59.4% female) were included. eTIV, and MUCCA and SCaA at C2/C3 were determined on 3D-T1w brain MRI. Factors were associated to MUCCA and remaining anatomical dependency was determined using linear regression. Sensitivity analyses were performed. Findings were validated in pwMS. Results: eTIV and SCaA were similar between HC and PwMS (p>0.05). MUCCA (PwMS: 62.12±10.40 mm2, HC: 68.00±9.89mm2, p<0.001) and height (PwMS: 173.35±9.20 cm, HC: 177.22±10.47cm, p=0.022) were lower in pwMS. In HCs, eTIV (std.β=0.326), height (std.β=0.312) and SCaA (std.β=0.322) were similarly related to MUCCA and resulted in similar reduction of variance due to anatomical dependency (R2=25%->10%) but multivariable normalisation (eTIV+SCaA) performed best (R2=0%). All factors were similarly robust in HC. In MS, SCaA was susceptible to disease-related variability and normalisation altered clinical relations. Only height was applicable for proportional normalisation. Conclusion: eTIV, height and SCaA were valid normalisation factors of MUCCA. Multivariable normalisation (eTIV+SCaA) performed reduced anatomical dependency best but masked clinical-anatomical relations. Proportional normalisation using height allows for individual clinical assessment of spinal cord atrophy.

KW - Biological variation

KW - Image analysis

KW - Magnetic Resonance Imaging

KW - Multiple sclerosis

KW - Spinal canal

KW - Spinal cord

UR - https://www.scopus.com/pages/publications/105030529958

U2 - 10.1016/j.msard.2026.107079

DO - 10.1016/j.msard.2026.107079

M3 - Article

C2 - 41719900

AN - SCOPUS:105030529958

SN - 2211-0348

VL - 108

JO - MULTIPLE SCLEROSIS AND RELATED DISORDERS

JF - MULTIPLE SCLEROSIS AND RELATED DISORDERS

M1 - 107079

ER -

Enhancing the interpretability of spinal cord atrophy in multiple sclerosis by reducing interindividual variability due to anatomical differences

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