Biomarkers for Lewy body diseases and other alpha-synucleinopathies in biofluids: current evidence and future directions

Synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are a group of proteinopathies characterized by neuronal and glial aggregated alpha-synuclein (α-syn) inclusions. Pathologically, these disorders are typically classified into two categories based on the distribution of α-syn: Lewy body diseases (LBDs), such as PD and DLB, which are characterized by α-syn aggregates in neuronal perikarya and neurites in the form of Lewy bodies (LBs) and Lewy neurites (LNs), and MSA, which shows α-syn aggregates in oligodendrocytes as glial cytoplasmic inclusions (GCIs). The clinical distinction between these disorders is challenging, especially in the early stages, due to the overlap of symptoms. This highlights the urgent need for reliable biomarkers to enable more accurate diagnosis and to guide the development of targeted therapeutic strategies. Current research focuses on α-syn which is recognized as a key protein in the pathology of PD, although its potential as a biomarker remains debated due to inconsistent findings. This review provides an overview of recent advancements in biomarkers research for synucleinopathies, focusing on α-syn, neurofilament light chain (NfL), tau, synapsin III (SynIII), and extracellular vesicles (EVs). These biomarkers have been identified in various biofluids and non-invasive sources, including cerebrospinal fluid (CSF), blood, olfactory mucosa (OM), and urine, suggesting promising avenues for the development of future diagnostic tools. α-syn SAAs provide high sensitivity and specificity for distinguishing LBDs from other neurodegenerative disorders. α-syn, tau, and NfL correlate with clinical features, disease severity, and progression. SynIII shows potential as a biomarker for synucleinopathies due to its interaction with α-syn and its accumulation in affected brain regions. Biomarkers panel combining α-syn, NfL, tau, SynIII, and EVs offer improved diagnostic accuracy over single markers. Urine and OM are promising new non-invasive and potential sources for biomarkers.