Skin α-synuclein deposits differ in clinical variants of synucleinopathy: an in vivo study

Abstract

We aimed to characterize in vivo α-synuclein (α-syn) aggregates in skin nerves to ascertain: 1) the optimal marker to identify them; 2) possible differences between synucleinopathies that may justify the clinical variability. We studied multiple skin nerve α-syn deposits in 44 patients with synucleinopathy: 15 idiopathic Parkinson’s disease (IPD), 12 dementia with Lewy Bodies (DLB), 5 pure autonomic failure (PAF) and 12 multiple system atrophy (MSA). Ten healthy subjects were used as controls. Antibodies against native α-syn, C-terminal α-syn epitopes such as phosphorylation at serine 129 (p-syn) and to conformation-specific for α-syn mature amyloid fibrils (syn-F1) were used. We found that p-syn showed the highest sensitivity and specificity in disclosing skin α-syn deposits. In MSA abnormal deposits were only found in somatic fibers mainly at distal sites differently from PAF, IPD and DLB displaying α-syn deposits in autonomic fibers mainly at proximal sites. PAF and DLB showed the highest p-syn load with a widespread involvement of autonomic skin nerve fibers. In conclusion: 1) p-syn in skin nerves was the optimal marker for the in vivo diagnosis of synucleinopathies; 2) the localization and load differences of aggregates may help to identify specific diagnostic traits and support a different pathogenesis among synucleinopathies.

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

“…[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. Thick cryosections examined with double immunofluorescence technique enable evaluation of larger areas and tracing of the nerve compared to thin paraffin sections, which would make distinction of abnormal α-syn deposits in neurites from nonspecific immunostaining easier.…”

“…Differentiating PD from other diseases that can also display abnormal α-syn deposits and identification of prodromal PD are important topics. Other Lewy body disorders, such as DLB and PAF, as well as RBD, which is often considered as prodromal PD, can exhibit α-syn immunoreactivity in a pattern similar to that of PD, 14,22,24,25,43 whereas MSA can exhibit α-syn immunoreactivity in a pattern different from that observed in PD. For example, studies using skin biopsy have suggested that MSA presents with selective somatosensory fiber involvement, which is in contrast to the selective involvement of autonomic fibers in PD.…”

“…For example, studies using skin biopsy have suggested that MSA presents with selective somatosensory fiber involvement, which is in contrast to the selective involvement of autonomic fibers in PD. 22,27 The impact of simultaneous examination of peripheral tissues form multiple organs in combination with examination of the cerebrospinal fluid, plasma, and saliva, which are other potential α-syn-based biomarkers investigated in recent years, 51,52 is also an interesting topic. This will be presented in the forthcoming clinical trial, namely the Systemic Synuclein Sampling Study.…”

Antibodies against alpha‐synuclein: tools and therapies

“…), human skin biopsy of patients with idiopathic PD (Donadio et al . ), and in human post‐mortem brain tissues from PD, DLB, AD, and control cases (Vaikath et al . )…”

“…2). Furthermore, the conformational specificity of these antibodies have been utilized to detect a-syn aggregates in biochemical studies (Leung et al 2015), in neurons of Caenorhabditis elegans (Kim et al 2016) and rats (Duffy et al 2018), guinea-pig ileum (Sharrad et al 2017), human skin biopsy of patients with idiopathic PD (Donadio et al 2018), and in human post-mortem brain tissues from PD, DLB, AD, and control cases (Vaikath et al 2018)…”