Cerebrospinal fluid profile, including α-Synuclein seeding activity, of p.A53T SNCA mutation carriers: Data from the PPMI Study.

We report here, based on Parkinson's Progression Markers Initiative (PPMI) data, on the Cerebrospinal Fluid (CSF) profile of a group of 12 Parkinson's Disease (PD) subjects with the prototypical p.A53T SNCA mutation, comparing them to 36 matched Healthy Controls (HCs) and 36 idiopathic PD (iPD) cases. We furthermore assessed the CSF profile of 7 asymptomatic carriers of this mutation. There was no significant difference between the 3 groups of A53T-PD, HC and iPD in total alpha synuclein (a-syn) levels, beta-amyloid 1-42, total-Tau and p-Tau, although A53T-PD subjects tended to have slightly lower beta-amyloid 1-42, total-Tau and especially total a-syn levels. All A53T-PD cases had a positive CSF a-syn Seeding Amplification Assay (SAA). Four out of 7 asymptomatic carriers also had a positive SAA, in 3 without motor symptoms or signs and absence of clear prodromal manifestations. Conversion to motoric manifestations has occurred in one out of these 3 subjects, 8 years after SAA positivity, while one other subject only has hyposmia 8 years later. Overall, these results indicate that at least in early stages of PD, CSF Alzheimer's Disease profiles are not significantly different in A53T-PD compared to HCs or iPD, while the CSF a-syn SAA is universally positive in this group. Furthermore, the assay may be positive in asymptomatic carriers at a time with no prodromal manifestations and many years before motor disease onset, opening a window into very early stages of disease pathobiology and opportunities for early therapeutic intervention.