Faster reaction times of CSF alpha-synuclein seed amplification assay predict the diffuse malignant subtype of Parkinson's disease at 10-year follow-up

Parameters of Alpha-Synuclein Seed Amplification Assay on Cerebrospinal Fluid predict the clinical subtype of Parkinson's Disease 10 years laterPlain language summaryBackgroundThe diagnosis of Parkison's Disease is drastically changing by the development of Alpha-Synuclein Seed Amplification Assay. The assay enables, for the first time, the detection of pathological forms of alpha-synuclein in cerebrospinal fluid in living patients. Alpha-Synuclein Seed Amplification is very accurate in discerning individuals with Parkinson's Disease versus healthy subjects, but it remains unknown whether it can also inform about prognosis.ObjectiveWe assessed the ability of the assay to predict the 10-year clinical progression of Parkinson's Disease.MethodsPublic data from an international cohort were used. At time of diagnosis, we classified 323 individuals with Parkinson's Disease into three clinical subtypes: Mild Motor Predominant, Intermediate, and Diffuse Malignant. These subtypes were characterized by a progressively increasing burden of motor and non-motor symptoms. Subjects with available follow-up data were re-classified using the same subtypes after 10 years of disease. Time-dependent signal changes of Alpha-Synuclein Seed Amplification Assay in Cerebrospinal Fluid were measured at baseline and used to predict the 10-year phenotype.ResultsFirstly, we found that subtypes were not stable categories. Around a half of participants changed subtype over time, mostly shifting towards a more aggressive one. Notably, our results showed that faster reactions on Alpha-Synuclein Seed Amplification Assay at baseline were associated with a 10-year phenotype more aggressive in terms of motor symptoms, dysautonomia, sleep and cognitive impairment, i.e the Diffuse Malignant subtype.ConclusionCharacteristics of the assay underlying the final positivity or negativity outcomes performed at a milder and early stage of PD may identify a subgroup of subjects that are more likely to undergo a more rapid clinical deterioration. Further studies, however, are needed to confirm and expand this result.