Objective:

To investigate whether donor-specific pathological features in MS reflect biological processes associated with genetics, lesion patterns, and clinical disease course.

Approach:

• Study Cohort: Utilized a well-characterized Netherlands Brain Bank MS autopsy cohort (NBB-MS) comprising 287 donors with confirmed MS pathology.
• Tissue Sampling: Post-mortem brain tissue was dissected from standardized locations, with lesions identified macroscopically and through MRI.
• Histopathological Analysis: Tissue blocks were double-immunostained to visualize activated microglia/macrophages and myelin, and lesions were classified based on inflammatory activity and myelin status.
• Donor Stratification: Donors were stratified based on the presence of pathological features such as perivascular cuffs, microglial nodules, broad rim lesions, and remyelination efficiency.

Key Findings:

• Substantial inter-individual heterogeneity in MS was observed, influenced by donor-specific pathological features.
• Higher lesion load and mixed lesions correlate with faster disability accumulation.
• Pathological features may reflect persistent inflammatory and reparative processes in MS.

Interpretation:

Limitations:

• Exclusion of donors with relevant neurological or systemic comorbidities may limit generalizability.
• Only donors with Braak scores ≤ 3 were included, potentially affecting the findings.

Conclusion: