Ryul Kim, MD,^1,2 Jee-Young Lee, MD, PhD,^2* Yu Kyeong Kim, MD, PhD,^3* Heejung Kim, PhD,^3,4 Eun Jin Yoon, PhD,³ Jung Hwan Shin, MD, PhD,⁵ Dallah Yoo, MD,⁶ Hyunwoo Nam, MD, PhD,² and Beomseok Jeon, MD, PhD⁵

¹Department of Neurology, Inha University Hospital, Incheon, South Korea ²Department of Neurology, Seoul National University-Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, South Korea ³Department of Nuclear Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, South Korea ⁴Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, South Korea ⁵Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea ⁶Department of Neurology, Kyung Hee University Hospital, Seoul, South Korea

^*Corresponding author.

Background
It remains unclear whether and how the isolated rapid eye movement (REM) sleep behavior disorder (iRBD)-related metabolic pattern (RBDRP) changes with disease progression in iRBD.

Objective
To examine longitudinal changes in RBDRP expression in iRBD patients and to explore trajectories of relative metabolic activities of individual brain regions constituting RBDRP.

Methods
In this cohort study, 25 iRBD patients (mean age [±standard deviation], 69.2 ± 5.3 years; 12 [48%] patients were men) and 24 age-matched healthy controls were included. The patients underwent at least two ¹⁸F-fluorodeoxyglucose positron emission tomography scans at baseline and at the 2-year and/or 4-year follow-ups. We measured the RBDRP expression of the patients and controls which was validated by reproduction in a separate iRBD cohort (n = 13).

Results
At baseline, the RBDRP expression discriminated iRBD patients from healthy controls. However, the RBDRP expression z scores tended to decrease over time in the patients, especially with longer follow-ups, and this tendency was observed even in patients with high-risk of phenoconversion. Furthermore, the degree of RBDRP expression at baseline did not predict the disease conversion. The RBDRP breakdown was mainly provoked by the attenuation of relative hypermetabolism in the frontal cortex including premotor areas and relative hypometabolism in the occipital cortex. The putaminal metabolic activity increased steadily with the disease progression.

Conclusions
The RBDRP expression in iRBD patients was altered significantly over time. Some of the brain metabolic changes seem to represent attempted functional compensation against ongoing neurodegeneration. The RBDRP expression measurement at one time point may not be a reliable biomarker for predicting disease conversion.