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

Central 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. To 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. Participants 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. High-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. NM-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.