Ilaria Linda Dellarole, Elena Vacchi, Inigo Ruiz-Barrio, Sandra Pinton, Andrea Raimondi, Stefania Rossi, Sara Morandi, Giovanni Bianco, Merve Begum Bacinoglu, Annalisa Lombardo, Luigi Celauro, Claudio Staedler, Salvatore Galati, Javier Pagonabarraga, Jaime Kulisevsky, Giuseppe Legname, Claudio Gobbi, Alain Kaelin-Lang, Fabio Moda, Giorgia Melli
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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. 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引用次数: 0
摘要
大多数神经退行性疾病都缺乏明确的诊断测试,因此鉴定易于获得且可靠的生物标记物仍是一项尚未满足的关键需求。由于tau蛋白在tau病患者的皮肤中高度表达,我们旨在利用超灵敏播种活性测定(SAA)来评估tau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,我们连续招募了tau蛋白病患者和突触核蛋白病患者,并与健康对照组(HC)进行了性别匹配。受试者在颈部和踝部接受了双层 3 毫米皮肤活检。以TauK18和TauK19作为4R和3R同工酶的反应底物,对皮肤tau-SAA、播种评分、临床评分、SAA终产物的生化和形态特征进行了评估。我们对 58 名受试者进行了分析:24 例 tauopathies(18 例进行性核上性麻痹(PSP)和 6 例皮质基底变性(CBD))、20 例 synucleinopathies(14 例帕金森病(PD)和 6 例多发性系统萎缩(MSA))和 14 例 HC。帕金森病和CBD在两个解剖部位都显示出较高的tau种子活性。与 3R-SAA 相比,4R-SAA 的灵敏度更高。4R tau-SAA鉴定牛头蛋白病的敏感性为71%,特异性为93%。PSP的准确性高于CBD:PSP vs HC / PD(AUC 0.825),CBD vs HC / PD(AUC 0.797),PSP vs MSA(AU 0.778)。根据解剖部位的不同,SAA终产物的生化和形态特征也有所不同。皮肤tau-SAA能准确识别tau病,可用于神经退行性疾病患者的体内临床诊断。对皮肤外周tau种子的进一步表征可能会阐明大脑中tau沉积物的结构。
Tau seeding activity in skin biopsy differentiates tauopathies from synucleinopathies
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.
期刊介绍:
npj Parkinson's Disease is a comprehensive open access journal that covers a wide range of research areas related to Parkinson's disease. It publishes original studies in basic science, translational research, and clinical investigations. The journal is dedicated to advancing our understanding of Parkinson's disease by exploring various aspects such as anatomy, etiology, genetics, cellular and molecular physiology, neurophysiology, epidemiology, and therapeutic development. By providing free and immediate access to the scientific and Parkinson's disease community, npj Parkinson's Disease promotes collaboration and knowledge sharing among researchers and healthcare professionals.