Neuropathological correlates of imaging in dementia with Lewy bodies

Abstract Dementia with Lewy bodies (DLB) is a common yet underdiagnosed neurodegenerative dementia, characterised neuropathologically by nigrostriatal dopaminergic degeneration and widespread α-synuclein aggregation. Clinical diagnosis remains challenging due to marked heterogeneity in presentation and substantial overlap with Alzheimer’s disease (AD), resulting in diagnostic delays and frequent misdiagnosis. The ability to identify underlying pathological processes ante-mortem is essential to improve diagnostic accuracy, refine prognosis, stratify patients for clinical trials, and ultimately enable personalised therapeutic approaches. Over recent decades, major advances have been made in the development of neuroimaging biomarkers that reflect key features in Lewy body disease pathology, many of which have informed diagnostic criteria. In addition to dopaminergic dysfunction and α-synuclein pathology, co-existing neuropathologies including amyloid-β, tau, neuroinflammation, and vascular changes are increasingly recognised as important modifiers of clinical phenotype and disease trajectory in DLB. This review summarises the current landscape of neuroimaging modalities in DLB and critically examines their relationships with confirmed neuropathological correlates. We discuss indicative biomarkers such as striatal dopamine imaging and 123 I-metaiodobenzylguanidine myocardial scintigraphy, alongside supportive imaging markers derived from structural magnetic resonance imaging and Fluorodeoxyglucose Positron Emission Tomography (FDG-PET). Emerging PET approaches targeting α-synuclein, as well as established amyloid and tau-PET techniques for assessing co-pathologies, are reviewed in the context of post-mortem validation studies. Finally, we consider Translocator protein PET imaging as a marker of neuroinflammation and highlight key methodological limitations and knowledge gaps. Together, these neuroimaging–pathological correlations provide critical insights into disease mechanisms and outline future directions toward earlier, biologically informed diagnosis and precision medicine in DLB.