Skin α-Synuclein Aggregation Seeding Activity as a Novel Biomarker for Parkinson Disease.
Skin α-Synuclein Aggregation Seeding Activity as a Novel Biomarker for Parkinson Disease.
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DOI：
10.1001/jamaneurol.2020.3311
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发表时间：
2020-09-28
期刊：
影响因子：
29
通讯作者：
Zou WQ
中科院分区：
文献类型：
--
作者：
Wang Z;Becker K;Donadio V;Siedlak S;Yuan J;Rezaee M;Incensi A;Kuzkina A;Orrú CD;Tatsuoka C;Liguori R;Gunzler SA;Caughey B;Jimenez-Capdeville ME;Zhu X;Doppler K;Cui L;Chen SG;Ma J;Zou WQ
帕金森病（PD）患者皮肤中免疫组化检测到的病理性α-突触核蛋白（αSynP）是否具有聚集播种活性，皮肤αSynP播种活性是否是诊断PD和其他突触核蛋白病的潜在生物标志物？在这项诊断研究中，包括160例尸检和41例活检的皮肤样本，与tau蛋白病和非神经退行性疾病的对照组相比，PD和突触核蛋白病患者的αSynP播种活性在统计学上显著增加。皮肤αSynP在PD和非PD突触核蛋白病患者中具有聚集播种活性，可能是PD和其他突触核蛋白病的生前诊断的生物标志物。本诊断研究调查敏感和特异性的皮肤生物标志物，用于帕金森病和其他突触核蛋白病的生前诊断。病理性α-突触核蛋白（α-synuclein，αSynP）在脑内的沉积是突触核蛋白病的标志，包括帕金森病（Parkinson disease，PD）、路易体痴呆（Lewy body dementia，LBD）和多系统萎缩（multiple system atrophy，MSA）。实时振荡诱导转换（RT-QuIC）和蛋白质错误折叠循环扩增（PMCA）测定是否可以灵敏地检测PD和非PD突触核蛋白病的皮肤生物标志物仍然未知。开发敏感和特异的皮肤生物标志物，用于PD和其他突触核蛋白病的生前诊断。这项回顾性和前瞻性诊断研究评价了神经病理学和临床诊断为PD的患者和无PD的对照组的尸检和活检皮肤样本。2016年8月至2019年9月在3家医疗中心获得了尸检皮肤样本，2018年8月至2019年11月从3家机构采集了活检样本。根据神经病理学和临床诊断，57具尸体与synucleinopathies和73具尸体与nonsynucleinopathies，以及20例PD和21例非PD的生活对照。具体而言，尸体和参与者患有PD，LBD，MSA，阿尔茨海默病，进行性核上性麻痹或皮质基底节变性或非神经退行性对照（NNC）。共有8名接近活检的参与者拒绝参与或因临床诊断不确定而被排除在本研究之外。数据分析时间为二零一九年九月至二零二零年四月。通过RT-QuIC和PMCA测定分析皮肤αSynP接种活性。分析了来自140具尸体（85具男性尸体[60.7%];死亡时的平均[SD]年龄，76.8 [10.1]岁）和41份死前皮肤活检（27名男性参与者[66%];活检时的平均[SD]年龄，65.3 [9.2]岁）的共160份尸检皮肤标本。47例PD尸体和43例NNC尸检腹部皮肤样本中αSynP接种活性的RT-QuIC分析显示，灵敏度为94%（95% CI，85-99），特异性为98%（95% CI，89-100）。作为组，RT-QuIC还在57具具有突触核蛋白病（PD、LBD和MSA）的尸体和73具没有突触核蛋白病（阿尔茨海默病、进行性核上性麻痹、皮质基底节变性和NNC）的尸体中产生93%的灵敏度（95%CI，85-97）和93%的特异性（95%CI，83-97）。PMCA对PD尸体尸检腹部皮肤样本的敏感性为82%（95% CI，76-88），特异性为96%（95% CI，85-100）。从PD患者和非PD对照的后部颈部和腿部皮肤活检组织中，RT-QuIC的灵敏度和特异性分别为95%（95%CI，77-100）和100%（95%CI，84-100），PMCA的灵敏度和特异性分别为80%（95%CI，49-96）和90%（95%CI，60-100）。这项研究提供了概念证明，皮肤αSynP播种活性可能作为一种新的生物标志物，用于PD和其他突触核蛋白病的生前诊断。
Does the pathological α-synuclein (αSynP) detected by immunohistochemistry in the skin of individuals with Parkinson disease (PD) have aggregation seeding activity, and is skin αSynP seeding activity a potential biomarker for diagnosis of PD and other synucleinopathies? In this diagnostic study including skin samples from 160 autopsies and 41 biopsies, a statistically significant increase in αSynP seeding activity was observed in individuals with PD and synucleinopathies compared with controls with tauopathies and nonneurodegenerative diseases. Skin αSynP has aggregation seeding activity in patients with PD and non-PD synucleinopathies and may be a biomarker for antemortem diagnosis of PD and other synucleinopathies. This diagnostic study investigates sensitive and specific skin biomarkers for antemortem diagnosis of Parkinson disease and other synucleinopathies. Deposition of the pathological α-synuclein (αSynP) in the brain is the hallmark of synucleinopathies, including Parkinson disease (PD), Lewy body dementia (LBD), and multiple system atrophy (MSA). Whether