Molecular determinants of multiple sclerosis spinal cord pathology

Thesis

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and degenerative disorder of the central nervous system (CNS). Disease progression commonly presents as a relentless myelopathy, nominating the spinal cord as an essential anatomical site to investigate in detail. In the current thesis, we leveraged the power of deeply endophenotyped post-mortem and clinical MS cohorts to better understand the molecular determinants of spinal cord pathology. Pathologically, we assessed the interplay between demyelination, inflammation, and neurodegeneration. We observed that demyelination was common, highly inflammatory, and related to clinical measures of disability even at late disease stages. Lesions commonly spared the subpial surface and were vascularly-associated, arguing against a pathological gradient of spinal cord demyelination. We also observed that axonal loss in the normal-appearing white matter motor tracts was a common feature of MS spinal cord pathology. Spinal cord cross- sectional area at end-stage disease woefully underestimated the extent of axonal loss. Activated myeloid cell inflammation but not lesion load was predictive of more severe axonal loss. Given that biomarkers of axonal loss have remained elusive, we also performed proteomics on post- mortem cerebrospinal fluid (CSF), a translational biospecimen. Network analysis identified a signature, enriched in opsonins, that segregated with the degree of axonal loss and presence of spinal cord demyelination. We subsequently performed validation studies of this signature using a well-characterised clinical MS cohort. While this signature distinguished MS and control patients, it did not relate to measures of clinicoradiographic disability. These findings underscore the insensitivity of clinicoradiographic assessments in the short-term and highlight the power of a pathology-driven approach to biomarker discovery. Taken together, our findings nominate vascular dysfunction, CSF opsonins in the perivascular space, and activated myeloid cells as key players in the pathogenesis of MS spinal cord pathology.

Authors: Waldman, AD

• DOI: 10.5287/ora-wv2mqrdj4
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: spinal cord; multiple sclerosis; biomarkers
• Subjects: Neuroimmunology