White matter lesions in an unselected cohort of the elderly: astrocytic, microglial and oligodendrocyte precursor cell responses

Abstract

White matter lesions in an unselected cohort of the elderly: astrocytic, microglial and oligodendrocyte precursor cell responsesHyperintense lesions are frequently identified in T2-weighted magnetic resonance images (MRI) in the ageing brain. The pathological correlate and pathogenesis of white matter lesions (WML) remain unclear, and it is uncertain whether pathology and pathogenesis differ in periventricular lesions (PVL) compared with deep subcortical lesions (DSCL). Therefore we characterized astrocytic, microglial and oligodendrocyte responses in PVL and DSCL and compared them with control white matter using immunohistochemistry. Both PVL and DSCL were associated with severe myelin loss and increased microglia (P = 0.069 and P < 0.001), compared with nonlesional aged brain. Clasmatodendritic astroglia, immunoreactive for the serum protein fibrinogen, were present in 67% of PVL examined and 42% of DSCL. Compared with control and DSCL cases, more MAP-2 +13 positive remyelinating oligodendrocytes (P = 0.003 and P = 0.035) and platelet-derived growth factor alpha receptor positive reactive astrocytes (P < 0.001) were present in the perilesional white matter of PVL. In addition to a role for hypoperfusion, our data suggest that dysfunction of the blood-brain barrier may also contribute to the pathogenesis of a proportion of cerebral WML associated with ageing, and that attempts at remyelination are only associated with PVL and not DSCL.

Heterogeneity in age-related white matter changes

“…Clasmatodendritic astroglia immunoreactive for fibrinogen were more commonly present in periventricular lesions which also showed more MAP-2 ?13 positive remyelinating B7-2 CD86, provides costimulatory signals necessary for T cell activation and survival, CD40 and CD40 ligand immune costimulatory molecules, CD68 immunocytochemical marker for staining of monocytes/macrophages, Col IV collagen-IV, DWMH deep white matter hyperintensities, GFAP glial fibrilary acidic protein, HE hematoxylin-eosin, HIF hypoxia inducible factor, HLA-DR human leucocyte antigen-DR, ICAM1 intercellular adhesion molecule, KB Kluvere-Barrera, LFB Luxol fast blue, MAP-2 ?13 microtubule associated protein 2 expressing exon 13, MBP myelin basic protein, Mcm2 DNA replication licensing factor MCM2, MMP7 matrix metalloproteinase 7, NAWM normalappearing white matter, Ngb neuroglobin, NMBR neuromedin B receptor, PCNA and Ki67 molecules related to cell proliferation, PDGFalphaR platelet-derived growth factor alpha receptor, PVH periventricular white matter hyperintensities, VEGFR2 vascular endothelial growth factor receptor 2, WMH white matter hyperintensities oligodendrocytes and platelet-derived growth factor a receptor-positive reactive astrocytes. The authors interpreted these findings as an indication for blood-brain barrier dysfunction in a proportion of white matter lesions and emphasize that attempts of remyelination appear to be solely associated with periventricular white matter abnormalities [77]. The important role of the blood-brain barrier in the pathogenesis of periventricular white matter changes is also supported by the study's finding that this lesion type contains significantly higher levels of ramified activated microglia which may result from blood-brain barrier disruption [77].…”

“…The authors interpreted these findings as an indication for blood-brain barrier dysfunction in a proportion of white matter lesions and emphasize that attempts of remyelination appear to be solely associated with periventricular white matter abnormalities [77]. The important role of the blood-brain barrier in the pathogenesis of periventricular white matter changes is also supported by the study's finding that this lesion type contains significantly higher levels of ramified activated microglia which may result from blood-brain barrier disruption [77]. In contrast, activated microglia seen in deep/ subcortical abnormalities may rather reflect an innate amoeboid phenotype, which is involved in phagocytosis of myelin breakdown products [78].…”

“…This supports a hypoxic etiology for deep lesions and lends further evidence for periventricular white matter changes being non-ischemic in etiology probably caused by increased fluid accumulation related to the proximity of the ventricles. Moreover, MRC-CFAS also studied the astrocytic, microglial and oligodendroglial responses in white matter abnormalities, and described that both periventricular and deep/subcortical lesions are associated with severe myelin loss and increased microglia compared with non-lesional brain tissue [77]. Clasmatodendritic astroglia immunoreactive for fibrinogen were more commonly present in periventricular lesions which also showed more MAP-2 ?13 positive remyelinating B7-2 CD86, provides costimulatory signals necessary for T cell activation and survival, CD40 and CD40 ligand immune costimulatory molecules, CD68 immunocytochemical marker for staining of monocytes/macrophages, Col IV collagen-IV, DWMH deep white matter hyperintensities, GFAP glial fibrilary acidic protein, HE hematoxylin-eosin, HIF hypoxia inducible factor, HLA-DR human leucocyte antigen-DR, ICAM1 intercellular adhesion molecule, KB Kluvere-Barrera, LFB Luxol fast blue, MAP-2 ?13 microtubule associated protein 2 expressing exon 13, MBP myelin basic protein, Mcm2 DNA replication licensing factor MCM2, MMP7 matrix metalloproteinase 7, NAWM normalappearing white matter, Ngb neuroglobin, NMBR neuromedin B receptor, PCNA and Ki67 molecules related to cell proliferation, PDGFalphaR platelet-derived growth factor alpha receptor, PVH periventricular white matter hyperintensities, VEGFR2 vascular endothelial growth factor receptor 2, WMH white matter hyperintensities oligodendrocytes and platelet-derived growth factor a receptor-positive reactive astrocytes.…”

High-mobility group box-1 as an autocrine trophic factor in white matter stroke

“…Ischemic stroke that occurs in the white matter often results in degeneration of OLs and demyelination (5,6). Consequently, patients with white matter stroke suffer from a wide range of neurological dysfunctions.…”

The heart-brain connection: mechanistic insights and models

“…Inflammation, in turn, enhances oxidative stress by upregulating the expression of reactive oxygen species-producing enzymes and downregulating antioxidant defences [35]. Furthermore, oxidative stress and inflammation compromise the repair mechanism of the damaged white matter, by interfering with proliferation, migration and differentiation of oligodendrocyte progenitor cells [36][37][38]. The loss of growth factors produced by the brain, which has been observed in both Alzheimer's disease and VCI, further compromises repair mechanisms [39].…”