Combining alpha-synuclein PET and seeded-amplification to improve diagnostic accuracy of Multiple System Atrophy

Biomarkers that facilitate early detection and track disease progression are an enormous unmet need in neurodegenerative diseases and their clinical trials. Accurate diagnosis in the early stage of Parkinsonian disorders is particularly challenging. Multiple system atrophy (MSA) and Parkinson’s disease (PD) share many clinical features and are associated with alpha-synuclein (αSyn) aggregation. However, these diseases have distinct biology and disease trajectories and are likely to respond differently to experimental therapies. Gold-standard diagnosis is only achieved at postmortem examination. Here, we combined two emerging technologies: brain imaging with αSyn [18F]ACI-12589 PET tracer with a skin αSyn seed-amplification assay (αSyn-SAA). These assays have the potential to increase diagnostic precision in vivo by delineating the spatial distribution and conformation of αSyn pathology, respectively. Of 8 clinically probable or established MSA patients, combining brain imaging with αSyn [18F]ACI-12589 PET tracer and skin αSyn-SAA helped confirm the diagnosis in 6 of the 8 patients and led to the reclassification of two cases to Parkinson’s disease and idiopathic late-onset cerebellar ataxia. Each test provided critical evidence of diagnosis even when the other was equivocal, supporting the combination of these tests. These αSyn biomarkers should now be used systematically to facilitate early and precise diagnosis across synucleinopathies.