Cutaneous phosphorylated-synuclein: an early diagnostic biomarker for pure autonomic failure

<h3>Introduction</h3> Pure autonomic failure (PAF) presents with progressive autonomic failure without other neurological features. Atypical presentations may lead to diagnostic uncertainty. We studied whether cutaneous phosphorylated-synuclein (p-syn) could distinguish between PAF, multiple system atrophy (MSA), and non-synucleinopathy related autonomic failure, and its correlation with quantitative markers of autonomic failure. <h3>Methods</h3> Patients underwent autonomic questionnaires, cardiovascular autonomic testing and bilateral distal leg skin biopsies. We noted whether p-syn was present in nerves supplying autonomic adnexa, including sweat glands, blood vessels, arrector pili muscles, and subepidermal fibres, dermal fibres and nerve fascicles (maximum autonomic subscore 3 and total p-syn score 6 for each sample, average calculated for both sides). <h3>Results</h3> Thirty-six individuals were studied (11 PAF, 13 MSA, 12 non-synucleinopathy related autonomic failure). P-syn was present in 22/22 (100%) PAF biopsies, 19/26 (73%) MSA biopsies, and 0/22 (0%) non-synucleinopathy biopsies. Total p-syn score was significantly higher in PAF (median 4.5) compared to MSA (median 1, <i>P</i>&lt;.001). Autonomic p-syn subscores correlated with orthostatic intolerance ratio on tilt (ρ=0.63, <i>P</i>=.0004), blood pressure recovery time following Valsalva manoeuvre (ρ=0.44, <i>P</i>=.03), and patient-reported orthostatic intolerance (ρ=0.57, <i>P</i>=.006). <h3>Conclusion</h3> Cutaneous p-syn was abundant in PAF, a predominantly peripheral alpha-synucleinopathy. It is a promising early diagnostic biomarker to help distinguish between PAF, MSA and non- synucleinopathy related autonomic failure. P-syn deposition on autonomic nerves may impair control of total peripheral resistance giving rise to symptomatic orthostatic hypotension.