Towards Understanding Disease Progression in Multiple Sclerosis: Making Clinical Care More Accessible with Biomarker Research

This thesis provides a comprehensive and integrative analysis of disease progression in MS by combining clinical, imaging, and biomarker data to capture underlying pathophysiological processes and to elucidate their variation across disease stages and patient characteristics. Particular attention was given to the role of chronological age and disease duration as modifiers of inflammation, neurodegeneration, and biomarker dynamics. By bridging biology with clinical interpretation, this thesis lays the foundation for more personalized, age-informed, and biomarker-driven approaches to MS care.

One of the most consistent findings of this thesis is that biological age—more than disease duration—shapes MS pathophysiology. As inflammatory activity declines and neurodegeneration becomes more prominent with advancing age, therapeutic strategies and biomarker interpretation need to be recalibrated across the MS lifespan.

Notably, while older patients presented with lower baseline brain volumes and greater neurodegenerative burden, their rates of brain atrophy were reduced compared to younger individuals—likely reflecting immunosenescence and the waning of inflammation-driven damage.

These findings reinforce the need to account for biological age when interpreting disease trajectories and align with a broader shift in the field, where MS is increasingly conceptualized as a continuum of overlapping and dynamic mechanisms rather than discrete subtypes. This reconceptualization paves the way for more precise, biomarker-guided monitoring strategies that move beyond traditional diagnostic categories.

Retinal imaging exemplifies this shift by providing a sensitive, non-invasive window into CNS pathology. OCT, in particular, correlates strongly with brain atrophy and disability and detects both global and regional neurodegeneration—even in early or clinically silent stages. The growing recognition of OCT has recently been further reinforced by its inclusion in the revised 2025 diagnostic criteria, which now include the optic nerve as a fifth anatomical location, as well as by its increasing use as a surrogate endpoint in clinical trials.

When combined with MRI, fluid biomarkers such as sNfL, and exploratory measures like VH, OCT contributes to a multimodal framework that links clinical outcomes to underlying mechanisms and may accelerate the evaluation of neuroprotective and disease-modifying therapies.

Taken together, the findings of this thesis support a more nuanced, age-informed framework for monitoring MS that integrates multimodal biomarkers with clinical and imaging measures. Specifically, they show that age-related changes influence both the trajectory of disease progression and the interpretation of key biomarkers. By incorporating biological age, disease stage, and multimodal biomarker thresholds into clinical algorithms and trial designs, these insights provide a foundation for optimizing treatment decisions and improving long-term outcomes across the MS spectrum. In doing so, this work advocates for research and clinical strategies that align with individual disease trajectories and move the MS field beyond one-size-fits-all paradigms.