Altered Brain Glymphatic Flow at Diffusion-Tensor MRI in Rapid Eye Movement Sleep Behavior Disorder.

Background Brain glymphatic dysfunction may contribute to the development of α-synucleinopathies. Yet, noninvasive imaging and quantification remain lacking. Purpose To examine glymphatic function of the brain in isolated rapid eye movement sleep behavior disorder (RBD) and its relevance to phenoconversion with use of diffusion-tensor imaging (DTI) analysis along the perivascular space (ALPS). Materials and Methods This prospective study included consecutive participants diagnosed with RBD, age- and sex-matched control participants, and participants with Parkinson disease (PD) who were enrolled and examined between May 2017 and April 2020. All study participants underwent 3.0-T brain MRI including DTI, susceptibility-weighted and susceptibility map-weighted imaging, and/or dopamine transporter imaging using iodine 123-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane SPECT at the time of participation. Phenoconversion status to α-synucleinopathies was unknown at the time of MRI. Participants were regularly followed up and monitored for any signs of α-synucleinopathies. The ALPS index reflecting glymphatic activity was calculated by a ratio of the diffusivities along the x-axis in the projection and association neural fibers to the diffusivities perpendicular to them and compared according to the groups with use of the Kruskal-Wallis and Mann-Whitney U tests. The phenoconversion risk in participants with RBD was evaluated according to the ALPS index with use of a Cox proportional hazards model. Results Twenty participants diagnosed with RBD (12 men; median age, 73 years [IQR, 66-76 years]), 20 control participants, and 20 participants with PD were included. The median ALPS index was lower in the group with RBD versus controls (1.53 vs 1.72; P = .001) but showed no evidence of a difference compared with the group with PD (1.49; P = .68). The conversion risk decreased with an increasing ALPS index (hazard ratio, 0.57 per 0.1 increase in the ALPS index [95% CI: 0.35, 0.93]; P = .03). Conclusion DTI-ALPS in RBD demonstrated a more severe reduction of glymphatic activity in individuals with phenoconversion to α-synucleinopathies. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Filippi and Balestrino in this issue.

Structural and functional brain alterations in patients with idiopathic rapid eye movement sleep behavior disorder.

OBJECTIVE: To investigate structural and functional alterations in patients with idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) compared with healthy controls. METHODS: Twenty-seven patients with polysomnography-confirmed iRBD and 33 healthy subjects were recruited. All subjects underwent a 3-tesla structural and resting-state functional magnetic resonance imaging (fMRI) examination. Voxel-based morphometry (VBM) analysis was performed to assess grey matter alterations between groups. The amplitude of low-frequency fluctuations (ALFF) was calculated and then compared to measure differences in spontaneous brain activity. Correlations were performed to explore associations between imaging metrics and clinical characteristics in iRBD patients. RESULTS: Compared with healthy controls, patients with iRBD had decreased grey matter volume in the frontal, temporal, parietal, occipital cortices as well as increased grey matter volume in cerebellum posterior lobe, putamen, and thalamus. Patients with iRBD also exhibited increased ALFF values in the right parahippocampal gyrus. Olfaction correlated with ALFF value changes in occipital cortices. CONCLUSIONS: Patients with iRBD had widespread decreases of grey matter volume. Increases of grey matter volume in cerebellum, putamen, and thalamus may suggest a compensatory effect, while the altered ALFF values in parahippocampal gyrus and occipital cortices may play a role in the underlying process of neurodegeneration in this disorder.

Altered sensorimotor cortex noradrenergic function in idiopathic REM sleep behaviour disorder - A PET study.

