Identifying mechanisms underlying the pathogenesis of age-associated periventricular white matter lesions

Abstract

Age-associated white matter lesions (WML) appear as hyperintense signals on T2- weighted magnetic resonance imaging (MRI) scans and are associated with dementia and cognitive decline. Based on their anatomical location, WML are classified into deep subcortical lesions (DSCL), which are associated with high levels of CD68+ amoeboid microglia; periventricular lesions (PVL), which are characterised by increased levels of MHC II+ immune activated microglia; and confluent lesions which encompass both periventricular and deep subcortical regions. As the microglial phenotype is significantly different in PVL compared to DSCL, the profile of CD68+ and MHC-II+ microglia in confluent lesions was immunohistologically assessed to test the hypothesis that confluent lesions arise as a result of combined PVL and DSCL spread. The immunoreactive profile of microglia within confluent lesions was classified into four lesion subtypes with distinct staining patterns: MHC II+ and CD68+ microglia primarily associated with the periventricular region and deep subcortical region, respectively; MHC II+ microglia predominantly throughout all regions; CD68+ microglia predominantly throughout all regions; a mix of both CD68+ and MHC II+ microglia present throughout the confluent lesions. The current study demonstrates a range of confluent lesion subtypes which may reflect a spread of DSCL pathology, PVL lesion pathology or both, suggesting that a variety of mechanisms may be associated with the pathogenesis of confluent lesions. While transcriptomic profiling of DSCL has previously been performed to identify the underlying mechanisms associated with the formation of these lesions, the current study is the first in the field to employ this approach to identify gene expression changes which may underlie the formation of PVL. Interestingly, histological characterisation of radiologically control white matter identified a subgroup of control cases which displayed intact myelin, but also high levels of MHC-II+ microglia and were subsequently reclassified as “pre-lesional”. The current study characterised the gene expression profile of age-associated periventricular white matter using two independent approaches, namely microarray analysis and Nanostring. The research presented in this thesis suggests that established PVL are part of a continuous spectrum of white matter injury. Bioinformatic analysis of the datasets revealed both “pre-lesions” and established PVL are associated with the significant down-regulation of an immune response. Furthermore, increased signalling pathways in “pre-lesions”, including calcium and glutamate signalling, may indicate a neuroprotective mechanism to prevent the formation of PVL.