Detection of α-synuclein aggregates in synucleinopathies: current approaches, biomarkers and challenges

Synucleinopathies are neurodegenerative disorders characterized by the aggregation of α-synuclein (αSyn) in the brain, including Parkinson’s disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). In PD and DLB, αSyn aggregates primarily in neurons as Lewy bodies, whereas in MSA it accumulates in oligodendrocytes as glial inclusions. Although these aggregates represent pathological hallmarks, definitive diagnosis relies on post-mortem neuropathological examination. This limitation has encouraged intense efforts to develop biomarkers capable of detecting pathological αSyn in living patients. Recent advances include seed amplification, biochemical measurements in cerebrospinal fluid and peripheral tissues, and imaging approaches to visualize αSyn pathology in vivo. These strategies look promising for improving early diagnosis, differentiating synucleinopathies, and monitoring disease progression. In this review, we summarize current approaches for detecting αSyn aggregates, including amplification-based assays, biochemical detection, histopathology, imaging techniques, and emerging biosensor technologies, and discuss their strengths, limitations, and future prospects for clinical application.