Objective: We hypothesized that early structural changes in the brain olfactory relevant structures may help early identification of those at risk of future disease conversion to synucleinopathy in patients with iRBD.

Background: The olfactory structures represent one of the earliest sites of a-synuclein pathology in the brain. In the Braak staging system, Lewy pathology is first observed in the olfactory bulb and the dorsal motor nucleus of vagus, followed by amygdala and pons before the nigral dopaminergic neurons are affected. Alternative hypotheses also suggest that Lewy pathology may start intracranial in the olfactory entry route or the amygdala and spread within the brain.

Method: We recruited patients with iRBD and performed baseline assessments for prodromal parkinsonian symptoms, olfactory function, and cognition, along with structural, dopaminergic, and functional imaging. The patients were prospectively followed up for development of overt parkinsonism, and subgroups of patients underwent repeated structural and functional MRI after 4 years.

Results: Twenty patients out of the 51 iRBD patients developed overt synucleinopathy over a mean follow-up period of 4.11 years. At baseline, the iRBD patients had significant atrophy in the olfactory cortex, gyrus rectus, and amygdala, which correlated with severity of depression, urinary problem, and constipation. Amygdala FP-CIT uptake was reduced in the iRBD patients with hyposmia compared to those with normosmia and controls. Brain MRI followed up after 4 years in 22 iRBD patients showed progression of olfactory cortex, gyrus rectus, and amygdala atrophy, with the progression of amygdala atrophy more pronounced in patients with baseline olfactory dysfunction and synucleinopathy converters. Resting-state fMRI in 25 iRBD patients showed that the gyrus rectus-seeded global functional connectivity correlated with mild parkinsonian signs in iRBD. In Cox regression analysis adjusting for age and sex, olfactory cortex, gyrus rectus, and amygdala atrophy significantly predicted disease conversion, respectively.

Conclusion: Our findings demonstrate that alterations in the brain olfactory-related structures, namely the olfactory cortex, gyrus rectus, and amygdala, are closely related to early nonmotor features in the prodromal stages of synucleinopathy, and may be potential indicators of impending overt synucleinopathy.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/central-olfactory-structure-atrophy-is-linked-to-synucleinopathy-conversion-in-idiopathic-rem-sleep-behavior-disorder/