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      Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson’s disease

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          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.

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          The online version of this article (doi:10.1007/s00401-017-1684-z) contains supplementary material, which is available to authorized users.

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          European multicentre database of healthy controls for [123I]FP-CIT SPECT (ENC-DAT): age-related effects, gender differences and evaluation of different methods of analysis.

          Dopamine transporter (DAT) imaging with [(123)I]FP-CIT (DaTSCAN) is an established diagnostic tool in parkinsonism and dementia. Although qualitative assessment criteria are available, DAT quantification is important for research and for completion of a diagnostic evaluation. One critical aspect of quantification is the availability of normative data, considering possible age and gender effects on DAT availability. The aim of the European Normal Control Database of DaTSCAN (ENC-DAT) study was to generate a large database of [(123)I]FP-CIT SPECT scans in healthy controls. SPECT data from 139 healthy controls (74 men, 65 women; age range 20-83 years, mean 53 years) acquired in 13 different centres were included. Images were reconstructed using the ordered-subset expectation-maximization algorithm without correction (NOACSC), with attenuation correction (AC), and with both attenuation and scatter correction using the triple-energy window method (ACSC). Region-of-interest analysis was performed using the BRASS software (caudate and putamen), and the Southampton method (striatum). The outcome measure was the specific binding ratio (SBR). A significant effect of age on SBR was found for all data. Gender had a significant effect on SBR in the caudate and putamen for the NOACSC and AC data, and only in the left caudate for the ACSC data (BRASS method). Significant effects of age and gender on striatal SBR were observed for all data analysed with the Southampton method. Overall, there was a significant age-related decline in SBR of between 4 % and 6.7 % per decade. This study provides a large database of [(123)I]FP-CIT SPECT scans in healthy controls across a wide age range and with balanced gender representation. Higher DAT availability was found in women than in men. An average age-related decline in DAT availability of 5.5 % per decade was found for both genders, in agreement with previous reports. The data collected in this study may serve as a reference database for nuclear medicine centres and for clinical trials using [(123)I]FP-CIT SPECT as the imaging marker.
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            Olfactory dysfunction predicts early transition to a Lewy body disease in idiopathic RBD.

            The aim of the present study was to determine the predictive value of olfactory dysfunction for the early development of a synuclein-mediated neurodegenerative disease in subjects with idiopathic REM sleep behavior disorder (iRBD) over an observational period of 5 years.
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              Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy--a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group.

              We aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD.
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                Author and article information

                Contributors
                ++49 931 20123787 , Doppler_K@ukw.de
                Journal
                Acta Neuropathol
                Acta Neuropathol
                Acta Neuropathologica
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0001-6322
                1432-0533
                8 February 2017
                8 February 2017
                2017
                : 133
                : 4
                : 535-545
                Affiliations
                [1 ]ISNI 0000 0001 1378 7891, GRID grid.411760.5, Department of Neurology, , University Hospital Würzburg, ; Josef-Schneider-Str. 11, 97080 Würzburg, Germany
                [2 ]ISNI 0000 0004 1936 9756, GRID grid.10253.35, Department of Neurology, , Philipps University Marburg, ; Baldingerstr., 35043 Marburg, Germany
                [3 ]ISNI 0000 0004 1936 9756, GRID grid.10253.35, Department of Nuclear Medicine, , Philipps University Marburg, ; Baldingerstr., 35043 Marburg, Germany
                [4 ]ISNI 0000 0001 1378 7891, GRID grid.411760.5, Department of Nuclear Medicine, , University Hospital Würzburg, ; Oberdürrbacher Str. 6, 97080 Würzburg, Germany
                [5 ]ISNI 0000000084992262, GRID grid.7177.6, Department of Nuclear Medicine, Academic Medical Centre, , University of Amsterdam, ; Meibergdreef 9, 1105 Amsterdam, The Netherlands
                [6 ]ISNI 0000 0000 9428 7911, GRID grid.7708.8, Department of Neurology, , University Hospital Freiburg, ; Breisacher Str. 64, 79106 Freiburg, Germany
                [7 ]Institute for Neurogenomics, Helmholtz Institute for Health and Environment, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
                Article
                1684
                10.1007/s00401-017-1684-z
                5348554
                28180961
                88b53e2a-8495-4c57-b88d-bf047f0464dc
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 20 January 2017
                : 31 January 2017
                : 4 February 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100008383, Stichting ParkinsonFonds;
                Award ID: none
                Award Recipient :
                Categories
                Original Paper
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2017

                Neurology
                rem sleep behaviour disorder,parkinson’s disease,alpha-synuclein,skin biopsy,fp-cit-spect

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