Since RBD is known as a prodromal stage of alpha-synucleinopathy related neurodegenerative disease, an objective marker of iRBD may suggest or predict the presence of alpha-synucleinopathy. In this study, we identified the decrease in MIBG uptake in patients with iRBD compared to healthy controls, and, also found that RWA is correlated with the degree of decreased MIBG uptake. Previous studies have reported a decrease in MIBG uptake in patients with iRBD.17,18,22,34 The pattern of MIBG uptake in RBD patients is analogous to that of PD/DLB.35 Therefore, a decrease of MIBG uptake before the occurrence of presynaptic dopaminergic neuronal loss indicates that MIBG cardiac scintigraphy may be a biomarker. However, there is insufficient evidence to determine whether reduced MIBG absorption in RBD patients predicts a conversion to PD or suggests a worse outcome.
A previous study has reported that cognitive functions of patients with RBD may deteriorate after the diagnosis of PD, not before conversion to PD.36 However, decreased MIBG uptake in cardiac scintigraphy, which stands for sympathetic denervation of heart is profound in PD with RBD, PD with orthostatic hypotension, and PD with wearing off.37,38 In addition, low MIBG uptake predict Lewy body pathology before the motor symptoms of parkinsonism.19,39 This suggests that the decreased uptake in MIBG cardiac scintigraphy may be an indicator of disease progression in alpha synucleinopathy.40
There have been several studies that suggested cut-off value of MIBG uptake value for differentiation between iRBD and normal controls, PD, or OSA.18,41,42 RWA is associated with increased rigidity, progression of Lewy body dementia, and PD development.43–45 Consequently, recent studies indicated that RWA may serve as a biomarker for neurodegenerative disease emerged from iRBD.46,47 To the best of our knowledge, this is the first study that demonstrated the lower HMR may predict higher RWA. In this study, we set the cut-off value within the iRBD group and showed the association between decreased MIBG uptake and RWA. This suggests clinical applicability of MIBG cardiac scintigraphy to predict the diagnosis or disease progression of alpha-synucleinopathy. It is unclear why there was a relationship between MIBG uptake and RWA severity. It has been suggested that the medullary magnocellular reticular formation is related to the mechanism of RWA in RBD.48 In addition, ventromedial medulla, tegmental periacqueductal grey matter, and mesopontine cholinergic nuclei also suggested to be related to RBD.49,50 Since these brain stem structures are close to the sympathetic nerve activation center, there is abundant probability of a connection between them.
Although this study failed to show statistical quantitative associations, we believe that there will be a significant correlation between the severity of RWA and HMR. We surmise that the widely distributed RWA (%) might resulted in non-significance. In other words, the significance of this study is that we found clinical significance of MIBG cardiac scintigraphy based on the cut-off value, although we could not show statistical correlation between RWA and MIBG uptake due to the sharp changes in RWA.
In subgroup analysis in the patients with iRBD, when comparing the total, factor 1 (dream-related), and factor 2 (behavioral manifestation) scores of RBDQ-KR, there was no difference between the two groups. This means that changes in HMR precede differences in RBD symptoms, such as dream related or behavioral manifestations. Although statistical significance was not observed, in the group where HMR was higher than the cut-off value, the RBD onset age was younger, and the disease duration and interval of symptoms to PSG were longer. Even if the age of MIBG cardiac scintigraphy was similar, it can be considered that postganglionic heart sympathetic nerve endings is more preserved in patients whose RBD symptoms begin at a younger age. Although advanced age is known as a risk factor for PD incidence in patients with iRBD,51 no research has been reported on RBD onset age.
There are several limitations in this study. First, the small number of subjects from a single hospital. Second, we cannot exclude secondary RBD caused by structural brain lesion. Third, no quantified autonomic function test performed in all subjects, and PSG was not performed in the healthy control group. Fourth, when sub-analysis was performed within the iRBD group, there was a large numerical difference between the two subgroups. Lastly, if this study had a comparative group of neurological degenerative diseases, it would have been a better study.
This study showed decreased uptake of MIBG cardiac scintigraphy in patients with iRBD were associated with severity of RWA. Combination of MIBG cardiac scintigraphy and RWA is a potential biomarker that may predict the emergence of neurodegenerative disease. Further long-term follow-up study of the iRBD with the high and low levels of HMR is needed.