Amplification parameters of the alpha-synuclein seed amplification assay on CSF predict the clinical subtype of Parkinson's Disease at 10-year follow-up

BackgroundData-driven approaches identified Mild Motor Predominant (MMP), Intermediate (IM), and Diffuse Malignant (DM) as Parkinsons Disease (PD) subtypes with different motor and non-motor impairment at diagnosis. It remains unclear whether these subtypes remain stable over time or whether they represent distinct biological substrates. The alpha-synuclein seed amplification assay in CSF (CSF-Syn-SAA) might provide further insights. Objectiveto evaluate the association between baseline CSF-Syn-SAA parameters and 10-year clinical evolution of PD subtypes. Methods323 sporadic PD patients from PPMI dataset were classified as MMP, IM, or DM at baseline and 10-year follow-up based on motor, cognitive, sleep and dysautonomia features. CSF-Syn-SAA parameters were collected at baseline using a 150-hrs protocol. CSF A{beta}1-42, tTau and pTau181, CSF and serum NfL were also considered at baseline. ResultsReaction times (T50, TTT) and area under the curve (AUC) respectively were shorter and larger in DM compared to IM/MMP. The difference in baseline amplification parameters was more evident when comparing subtypes based on 10-year clinical features (T50, 2=0.036; TTT, 2=0.031; AUC, 2=0.033; all p values < 0.05) than when comparing subtypes based on baseline clinical features (T50, 2=0.012; TTT, 2=0.012; AUC, 2=0.013; all p<0.05). Shorter T50 and TTT at baseline were associated with greater risk of DM versus MMP at 10-year follow-up (T50, OR=3.3, 95%CI: 1.3-8.1, p=0.010; TTT, OR=4.6, 95%CI: 1.8-11.6, p=0.001). A{beta}, Tau and NfL were similar between groups. ConclusionsBaseline CSF-Syn-SAA parameters predicted long-term PD progression. Faster reactions were associated with a more severe 10-year PD phenotype considering motor and non-motor features. Plain Language SummaryO_ST_ABSBackgroundC_ST_ABSThe diagnosis of Parkisons 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 Parkinsons 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 Parkinsons Disease. MethodsPublic data from an international cohort were used. At time of diagnosis, we classified 323 individuals with Parkinsons 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.