BACKGROUND:An extensive analysis of white matter plaques in a large sample of MS autopsies provides insights into the dynamic nature of MS pathology.
METHODS:120 MS cases (1220 tissue blocks) were included. Plaque types were classified according to demyelinating activity based on stringent criteria. Early-active, late-active, smoldering, inactive, and shadow plaques were distinguished. 2476 MS white matter plaques were identified. Plaque type distribution was analyzed in relation to clinical data.
FINDINGS:Active plaques were most often found in early disease, whereas at later stages, smoldering, inactive and shadow plaques predominated. The presence of early-active plaques rapidly declined with disease duration. Plaque type distribution differed significantly by clinical course. The majority of plaques in acute-monophasic and RRMS were active. Among SPMS cases with attacks, all plaque types could be distinguished including active plaques, in contrast to SPMS without attacks in whom inactive plaques predominated. Smoldering plaques were frequently and almost exclusively found in progressive MS. At 47-years of age, an equilibrium was observed between active and inactive plaques, whereas smoldering plaques began to peak. Men displayed a higher proportion of smoldering plaques.
INTERPRETATION: Disease duration, clinical course, age and gender contribute to the dynamic nature of white matter MS pathology. Active MS plaques predominate in acute and early RRMS and are the likely substrate of clinical attacks. Progressive MS transitions to an accumulation of smoldering plaques characterized by microglial activation and slow expansion of pre-existing plaques. Whether current MS therapeutics impact this pathological driver of disease progression remains uncertain.
It has been asked “will the real MS stand up” and based on the clinical profile, MS comes in two main flavours relapsing and progressive.
After a hundred and fifty years the pathologists are saying yes their are two pathologies – the smouldering and the active lesion, because we have known about the slow-burn causing progression for a long time.
The smouldering lesion has an active edge with lots of microglia and few macrophages and limited amounts of myein engulfment
The active lesions are associated with relapsing MS and the smouldering is associated with progressive MS with (SP+) or without (SP-) super imposed relapses
The older you are the more the smouldering progressive lesion occurs but they occur early after diagnosis
Yet it makes perfect sense for their to be two lesion types
In EAE the relapse is caused by resolving peri-vascular lesions around blood vessels. The progressive lesion has glial activity in and around the edge of damage in MS. In this study they say the progressive lesion is the same. Therefore MS and EAE are the same.
The peri-vascular cuff is an acute peri-vascular lesion. In ths study the early active lesion is a lesion full of macrophages gobling up myelin.
In EAE the active lesion responses to lymphocyte treatment the smouldering lesion does not and an anti-glial treatment is needed.
In this study in early lesions they are active and end inactive lesions.
This sounds fantastic but is it too good to be true?
Do other pathologists agree?…(.Please, make up your minds quickly and repeat this). This current group gave us four MS lesion types but the rest of the pathology world did not agree. Will it be the same here?
However this may help the lymphocytes are everything-world (This is a large part of science including the MS science mafia-otherwise why would we see this endless trail of failed progressive MS trials. They influence pharma direction!) to see that a different world view is needed.