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INTRODUCTION: The α-synuclein (αSyn) seed amplification assay (αSyn-SAA) is an accurate tool to detect αSyn seeds in patients with Parkinson's disease (PD). However, a minority of clinically diagnosed PD patients are negative for αSyn.

METHODS: The αSyn-SAA was performed in cerebrospinal fluid (CSF) of individuals with PD (n = 93), multiple system atrophy (MSA, n = 26), progressive supranuclear palsy (PSP, n = 18), corticobasal syndrome (n = 3), and healthy controls (n = 29).

RESULTS: The αSyn-SAA detected αSyn in 90% of PD and 81% of MSA patients, while exhibiting high specificity (97%). SAA– PD patients had a distinct phenotype compared to SAA+ PD, including a marked postural instability/gait disorder (P = 0.002), impaired episodic memory, and lower CSF amyloid beta42 (P = 0.03). SAA+ PSP also displayed distinctive traits.

DISCUSSION: A negative αSyn-SAA in PD is associated with a distinct phenotype and pathological findings suggesting that these patients may have a motor subtype of Alzheimer's disease. This could influence future clinical trials.

Highlights: The α-synuclein seed amplification assay (αSyn-SAA) is a robust assay. αSyn-SAA–negative Parkinson's disease shows a distinct motor–cognitive phenotype. Autopsy showed Alzheimer's disease (AD) pathology in parkinsonian diseases. AD stands as a major clinical confounder for the diagnosis of movement disorders.