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. • White matter injury in vascular disease spans from micro- to macro-scale pathology, and is associated with diverse cognitive outcomes • Desynchronisation, disconnection, reorganisation and collapse (DDRC) mark key stages along the pathological spectrum of white matter injury which may help to explain the shifts in cognitive profiles • Dynamic grey matter and functional connectivity changes are also likely consequences of white matter injury progression, which further underpin the proposed framework • The DDRC framework draws together vascular health, neuroimaging and cognition to explain the relationship between these variables along the spectrum of white matter injury