Cutaneous α-synuclein is correlated with autonomic impairment in isolated rapid eye movement sleep behavior disorder

Abstract

Study Objectives To define the clinical implications of cutaneous phosphorylated α-synuclein (p-syn) and its association with subjective and objective measures of autonomic impairment and clinical features including antidepressant use in isolated REM sleep behavior disorder (iRBD). Methods Twenty-five iRBD patients had quantified neurological and cognitive examinations, olfactory testing, questionnaires, autonomic function testing, and 3 punch skin biopsies (distal thigh, proximal thigh, neck). Skin biopsies were stained for the pan-axonal marker PGP 9.5 and co-stained with p-syn, and results were compared to 28 patients with Parkinson’s disease (PD) and 18 healthy controls. Equal numbers of iRBD patients on and off antidepressants were recruited. The composite autonomic severity scale (CASS) was calculated for all patients. Results P-syn was detected in 16/25 (64%) of iRBD patients, compared to 27/28 (96%) of PD and 0/18 controls. The presence of p-syn at any biopsy site was correlated with both sympathetic (CASS adrenergic r = 0.6, p < 0.05) and total autonomic impairment (CASS total r = 0.6, p < 0.05) on autonomic reflex testing in iRBD patients. These results were independent of the density of p-syn at each site. There was no correlation between p-syn and antidepressant use. Conclusions In patients with iRBD, the presence of cutaneous p-syn was detected in most patients and was associated with greater autonomic dysfunction on testing. Longitudinal follow-up will aid in defining the predictive role of both skin biopsy and autonomic testing in determining phenoconversion rates and future disease status.

Fluid and Tissue Biomarkers of Lewy Body Dementia: Report of an LBDA Symposium

“…The Braak staging system for PD suggests that pathology begins in the peripheral autonomic nervous system or olfactory bulb and then migrates proximally to the amygdala and brainstem and in the more severe cases, to the cerebral cortex (50). This model is supported by some human studies, such as those of multiple groups finding high levels of alpha-synuclein pathology in skin biopsies in early PD and in REM-sleep behavior disorder (RBD) without other clinical evidence of synucleinopathy (20,21,(51)(52)(53)(54). However, the model is not supported by other large autopsy-based studies that find no evidence of peripheral-first synucleinopathy (e.g.…”

“…The skin biopsies prepared in this manner can also be quantified, and the first quantitative studies show significant autonomic and sensory nerve fiber density differences between groups, individuals with DLB having the most severe autonomic and sensory neuropathies, followed by idiopathic PD, and finally Multiple System Atrophy (MSA), without evidence of peripheral nerve degeneration. Dr. Gibbon's group also recently reported that cutaneous phospho-alpha-synuclein is moderately correlated (r = 0.6) with both sympathetic and total autonomic impairment in individuals with isolated REM sleep behavior disorder (iRBD) and is more common in iRBD with hyposmia (21).…”

Fluid and Tissue Biomarkers of Lewy Body Dementia: Report of an LBDA Symposium

“…The Braak staging system for PD suggests that pathology begins in the peripheral autonomic nervous system or olfactory bulb and then migrates proximally to the amygdala and brainstem and in the more severe cases, to the cerebral cortex (76). This model is supported by some human studies, such as those of multiple groups finding high levels of alpha-synuclein pathology in skin biopsies in early PD and REM-sleep behavior disorder (RBD) without other clinical evidence of synucleinopathy (12,25,26,(77)(78)(79). However, the model is not supported by other large autopsy-based studies that find no evidence of peripheral-first synucleinopathy (e.g., stomach vs. brain) and that peripheral synucleinopathy is more common and severe in later stages (80,81).…”

“…The skin biopsies prepared in this manner can also be quantified, and the first quantitative studies show significant autonomic and sensory nerve fiber density differences between groups, individuals with DLB having the most severe autonomic and sensory neuropathies, followed by idiopathic PD, and finally multiple system atrophy (MSA), without evidence of peripheral nerve degeneration. Dr. Gibbon's group also recently reported that cutaneous phospho-alpha-synuclein is moderately correlated (r = 0.6) with both sympathetic and total autonomic impairment in individuals with isolated REM sleep behavior disorder (iRBD) and is more common in iRBD with hyposmia (26).…”

Alpha-Synuclein at the Interface between Depression, Parkinson’s Disease and Dementia: Evidence from Epidemiology, Population Genetics and Gene-Environment Interactions

“…For example, it is now fairly well-established that idiopathic REM sleep behavior disorder (RBD), a parasomnia characterized by REM sleep without atonia and the "acting out" of dreams, often precedes the onset of neurodegeneration, particularly in Parkinson's disease and related synucleinopathies [29]. Low levels of cerebrospinal fluid α-synuclein have been associated with more severe symptoms of RBD in patients with early Parkinson's disease [30], while cutaneous levels of α-synuclein were associated with autonomic dysfunction -a non-motor symptom of Parkinsonism [31] -in patients with RBD but without any features of Parkinson's disease [32]. Thus, it is possible that the combination of RBD symptomatology and altered α-synuclein levels could identify a subset of patients at risk of progression to Parkinson's disease, and therefore suitable for trials of early interventions [25,33].…”