Objective: This study aimed to develop and validate novel plasma PSP biomarkers based on tau-species-containing neuron-derived extracellular vesicles (NDEVs) in two independent cohorts (discovery and validation)

Background: PSP is a severe neurodegenerative disorder, characterized by the deposition of 4R tau in brain cells. PSP is commonly misdiagnosed due to symptom overlap with Parkinson’s Disease (PD) and other atypical parkinsonisms. New biomarkers are needed for accurate and early diagnosis

Method: A total of 188 participants, including 70 PSP patients, 63 PD patients, and 55 healthy controls, were recruited from 3 centers in this study. A discovery cohort (40 PSP patients, 36 PD patients, and 31 HCs) and a multicenter validation cohort (30 PSP patients, 27 PD patients, and 24 HCs) were developed. NDEVs containing total tau, 4R tau,  ptau181, ptau231 or ptau396 in plasma samples were analyzed by using nano-scale flow cytometry

Results: In the discovery cohort, the concentrations of tau, 4R tau, and ptau181-containing NDEVs in PSP patients were significantly higher than those in HCs and PD patients (PSP vs. HCs: P < 0.001 for tau, P < 0.001 for 4R tau, P < 0.001 for ptau181; PSP vs. PD: P < 0.001 for tau, P < 0.001 for 4R tau, P = 0.029 for ptau181). The integrated model incorporating these biomarkers yielded an AUC of 0.954 for distinguishing PSP patients from HCs, with a sensitivity of 96.8% and specificity of 85%, and an AUC of 0.947 for distinguishing PSP from PD, with a sensitivity of 94.4% and specificity of 82.5%. In the validation cohort, the concentrations of tau, 4R tau, ptau181, and ptau396-containing NDEVs in plasma were significantly higher in PSP patients compared to HCs (PSP vs. HCs: P < 0.001 for tau and 4R tau, P = 0.03 for ptau181, P = 0.017 for ptau396). Similarly, concentrations of tau, 4R tau, and ptau181 were higher in PSP patients than in PD patients (PSP vs. PD: P < 0.001 for tau and 4R tau, P = 0.025 for ptau181). The integrated model incorporating these biomarkers yielded an AUC of 0.954 for distinguishing PSP patients from HCs and 0.921 for distinguishing PSP from PD

Conclusion: Tau-species-containing NDEVs in plasma are good PSP biomarkers, providing high sensitivity and specificity for distinguishing PSP from HCs and PD.

Figure 1 Characteristics of EVs

Figure 2 Nano-scale flow cytometry analysis

Figure 3

Figure 4

Table 1. Demographic and clinical features

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