Most neurodegenerative diseases lack definitive diagnostic tests, and the identification of easily accessible and reliable biomarkers remains a critical unmet need. Since tau protein is highly expressed in skin of tauopathies patients, we aimed to exploit the ultrasensitive seeding activity assay (SAA) to assess tau seeding activity in skin of patients with tauopathies. In this multicentric, case-control study, patients with tauopathies and synucleinopathies were consecutively recruited and sex-matched to healthy controls (HC). Subjects underwent a double 3 mm skin biopsy in cervical area and ankle. Skin tau-SAA, using TauK18 and TauK19 as reaction substrates for 4R and 3R isoforms, seeding score, clinical scales, biochemical and morphological characterization of SAA end-products were evaluated. We analyzed 58 subjects: 24 tauopathies (18 progressive supranuclear palsy, PSP, and 6 corticobasal degeneration, CBD), 20 synucleinopathies (14 Parkinson’s disease, PD, and 6 multiple system atrophy, MSA), and 14 HC. PSP and CBD showed higher tau seeding activity at both anatomical sites. A greater sensitivity of 4R-SAA than 3R-SAA was observed. 4R tau-SAA identified tauopathies with 71% sensitivity and 93% specificity. Accuracy was higher for PSP than CBD: PSP vs HC / PD (AUC 0.825), while CBD vs HC / PD (AUC 0.797), and PSP vs MSA (AU 0.778). SAA end-products showed differences in biochemical and morphological characterization according to the anatomical site. Skin tau-SAA identifies tauopathies with good accuracy and can be used to implement the in-vivo clinical diagnosis of patients with neurodegenerative diseases. Further characterization of peripheral tau seed in skin may elucidate the structure of tau deposits in brain.

大多数神经退行性疾病缺乏明确的诊断测试，并且识别易于获得且可靠的生物标志物仍然是一个未满足的关键需求。由于 tau 蛋白在 tau 蛋白病患者的皮肤中高表达，我们旨在利用超灵敏播种活性测定 (SAA) 来评估 tau 蛋白病患者皮肤中的 tau 播种活性。在这项多中心病例对照研究中，连续招募了 tau蛋白病和突触核蛋白病患者，并与健康对照 (HC) 进行性别匹配。受试者在颈部和脚踝处接受了双 3 毫米皮肤活检。使用 TauK18 和 TauK19 作为 4R 和 3R 同工型的反应底物，对皮肤 tau-SAA、SAA 最终产物的播种评分、临床规模、生化和形态特征进行了评估。我们分析了 58 名受试者：24 名 tau蛋白病（18 名进行性核上性麻痹（PSP）和 6 名皮质基底节变性（CBD））、20 名突触核蛋白病（14 名帕金森病（PD）和 6 名多系统萎缩（MSA））和 14 名 HC。 PSP 和 CBD 在两个解剖部位都显示出较高的 tau 播种活性。观察到 4R-SAA 的敏感性高于 3R-SAA。 4R tau-SAA 识别 tau 蛋白病的敏感性为 71%，特异性为 93%。 PSP 的准确率高于 CBD：PSP 与 HC / PD (AUC 0.825)、CBD 与 HC / PD (AUC 0.797) 以及 PSP 与 MSA (AU 0.778)。 SAA 最终产品根据解剖部位的不同，在生化和形态学特征上表现出差异。皮肤tau-SAA能够准确地识别tau蛋白病，可用于实施神经退行性疾病患者的体内临床诊断。皮肤中外周 tau 种子的进一步表征可能会阐明大脑中 tau 沉积物的结构。