Isonaka Risa, Sullivan Patti, Goldstein David S
From the Autonomic Medicine Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD.
Neurology. 2025 Feb 11;104(3):e210215. doi: 10.1212/WNL.0000000000210215. Epub 2025 Jan 13.
Lewy body diseases (LBDs) such as Parkinson disease (PD) feature increased deposition of α-synuclein (α-syn) in cutaneous sympathetic noradrenergic nerves. The pathophysiologic significance of sympathetic intraneuronal α-syn is unclear. We reviewed data about immunoreactive α-syn, tyrosine hydroxylase (TH, a marker of catecholaminergic fibers), and the sympathetic neurotransmitter norepinephrine (NE) in skin biopsies from control participants and patients with PD, the related LBD pure autonomic failure (PAF), the non-LBD synucleinopathy multiple system atrophy (MSA), or neurologic postacute sequelae of severe acute respiratory syndrome coronavirus 2 (neuro-PASC).
In a retrospective observational study, we reviewed data about α-syn-TH colocalization indexes and immunoreactive α-syn and TH signal intensities in arrector pili muscles, blood vessels, and sweat glands from neck skin biopsies and NE concentrations in simultaneously obtained thigh skin biopsies from participants studied at the NIH Clinical Center. LBD, MSA, and control group data were assessed by analyses of variance with the Tukey post hoc test for multiple comparisons. Similar analyses were performed for patients with PD or neuro-PASC vs control.
Dermal α-syn-TH colocalization indexes and α-syn signal intensities from neck skin biopsies were examined in 18 controls (mean age 58 years, 50% female) and 53 LBD (66, 34%), 15 MSA (61, 33%), and 11 neuro-PASC (52, 82%) patients. The LBD group had higher α-syn-TH colocalization indexes than the controls (mean difference = 1.495, 95% CI 1.081-1.909, < 0.0001) and increased α-syn signal intensities in all 3 skin constituents (arrector pili: mean difference = 2.743, 95% CI 1.608-3.879, < 0.0001; blood vessels: mean difference = 2.157, 95% CI 1.095-3.219, < 0.0001; sweat glands: mean difference = 4.136, 95% CI 1.704-6.567, < 0.0001). The groups did not differ in either immunoreactive TH or NE. The neuro-PASC and PD groups had elevated α-syn-TH colocalization indexes compared with the controls, also with no group differences in immunoreactive TH or NE contents.
LBDs and neuro-PASC entail increased α-syn-TH colocalization indexes in skin biopsies, without evidence of local denervation or noradrenergic deficiency. The results fail to support toxicity of intraneuronal α-syn in cutaneous sympathetic noradrenergic nerves in either LBDs or neuro-PASC. The neuro-PASC data raise the possibility of sympathetic intraneuronal α-syn deposition as part of postinfectious immune or inflammatory processes.
路易体病（LBDs），如帕金森病（PD），其特征是皮肤交感去甲肾上腺素能神经中α-突触核蛋白（α-syn）沉积增加。交感神经内神经元α-syn的病理生理意义尚不清楚。我们回顾了来自对照参与者以及PD、相关的LBD纯自主神经功能衰竭（PAF）、非LBD突触核蛋白病多系统萎缩（MSA）或严重急性呼吸综合征冠状病毒2的神经系统急性后遗症（神经-PASC）患者的皮肤活检中免疫反应性α-syn、酪氨酸羟化酶（TH，儿茶酚胺能纤维的标志物）和交感神经递质去甲肾上腺素（NE）的数据。
在一项回顾性观察研究中，我们回顾了来自美国国立卫生研究院临床中心研究的参与者颈部皮肤活检的竖毛肌、血管和汗腺中α-syn-TH共定位指数以及免疫反应性α-syn和TH信号强度的数据，以及同时获取的大腿皮肤活检中的NE浓度。通过方差分析及Tukey事后检验进行多重比较，评估LBD、MSA和对照组的数据。对PD或神经-PASC患者与对照组进行类似分析。
对18名对照者（平均年龄58岁，50%为女性）以及53例LBD患者（66岁，34%为女性）、15例MSA患者（61岁，33%为女性）和11例神经-PASC患者（52岁，82%为女性）的颈部皮肤活检的真皮α-syn-TH共定位指数和α-syn信号强度进行了检测。LBD组的α-syn-TH共定位指数高于对照组（平均差异 = 1.495，95%置信区间1.081 - 1.909，P < 0.0001），并且在所有3种皮肤成分中α-syn信号强度均增加（竖毛肌：平均差异 = 2.743，95%置信区间1.608 - 3.879，P < 0.0001；血管：平均差异 = 2.157，95%置信区间1.095 - 3.219，P < 0.0001；汗腺：平均差异 = 4.136，95%置信区间1.704 - 6.567，P < 0.0001）。各组在免疫反应性TH或NE方面无差异。与对照组相比，神经-PASC组和PD组的α-syn-TH共定位指数升高，免疫反应性TH或NE含量也无组间差异。
LBDs和神经-PASC患者的皮肤活检中α-syn-TH共定位指数增加，且无局部去神经支配或去甲肾上腺素能缺乏的证据。结果不支持LBDs或神经-PASC中神经元内α-syn对皮肤交感去甲肾上腺素能神经有毒性作用。神经-PASC的数据增加了交感神经内神经元α-syn沉积作为感染后免疫或炎症过程一部分的可能性。
