Role of alpha-synuclein seed amplification assay in Parkinson's disease clinical trials: A case of misdiagnosis

Abstract

•Early differentiation between PD and atypical parkinsonism is challenging.•Variability in diagnosis can weaken statistical power in trials.•Precise diagnostic tools are needed for trial population homogeneity.•This patient initially diagnosed with PD, was diagnosed with MSA via CSF αSyn-SAA.•Adding αSyn-SAA to inclusion criteria could enhance subject selection in trials.

Keywords: Alpha-synuclein; Clinical trial; Multiple System Atrophy; Parkinson’s disease.

Fig. 1

Clinical and neuroimaging characteristics in a subject initially misdiagnosed with Parkinson’s Disease whose diagnosis was subsequently corrected as Multiple System Atrophy during a Phase 2b clinical trial using alpha-synuclein seed amplification (αSyn-SAA). A. Longitudinal changes in motor and non-motor assessments. B-D. Baseline magnetic resonance imaging (MRI) without contrast sequences in T2 with axial sections of the cerebellum, cerebellar nuclei, middle cerebellar peduncles (B), midbrain (C), and basal ganglia (D), showing age-expected mild atrophy with no other relevant changes. E. α-Syn-SAA from the patient’s CSF sample using the protein misfolding cyclic amplification (PMCA) method showing a typical MSA aggregation pattern5: faster aggregation but lower maximum fluorescence compared to a standard PD control. A.U.: Arbitrary Units. DBP: Diastolic Blood Pressure. HR: Heart Rate. MDS-UPDRS: The Movement Disorder Society Unified Parkinson's Disease Rating Scale. MSA: Multiple System Atrophy. NA: Not Available. NMSQ: Non-Motor Symptoms Questionnaire. T₅₀: Time (hours) to reach 50% of maximum aggregation, and F_max: The maximum ThT fluorescence at the plateau. SBP: Systolic Blood Pressure. PD: Parkinson’s Disease. Error bars indicate the standard error of the mean (SEM).