Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time

TLDR

Multiple sclerosis is morphologically defined by demyelination, inflammation, gliosis, and axonal damage, with the latter being the main substrate of permanent clinical disability. The study aimed to determine the occurrence of acute axonal damage in MS lesions using amyloid precursor protein immunocytochemistry. APP‑positive axons were quantified in lesions and their numbers were correlated with disease duration and clinical course. Acute axonal damage peaked within the first year after onset, persisted at low levels even after ten years, correlated with CD8⁺ T cells and macrophage/microglia counts, and was absent in remyelinated shadow plaques, indicating that early axon‑protective therapy targeting T cell/macrophage‑mediated injury and promoting remyelination is warranted.

Abstract

Multiple sclerosis is characterized morphologically by the key features demyelination, inflammation, gliosis and axonal damage. In recent years, it has become more evident that axonal damage is the major morphological substrate of permanent clinical disability. In our study, we investigated the occurrence of acute axonal damage determined by immunocytochemistry for amyloid precursor protein (APP) which is produced in neurones and accumulates at sites of recent axon transection or damage. The numbers of APP‐positive axons in multiple sclerosis lesions were correlated with the disease duration and course. Most APP‐positive axons were detected within the first year after disease onset, but acute axonal damage was also detected to a minor degree in lesions of patients with a disease duration of 10 years and more. This effect was not due to the lack of active demyelinating lesions in the chronic disease stage. Late remyelinated lesions (so‐called shadow plaques) did not show signs of axon destruction. The number of inflammatory cells showed a decrease over time similar to that of the number of APP‐positive axons. There was a significant correlation between the extent of axon damage and the numbers of CD8‐positive cytotoxic T cells and macrophages/microglia. Our results indicate that a putative axon‐protective treatment should start as early as possible and include strategies preventing T cell/macrophage‐mediated axon destruction and leading to remyelination of axons.