INTRODUCTION: Noradrenergic denervation is thought to aggravate motor dysfunction in Parkinson's disease (PD). In a previous PET study with the norepinephrine transporter (NART) ligand 11C-MeNER, we detected reduced NART binding in primary sensorimotor cortex (M1S1) of PD patients. Idiopathic rapid-eye-movement sleep behaviour disorder (iRBD) is a phenotype of prodromal PD. Using 11C-MeNER PET, we investigated whether iRBD patients showed similar NART binding reductions in M1S1 cortex as PD patients. Additionally, we investigated whether 11C-MeNER binding and loss of nigrostriatal dopamine storage capacity measured with 18F-DOPA PET were correlated. METHODS: 17 iRBD patients, 16 PD patients with (PDRBD+) and 14 without RBD (PDRBD-), and 25 control subjects underwent 11C-MeNER PET. iRBD patients also had 18F-DOPA PET. Volume-of-interest analyses and voxel-level statistical parametric mapping were performed. RESULTS: Partial-volume corrected 11C-MeNER binding potential (BPND) values in M1S1 differed across the groups (P = 0.022) with the iRBD and PDRBD+ groups showing significant reductions (controls vs. iRBD P = 0.007; control vs. PDRBD+P = 0.008). Voxel-wise comparisons confirmed reductions of M1S1 11C-MeNER binding in PD and iRBD patients. Significant correlation was seen between putaminal 18F-DOPA uptake and thalamic 11C-MeNER binding in iRBD patients (r2 = 0.343, P = 0.013). CONCLUSIONS: This study found altered noradrenergic neurotransmission in the M1S1 cortex of iRBD patients. The observed reduction of M1S1 11C-MeNER binding in iRBD may represent noradrenergic terminal degeneration or physiological down-regulation of NARTs in this prodromal phenotype of PD. The correlation between thalamic 11C-MeNER binding and putaminal 18F-DOPA binding suggests that these neurotransmitter systems degenerate in parallel in the iRBD phenotype of prodromal PD.

Smaller subcortical volume in Parkinson patients with rapid eye movement sleep behavior disorder.

Parkinson disease (PD) patients with rapid eye movement (REM) sleep behavior disorder (RBD) have worse motor symptoms and non-motor symptoms than patients without RBD. The aim of this study was to examine underlying differences in brain structure from a network perspective. Baseline data were obtained from Parkinson's Progression Markers Initiative (PPMI) participants. We divided PD patients and healthy controls (HC) into RBD positive and RBD negative using a cutoff score of ≥5 on the RBD screening questionnaire. HC with probable RBD were excluded. We first carried out a region-of-interest analysis of structural MRIs using voxel-based morphometry to study volumetric differences for the putamen, thalamus and hippocampus in a cross-sectional design. Additionally, an exploratory whole-brain analysis was performed. To study group differences from a network perspective, we then performed a 'seed-based' analysis of structural covariance, using the bilateral dorsal-caudal putamen, mediodorsal thalamus and anterior hippocampus as seed regions. The volume of the right putamen was smaller in PD patients with RBD. RBD symptom severity correlated negatively with volume of the right putamen, left hippocampus and left thalamus. We did not find any differences in structural covariance between PD patients with and without RBD. Presence of RBD and severity of RBD symptoms in PD are associated with smaller volumes of the putamen, thalamus and hippocampus.

Extrastriatal monoaminergic dysfunction and enhanced microglial activation in idiopathic rapid eye movement sleep behaviour disorder.

BACKGROUND: The majority of patients diagnosed with idiopathic rapid eye movement sleep behaviour disorder (iRBD) progress over time to a Lewy-type α-synucleinopathy such as Parkinson's disease or dementia with Lewy bodies. This in vivo molecular imaging study aimed to investigate if extrastriatal monoaminergic systems are affected in iRBD patients and if this coincides with neuroinflammation. METHODS: We studied twenty-one polysomnography-confirmed iRBD patients with 18F-DOPA and 11C-PK11195 positron emission tomography (PET) to investigate extrastriatal monoaminergic function and microglial activation. Twenty-nine healthy controls (n = 9 18F-DOPA and n = 20 11C-PK11195) were also investigated. Analyses were performed within predefined regions of interest and at voxel-level with Statistical Parametric Mapping. RESULTS: Regions of interest analysis detected monoaminergic dysfunction in iRBD thalamus with a 15% mean reduction of 18F-DOPA Ki values compared to controls (mean difference = -0.00026, 95% confidence interval [-0.00050 to -0.00002], p-value = 0.03). No associated thalamic changes in 11C-PK11195 binding were observed. Other regions sampled showed no 18F-DOPA or 11C-PK11195 PET differences between groups. Voxel-level interrogation of 11C-PK11195 binding identified areas with significantly increased binding within the occipital lobe of iRBD patients. CONCLUSION: Thalamic monoaminergic dysfunction in iRBD patients may reflect terminal dysfunction of projecting neurons from the locus coeruleus and dorsal raphe nucleus, two structures that regulate REM sleep and are known to be involved in the early phase of PD. The observation of significantly raised microglial activation in the occipital lobe of these patients might suggest early local Lewy-type α-synuclein pathology and possibly an increased risk for later cognitive dysfunction.

