Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson\u2019s disease

Kathrin Doppler,Joachim Brumberg,Stephan Klebe,Jan Booij,Elisabeth Sittig-Wiegand,Wolfgang H Oertel,Annette Janzen,Claudia Sommer,Thomas Musacchio,Helmut Höffken,Jens Volkmann,Lena Schulmeyer,Markus Luster,Hanna-Maria Jentschke,Geert Mayer,David Vadasz

doi:10.1007/s00401-017-1684-z

Abstract

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.

Highlights

Parkinson’s disease (PD), like other neurodegenerative disorders, does not start suddenly, but progresses through early “prodromal” stages, in which the defining motor symptoms have not yet emerged
We address the potential value of dermal p-alpha-syn deposition as a premotor histopathological biomarker of PD by evaluating skin biopsies in patients with REM sleep behaviour disorder (RBD), a well-established clinical non-motor risk marker of PD [16, 18]
The severity of motor symptoms was assessed in RBD and PD patients using the Unified Parkinson’s Disease Rating Scale (UPDRS) part 3 [13] and non-motor symptoms were measured by the German version of the non-motor symptom scale [36]

Summary

Introduction

Parkinson’s disease (PD), like other neurodegenerative disorders, does not start suddenly, but progresses through early “prodromal” stages, in which the defining motor symptoms have not yet emerged. We address the potential value of dermal p-alpha-syn deposition as a premotor histopathological biomarker of PD by evaluating skin biopsies in patients with REM sleep behaviour disorder (RBD), a well-established clinical non-motor risk marker of PD [16, 18]. Research criteria for prodromal PD have been proposed as a hypothetical concept by the International Parkinson and Movement Disorder Society (MDS) [2] for validation and updating in future studies, as recently employed in a cohort of elderly people [21] In this case control study, we compare the presence and extent of dermal p-alpha-syn depositions in patients with a high risk of prodromal PD, i.e. RBD patients, with early motor stages of PD and healthy controls

Materials and methods

Results

Discussion

Compliance with ethical standards