Disentangling Age-Related and Disease-Specific Upper Cervical Cord Atrophy in Multiple Sclerosis - European Medical Journal

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Disentangling Age-Related and Disease-Specific Upper Cervical Cord Atrophy in Multiple Sclerosis

1 Mins
Neurology
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Authors:
Maria A. Rocca , 1-3 Kshiteeja Jain , 1 Loredana Storelli , 1 Paola Valsasina , 1 Paolo Preziosa , 1-3 Alessandro Meani , 1 Patrizia Pantano , 4,5 Claudia Piervincenzi , 4 Antonio Gallo , 6 Alessandro D’Ambrosio , 6 Nicola De Stefano , 7 Rosa Cortese , 7 Massimo Filippi 1-3,8,9
  • 1. Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
  • 2. Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
  • 3. Vita-Salute San Raffaele University, Milan, Italy
  • 4. Department of Human Neuroscience, Sapienza University, Rome, Italy
  • 5. IRCCS Neuromed, Pozzilli, Italy
  • 6. Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy
  • 7. Department of Medicine, Surgery and Neuroscience, University of Siena, Italy
  • 8. Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
  • 9. Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy
*Correspondence to [email protected]
Disclosure:

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Acknowledgements:

This study was supported by Fondazione Italiana Sclerosi Multipla (FISM) cod. 2025/S/2 and financed or co-financed with the ‘5 per mille’ public funding.

Citation:
Neurol AMJ. ;3[1]:30-32. https://doi.org/10.33590/neurolamj/6423H9TY.
Keywords:
Aging, atrophy, disease-specific, multiple sclerosis (MS), upper cervical cord.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

BACKGROUND AND AIMS

Spinal cord atrophy has been consistently reported in multiple sclerosis (MS), and represents a key predictor of clinical disability and disease progression.1-3 Mean upper cervical cord area (MUCCA), i.e., cross-sectional area measured at the level of the first two cervical segments, has proven to be a reliable surrogate marker of cord atrophy measurement in both early and late MS.4 However, the distinct contributions of physiological aging versus MS-related neurodegeneration5 remain poorly characterized. The aim of this study1 was to model aging trajectories of upper cervical cord atrophy in healthy controls (HC) and subsequently identify MS-specific patterns of spinal cord atrophy in a large, multicenter cohort.

MATERIALS AND METHODS

The authors analyzed 3D T1-weighted brain MRIs and clinical data from 480 HC and 1,295 patients with MS (ages: 18–70 years). MUCCA was measured between the C1 and C2/3 intervertebral discs using the active surface method and normalized for head size (nMUCCA). Aging trajectories of nMUCCA were modelled in HC using a polynomial regression model accounting for age, age-squared, sex, scanner, and interaction terms. This model was then applied to the MS cohort generating nMUCCA Z-scores, capturing disease-specific atrophy beyond normal aging. Effect of sex and age at onset (pediatric-onset <18 years, adult-onset 18–49 years, late-onset ≥50 years) on Z-scores age dependence was evaluated.

RESULTS

In HC, nMUCCA showed a non-linear age relationship, increasing until late 30s (p≤0.033) and subsequently declining after age 50 years (p≤0.008; Figure 1). In patients with MS, nMUCCA Z-scores exhibited a non-linear decline with age: a steep reduction was observed in early adulthood, while decline attenuated up to late 40s (p<0.001); deviations from age-expected values decreased in later decades (Figure 1). Sex did not significantly influence atrophy patterns in either HC (p=0.256) or patients with MS (p=0.422). Patients with pediatric-onset MS exhibited significantly lower Z-scores compared to adult-onset MS and late-onset MS (p<0.001), although MS-driven decline with age did not differ among onset groups. Lower Z-scores were associated with higher disability and worse structural MRI measures (rho range=−0.355–0.372, all p<0.001).

Figure 1: Cord age.
Lifespan average nMUCCA and nMUCCA Z-score trajectories in HC and patients with MS.
A) Sex- and scanner-adjusted estimated lifespan trajectory of nMUCCA in HC, illustrating the significant non-linear relationship with age. B) Non-linear nMUCCA Z-score trajectory with age in patients with MS. The shaded gray area
represents the 95% CI.
HC: healthy control; MS: multiple sclerosis; nMUCCA: normalized mean upper cervical cord area; y: years.

CONCLUSION

In MS, upper cervical cord atrophy exceeded effects of normal aging, especially during early adulthood and midlife, suggesting that the relative contribution of normal aging increased with age, while disease-specific atrophy predominated early, independent of sex. Differences across onset groups largely reflected disease duration. Upper cord atrophy was associated with disability, supporting its role as a sensitive biomarker of MS-related neurodegeneration beyond aging.

References
Filippi M et al. Disentangling age-related and disease-specific upper cervical cord atrophy in multiple sclerosis. Abstract S40.006. AAN Annual Meeting, April 18-22, 2026. Rocca MA et al. Clinically relevant cranio-caudal patterns of cervical cord atrophy evolution in MS. Neurology 2019;93(20):e1852-66. Moccia M et al. Advances in spinal cord imaging in multiple sclerosis. Ther Adv Neurol Disord 2019;12:1756286419840593. Weeda MM et al. Validation of mean upper cervical cord area (MUCCA) measurement techniques in multiple sclerosis (MS): high reproducibility and robustness to lesions, but large software and scanner effects. Neuroimage Clin. 2019;24:101962. Filippi M et al. The ageing central nervous system in multiple sclerosis: the imaging perspective. Brain. 2024;147:3665-80.

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