Diffuse occipital hypometabolism on [18 F]-FDG PET scans in patients with idiopathic REM sleep behavior disorder: prodromal dementia with Lewy bodies?

BACKGROUND: Previous longitudinal studies have revealed that specific patterns on [(18) F]-fluoro-d-glucose (FDG) positron emission tomography (PET) scans in patients with amnesic mild cognitive impairment can predict Alzheimer's disease (AD). However, the significance of particular patterns on [(18) F]-FDG PET scans in prodromal patients with dementia with Lewy bodies (DLB) remains unclear. METHODS: Based on the prevailing evidence that rapid eye movement (REM) sleep behavior disorder (RBD) often precedes the onset of DLB, [(18) F]-FDG PET scans of nine non-demented patients reporting recurrent nocturnal dream-enactment behavior in our memory clinic were compared with the normative database using three-dimensional stereotactic surface projection (3D-SSP) images. All patients underwent clinical and neuropsychological examinations as well as cardiac [(123) I]-metaiodobenzylguanidine ([(123) I]-MIBG) scintigraphy. RESULTS: Four patients were found to have diffuse areas of reduced cerebral metabolic rate of glucose (CMRglc), predominantly in the occipital lobe, which is the preferentially affected region in DLB patients. In contrast, five patients showed no such occipital hypometabolism; instead, these five patients showed hypometabolism in the left anterior cingulate gyrus (Broadmann area (BA) 24), right frontal lobe (BA 32) and right anterior temporal lobe (BA 38), which are the preferentially affected regions in Parkinson's disease rather than DLB. The extent of the reduction in CMRglc in the left occipital lobe was correlated with scores on the Bender Gestalt Test, which reflects visuospatial ability, but not with global cognitive measures. All patients showed reduced cardiac [(123) I]-MIBG levels, consistent with underlying Lewy body disease. CONCLUSION: These variations in [(18) F]-FDG PET scans raise the possibility that the specific pattern of CMRglc reduction may predict developing DLB in patients with idiopathic RBD. Further follow-up studies are needed, particularly on patients with diffuse occipital hypometabolism.

The implication of nigrostriatal dopaminergic degeneration in the pathogenesis of REM sleep behavior disorder.

BACKGROUND AND PURPOSE: The pathogenesis of rapid eye movement (REM) sleep behavior disorder (RBD) is not clear despite its frequent association with Parkinson's disease (PD). We investigated whether the nigrostriatal dopaminergic system is involved in the development of idiopathic RBD. METHODS: Fourteen patients with RBD, 14 patients with PD and 12 normal controls were included in the study. The diagnosis of RBD was confirmed on polysomnography. All the participants performed single-photon emission computed tomography imaging 3 h after injection of [(123)I]FP-CIT. During REM sleep of the RBD patients, each 30-s epoch was rated as 'tonic' when there was at least 50% of tonically maintained chin electromyography (EMG) activity in the epoch. Phasic EMG activities were calculated as the percentage of 3-s mini-epoch containing phasic EMG events (leg and chin, separately). RESULTS: The RBD patients showed a trend of lower binding in the striatum than the normal controls (P = 0.07), and the significance was revealed in the putamen (P = 0.02). However, in 11 individual cases of the 14 RBD patients, the dopamine transporter (DAT) densities in the putamen still remained within the normal range. In the RBD patients, there was no correlation between EMG activities and DAT densities. CONCLUSIONS: Nigrostriatal dopaminergic degeneration could be a part of the pathogenesis of RBD, but not essential for the development of RBD. The lack of correlation between RBD severity and DAT densities suggests that another pathogenic process not related to nigrostriatal dopaminergic transmission may be implicated in RBD.