The contribution of gliovascular pathology to brain ageing: an epidemiological perspective

The papers selected present studies related to the pathobiology of dementia in a population setting, in particular the contribution of cellular pathology of the gliovascular system to ageing brain pathology in white and grey matter. This work was performed using cases from the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS) neuropathology population-based cohort. The general introduction discusses the structure of CFAS and the scope of neuropathological studies within it. This introduces the role of population-based studies to gain an unbiased understanding of the relationship of pathologies, both cellular and molecular, to dementia and to each other. CFAS has shown the limitations of current pathological models of dementia, and this is explored in paper 1, which examines the changing relationship of pathology, particularly Alzheimer’s neuropathology, to dementia with increasing age. Much of the focus of dementia neuropathology research has been on the role of classical neuropathologies in grey matter, namely Alzheimer’s neuropathology, Lewy bodies and stroke, and on pathology within neurones. However, the epidemiological studies in CFAS indicate the need to explore the contribution of non-classical pathologies to brain ageing and dementia in both cortex and subcortex, and the role of non-neuronal cell types.
The remaining papers examine such alternative pathological mechanisms, namely the role of astrocyte and endothelial pathology, in grey and white matter of the ageing brain. Papers 2-6 show that specific molecular pathology also affects the gliovascular compartment in cerebral cortex in brain ageing and they examine the relationship of gliovascular pathology to the progression of Alzheimer’s neuropathology and dementia.
White matter lesions, thought to be of ischaemic origin, are common in brain ageing and are increasingly recognised as a contributor to cognitive impairment, independently of, and interacting with, Alzheimer’s type neuropathology. Papers 7-9 examine the glial and endothelial pathology of these lesions, and show that, although chronic, they involve active processes and that lesions are present in a background of more widespread abnormalities (a field-effect) in apparently normal white matter.
The studies provide evidence that pathology of glia and endothelium are not just secondary effects of classical neurodegenerative pathologies, but that they may be important contributors to disease progression and cognitive impairment in brain ageing through loss of normal gliovascular function and through inflammatory mechanisms.