Over the last two decades, considerable efforts have been made to identify novel biomarkers that can biologically define Parkinson's disease (PD). The cerebrospinal fluid α-synuclein seed amplification assay (α-syn-SAA) has emerged as a promising tool for detecting aggregated α-synuclein, a pathological hallmark of PD, and α-syn-SAA positivity has been proposed as the core criterion in two recent research frameworks for a biological definition of PD [1,2]. However, recent findings from the Parkinson's Progression Markers Initiative (PPMI) cohort challenge a simplistic interpretation of its role. While SAA+ PD more frequently exhibited hyposmia, SAA- patients showed greater subcortical atrophy, including the substantia nigra [3]. Crucially, longitudinal analyses showed faster time to reach motor disability milestones in SAA-PD compared to SAA+PD, although these findings should be interpreted cautiously given the relatively small SAA- sample size (n=80). Notably, approximately one in seven patients originally diagnosed as SAA- PD received a change in diagnosis during follow-up a proportion that, while a minority, carries meaningful clinical implications. Together, this evidence suggests that detectable α-synuclein aggregation is not strictly necessary for the manifestation of PD, nor does it consistently predict disease progression. Therefore, the proposed biological definitions of PD solely anchored on α-synuclein aggregation should be interpreted with caution [4]. These findings raise the possibility that α-synuclein aggregation might be a biological adaptive response rather than the main disease-causing factor, or that other biological pathways may lead to a clinically identical PD phenotype. Therefore, while a positive α-syn-SAA supports a diagnosis of PD, it does not replace clinical assessment, nor does a negative result exclude PD. Further research is essential to fully understand the diverse biological underpinnings of this complex and heterogeneous disease.
Key Points:
- Two recent research frameworks proposed a biological definition of Parkinson's disease (PD) based on cerebrospinal fluid α-synuclein seed amplification assay (SAA) positivity
- SAA-negative patients showed greater subcortical atrophy and faster motor progression compared to SAA+ PD
- A nuanced and multimodal approach is warranted to identify novel biological subtypes of PD beyond α-synuclein-based definitions
References:
- Simuni, T. et al. A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research. Lancet Neurol. 23, 178–190 (2024).
- Höglinger, G. U. et al. A biological classification of Parkinson’s disease: the SynNeurGe research diagnostic criteria. Lancet Neurol. 23, 191–204 (2024).
- Brooker, S. M. et al. Clinical and Imaging Characteristics of Parkinson’s Disease with Negative Alpha‐Synuclein Seed Amplification Assay. Movement Disorders 41, 1114–1127 (2026).
- Espay, A. J. et al. The α-synuclein seed amplification assay: Interpreting a test of Parkinson’s pathology. Parkinsonism Relat. Disord. 131, 107256 (2025).
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