The functional brain connectome in isolated rapid eye movement sleep behavior disorder and Parkinson's disease.

BACKGROUND: Isolated rapid-eye-movement behavior disorder (iRBD) often precedes the development of alpha-synucleinopathies such as Parkinson's disease (PD). Magnetic resonance imaging (MRI) studies have revealed structural brain alterations in iRBD partially resembling those observed in PD. However, relatively little is known about whole-brain functional brain alterations in iRBD. Here, we characterize the functional brain connectome of iRBD compared with PD patients and healthy controls (HC) using resting-state functional MRI (rs-fMRI). METHODS: Eighteen iRBD subjects (67.3 ± 6.6 years), 18 subjects with PD (65.4 ± 5.8 years), and 39 age- and sex-matched HC (64.4 ± 9.2 years) underwent rs-fMRI at 3 T. We applied a graph theoretical approach to analyze the brain functional connectome at the global and regional levels. Data were analyzed using both frequentist and Bayesian statistics. RESULTS: Global connectivity was largely preserved in iRBD and PD individuals. In contrast, both disease groups displayed altered local connectivity mainly in the motor network, temporal cortical regions including the limbic system, and the visual system. There were some group specific alterations, and connectivity changes were pronounced in PD individuals. Overall, however, there was a good agreement of the connectome changes observed in both disease groups. CONCLUSIONS: This study provides evidence for widespread functional brain connectivity alterations in iRBD, including motor circuitry, despite normal motor function. Connectome alterations showed substantial resemblance with those observed in PD, underlining a close pathophysiological relationship of iRBD and PD.

Reduced Gastric Contraction in Rapid-Eye-Movement Sleep Behavior Disorder and De Novo Parkinson's Disease.

BACKGROUND: Reduced gastric motility in Parkinson's disease (PD) has been reported, but hardly any study exists in subjects with isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD), a specific prodrome of α-synucleinopathies. OBJECTIVES: We compared the gastric motility of 17 iRBD subjects with that of 18 PD subjects (15 drug naive, 3 early treated in defined off) and 15 healthy controls (HC) with real-time magnetic resonance imaging (rtMRI). METHODS: After overnight fasting, participants consumed a standardized breakfast and underwent a 3-T rtMRI of the stomach. Amplitude and velocity of the peristaltic waves were analyzed under blinded conditions. Gastric motility index (GMI) was calculated. The procedure was repeated in 12 of 17 iRBD subjects ~2.5 years later. Nine of these 12 iRBD subjects were hyposmic. RESULTS: In iRBD and PD subjects the amplitude of the peristaltic waves was significantly reduced compared with HCs (iRBD vs. HC: 8.7 ± 3.7 vs. 11.9 ± 4.1 mm, P = 0.0097; PD vs. HC: 6.8 ± 2.2 vs. 11.9 ± 4.1 mm, P = 0.0001). The amplitude in iRBD and PD subjects was decreased to the same extent. The GMI was reduced in only PD subjects (PD vs. HC: P = 0.0027; PD vs. iRBD: P = 0.0203). After ~2.5 years the amplitude in iRBD subjects did not significantly decrease further. CONCLUSION: The amplitude of the peristaltic waves was markedly reduced in iRBD, a prodrome of α-synucleinopathies. This reduction was similar to the extent observed already in manifest early PD. This finding implies that the α-synuclein pathology affects the innervation of the stomach already in the prodromal stage. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Occipital hypometabolism is a risk factor for conversion to Parkinson's disease in isolated REM sleep behaviour disorder.

