Disentangling Age-related and Disease-specific Upper Cervical Cord Atrophy in Multiple Sclerosis
Maria Rocca1, Kshiteeja Jain3, Loredana Storelli3, Paola Valsasina3, Paolo Preziosa1, Alessandro Meani3, Patrizia Pantano4, Claudia Piervincenzi5, Antonio Gallo6, Alessandro d'Ambrosio6, Nicola De Stefano7, Rosa Cortese7, Massimo Filippi2
1Neuroimaging Research Unit, Division of Neuroscience, and Neurology Unit, 2Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, Neurorehabilitation Unit, and Neurophysiology Service, IRCCS San Raffaele Scientific Institute, and Vita-Salute San Raffaele University, 3Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 4Department of Human Neuroscience, Sapienza University of Rome and IRCCS Neuromed Pozzilli, 5Department of Human Neuroscience, Sapienza University of Rome, 6Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 7Department of Medicine, Surgery and Neuroscience, University of Siena
Objective:
Spinal cord atrophy is a key predictor of clinical disability and disease progression in MS. The distinct contributions of physiological aging versus MS-related neurodegeneration remain poorly characterized.
Background:
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.
Design/Methods:
We analyzed 3D T1-weighted brain MRIs and clinical data from 480 HC and 1295 MS patients (ages:18–70). The mean upper cervical cord cross-sectional area (MUCCA) was measured between the C1 and C2/3 intervertebral disc 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, age2, sex, scanner, and interaction terms, thereafter, applied to the MS cohort to quantify nMUCCA Z-scores, capturing disease-specific atrophy beyond normal aging. Analyses were stratified by sex and age at onset (pediatric-onset [POMS], adult-onset [AOMS], late onset [LOMS]).
Results:
In HC, nMUCCA showed a non-linear relationship with age, significantly declining after 50 years (p<0.008). In MS patients, nMUCCA Z-scores significantly decreased up to 50 years of age (p<0.001), with a rate gradually declining over decades. Sex did not significantly influence atrophy patterns in either HC or MS patients. POMS patients exhibited significantly lower Z-scores compared to AOMS and LOMS (p<0.001), although MS-driven decline with age did not differ among onset groups. Lower Z-scores were associated with longer disease duration and more severe disability (all p<0.001).
Conclusions:
In MS, upper cervical cord atrophy exceeds effects of normal aging, especially during midlife, and is significantly associated with longer disease duration and disability. Sex and age of disease onset do not influence patterns of MS-driven upper cervical cord atrophy with age. Spinal cord imaging holds promise as a sensitive biomarker for tracking MS progression beyond aging effects.
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