Brain Metabolism Related to Mild Cognitive Impairment and Phenoconversion in Patients With Isolated REM Sleep Behavior Disorder

Abstract

Background and objectives: Mild cognitive impairment (MCI) in isolated REM sleep behavior disorder (iRBD) is a risk factor for subsequent neurodegeneration. We aimed to identify brain metabolism and functional connectivity changes related to MCI in patients with iRBD and the neuroimaging markers' predictive value for phenoconversion.

Methods: This is a prospective cohort study of patients with iRBD with a mean follow-up of 4.2 ± 2.6 years. At baseline, patients with iRBD and age- and sex-matched healthy controls (HCs) underwent ¹⁸F-fluorodeoxyglucose (FDG)-PET and resting-state fMRI scans and a comprehensive neuropsychological test battery. Voxel-wise group comparisons for FDG-PET data were performed using a general linear model. Seed-based connectivity maps were computed using brain regions showing significant hypometabolism associated with MCI in patients with iRBD and compared between groups. A Cox regression analysis was applied to investigate the association between brain metabolism and risk of phenoconversion.

Results: Forty patients with iRBD, including 21 with MCI (iRBD-MCI) and 19 with normal cognition (iRBD-NC), and 24 HCs were included in the study. The iRBD-MCI group revealed relative hypometabolism in the inferior parietal lobule, lateral and medial occipital, and middle and inferior temporal cortex bilaterally compared with HC and the iRBD-NC group. In seed-based connectivity analyses, the iRBD-MCI group exhibited decreased functional connectivity of the left angular gyrus with the occipital cortex. Of 40 patients with iRBD, 12 patients converted to Parkinson disease (PD) or dementia with Lewy bodies (DLB). Hypometabolism of the occipital pole (hazard ratio [95% CI] 6.652 [1.387-31.987]), medial occipital (4.450 [1.143-17.327]), and precuneus (3.635 [1.009-13.093]) was associated with higher phenoconversion rate to PD/DLB.

Discussion: MCI in iRBD is related to functional and metabolic changes in broad brain areas, particularly the occipital and parietal areas. Moreover, hypometabolism in these brain regions was a predictor of phenoconversion to PD or DLB. Evaluation of cognitive function and neuroimaging characteristics could be useful for risk stratification in patients with iRBD.

Figure 1. Brain Glucose Metabolism in Patients With iRBD Associated With Their Cognitive Function

(A) The isolated REM sleep behavior disorder (iRBD)–mild cognitive impairment (MCI) group revealed relative hypometabolism in the bilateral inferior parietal lobule, lateral and medial occipital, precuneus, and middle and inferior temporal cortex compared with the iRBD–normal cognition (NC) group and healthy controls (HC). (B) In patients with iRBD, the left temporo-occipital region showed positive correlation with Color–Word Stroop Test (CWST) and the right angular gyrus showed positive correlation with Seoul Verbal Learning Test (SVLT) delayed recall.

Figure 2. Group Differences in Functional Connectivity of the Left Angular Gyrus

(A) Seed region in the left angular gyrus was overlaid on the hypometabolism map comparing the isolated REM sleep behavior disorder (iRBD)–mild cognitive impairment (MCI) group and the iRBD–normal cognition (NC) group. (B) The iRBD-MCI group exhibited reduced functional connectivity of the left angular gyrus with the bilateral lingual and superior part of lateral occipital cortex and inferior part of lateral occipital cortex compared with healthy controls (HC).

Figure 3. Survival Curves of Phenoconversion to Parkinson Disease or Dementia With Lewy Bodies

(A) Mild cognitive impairment (MCI)–normal cognition (NC) was not associated with phenoconversion to Parkinson disease (PD)/dementia with Lewy bodies (DLB). (B) Mean FDG uptake within the clusters showing significant hypometabolism in the isolated REM sleep behavior disorder (iRBD)–MCI group compared with the iRBD–NC group was extracted from each participant. The clusters were divided into anatomical structures using the Harvard-Oxford atlas. (C) Baseline glucose metabolism in the occipital pole, medial occipital, and precuneus predicted phenoconversion to PD/DLB after adjusting for age and duration of iRBD. The cutpoint was defined as the 1 SD value of the mean ¹⁸F-fluorodeoxyglucose (FDG) uptake in HC. HR = hazard ratio.