Wallerian Degeneration: A Major Component of Early Axonal Pathology in Multiple Sclerosis

Abstract

Axonal loss is a major component of the pathology of multiple sclerosis (MS) and the morphological basis of permanent clinical disability. It occurs in demyelinating plaques but also in the so-called normal-appearing white matter (NAWM). However, the contribution of Wallerian degeneration to axonal pathology is not known. Here, we analyzed the extent of Wallerian degeneration and axonal pathology in periplaque white matter (PPWM) and lesions in early multiple sclerosis biopsy tissue from 63 MS patients. Wallerian degeneration was visualized using an antibody against the neuropeptide Y receptor Y1 (NPY-Y1R). The number of SMI-32-positive axons with non-phosphorylated neurofilaments was significantly higher in both PPWM and plaques compared to control white matter. APP-positive, acutely damaged axons were found in significantly higher numbers in plaques compared to PPWM. Strikingly, the number of NPY-Y1R-positive axons undergoing Wallerian degeneration was significantly higher in PPWM and plaques than in control WM. NPY-Y1R-positive axons in PPWM were strongly correlated to those in the lesions. Our results show that Wallerian degeneration is a major component of axonal pathology in the periplaque white matter in early MS. It may contribute to radiological changes observed in early MS and most likely plays a major role in the development of disability.

Analysis of White Matter Damage in Patients with Multiple Sclerosis via a Novel In Vivo MR Method for Measuring Myelin, Axons, and G-Ratio

“…This corresponds to the results of previous histologic studies showing that demyelination is the primary event in patients with MS, and axons are relatively preserved in chronic plaques. 28 Even though Wallerian degeneration is known to cause axonal loss and contribute to secondary myelin degradation in PWM, 29,30 myelin loss may be the primary event in PWM as well as in plaques. 28 However, there is growing evidence that axonal damage is also a feature of MS that is associated with long-term disability and functional deficits.…”

Utility of a Multiparametric Quantitative MRI Model That Assesses Myelin and Edema for Evaluating Plaques, Periplaque White Matter, and Normal-Appearing White Matter in Patients with Multiple Sclerosis: A Feasibility Study

“…4 Specifically, histologic studies have shown that Wallerian degeneration and retrograde degeneration of the cell body occur around demyelinating plaques. 23,24 The fact that axonal degeneration causes myelin degradation 25 suggests that demyelination in plaques leads to reduced V MY in PWM. Another explanation for decreased V MY in PWM can be found in the natural history of MS plaque evolution and regression.…”

Exploring the origins of grey matter damage in multiple sclerosis

“…gadolinium-enhanced on contrast MRI) could lead indirectly to anterograde and retrograde degeneration (Figure 2) of axons running within the thalamus and basal ganglia. Axon loss might also contribute to demyelination and/or Wallerian degeneration by reducing local metabolic activity 21,22 . A correlation between white matter lesion load and thalamic atrophy was found in patients with clinically isolated syndrome 23 and early relapsing remitting multiple sclerosis (RRMS) 24 .…”