483-P: Understanding the Macrostructural Foundations of Nerve Dysfunction in Diabetic Neuropathy

Background & Objectives: Focal fascicular lesions have been identified in the sciatic nerves of individuals with diabetic neuropathy (DN). The presence of these lesions, which occurs in proximal-to-distal gradient, closely correlates with the severity of clinical symptoms. The objective of this study was to understand the structural nature of the fascicular lesions and gain insights into their pathophysiology.

Methods: A combinational approach of ex vivo magnetic resonance neurography (MRN) and in vitro imaging was used to identify, isolate, and analyze the structural nature of fascicular lesions from the sciatic nerves of individuals with and without type-2 diabetes (T2D). Comparative spatial proteomic analysis was then used to decipher the molecular composition of the lesions.

Results: Three fascicle types were identified: normal appearing fascicles (NAF-Ctrl), T2D-fascicles (NAF-T2D), and T2D-fascicles with lesions (T2D lesions). The T2D lesions, identified as hypertensive based on MRN signals, showed distinct differences from other fascicles—increased area, perineurium loss, accumulation of acid mucin, and reduced myelinated axons, suggesting endoneurial edema. 346 proteins were common across all types, with significant variations between NAF-Ctrl and T2D lesions. Notably, T2D lesions exhibited reduced neuroprotective pathways, such as such as protein kinase A, the pentose-phosphate pathway, and aldo-keto reductase/aldehyde dehydrogenase metabolism and activation of pathways linked to liver-derived autoantibody complement activation.

Conclusion: The combination of MRN imaging with histological analysis, had led to a deeper understanding of structural nature of fascicular lesions. The incorporation of spatial proteomics has furthered insights into lesion pathophysiology, unveiling potential therapeutic treatment strategies for this complex condition.