Microglia activation in periplaque white matter in multiple sclerosis depends on age and lesion type, but does not correlate with oligodendroglial loss

Multiple sclerosis (MS) is the most frequent inflammatory and demyelinating disease of the CNS. The disease course in MS is highly variable and driven by a combination of relapse-driven disease activity and relapse-independent disease progression. The formation of new focal demyelinating lesions is associated with clinical relapses; however, the pathological mechanisms driving disease progression are less well understood. Current concepts suggest that ongoing focal and diffuse inflammation within the CNS in combination with an age-associated failure of compensatory and repair mechanisms contribute to disease progression. The aim of our study was to characterize the diffuse microglia activation in periplaque white matter (PPWM) of MS patients, to identify factors modulating its extent and to determine its potential correlation with loss or preservation of oligodendrocytes. We analyzed microglial and oligodendroglial numbers in PPWM in a cohort of 96 tissue blocks from 32 MS patients containing 100 lesions as well as a control cohort (n = 37). Microglia activation in PPWM was dependent on patient age, proximity to lesion, lesion type, and to a lesser degree on sex. Oligodendrocyte numbers were decreased in PPWM; however, increased microglia densities did not correlate with lower oligodendroglial cell counts, indicating that diffuse microglia activation is not sufficient to drive oligodendroglial loss in PPWM. In summary, our findings support the notion of the close relationship between focal and diffuse inflammation in MS and that age is an important modulator of MS pathology. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-023-02645-2.