Defining progression of cutaneous autonomic denervation in orthostatic hypotension and pure autonomic failure

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Synucleinopathies are a group of neurodegenerative disorders characterized by the pathological accumulation of the protein α-synuclein (α-Syn) in form of Lewy bodies and Lewy neurites. They include the more prevalent Parkinson’s disease (PD) and Lewy body dementia (LBD), as well as multiple system atrophy (MSA) and pure autonomic failure (PAF). Patients with PAF can either suffer from slowly progressive orthostatic hypotension without abnormalities of the central nervous system (CNS), or develop cognitive and/or motor deficits. They are then diagnosed with PD, LBD or MSA based on the observed clinical differences.Currently, efforts have been made in the search for predictors and markers of disease in individuals at risk of developing synucleinopathies, or, in the case of patients with PAF, phenoconverting to other synucleinopathies with widespread CNS involvement. Immunohistochemical detection of intraneural α-Syn deposition in autonomic small fibers of the skin has been shown in recent experimental studies to be a safe and reliable method to study pathology in synucleinopathies. However, the role of repeated assessments of skin nerve pathology in the early identification of which individuals will develop a synucleinopathy or evolve from PAF to a more severe form remains to be elucidated.We hypothesize that individuals at risk of developing a synucleinopathy or with PAF but at risk of evolution to a synucleinopathy with CNS involvement display a more pronounced neurodermal α-Syn deposition after one year when compared with baseline. We further hypothesize that measurements of clinical deterioration and parameters of autonomic cardiac function predict more rapid progression of cutaneous α-Syn deposition in these patients.A longitudinal study will be undertaken in 20 patients with newly diagnosed orthostatic hypotension, newly diagnosed PAF without CNS abnormalities or PAF with signs of disease spread to motor and/or cognitive neurons. Study participants will undergo detailed neurological and neuropsychiatric evaluation and autonomic cardiovascular phenotyping. Analysis of structural damage of autonomic small fibers mediated by α-synuclein deposition will be carried out using immunohistochemical assessment of superficial skin biopsies. Evaluations will be performed at baseline and after 12 months. We anticipate that the observations derived from this study might help solve the current search for reliable disease-specific biomarkers.