Progressive Olfactory Impairment and Cardiac Sympathetic Denervation in REM Sleep Behavior Disorder

Background: Isolated rapid eye movement sleep behavior disorder (iRBD) is prodromal for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Objective: We investigated the use of cardiac [123I]meta-iodo-benzyl-guanidine scintigraphy ([123I]MIBG) and olfactory testing— in comparison to [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single photon emission computed tomography ([123I]FP-CIT-SPECT)— for identifying iRBD patients as prodromal phenotype of PD/DLB. Methods: 37 RBD subjects underwent cardiac [123I]MIBG and brain [123I]FP-CIT-SPECT at baseline. Olfactory (Sniffin’ Sticks), cognitive and motor functions were tested annually for ∼4 years. Results: 29/37 (78.4%) subjects had a pathological [123I]MIBG, of whom 86.2% (25/29) presented at least a moderate hyposmia at baseline (threshold/discrimination/identification-(TDI-)score ≤25). 20/37 (54.1%) subjects had a pathological [123I]FP-CIT-SPECT, always combined with a pathological [123I]MIBG. In subjects with pathological [123I]MIBG, olfactory function worsened (mainly due to threshold and discrimination subscores) from baseline to follow-up (p = 0.005). Olfaction was more impaired in subjects with pathological [123I]MIBG compared to those with normal [123I]MIBG at baseline (p = 0.001) and follow-up (p < 0.001). UPDRS-III scores increased in subjects with both pathological [123I]MIBG and [123I]FP-CIT-SPECT. In this group, seven subjects phenoconverted to PD, all— except for one— presented with at least moderate hyposmia at baseline. Conclusion: A combination of the biomarkers “pathological [123I]MIBG” and “hyposmia” likely identifies iRBD patients in an early prodromal stage of PD/DLB, i.e., before nigrostriatal degeneration is visualized. One-third of the subjects with pathological [123I]MIBG had a normal [123I]FP-CIT-SPECT. Noteworthy, in iRBD subjects with pathological [123I]MIBG, olfactory impairment is progressive independent of the [123I]FP-CIT-SPECT status.