Biomarker Trajectories in Progressive Multiple Sclerosis: A Longitudinal Cohort Analysis

Abstract

Progressive multiple sclerosis has traditionally been understood as a distinct clinical phase that follows relapsing disease, but longitudinal cohort and trial evidence over the past decade has reframed much of the disability patients accumulate, even during nominally relapsing disease, as progression independent of relapse activity (PIRA) -- a gradual process running beneath the clinically defined relapsing-progressive divide. This article synthesizes the literature on the biomarkers now used to track that process longitudinally. We review blood-based fluid markers, principally serum neurofilament light chain and glial fibrillary acidic protein, which index axonal injury and astrocytic reactivity respectively and show complementary, combinable prognostic value for relapse-independent worsening; MRI-based markers, including chronic active paramagnetic-rim lesions and brain-age-derived atrophy measures, which offer a spatially specific window onto smoldering, non-relapsing inflammation and diffuse neurodegeneration; optical coherence tomography, which detects subclinical retinal neuroaxonal thinning even in eyes without a history of optic neuritis; and the earlier-stage literature on digital and wearable monitoring, which addresses the sampling-frequency limitations of episodic clinical and imaging assessment. Read together, the evidence supports a coherent, multimodal biomarker strategy for tracking progressive MS, while leaving definitional standardization of PIRA, validation in real-world populations, and individual-patient reference ranges as open priorities for the field.