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BackgroundPure autonomic failure (PAF) presents with autonomic failure without other neurological features. A third develop central neurological features, fulfilling criteria for multiple system atrophy (MSA) and Lewy body diseases (LBD), including Parkinson's disease and Dementia with Lewy bodies. We hypothesized multimodal autonomic biomarkers would identify differences between PAF, MSA, and LBD, and predict phenoconversion in patients presenting with PAF.MethodsThis observational cohort study included 391 alpha-synucleinopathy patients evaluated with cardiovascular autonomic testing, plasma noradrenaline, pupillometry, autonomic symptom, and quality-of-life questionnaires. PAF patients were monitored for the emergence of central neurological features. Logistic regression modeling was used to identify autonomic biomarkers at initial assessment that predicted future phenoconversion.ResultsPatients with PAF had more severe orthostatic hypotension, lower supine plasma noradrenaline, and frequent sympathetic pupillary deficits at initial assessment than MSA and LBD. 50/194 (26%) with PAF phenoconverted to MSA or LBD after a median of 13 years, with normal pupils, heart rate response to deep breathing ≥ 10 bpm, and supine plasma noradrenaline ≥ 200 pg/mL predicting future phenoconversion to MSA or LBD, with younger age at presentation and higher supine plasma noradrenaline levels associated with conversion to MSA.ConclusionIn patients presenting with PAF, normal pupillary function and supine plasma noradrenaline levels with intact cardiovagal responses were red flags for future phenoconversion. Younger patients with higher supine plasma noradrenaline levels were more likely to convert to MSA rather than LBD. A non-invasive multimodal autonomic assessment can help differentiate between alpha-synucleinopathies and predict phenoconversion from PAF to MSA or LBD.
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