Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Brück W. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain. 2002;125:2202-12.
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.
Amyloid precursor protein (APP) is shuttled down the nerve from the head to the feet, if there is a break the APP goes down the nerve then accumulates at the cut and makes a bleb. You can count the blebs.
Bruce Trapps group did this and found 11,000 in the active lesion and < 1 in health nerve areas. This was mentioned on the brain shred post by ProfG. This says that damage is associated with the amount of active inflammation, block this and you block the nerve damage. This current post says the same thing, that nerve damage correlates with the amount and duration of inflammation. They findmore active damage early on and less later in disease. This is what we would expect because inflammatory disease is more active early in disease. This we know from MRI where gadolinium enhancing lesions are more common early in disease. This study also shows that the amount of damage correlates with the amount of inflammation. This is associated with T cells and microglia. Therefore it makes sense to think the anti-inflammatory approach within the CNS is a way to go. Target this aspect and block it and then let’s see if it stops nerve transections. The doubting minnnies will say they are clearing up the damage. Let’s see.
They show that this damage occurs early so lets start treating this early. That is what we are trying with some of the optic neuritis trials. Protecting the nerves from the effects of inflammation, put this on top of stopping the inflammatory cells getting into the brain and you get a double whammy. This is what we are doing with the PROXIMUS trial. My gut feeling is that this early activity takes out the vulnerable nerve pools leaving the more sturdy nerves and these are damaged more slowly. Let’s see what the trials bring.