Heterogeneous Deep Gray Matter Iron Deposition Patterns across Multiple Sclerosis Subgroups Defined by the...

Area of Science:

• Neuroimaging
• Neurology
• Biomarkers

Background:

• The clinico-radiological paradox in multiple sclerosis (MS) highlights a discrepancy between white matter lesion load and clinical disability.
• Deep gray matter (DGM) iron deposition is increasingly recognized as a factor influencing MS pathology and clinical outcomes.

Purpose of the Study:

• To investigate the role of DGM iron deposition in the clinico-radiological paradox of MS, particularly concerning cognitive impairment.
• To explore the relationship between DGM iron, atrophy, and cognitive function in MS patients.

Main Methods:

• Quantitative susceptibility mapping (QSM) and volumetric analysis to assess DGM iron content and atrophy.
• Classification of 134 MS patients into subgroups based on lesion volume and disability (EDSS).
• Cognitive testing using Montreal Cognitive Assessment (MoCA) and Symbol Digit Modalities Test (SDMT).

Main Results:

• MS subgroups with high lesion burden exhibited significantly increased iron and atrophy in the globus pallidus, putamen, and caudate compared to healthy controls.
• Putaminal volume was identified as a mediator of the effect of iron on cognitive function, impacting SDMT and MoCA scores.
• In the high lesion burden/high disability subgroup, putaminal iron-induced atrophy explained a substantial portion of the effect on processing speed.

Conclusions:

• Heterogeneous DGM iron deposition is present in MS, contributing to cognitive deficits.
• Putaminal iron accumulation leading to atrophy represents a key mechanistic pathway for cognitive impairment in MS.
• This pathway offers a novel explanation for the clinico-radiological paradox and suggests potential biomarkers for cognitive risk stratification.