Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson's disease.
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.
Department of Neurology, University Hospital Würzburg, Josef-Schneider-Str. 11, 97080, Würzburg, Germany. Doppler_K@ukw.de.
Kathrin
K
Doppler
Department of Neurology, Philipps University Marburg, Baldingerstr., 35043, Marburg, Germany.
Hanna-Maria
HM
Jentschke
Department of Neurology, University Hospital Würzburg, Josef-Schneider-Str. 11, 97080, Würzburg, Germany.
Lena
L
Schulmeyer
Department of Neurology, Philipps University Marburg, Baldingerstr., 35043, Marburg, Germany.
David
D
Vadasz
Department of Neurology, Philipps University Marburg, Baldingerstr., 35043, Marburg, Germany.
Annette
A
Janzen
Department of Nuclear Medicine, Philipps University Marburg, Baldingerstr., 35043, Marburg, Germany.
Markus
M
Luster
Department of Nuclear Medicine, Philipps University Marburg, Baldingerstr., 35043, Marburg, Germany.
Helmut
H
Höffken
Department of Neurology, Philipps University Marburg, Baldingerstr., 35043, Marburg, Germany.
Geert
G
Mayer
Department of Nuclear Medicine, University Hospital Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Germany.
Joachim
J
Brumberg
Department of Nuclear Medicine, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105, Amsterdam, The Netherlands.
Jan
J
Booij
Department of Neurology, University Hospital Würzburg, Josef-Schneider-Str. 11, 97080, Würzburg, Germany.
Thomas
T
Musacchio
Department of Neurology, University Hospital Würzburg, Josef-Schneider-Str. 11, 97080, Würzburg, Germany.|Department of Neurology, University Hospital Freiburg, Breisacher Str. 64, 79106, Freiburg, Germany.
Stephan
S
Klebe
Department of Neurology, Philipps University Marburg, Baldingerstr., 35043, Marburg, Germany.
Elisabeth
E
Sittig-Wiegand
Department of Neurology, University Hospital Würzburg, Josef-Schneider-Str. 11, 97080, Würzburg, Germany.
Jens
J
Volkmann
Department of Neurology, University Hospital Würzburg, Josef-Schneider-Str. 11, 97080, Würzburg, Germany.
Claudia
C
Sommer
Department of Neurology, Philipps University Marburg, Baldingerstr., 35043, Marburg, Germany.|Institute for Neurogenomics, Helmholtz Institute for Health and Environment, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
Wolfgang H
WH
Oertel
D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D016022:Case-Control Studies; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007866:Leg / Q000294:innervation / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D062706:Prodromal Symptoms; D011446:Prospective Studies; D020187:REM Sleep Behavior Disorder / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D019275:Radiopharmaceuticals; D012867:Skin / Q000294:innervation / Q000378:metabolism* / Q000473:pathology*; D012903:Smell; D015899:Tomography, Emission-Computed, Single-Photon; D014326:Tropanes; D051844:alpha-Synuclein / Q000378:metabolism*
D015415:Biomarkers; D050483:Dopamine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals; C497604:SNCA protein, human; D014326:Tropanes; D051844:alpha-Synuclein; C087552:2-carbomethoxy-8-(3-fluoropropyl)-3-(4-iodophenyl)tropane
Alpha-synuclein; FP-CIT-SPECT; Parkinson’s disease; REM sleep behaviour disorder; Skin biopsy