Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque

Abstract

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.

Dark Rims: Novel Sequence Enhances Diagnostic Specificity in Multiple Sclerosis

“…23 This phenomenon could very well be another explanation of the rims seen in our study, but most of our data is from early MS course when smoldering lesions are typically not expected. 25 Unfortunately, we did not have SWI imaging available on all cases. Prior studies have shown that 10–15% of MS lesions have iron accumulation at the edge, 23,26 which is lower than the frequency of our rim detection.…”

Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial

“…5 Despite the presence of oligodendrocyte precursors in multiple sclerosis lesions, [6][7][8] remyelination is generally unsuccessful-and at best partial-after demyelinating injury in multiple sclerosis. 9,10 Current treatments for multiple sclerosis block access of immune cells to their target tissue or otherwise suppress inflammatory injury, but do not fully prevent neuroaxonal degeneration and disability. 11,12 No proven treatments are available to remyelinate or otherwise sustainably repair myelin-related injury.…”

The link of inflammation and neurodegeneration in progressive multiple sclerosis

“…Inflammatory released products as reactive oxygen or nitric oxide species (ROS and RNS), excitotoxins as glutamate, and cytotoxic cytokines alter myelin sheaths and cellular metabolism in neurons and their axons. However inflammation declines with disease duration while neurodegeneration proceeds and activated microglia persists in all lesions in PMS [29].…”