Cervical skin denervation associates with alpha‐synuclein aggregates in Parkinson disease

Abstract

ObjectiveAutonomic nervous system is involved at the onset of Parkinson disease (PD), and alpha‐synuclein (α‐Syn) and its phosphorylated form (p‐αSyn) have been detected in dermal autonomic nerve fibers of PD. We assessed disease specific conformation variant of α‐Syn immunoreactivity in cutaneous nerves and characterized skin denervation patterns in PD and atypical parkinsonism (AP).MethodsWe enrolled 49 subjects, 19 with PD, 17 age‐matched healthy controls, and 13 with AP. The manifestations of disease were rated on clinical scales. Skin biopsies from ankle, thigh, and neck were analyzed by immunofluorescence for p‐αSyn, 5G4 as a conformation specific antibody to pathogenic α‐Syn and PGP9.5 as axonal marker. Intraepidermal nerve fiber density was measured in all anatomical sites as marker of neurodegeneration. Thirteen of the 19 PD underwent a 1 year follow‐up visit plus skin biopsies.ResultsPD subjects displayed more severe cervical skin denervation (P < 0.03), which correlated to disease duration and worsened between initial and follow‐up examination (P < 0.001). p‐αSyn and 5G4 were equally sensitive and specific for the diagnosis of PD (area under the ROC was 0.839 for p‐αSyn and 0.886 for 5G4). PD and AP with possible alpha‐synucleinopathies share the features of marked cervical denervation and the presence of 5G4. In contrast AP with possible tauopathies were normal.InterpretationConformational specific forms of α‐Syn are detectable in skin biopsy by immunofluorescence in PD, with a promising diagnostic efficiency similar to p‐αSyn. Cervical cutaneous denervation correlates with disease duration and increases over time standing out as a potential biomarker of PD progression.

Value of in vivo α‐synuclein deposits in Parkinson's disease: A systematic review and meta‐analysis

“…In the skin, abnormal α-syn deposits are mainly seen in small cutaneous autonomic fibers around the vessels, sweat glands, and pilomotor muscles. [22][23][24][25][26][27][28][29][30][31][32] Although a decrease in nerve fiber density in patients with PD was reported earlier using an in vivo skin biopsy sample, 49 the study by Wang and colleagues conducted in 2013 was the first to show α-syn pathology in the skin biopsy samples using anti-nSyn antibody; it was demonstrated that the degree of α-syn deposition in cutaneous autonomic fibers may increase in patients with PD and, notably, correlates with the disease stage and severity of autonomic symptoms. 32 However, it became clear that α-syn is also physiologically expressed in the normal skin 25,26,32 and that anti-pSyn antibody may be better for diagnostic purposes than anti-nSyn antibody.…”

“…25,50 In line with this, our meta-analysis confirmed that, for the skin biopsy samples, anti-pSyn antibody seems more appropriate for diagnostic purposes than anti-nSyn antibody, and examination of skin biopsies using anti-nSyn antibody showed high pooled sensitivity and, notably, perfect pooled specificity. [16][17][18][19][20][21][22][23][24] This observed high diagnostic accuracy of skin biopsy examination using anti-pSyn antibody may be because the majority of the studies used thick cryosections from multiple sampling sites with the double immunofluorescence technique to investigate abnormal α-syn deposits in cutaneous autonomic fibers. Some researchers reported that sensitivity varies depending on the location of the sampling site with the posterior region of the neck showing the best sensitivity, 22,25,31 and examining multiple sampling sites would obviously improve sensitivity, as was shown by our subgroup analysis.…”

Where and how alpha‐synuclein pathology spreads in Parkinson’s disease:

“…30,33,[85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100] Subsequent biopsy studies revealed the frequent occurrence of alpha-synuclein pathology in the skin of patients with PD, DLB, and pure autonomic failure. [87][88][89][90][91][92][93][94][95][96][97][98][99][100] Doppler et al reported that alphasynuclein pathology was found in the skin in 16 of 31 patients with PD, and that the highest density of alpha-synuclein deposits was found in the back with 11 cases, while there were six cases in the proximal leg, four in the distal leg, and five in the finger, suggesting a decline in density from proximal to distal sites. 90 The presence of alpha-synuclein pathology in the skin might be related to the dyshidrosis and hypersteatosis that accompany PD.…”

Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

“…In fact, in PD and DLB, αSyn aggregates have been detected throughout the PNS in sympathetic ganglia, enteric nervous system, cardiac and pelvic plexus, submandibular glands, adrenal medulla, and skin [ 241 ]. In MSA, αSyn aggregates have been demonstrated in sympathetic ganglia [ 242 ], in Schwann cells cytoplasm [ 243 ] and in skin autonomic nerves [ 244 ]; of note, a study on sural biopsy showed a reduction of small unmyelinated fibers (somatosensory and autonomic) in 23% of MSA cases [ 245 ] and a mild degeneration of cardiac sympathetic nerves has been described [ 206 ]. These findings have important implications for the discovery of in vivo biomarkers of disease that are so urgently needed for neurodegenerative diseases.…”

“…Indeed, phosphorylated αSyn has been found in skin small fibers nerves innervating autonomic structures [ 247 ] in PD, and of note also in RBD patients, suggesting the potential value of skin biopsy as an early biomarker of disease [ 248 , 249 ]. More recently, aggregated αSyn has been demonstrated in skin nerves by conformational antibodies, recognizing oligomeric forms of the protein [ 244 , 250 ] and by using proximity ligation assay technology in the skin [ 251 ]. In addition, skin biopsy offers the great advantages of being minimally invasive, compared to other biopsy sites like the gastro-enteric system; it can be repeated in time during follow-ups and offers the unique opportunity to access the sympathetic structures in the skin (sweat glands, small arterioles, muscle arrector pili), which animal models have demonstrated as possibly involved early [ 239 ].…”