CSF α-Synuclein Seed Amplification Assays and Skin Immunofluorescence: Clinical Applications, Research Opportunities, and Knowledge Gaps.

The development of biomarkers capable of reliably detecting pathologic forms of α-synuclein (aSyn) in vivo marks a significant step forward in the field of neurodegeneration. Over the recent years, CSF aSyn seed amplification assays (aSyn-SAA) and skin biopsy phospho-aSyn immunofluorescence (skin aSyn-IF) testing were developed that detect pathologic aSyn seeds and phosphorylated aSyn aggregates, respectively, in patients with synucleinopathies, which include Parkinson disease, dementia with Lewy bodies, and also multiple system atrophy. High rates of positivity have also been documented in research participants at a risk of developing future aSyn-related disease (e.g., hyposmia and REM sleep behavior disorder), as well as other contexts. These assays have numerous potential applications in research settings and clinical care. Here, we review the currently published evidence supporting CSF aSyn-SAA and skin aSyn-IF testing and discuss their potential research applications in clinical trials. As CSF aSyn-SAA and skin aSyn-IF testing is now commercially available to clinicians in nonresearch settings, we also explore their current utility and limitations as diagnostic tools and call for the development of a formal clinical use guidelines. We also highlight where critical knowledge gaps remain and explore emerging developments related to these assays.