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Abstract
Objective: To investigate structural and functional connectivity changes in brain olfactory-related structures in a longitudinal prospective cohort of isolated REM sleep behavior disorder (iRBD) and their clinical correlations, longitudinal evolution, and predictive values for phenoconversion to overt synucleinopathies, especially Lewy body diseases.

Methods: The cohort included polysomnography-confirmed iRBD patients and controls. Participants underwent baseline assessments including olfactory tests, neuropsychological evaluations, the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, 3T brain MRI, and 18 F-FP-CIT PET scans. Voxel-based morphometry (VBM) was performed to identify regions of atrophy in iRBD, and volumes of relevant olfactory-related regions of interest (ROI) were estimated. Subgroups of patients underwent repeated volumetric MRI and resting-state functional MRI (fMRI) scans after four years.

Results: A total of 51 iRBD patients were included, with 20 of them converting to synucleinopathy (mean time to conversion 3.08 years). Baseline VBM analysis revealed atrophy in the right olfactory cortex and gyrus rectus in iRBD. Subsequent ROI comparisons with controls showed atrophy in the amygdala. These olfactory-related atrophies tended to be associated with worse depression, anxiety, and urinary problems in iRBD. Amygdala 18 F-FP-CIT uptake tended to be reduced in iRBD patients with hyposmia (nonsignificant after multiple comparison correction) and correlated with urinary problems. Resting-state fMRI of 23 patients and 32 controls revealed multiple clusters with aberrant olfactory-related functional connectivity. Hypoconnectivity between the putamen and olfactory cortex was associated with mild parkinsonian signs in iRBD. Longitudinal analysis of volumetric volumetric MRI in 22 iRBD patients demonstrated four-year progression of olfactory-related atrophy. Cox regression analysis revealed that this atrophy significantly predicted phenoconversion.

Interpretation: Progressive atrophy of central olfactory structures may be a potential indicator of Lewy body disease progression in iRBD.

Affiliations

Kyung Ah Woo # 1, Heejung Kim # 2 3, Eun Jin Yoon 2 4, Jung Hwan Shin 5, Hyunwoo Nam 1, Beomseok Jeon 5, Yu Kyeong Kim 2, Jee-Young Lee 1
1Department of Neurology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea.
2Department of Nuclear Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea.
3Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea.
4Memory Network Medical Research Center, Seoul National University, Seoul, Republic of Korea.
5Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
#Contributed equally.