The early differential diagnosis of Parkinson's disease (PD) and atypical Parkinsonian
syndromes (APS), including corticobasal degeneration (CBD) and progressive supranuclear
palsy (PSP), is challenging because of an overlap of clinical features and the lack
of reliable biomarkers. Neural-derived extracellular vesicles (NDEVs) isolated from
blood provide a window into the brain's biochemistry and may assist in distinguishing
between PD and APS. We verified in a case-control study whether oligomeric α-Synuclein
and Tau aggregates isolated from NDEVs could allow the differential diagnosis of these
conditions. Blood sampling and clinical data, including disease duration, motor severity,
global cognition, and levodopa equivalent daily dose (LEDD), were collected from patients
with a diagnosis of either PD (n = 70), PSP (n = 21), or CBD (n = 19). NDEVs were
isolated from serum by immunocapture using an antibody against the neuronal surface
marker L1CAM; oligomeric α-Synuclein and aggregated Tau were measured by ELISA. NDEVs
analyses showed that oligomeric α-Synuclein is significantly augmented in PD compared
to APS, whereas Tau aggregates are significantly increased in APS compared to PD (p < 0.0001).
ROC analyses showed that these two biomarkers have a "good" power of classification
(p < 0.0001 for both proteins), with high sensitivity and specificity, with NDEVs
concentration of Tau aggregates and oligomeric α-Synuclein being respectively the
best biomarker for PD/PSP and PD/CBD diagnostic differentiation. Logistic and multiple
regression analysis confirmed that NDEVs-derived oligomeric α-Synuclein and Tau aggregates
differentiate PD from CBD and PSP (p < 0.001). Notably, a positive correlation between
NDEVs oligomeric α-Synuclein and disease severity (disease duration, p = 0.023; Modified
H&Y, p = 0.015; UPDRS motor scores, p = 0.004) was found in PD patients and, in these
same patients, NDEVs Tau aggregates concentration inversely correlated with global
cognitive scores (p = 0.043). A minimally invasive blood test measuring the concentration
of α-synuclein and Tau aggregates in NDEVs can represent a promising tool to distinguish
with high sensitivity and specificity PD from CBD or PSP patients. Optimization and
validation of these data will be needed to confirm the diagnostic value of these biomarkers
in distinguishing synucleinopathies from taupathies.