We investigated how chronic inflammatory lesions in multiple sclerosis evolve over time by studying their expansion patterns and relationship to disease progression in patients with relapsing-remitting MS over a 4-year period.

Key Findings:

• The expansion of chronic lesions, rather than formation of new lesions, accounts for most (67%) of total brain lesion volume increase in MS patients
• Nearly half (46%) of chronic lesions showed significant expansion, while only 12% shrank over time
• Lesion expansion strongly correlated with both brain atrophy and increased disability, suggesting it drives disease progression
• Older patients showed higher rates of lesion expansion, potentially explaining accelerated disability in aging MS patients

Novel Technical Advances:

• Developed sophisticated imaging analysis methods to precisely track individual lesion changes over time
• Created automated algorithms to distinguish between expanding chronic lesions and new lesion formation
• Established quantitative measures to assess tissue damage within expanding lesions using diffusion imaging
• Implemented rigorous controls for brain atrophy effects on lesion measurements

Clinical Implications:

• The dominant role of chronic lesion expansion in disease progression suggests new therapeutic targets are needed
• Treatments focusing only on preventing new lesions may not adequately address ongoing tissue damage
• Monitoring chronic lesion expansion could help identify patients at higher risk of progression
• Age-related increases in lesion expansion indicate older patients may need different therapeutic approaches

Why It Matters:

This study fundamentally changes our understanding of how MS progresses by showing that the slow expansion of existing lesions, rather than formation of new ones, is the primary driver of accumulating disability. This challenges the traditional focus on preventing new lesion formation and suggests that therapies targeting chronic inflammation at lesion edges could help prevent disease progression. The findings explain why current treatments, while effective at reducing new lesions, may not fully prevent advancing disability, especially in older patients. This work provides crucial evidence for developing new therapeutic strategies aimed at the smoldering inflammation that causes lesion expansion.

This study delves into the long-term progression of Chronic Lesion Tissue (CLT) in relapsing-remitting multiple sclerosis (RRMS) patients, examining its effects on clinical and radiological indicators of disease progression.

Key Findings:

• Consistent Growth: CLT increases at a steady annual rate of 7.75%, significantly impacting brain atrophy and disability.
• Clinical Impact: Patients with higher CLT expansion exhibit faster central brain atrophy, particularly in deep grey matter, and worsening disability scores.

Implications for Clinical Trials:

• CLT expansion provides a promising biomarker for RRMS progression, offering a basis for designing smaller, targeted trials to evaluate therapies aimed at mitigating smouldering inflammation.
• Calculations show that trials targeting CLT expansion require relatively small cohorts, making them feasible and efficient.

Why It Matters:

This research highlights the potential of monitoring CLT dynamics to better understand RRMS progression, tailor interventions, and refine clinical trial design.