Reduced intraepidermal nerve fiber density in patients with REM sleep behavior disorder

Abstract Background Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) has been increasingly acknowledged to be an initial specific manifestation of alpha-synucleinopathies such as Parkinson’s disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB). Recent findings suggest that cutaneous abnormalities like small fiber neuropathy and alpha-synuclein deposition might reflect brain pathology and might function as early biomarkers in PD. This is the first study to elucidate whether iRBD patients already suffer from distinctive cutaneous features. Methods We examined skin punch biopsies from the distal leg of 18 iRBD patients and 22 age- and sex-matched controls using immunohistochemistry and microscopy. Further clinical evaluation included structured interviews, clinical motor and non-motor questionnaires and rating scales (e.g. Unified Parkinson’s disease rating scale [UPDRS], non-motor symptoms questionnaire [NMS-Quest] and Beck Depression Inventory, Epworth Sleepiness Scale, evaluation of cognitive and olfactory functioning as well as blood samples. Results Intraepidermal nerve fiber density (IEFND) was reduced in iRBD patients compared to controls ( p  = 0.037), whereas the axon swelling ratio did not differ between groups. Patients with iRBD reported non-motor symptoms more frequently than controls (UPDRS I, NMS-Quest). Olfaction and daytime sleepiness differed between both groups, whereas there were no differences regarding cognition. Conclusions These in vivo findings demonstrate small fiber neuropathy in iRBD patients that are associated with non-motor symptoms indicating that peripheral abnormalities may occur early in iRBD. However, the prognostic value has to be further investigated in longitudinal studies.