Cerebrospinal fluid
Seeding aggregation assays, such as protein-misfolding cyclic amplification (PMCA) and real-time quaking-induced conversion (RT-QuIC), detect misfolded proteins prone to aggregation by exploiting their prion-like behavior [16]. In PD, the total concentration of a-syn in the CSF seems to be lower, whereas the CSF levels of a-syn oligomers and phosphorylated a-syn are elevated as compared with healthy controls [9, 17]. These measures can serve as useful biomarkers for the early detection of Lewy body disorders and distinguishing PD from Alzheimer’s disease [18].
The activity of various lysosomal enzymes is changed in the CSF of PD patients as compared to healthy controls [9]. Mutations inGBA1 gene cause changes in beta-glucocerebrosidase activity and levels of glycosphingolipids in various body fluids which underlines development of GBA-associated PD and can be measured to diagnose this subtype of the disease [19]. The diagnostic accuracy can be improved when combining several lysosomal enzyme activity measurements, and further increased when Aβ, tau and a-syn pathology markers are added to the model [20, 21]. Defining the subtype of prodromal PD may guide future neurorestorative therapies [22].
Reduced levels of circulating cell-free mitochondrial DNA measured from the CSF of PD patients have also been proposed as a potential biomarker for the disease onset and progression, but several factors such as concomitant treatments and comorbidities are likely to confound the reliability of the readout [23, 24].