Objective: To assess the utility of neuromelanin-MRI (NM-MRI) methods in a prodromal alpha-synuclein disorder, Pure Autonomic Failure (PAF).

Background: PAF is a peripheral alpha-synucleinopathy (AS) characterized by denervation of peripheral autonomic fibers and resulting autonomic dysfunction. PAF patients are at high risk of converting to a central AS (PD, MSA, or DLB), and do so at a rate of 14% per year [1]. There is a need for validated predictors of phenoconversion, given the goal of developing disease-modifying treatments. NM is an endogenous pigment created as a by-product of dopamine synthesis in the substantia nigra (SN), and is detectable using MRI methods. Previous studies have validated its use in PD and prodromal REM behavior disorder (RBD).

Method: We applied NM-MRI methods to assay SN integrity in 9 healthy controls and 9 with PAF. All participants completed a UPDRS-Motor exam, Mayo Sleep Questionnaire (history of RBD), and clinical evaluation of anosmia. To measure SN integrity, the signal contrast ratio (CR) between the SN and a reference region, the crus cerebri (CC), was determined. Bilateral 6×6-voxel ROIs were placed in the CC and the medial, central, and lateral parts of the SN, in 4 consecutive axial slices. The CR between the CC and each SN subregion was calculated using established methods.

Results: The mean age of the healthy control group was 61 years, with 5 male participants. The mean age of the PAF group was 69 years, with 6 males; the mean UPDRS-Motor score was 10.75 (range 3-26), 5 had both RBD and anosmia, 2 had RBD only, and 2 had anosmia only. 2 patients had recently been diagnosed with a manifest central AS (1 PD, 1 possible MSA). The main finding on NM-MRI was that the PAF group had decreased CR in the lateral SN compared to controls, while the CR in the medial SN was similar between the two groups.

Conclusion: Our findings suggest early lateral greater than medial SN loss in PAF. Notably, this pattern of SN degeneration has been observed in numerous studies of SN integrity in patients diagnosed with parkinsonian disorders. Continued study of the PAF population on a large scale will be beneficial for elucidating early brain changes in AS disorders; following these patients longitudinally may additionally help distinguish more subtle differences between those that develop PD, MSA, or DLB, as well as those who remain as PAF.

References: 1. Kaufmann H, Norcliffe-Kaufmann L, Palma J-A, et al. The Natural History of Pure Autonomic Failure: a U.S. Prospective Cohort. Ann Neurol. 2017;81(2):287-297. doi:10.1002/ana.24877

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neuromelamin-mri-in-patients-with-pure-autonomic-failure/