Defining progression of cutaneous autonomic denervation in orthostatic hypotension and pure autonomic failure

突触核蛋白病是一组以α-突触核蛋白（α-Syn）蛋白以路易小体和路易神经突的形式病理积累为特征的神经退行性疾病。它们包括更普遍的帕金森病（PD）和路易体痴呆（LBD），以及多系统萎缩（MSA）和纯粹自主神经衰竭（PAF）。PAF患者可能患有缓慢进行性直立性低血压，但没有中枢神经系统（CNS）异常，或出现认知和/或运动缺陷。然后根据观察到的临床差异诊断为PD、LBD或MSA。目前，人们正在努力寻找具有发生突触核蛋白病风险的个体的疾病预测因子和标志物，或者在PAF患者的情况下，表型转化为广泛涉及中枢神经系统的其他突触核蛋白病。近年来的实验研究表明，免疫组化检测皮肤自主小纤维中神经内α-Syn沉积是研究突触核蛋白病病理的一种安全可靠的方法。然而，反复评估皮肤神经病理在早期识别哪些个体将发展为突触核蛋白病或从PAF演变为更严重的形式中的作用仍有待阐明。我们假设，与基线相比，有发生突触核蛋白病风险的个体或有PAF但有发展为累及中枢神经系统的突触核蛋白病风险的个体在一年后表现出更明显的神经真皮α-Syn沉积。我们进一步假设，临床恶化和自主心功能参数的测量可以预测这些患者皮肤α-Syn沉积的更快进展。将对20例新诊断的直立性低血压、新诊断的无中枢神经系统异常的PAF或有疾病扩散到运动和/或认知神经元迹象的PAF患者进行纵向研究。研究参与者将接受详细的神经和神经精神评估和自主心血管表型分析。α-突触核蛋白沉积介导的自主小纤维结构损伤分析将采用皮肤活检免疫组化评估。评估将在基线和12个月后进行。我们预计，从这项研究中得出的观察结果可能有助于解决目前寻找可靠的疾病特异性生物标志物的问题。

Synucleinopathies are a group of neurodegenerative disorders characterized by the pathological accumulation of the protein α-synuclein (α-Syn) in form of Lewy bodies and Lewy neurites. They include the more prevalent Parkinson’s disease (PD) and Lewy body dementia (LBD), as well as multiple system atrophy (MSA) and pure autonomic failure (PAF). Patients with PAF can either suffer from slowly progressive orthostatic hypotension without abnormalities of the central nervous system (CNS), or develop cognitive and/or motor deficits. They are then diagnosed with PD, LBD or MSA based on the observed clinical differences.Currently, efforts have been made in the search for predictors and markers of disease in individuals at risk of developing synucleinopathies, or, in the case of patients with PAF, phenoconverting to other synucleinopathies with widespread CNS involvement. Immunohistochemical detection of intraneural α-Syn deposition in autonomic small fibers of the skin has been shown in recent experimental studies to be a safe and reliable method to study pathology in synucleinopathies. However, the role of repeated assessments of skin nerve pathology in the early identification of which individuals will develop a synucleinopathy or evolve from PAF to a more severe form remains to be elucidated.We hypothesize that individuals at risk of developing a synucleinopathy or with PAF but at risk of evolution to a synucleinopathy with CNS involvement display a more pronounced neurodermal α-Syn deposition after one year when compared with baseline. We further hypothesize that measurements of clinical deterioration and parameters of autonomic cardiac function predict more rapid progression of cutaneous α-Syn deposition in these patients.A longitudinal study will be undertaken in 20 patients with newly diagnosed orthostatic hypotension, newly diagnosed PAF without CNS abnormalities or PAF with signs of disease spread to motor and/or cognitive neurons. Study participants will undergo detailed neurological and neuropsychiatric evaluation and autonomic cardiovascular phenotyping. Analysis of structural damage of autonomic small fibers mediated by α-synuclein deposition will be carried out using immunohistochemical assessment of superficial skin biopsies. Evaluations will be performed at baseline and after 12 months. We anticipate that the observations derived from this study might help solve the current search for reliable disease-specific biomarkers.