Central Involvement in Pure Autonomic Failure: Insights from Neuromelanin‐Sensitive Magnetic Resonance Imaging and 18F‐Fluorodopa‐Positron Emission Tomography

BackgroundCentral synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), involve alpha‐synuclein accumulation and dopaminergic cell loss in the substantia nigra (SN) and locus coeruleus (LC). Pure autonomic failure (PAF), a peripheral synucleinopathy, often precedes central synucleinopathies.ObjectivesTo assess early brain involvement in PAF using neuromelanin‐sensitive magnetic resonance imaging (NM‐MRI) and fluorodopa‐positron emission tomography (FDOPA‐PET), and to determine whether PAF patients with a high likelihood ratio (LR) for conversion to a central synucleinopathy exhibit reduced NM‐MRI contrast in the LC and SN compared with controls and low‐LR patients.MethodsParticipants with PAF (n = 23) were categorized as high‐LR (n = 13) or low‐LR (n = 10) for conversion to central synucleinopathy. Additional participants included PD (n = 22), DLB (n = 8), and age‐ and sex‐matched healthy controls (n = 23). NM‐MRI at 3 T was used to quantify contrast ratios in the LC and SN, while FDOPA‐PET measured presynaptic dopamine synthesis. Linear regression analyses, adjusted for age and sex, were used to compare NM‐MRI contrast across groups.ResultsHigh‐LR PAF patients showed reduced contrast in the LC and SN compared with controls and low‐LR PAF patients, with values similar to PD and DLB. The NM‐MRI contrast in the SN correlated with dopamine uptake in the striatum. Longitudinal imaging in PAF patients (n = 6) demonstrated reduced NM‐MRI and PET values in individuals who developed central synucleinopathies.ConclusionsNM‐MRI and FDOPA‐PET may serve as potential biomarkers for early brain involvement and predicting progression to central synucleinopathies in PAF and could help identify patients for early intervention. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.