PURPOSE: Isolated REM sleep behaviour disorder (iRBD) patients are at high risk of developing clinical syndromes of the α-synuclein spectrum. Progression markers are needed to determine the neurodegenerative changes and to predict their conversion. Brain imaging with 18F-FDG PET in iRBD is promising, but longitudinal studies are scarce. We investigated the regional brain changes in iRBD over time, related to phenoconversion. METHODS: Twenty iRBD patients underwent two consecutive 18F-FDG PET brain scans and clinical assessments (3.7 ± 0.6 years apart). Seventeen patients also underwent 123I-MIBG and 123I-FP-CIT SPECT scans at baseline. Four subjects phenoconverted to Parkinson's disease (PD) during follow-up. 18F-FDG PET scans were compared to controls with a voxel-wise single-subject procedure. The relationship between regional brain changes in metabolism and PD-related pattern scores (PDRP) was investigated. RESULTS: Individual hypometabolism t-maps revealed three scenarios: (1) normal 18F-FDG PET scans at baseline and follow-up (N = 10); (2) normal scans at baseline but occipital or occipito-parietal hypometabolism at follow-up (N = 4); (3) occipital hypometabolism at baseline and follow-up (N = 6). All patients in the last group had pathological 123I-MIBG and 123I-FP-CIT SPECT. iRBD converters (N = 4) showed occipital hypometabolism at baseline (third scenario). At the group level, hypometabolism in the frontal and occipito-parietal regions and hypermetabolism in the cerebellum and limbic regions were progressive over time. PDRP z-scores increased over time (0.54 ± 0.36 per year). PDRP expression was driven by occipital hypometabolism and cerebellar hypermetabolism. CONCLUSIONS: Our results suggest that occipital hypometabolism at baseline in iRBD implies a short-term conversion to PD. This might help in stratification strategies for disease-modifying trials.

Dermal Real-Time Quaking-Induced Conversion Is a Sensitive Marker to Confirm Isolated Rapid Eye Movement Sleep Behavior Disorder as an Early α-Synucleinopathy.

BACKGROUND: Skin biopsy is a potential tool for the premortem confirmation of an α-synucleinopathy. OBJECTIVE: The aim was to assess the aggregation assay real-time quaking-induced conversion (RT-QuIC) of skin biopsy lysates to confirm isolated rapid eye movement sleep behavior disorder (iRBD) as an α-synucleinopathy. METHODS: Skin biopsies of patients with iRBD, Parkinson's disease (PD), and controls were analyzed using RT-QuIC and immunohistochemical detection of phospho-α-synuclein. RESULTS: α-Synuclein aggregation was detected in 97.4% of iRBD patients (78.4% of iRBD biopsies), 87.2% of PD patients (70% of PD biopsies), and 13% of controls (7.9% of control biopsies), with a higher seeding activity in iRBD compared to PD. RT-QuIC was more sensitive but less specific than immunohistochemistry. CONCLUSIONS: Dermal RT-QuIC is a sensitive method to detect α-synuclein aggregation in iRBD, and high seeding activity may indicate a strong involvement of dermal nerve fibers in these patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Progressive Olfactory Impairment and Cardiac Sympathetic Denervation in REM Sleep Behavior Disorder.

BACKGROUND: Isolated rapid eye movement sleep behavior disorder (iRBD) is prodromal for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). OBJECTIVE: We investigated the use of cardiac [123I]meta-iodo-benzyl-guanidine scintigraphy ([123I]MIBG) and olfactory testing- in comparison to [123I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane single photon emission computed tomography ([123I]FP-CIT-SPECT)- for identifying iRBD patients as prodromal phenotype of PD/DLB. METHODS: 37 RBD subjects underwent cardiac [123I]MIBG and brain [123I]FP-CIT-SPECT at baseline. Olfactory (Sniffin' Sticks), cognitive and motor functions were tested annually for ∼4 years. RESULTS: 29/37 (78.4%) subjects had a pathological [123I]MIBG, of whom 86.2% (25/29) presented at least a moderate hyposmia at baseline (threshold/discrimination/identification-(TDI-)score ≤25). 20/37 (54.1%) subjects had a pathological [123I]FP-CIT-SPECT, always combined with a pathological [123I]MIBG. In subjects with pathological [123I]MIBG, olfactory function worsened (mainly due to threshold and discrimination subscores) from baseline to follow-up (p = 0.005). Olfaction was more impaired in subjects with pathological [123I]MIBG compared to those with normal [123I]MIBG at baseline (p = 0.001) and follow-up (p < 0.001). UPDRS-III scores increased in subjects with both pathological [123I]MIBG and [123I]FP-CIT-SPECT. In this group, seven subjects phenoconverted to PD, all- except for one- presented with at least moderate hyposmia at baseline. CONCLUSION: A combination of the biomarkers "pathological [123I]MIBG" and "hyposmia" likely identifies iRBD patients in an early prodromal stage of PD/DLB, i.e., before nigrostriatal degeneration is visualized. One-third of the subjects with pathological [123I]MIBG had a normal [123I]FP-CIT-SPECT. Noteworthy, in iRBD subjects with pathological [123I]MIBG, olfactory impairment is progressive independent of the [123I]FP-CIT-SPECT status.

Eye tracking identifies biomarkers in α-synucleinopathies versus progressive supranuclear palsy.

OBJECTIVES: This study (1) describes and compares saccade and pupil abnormalities in patients with manifest alpha-synucleinopathies (αSYN: Parkinson's disease (PD), Multiple System Atrophy (MSA)) and a tauopathy (progressive supranuclear palsy (PSP)); (2) determines whether patients with rapid-eye-movement sleep behaviour disorder (RBD), a prodromal stage of αSYN, already have abnormal responses that may indicate a risk for developing PD or MSA. METHODS: Ninety (46 RBD, 27 PD, 17 MSA) patients with an αSYN, 10 PSP patients, and 132 healthy age-matched controls (CTRL) were examined with a 10-min video-based eye-tracking task (Free Viewing). Participants were free to look anywhere on the screen while saccade and pupil behaviours were measured. RESULTS: PD, MSA, and PSP spent more time fixating the centre of the screen than CTRL. All patient groups made fewer macro-saccades (> 2◦ amplitude) with smaller amplitude than CTRL. Saccade frequency was greater in RBD than in other patients. Following clip change, saccades were temporarily suppressed, then rebounded at a slower pace than CTRL in all patient groups. RBD had distinct, although discrete saccade abnormalities that were more marked in PD, MSA, and even more in PSP. The vertical saccade rate was reduced in all patients and decreased most in PSP. Clip changes produced large increases or decreases in screen luminance requiring pupil constriction or dilation, respectively. PSP elicited smaller pupil constriction/dilation responses than CTRL, while MSA elicited the opposite. CONCLUSION: RBD patients already have discrete but less pronounced saccade abnormalities than PD and MSA patients. Vertical gaze palsy and altered pupil control differentiate PSP from αSYN.

Rapid Eye Movement Sleep Behavior Disorder: Abnormal Cardiac Image and Progressive Abnormal Metabolic Brain Pattern.

BACKGROUND: Isolated rapid eye movement sleep behavior disorder (iRBD) is prodromal for α-synucleinopathies. OBJECTIVE: The aim of this study was to determine whether pathological cardiac [123 I]meta-iodobenzylguanidine scintigraphy ([123 I]MIBG) is associated with progression of [18 F]fluorodeoxyglucose-positron emission tomography-based Parkinson's disease (PD)-related brain pattern (PDRP) expression in iRBD. METHODS: Seventeen subjects with iRBD underwent [18 F]fluorodeoxyglucose-positron emission tomography brain imaging twice ~3.6 years apart. In addition, [123 I]MIBG and [123 I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane single-photon emission computed tomography ([123 I]FP-CIT-SPECT) at baseline were performed. Olfactory, cognitive, and motor functions were tested annually. RESULTS: Twelve of 17 subjects had pathological [123 I]MIBG. At baseline, 6 of 12 of these expressed the PDRP (suprathreshold PDRP z score). At follow-up, 12 of 17 subjects had suprathreshold PDRP z scores, associated with pathological [123 I]MIBG in 92% and with pathological [123 I]FP-CIT-SPECT in 75%. Subjects with pathological [123 I]MIBG had higher PDRP z score change per year (P = 0.027). Three subjects phenoconverted to PD; all had pathological [123 I]MIBG and [123 I]FP-CIT-SPECT, suprathreshold baseline PDRP z scores, and hyposmia. CONCLUSIONS: Pathological [123 I]MIBG was associated with progressive and suprathreshold PDRP z scores at follow-up. Abnormal [123 I]MIBG likely identifies iRBD as prodromal PD earlier than pathological [123 I]FP-CIT-SPECT. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Olfactory Testing in Parkinson Disease and REM Behavior Disorder: A Machine Learning Approach.

