Multimodal autonomic biomarkers differentiate pure autonomic failure from other alpha- synucleinopathies

<h3>Introduction</h3> Pure autonomic failure (PAF) presents with progressive autonomic failure without other neurological features. A third later develop central neurological features, fulfilling criteria for multiple system atrophy (MSA) and Lewy body diseases (LBD). We hypothesised that multimodal autonomic biomarkers could distinguish between PAF, MSA and LBD, and predict phenoconversion in patients presenting with PAF. <h3>Methods</h3> 391 patients (146 PAF, 157 MSA, 88 LBD) were studied with cardiovascular autonomic testing, plasma catecholamines, pupillometry, and patient questionnaires. Patients presenting initially with PAF were followed up to monitor for the emergence of central neurological features. Autonomic biomarkers at initial assessment were used in a logistic regression model to identify predictors for final diagnosis. <h3>Results</h3> Patients with a final diagnosis of PAF had significantly greater orthostatic hypotension on tilt, lower supine noradrenaline, and sympathetic pupillary deficits at initial assessment compared to MSA/LBD. 26% presenting with PAF phenoconverted to MSA/LBD, with normal supine noradrenaline &gt;200pg/ml (OR 2.4; p&lt;.001) and pupils (OR 4.7; p=.01) at first assessment predicting future phenoconversion. Patients with PAF reported more severe orthostatic intolerance with similarly diminished quality of life compared to MSA. <h3>Discussion</h3> We found more severe orthostatic hypotension, lower supine noradrenaline and more frequent sympathetic pupillary deficits in PAF compared to other alpha-synucleinopathies, suggestive of greater post-ganglionic adrenergic denervation. Severe symptomatic orthostatic hypotension is associated with marked physical disability in PAF, even in the absence of other neurological features.