Desynchronise, disconnect, reorganise, collapse (DDRC): A theoretical framework linking white matter pathology and cognitive dysfunction in vascular disease.

White matter health is closely associated with cognitive function, particularly across the spectrum of cerebrovascular health. However, inconsistencies in the cognitive domains reported to be affected by white matter pathology have complicated efforts to define clear mechanisms of dysfunction. This review synthesises neuroimaging and neuropathological evidence to reveal the cascade of cognitive and neural consequences that follow white matter injury, from microstructural alterations to macroscale white matter hyperintensities. We discuss the contributions of grey matter atrophy and disrupted functional connectivity and evaluate four distinct stages within a wider mechanistic framework: desynchronisation, disconnection, network reorganisation and the network collapse theory. Together, this framework helps elucidate how structural and functional disruptions emerge over time and how they contribute to the complex and evolving pattern of cognitive impairment observed in vascular white matter pathology.