This scientific session will examine emerging concepts in spinal cord (SC)-focused MS and demyelinating disease, highlighting how advances in pathology, imaging, and mechanistic understanding are reshaping traditional models of central nervous system demyelination. Particular attention will be given to the SC as a critical yet understudied site of injury and disability. Attendees will explore evolving perspectives on vascular barrier biology, including how variability in blood–spinal cord barrier integrity may influence immune access, inflammatory activity, and tissue vulnerability — and potentially be disrupted by structural disease. The session will also address newly recognized or underappreciated disease phenotypes, emphasizing how distinct pathological patterns can challenge conventional diagnostic frameworks and expand the spectrum of demyelinating disorders. A key theme will be the disproportionate clinical impact of strategically located lesion(s) within the SC, and how limited lesion burden may nevertheless produce progressive neurological dysfunction. In addition, the discussion will consider the potential convergence of immune-mediated demyelination with structural and biomechanical factors affecting the spine, raising the possibility that degenerative changes, vascular compromise, and mechanical stress may interact with inflammatory mechanisms to shape disease expression. By integrating insights across neuropathology, neuroimaging, and spinal cord biology, this session aims to provide attendees with a broader conceptual framework for understanding the SC in MS demyelination, highlighting implications for diagnosis, phenotyping, and future research directions. Level of Information: Intermediate, AdvancedThis scientific session will examine emerging concepts in spinal cord (SC)-focused MS and demyelinating disease, highlighting how advances in pathology, imaging, and mechanistic understanding are reshaping traditional models of central nervous system demyelination. Particular attention will be given to the SC as a critical yet understudied site of injury and disability. Attendees will explore evolving perspectives on vascular barrier biology, including how variability in blood–spinal cord barrier integrity may influence immune access, inflammatory activity, and tissue vulnerability — and potentially be disrupted by structural disease. The session will also address newly recognized or underappreciated disease phenotypes, emphasizing how distinct pathological patterns can challenge conventional diagnostic frameworks and expand the spectrum of demyelinating disorders. A key theme will be the disproportionate clinical impact of strategically located lesion(s) within the SC, and how limited lesion burden may nevertheless produce progressive neurological dysfunction. In addition, the discussion will consider the potential convergence of immune-mediated demyelination with structural and biomechanical factors affecting the spine, raising the possibility that degenerative changes, vascular compromise, and mechanical stress may interact with inflammatory mechanisms to shape disease expression. By integrating insights across neuropathology, neuroimaging, and spinal cord biology, this session aims to provide attendees with a broader conceptual framework for understanding the SC in MS demyelination, highlighting implications for diagnosis, phenotyping, and future research directions. Level of Information: Intermediate, Advanced