Where do PDD and DLB SYNdromes fit in neuronal alpha-SYNuclein biological frameworks?

Abstract Lewy body disorders (LBD) are a spectrum of neurodegenerative diseases characterized by the presence of misfolded neuronal alpha-synuclein (aSYN) pathology in the central and peripheral nervous system. LBDs have heterogeneous clinical presentations, which include dementia with Lewy bodies (DLB), Parkinson’s disease (PD), and PD with dementia (PDD). Thus, LBD clinical syndromes (PD/PD/DLB) represent clinicopathologic entities (i.e. constellations of symptoms and supportive biomarkers with a high specificity for underlying aSYN pathology), but clinical features between PDD and DLB largely overlap. Indeed, there is longstanding debate over the utility of the clinical designation between PDD and DLB due to shared underlying pathology, genetic risk factors and prodromal features. Recent advances in the ability to detect pathological aSYN from peripheral fluids/tissues in living patients has ushered in a new era of biological classification of LBD, providing opportunity to improve antemortem diagnosis and facilitate disease-modifying therapeutic trials. The clinical interpretation of these and future aSYN-specific biological tests will be complex, and the reconciliation of classic LBD syndromes with emerging biological classification schemes for LBD and other neurodegenerative disorders is a priority. Indeed, varying burden of aSYN is also found postmortem in > 50% of clinical Alzheimer’s disease (AD), and to a lesser frequency as co-pathology in other neurodegenerative disorders, and incidentally in adults without neurologic disease. This review summarizes autopsy-confirmed data on the clinical expression of LBDs and the boundaries between PDD, DLB and mixed-pathology AD to inform the interpretation of emerging biological tests for aSYN and biological classification schemes for LBD and AD.