OBJECTIVE: We sought to identify an abbreviated test of impaired olfaction amenable for use in busy clinical environments in prodromal (isolated REM sleep behavior disorder [iRBD]) and manifest Parkinson disease (PD). METHODS: Eight hundred ninety individuals with PD and 313 controls in the Discovery cohort study underwent Sniffin' Stick odor identification assessment. Random forests were initially trained to distinguish individuals with poor (functional anosmia/hyposmia) and good (normosmia/super-smeller) smell ability using all 16 Sniffin' Sticks. Models were retrained using the top 3 sticks ranked by order of predictor importance. One randomly selected 3-stick model was tested in a second independent PD dataset (n = 452) and in 2 iRBD datasets (Discovery n = 241, Marburg n = 37) before being compared to previously described abbreviated Sniffin' Stick combinations. RESULTS: In differentiating poor from good smell ability, the overall area under the curve (AUC) value associated with the top 3 sticks (anise/licorice/banana) was 0.95 in the Development dataset (sensitivity 90%, specificity 92%, positive predictive value 92%, negative predictive value 90%). Internal and external validation confirmed AUCs ≥0.90. The combination of the 3-stick model determined poor smell, and an RBD screening questionnaire score of ≥5 separated those with iRBD from controls with a sensitivity, specificity, positive predictive value, and negative predictive value of 65%, 100%, 100%, and 30%. CONCLUSIONS: Our 3-Sniffin'-Stick model holds potential utility as a brief screening test in the stratification of individuals with PD and iRBD according to olfactory dysfunction. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a 3-Sniffin'-Stick model distinguishes individuals with poor and good smell ability and can be used to screen for individuals with iRBD.

Four-Year Follow-up of [18 F]Fluorodeoxyglucose Positron Emission Tomography-Based Parkinson's Disease-Related Pattern Expression in 20 Patients with Isolated Rapid Eye Movement Sleep Behavior Disorder Shows Prodromal Progression.

BACKGROUND: Isolated rapid eye movement sleep behavior disorder is known to be prodromal for alpha-synucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies. The [18 F]fluorodeoxyglucose-positron emission tomography (PET)-based PD-related brain pattern can be used to monitor disease progression. OBJECTIVE: We longitudinally investigated PD-related brain pattern expression changes in 20 subjects with isolated rapid eye movement sleep behavior disorder to investigate whether this may be a suitable technique to study prodromal PD progression in these patients and to identify potential phenoconverters. METHODS: Subjects underwent two [18 F]fluorodeoxyglucose-PET brain scans ~3.7 years apart, along with baseline and repeated motor, cognitive, and olfactory testing within roughly the same time frame. RESULTS: At baseline, 8 of 20 (40%) subjects significantly expressed the PD-related brain pattern (with z scores above the receiver operating characteristic-determined threshold). At follow-up, six additional subjects exhibited significant PD-related brain pattern expression (70% in total). PD-related brain pattern expression increased in all subjects (P = 0.00008). Four subjects (20%), all with significant baseline PD-related brain pattern expression, phenoconverted to clinical PD. CONCLUSIONS: Suprathreshold PD-related brain pattern expression and greater score rate of change may signify greater shorter-term risk for phenoconversion. Our results support the use of serial PD-related brain pattern expression measurements as a prodromal PD progression biomarker in patients with isolated rapid eye movement sleep behavior disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Convergent patterns of structural brain changes in rapid eye movement sleep behavior disorder and Parkinson's disease on behalf of the German rapid eye movement sleep behavior disorder study group.

STUDY OBJECTIVES: Rapid eye movement sleep behavior disorder (RBD) is considered a prodromal state of Parkinson's disease (PD). We aimed to characterize patterns of structural brain changes in RBD and PD patients using multimodal MRI. METHODS: A total of 30 patients with isolated RBD, 29 patients with PD, and 56 age-matched healthy controls (HC) underwent MRI at 3T, including tensor-based morphometry, diffusion tensor imaging, and assessment of cortical thickness. RESULTS: RBD individuals showed increased volume of the right caudate nucleus compared with HC, and higher cerebellar volume compared with both PD subjects and HC. Similar to PD subjects, RBD patients displayed increased fractional anisotropy (FA) in the corticospinal tracts, several tracts mainly related to non-motor function, and reduced FA of the corpus callosum compared with HC. Further, RBD subjects showed higher FA in the cerebellar peduncles and brainstem compared with both, PD patients and HC. PD individuals exhibited lower than normal volume in the basal ganglia, midbrain, pedunculopontine nuclei, and cerebellum. In contrast, volume in PD subjects was increased in the thalamus compared with both HC and RBD subjects. CONCLUSIONS: We found convergent patterns of structural brain alterations in RBD and PD patients compared with HC. The changes observed suggest a co-occurrence of neurodegeneration and compensatory mechanisms that fail with emerging PD pathology. Our findings strengthen the hypothesis of RBD and PD constituting a continuous disease spectrum.