real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) assays can sensitively detect skin biomarkers for PD and non-PD synucleinopathies remains unknown. To develop sensitive and specific skin biomarkers for antemortem diagnosis of PD and other synucleinopathies. This retrospective and prospective diagnostic study evaluated autopsy and biopsy skin samples from neuropathologically and clinically diagnosed patients with PD and controls without PD. Autopsy skin samples were obtained at 3 medical centers from August 2016 to September 2019, and biopsy samples were collected from 3 institutions from August 2018 to November 2019. Based on neuropathological and clinical diagnoses, 57 cadavers with synucleinopathies and 73 cadavers with nonsynucleinopathies as well as 20 living patients with PD and 21 living controls without PD were included. Specifically, cadavers and participants had PD, LBD, MSA, Alzheimer disease, progressive supranuclear palsy, or corticobasal degeneration or were nonneurodegenerative controls (NNCs). A total of 8 approached biopsy participants either refused to participate in or were excluded from this study due to uncertain clinical diagnosis. Data were analyzed from September 2019 to April 2020. Skin αSynP seeding activity was analyzed by RT-QuIC and PMCA assays. A total of 160 autopsied skin specimens from 140 cadavers (85 male cadavers [60.7%]; mean [SD] age at death, 76.8 [10.1] years) and 41 antemortem skin biopsies (27 male participants [66%]; mean [SD] age at time of biopsy, 65.3 [9.2] years) were analyzed. RT-QuIC analysis of αSynP seeding activity in autopsy abdominal skin samples from 47 PD cadavers and 43 NNCs revealed 94% sensitivity (95% CI, 85-99) and 98% specificity (95% CI, 89-100). As groups, RT-QuIC also yielded 93% sensitivity (95% CI, 85-97) and 93% specificity (95% CI, 83-97) among 57 cadavers with synucleinopathies (PD, LBD, and MSA) and 73 cadavers without synucleinopathies (Alzheimer disease, progressive supranuclear palsy, corticobasal degeneration, and NNCs). PMCA showed 82% sensitivity (95% CI, 76-88) and 96% specificity (95% CI, 85-100) with autopsy abdominal skin samples from PD cadavers. From posterior cervical and leg skin biopsy tissues from patients with PD and controls without PD, the sensitivity and specificity were 95% (95% CI, 77-100) and 100% (95% CI, 84-100), respectively, for RT-QuIC and 80% (95% CI, 49-96) and 90% (95% CI, 60-100) for PMCA. This study provides proof-of-concept that skin αSynP seeding activity may serve as a novel biomarker for antemortem diagnoses of PD and other synucleinopathies.
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DOI：
10.3233/jpd-179001
发表时间：
2017
期刊：
Journal of Parkinson's disease
影响因子：
--
作者：
Braak H;Del Tredici K
通讯作者：
Del Tredici K
影响因子：
12.7
作者：
Doppler K;Ebert S;Uçeyler N;Trenkwalder C;Ebentheuer J;Volkmann J;Sommer C
通讯作者：
Sommer C
影响因子：
11.2
作者：
Donadio, Vincenzo;Incensi, Alex;Liguori, Rocco
通讯作者：
Liguori, Rocco
影响因子：
5.2
作者：
Chahine, Lana M.;Beach, Thomas G.;Mollenhauer, Brit
通讯作者：
Mollenhauer, Brit
影响因子：
8.6
作者：
Doppler, Kathrin;Weis, Jessica;Sommer, Claudia
通讯作者：
Sommer, Claudia