Consistent skin α-synuclein positivity in REM sleep behavior disorder – A two center two-to-four-year follow-up study

https://doi.org/10.1016/j.parkreldis.2021.04.007Get rights and content

Highlights

  • Dermal p-syn deposition is consistent over time in patients with RBD.

  • Only RBD patients with dermal p-syn deposition converted to manifest PD/DLB.

  • Dermal p-syn-positivity was observed in patients who still had a normal FP-CIT-SPECT at follow-up.

Abstract

Objective/methods

Phosphorylated alpha-synuclein (p-syn) in dermal nerves of patients with isolated REM sleep behavior disorder (iRBD) is detectable by immunofluorescence-labeling. Skin-biopsy-p-syn-positivity was recently postulated to be a prodromal marker of Parkinson's disease (PD) or related synucleinopathies. Here, we provide two-to four-year clinical and skin biopsy follow-up data of 33 iRBD patients, whose skin biopsy findings at baseline were reported in 2017.

Results

Follow-up biopsies were available from 25 patients (18 positive at baseline) and showed consistent findings over time in 24 patients. One patient converted from skin-biopsy-negativity to -positivity. P-syn-positivity was observed in iRBD patients who still had a normal FP-CIT-SPECT two years later. Clinically, five of the 23 at baseline skin-biopsy-positive patients (21.7%) had converted to PD or dementia with Lewy bodies at follow-up, but none of the skin-biopsy-negative patients.

Conclusions

Dermal p-syn in iRBD is most probably an early consistent marker of synucleinopathy and may support other indicators of conversion to manifest disease state.

Introduction

Deposition of phospho-alpha-synuclein (p-syn) in dermal nerve fibers of patients with Parkinson's disease (PD) was independently reported and proposed as peripheral histopathological marker of idiopathic PD [1,2]. Establishing early diagnostic tests is a major goal of biomarker research, because a reliable target-specific diagnosis at premotor stages is essential for the application of disease-modifying treatment, which is currently developed. Isolated REM sleep behavior disorder (iRBD) is considered a specific prodromal stage of alpha-synucleinopathies as up to 80% of patients with iRBD develop manifest PD, dementia with Lewy bodies (DLB) or less frequently multiple system atrophy (MSA) within 15–20 years [3,4]. In 2017, dermal p-syn deposition in patients with iRBD was independently reported by two groups from Germany (Würzburg/Marburg) and Italy (Bologna) [5,6] and was recently confirmed by another study [7]. These results indicated that many iRBD patients may already present with an indicator of an alpha-synucleinopathy in the periphery and it was hypothesized that dermal p-syn deposition in iRBD might be considered a prodromal marker and a predictor of conversion to manifest PD, DLB or MSA [8].

In the collaborative study of the above two-centers, we performed clinical and skin biopsy follow-up investigations and studied the longitudinal consistency of initially skin biopsy positive and negative findings and aimed to investigate the predictive value of p-syn deposition in skin biopsies of iRBD patients for conversion to PD, DLB or MSA.

Section snippets

Patients

All participants (n = 30) of the two former studies on dermal p-syn deposition in iRBD conducted by the researchers at Bologna, Italy, between 2015 and 2017 [6] and by the researchers at Marburg/Würzburg between 2014 and 2016 [5] were asked for participation in the follow-up study. Additionally, five patients were recruited for a baseline skin biopsy shortly after completion of the former studies (Table 1). Two patients were lost to follow-up. Out of the remaining 33 patients 23 had been

Consistency of skin biopsy findings

All 18 at-baseline p-syn-positive patients remained positive in the follow-up biopsy. Six of the seven at-baseline p-syn-negative patients remained negative. One p-syn negative patient had converted to skin-biopsy-positive at follow-up. This particular patient (skin biopsy converter) had a normal FP-CIT-SPECT at baseline, but an impaired olfactory function. No follow-up FP-CIT-SPECT was performed nor had the iRBD patient converted to PD at follow-up.

To further assess the increase of p-syn over

Discussion

In the present follow-up study, we demonstrate consistency of skin biopsy findings during two to four years in 24 of 25 twice biopsied iRBD patients. In addition we report on the conversion to PD/DLB in 21.7% of at-baseline skin-biopsy-positive iRBD patients, but not in any at baseline p-syn-negative patient.

Positivity/negativity of skin biopsy and the number of positive biopsy sites were quite consistent over time and only a slight increase of positivity of distal biopsy sites was found that

Funding

The study was funded by a grant of International Parkinson Fonds to K. Doppler, W.H. Oertel and C. Sommer.

Authors’ roles

Kathrin Doppler, MD Study design, data analysis and interpretation, writing of the manuscript.

Elena Antelmi, MD, PhD Study design, data analysis and interpretation, revision of the manuscript.

Anastasia Kuzkina, MD Data acquisition and analysis.

Vincenzo Donadio, MD, PhD Data acquisition and interpretation of data.

Alex Incensi, BSc Data acquisition and analysis.

Giuseppe Plazzi, MD, PhD Interpretation of data, revision of the manuscript.

Fabio Pizza, MD, PhD Data acquisition and interpretation of

Financial disclosures

K. Doppler has nothing to disclose.

E. Antelmi has nothing to disclose.

A. Kuzkina has nothing to disclose.

V. Donadio has nothing to disclose.

A. Incensi has nothing to disclose.

G. Plazzi has nothing to disclose.

F. Pizza has nothing to disclose.

S. Marelli has nothing to disclose.

L. Ferini-Strambi has nothing to disclose.

M. Tinazzi has nothing to disclose.

A. Janzen has nothing to disclose.

E. Sittig has nothing to disclose.

G. Mayer has nothing to disclose.

J. Booij has nothing to disclose.

A. Sedghi

Acknowledgments

We thank Barbara Dekant, Antonia Kohl and Christine Höft for expert technical assistance. KD, CS, AJ and WHO were funded by a grant of International Parkinson Fonds. AK is supported by a grant of the Interdisciplinary Center of Clinical Research of the University Hospital Würzburg. WHO is Hertie-Senior-Research Professor supported by the Charitable Hertie Foundation, Frankfurt, Germany.

References (14)

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1

These authors contributed equally to the manuscript.

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