Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson's disease.
Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson's disease.
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DOI：
10.1007/s00401-017-1684-z
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发表时间：
2017-04
影响因子：
12.7
通讯作者：
Oertel WH
中科院分区：
文献类型：
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作者：
Doppler K;Jentschke HM;Schulmeyer L;Vadasz D;Janzen A;Luster M;Höffken H;Mayer G;Brumberg J;Booij J;Musacchio T;Klebe S;Sittig-Wiegand E;Volkmann J;Sommer C;Oertel WH
磷酸化的α-突触核蛋白（p-alpha-syn）沉积物，帕金森病（PD）的神经病理学标志之一，最近已被检测到皮肤神经纤维在PD患者具有良好的特异性和敏感性。在这里，我们研究了p-alpha-syn是否可以作为PD高风险患者的生物标志物，例如REM睡眠行为障碍（RBD）患者。我们比较了18例RBD患者、25例早期PD患者和20例正常对照者真皮神经纤维中p-alpha-syn沉积物的存在和分布。在C7、Th 10以及大腿和小腿处进行皮肤活检。在所有RBD患者和11例PD患者中使用FP-CIT-SPECT进行突触前多巴胺转运蛋白成像。所有RBD患者均接受嗅觉功能测试。根据已发表的研究标准计算每例患者前驱PD的似然比（LR）。在盲法条件下，通过用pSer 129-alpha-syn抗体进行双免疫荧光标记来评估皮肤连续切片。P-alpha-syn在10/18例RBD患者（灵敏度为55.6%）和20/25例早期PD患者（灵敏度为80%）中可见，但在对照组中均未可见（特异性为100%）。受p-alpha-syn-positive纤维支配的真皮结构的百分比与FP-CIT-SPECT中的多巴胺转运蛋白结合率（ρ = −0.377，p = 0.048）、嗅觉功能（ρ = −0.668，p = 0.002）呈负相关，与RBD表现为前驱PD的总LR呈正相关（ρ = 0.531，p = 0.023）。皮肤p-alpha-syn可以被认为是突触核蛋白病的外周组织病理学标志物，并且可以在可能代表前驱PD的RBD患者亚组中检测到。在没有PD运动症状的RBD患者中可检测到皮肤p-alpha-syn，从而对测试疾病修饰药物的临床试验非常感兴趣的患者组进行分层。本文的在线版本（doi：10.1007/s 00401 -017-1684-z）包含补充材料，可供授权用户使用。
Phosphorylated alpha-synuclein (p-alpha-syn) deposits, one of the neuropathological hallmarks of Parkinson’s disease (PD), have recently been detected in dermal nerve fibres in PD patients with good specificity and sensitivity. Here, we studied whether p-alpha-syn may serve as a biomarker in patients with a high risk of developing PD, such as those with REM sleep behaviour disorder (RBD). We compared the presence and distribution of p-alpha-syn deposits in dermal nerve fibres in 18 patients with RBD, 25 patients with early PD and 20 normal controls. Skin biopsy was taken at C7, Th10, and the upper and lower leg. Presynaptic dopamine transporter imaging using FP-CIT-SPECT was performed in all patients with RBD and in 11 patients with PD. All RBD patients underwent olfactory function testing. The likelihood ratio (LR) for prodromal PD was calculated for each patient based on published research criteria. Skin serial sections were assessed by double-immunofluorescence labelling with antibodies to pSer129-alpha-syn under blinded conditions. P-alpha-syn was visualized in 10/18 patients with RBD (sensitivity of 55.6%) and in 20/25 early PD patients (sensitivity of 80%) but in none of the controls (specificity of 100%). The percentage of dermal structures innervated by p-alpha-syn-positive fibres was negatively correlated with dopamine transporter binding in the FP-CIT-SPECT (ρ = −0.377, p = 0.048), with olfactory function (ρ = −0.668, p = 0.002), and positively correlated with the total LR for RBD to present prodromal PD (ρ = 0.531, p = 0.023). Dermal p-alpha-syn can be considered a peripheral histopathological marker of synucleinopathy and can be detected in a subgroup of RBD patients presumably representing prodromal PD. Dermal p-alpha-syn is detectable in RBD patients without PD motor symptoms, thereby stratifying a patient group that is of great interest for clinical trials testing disease-modifying drugs. The online version of this article (doi:10.1007/s00401-017-1684-z) contains supplementary material, which is available to authorized users.