Background Recent studies reported abnormal alpha‐synuclein deposition in biopsy‐accessible sites of the peripheral nervous system in Parkinson's disease (PD). This has considerable implications for clinical diagnosis. Moreover, if deposition occurs early, it may enable tissue diagnosis of prodromal PD. Objective The aim of this study was to develop and test an automated bright‐field immunohistochemical assay of cutaneous pathological alpha‐synuclein deposition in patients with idiopathic rapid eye movement sleep behavior disorder, PD, and atypical parkinsonism and in control subjects. Methods For assay development, postmortem skin biopsies were taken from 28 patients with autopsy‐confirmed Lewy body disease and 23 control subjects. Biopsies were stained for pathological alpha‐synuclein in automated stainers using a novel dual‐immunohistochemical assay for serine 129‐phosphorylated alpha‐synuclein and pan‐neuronal marker protein gene product 9.5. After validation, single 3‐mm punch skin biopsies were taken from the cervical 8 paravertebral area from 79 subjects (28 idiopathic rapid eye movement sleep behavior disorder, 20 PD, 10 atypical parkinsonism, and 21 control subjects). Raters blinded to clinical diagnosis assessed the biopsies. Results The immunohistochemistry assay differentiated alpha‐synuclein pathology from nonpathological‐appearing alpha‐synuclein using combined phosphatase and protease treatments. Among autopsy samples, 26 of 28 Lewy body samples and none of the 23 controls were positive. Among living subjects, punch biopsies were positive in 23 (82%) subjects with idiopathic rapid eye movement sleep behavior disorder, 14 (70%) subjects with PD, 2 (20%) subjects with atypical parkinsonism, and none (0%) of the control subjects. After a 3‐year follow‐up, eight idiopathic rapid eye movement sleep behavior disorder subjects phenoconverted to defined neurodegenerative syndromes, in accordance with baseline biopsy results. Conclusion Even with a single 3‐mm punch biopsy, there is considerable promise for using pathological alpha‐synuclein deposition in skin to diagnose both clinical and prodromal PD. © 2020 International Parkinson and Movement Disorder Society

Decades of research on neurodegenerative diseases such as Parkinson's disease (PD) have shifted our focus from clinical symptomatic stages to one step earlier, the prodromal stage. There is convincing evidence showing that sleep disorders such as excessive daytime somnolence, insomnia, obstructive sleep apnea, and particularly REM sleep behavior disorder (RBD) are potential prodromal features starting years and decades before conversion to PD. This review aims to provide an overview on various sleep disorders as prodromal features of PD. We start with a discussion of how neuroanatomy of sleep might link to PD pathology. Afterwards, specific sleep disorders that are either known or suspected to be a prodromal symptom for PD, namely insomnia, sleep apnea, somnolence, and RBD, are discussed. Disturbances in serotonergic, cholinergic, dopaminergic, and glutamatergic neurotransmitter systems have made sleep disorders potential candidates for prodromal PD. Nevertheless, the strength of such linkage varies considerably for different entities. While RBD is by far the strongest prodromal manifestation for PD with a high likelihood of phenoconversion and there is reasonable evidence that somnolence can predict PD, data on the prodromal role of sleep apnea and insomnia is limited. Treatment options are available for symptomatic relief of prodromal sleep disorders; however, there is a dearth of knowledge on neuroprotective agents to be used on people with prodromal sleep disorders to either prevent or postpone conversion to PD.