Objective: To determine whether the combination of spatial (PET [18F]ACI-12589) and conformational (skin seed amplification assay; SAA) a-syn data aids the early differential diagnosis of MSA-P.

Background: It is challenging to diagnose MSA early and specifically because the presentation can overlap with other neurodegenerative diseases. Recently, the [18F]ACI-12589 PET tracer has shown promise in visualizing the a-syn pathology in MSA patients. In parallel, α-syn seed amplification assays (SAA) have demonstrated distinct aggregation kinetics in MSA versus PD.

Method: Eight subjects who met the 2022 MDS diagnostic criteria for probable MSA (MSA-P = 5, MSA-C = 3) were enrolled. Subjects underwent scans 60–90 min after injection of 305 ± 39 MBq [18F]ACI-12589. PET images were motion-corrected and co-registered to MRI. Regions of interest (ROIs) were defined using the Automated Anatomical Labeling (AAL) atlas or manually delineated for the medial cerebellar peduncles (MCP). Three 5-mm skin biopsies were obtained in all subjects. The SAA reaction buffer included 1 mg/mL recombinant α-syn, 500 µM NaCl, 100 mM PIPES, 10 µM thioflavin T (ThT), and 2µl of 0.5% skin biopsy lysate. Four replicates per sample were incubated at 37°C for 48 hours. Samples were positive if ≥75% of the replicates crossed a predefined fluorescence threshold.

Results: All MSA-C cases showed [18F]ACI-12589 uptake in the MCP and had at least one positive SAA with an MSA pattern [Fig.1]. Among the five clinically probable MSA-P cases, two (MSA-P #2 and #5) had a faintly increased uptake in the MCP and a strong signal in the basal ganglia [Fig. 2]. These two also had a clear MSA pattern on SAA, as did one other case (MSA-P #4). The two remaining MSA-P subjects did not show retention with [18F]ACI-12589 PET and either a PD pattern in SAA (MSA-P #1) or a consistently negative SAA (MSA-P #1). Upon clinical re-evaluation, the diagnosis of MSA-P #1 was changed to PD, while a non-synucleinopathy diagnosis is being considered for MSA-P #3.

Conclusion: While the a-syn [18F]ACI-12589  PET tracer is sufficient for the diagnosis of MSA-C, the combination of both spatial (PET) and conformational (seeding amplification) α-syn biomarkers will improve the error-prone clinical differential diagnosis of MSA-P. These biomarkers promise to open up new precision medicine approaches for this devastating disease.

PET SUVR and corresponding skin SAA in MSA-C cases

PET SUVR and corresponding skin SAA in MSA-P cases

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MDS Abstracts - https://www.mdsabstracts.org/abstract/combining-alpha-synuclein-pet-and-seeded-amplification-assays-to-improve-the-diagnostic-accuracy-of-multiple-system-atrophy-of-the-parkinsonian-subtype-msa-p/