Staging and markers in Parkinson's disease and Lewy body disorders: narrative review

Currently, the diagnosis of Parkinson's disease (PD), Parkinson's disease dementia (PDD), and Lewy body dementia (DLB) relies on clinical symptoms, with Lewy body (LB) pathology serving as the gold standard. The co-pathology associated with Alzheimer's disease (AD) contributes to the clinical heterogeneity and rapid progression seen in Lewy body disorders (LBD). The AT(N) classification system may help identify the distinct biochemical, neuro-radiological, and clinical characteristics of both pure LB and PD. Recent advancements in biomarkers have improved the precise identification of pathological α-synuclein (i.e., misfolded and aggregated) in cerebrospinal fluid (CSF) through the seed amplification assay. Consequently, the Neuronal α-synuclein Integrated Staging System (NSD-ISS) has reclassified PD as a neuronal α-synuclein disease, rather than just a clinical syndrome. Although some debate the necessity of a biological definition for clinical diagnosis, biomarker-based systems continue to serve as diagnostic tools for these disorders. This narrative review will explain the definitions of the AT(N) and NSD-ISS systems and provide an updated list of research that supports the proposed biological definitions and staging systems. Additionally, it will discuss how the combination of LB-AD pathology, along with the neuronal concept of the disease, significantly influences the clinical phenotype, progression, and overall prognosis of PD. Finally, this review will overview current advancements in blood-based AD biomarkers that could facilitate faster screening of LBD patients for AD co-pathologies, thereby enhancing the diagnostic sensitivity of LBD-AD and its potential for prognostic, research, and diagnostic applications.