Progressive Neurodegeneration of Noradrenergic Locus Coeruleus in REM Sleep Behavior Disorder
Poster No:
151
Submission Type:
Abstract Submission
Authors:
Rahul Gaurav1, François-Xavier Lejeune1, Pauline Dodet1,2, Romain Valabrègue1, Graziella Mangone1,2, Smaranda Leu-Semenescu2, Jean-Christophe Corvol1,2, Marie Vidailhet1,2, Isabelle Arnulf1,2, Stéphane Lehéricy1,2
Institutions:
1Paris Brain Institute (ICM), Paris, France, 2Pitié-Salpêtrière Hospital, AP-HP, Paris, France
First Author:
Co-Author(s):
Pauline Dodet, MD
Paris Brain Institute (ICM)|Pitié-Salpêtrière Hospital, AP-HP
Paris, France|Paris, France
Paris Brain Institute (ICM)|Pitié-Salpêtrière Hospital, AP-HP
Paris, France|Paris, France
Graziella Mangone, MD, PhD
Paris Brain Institute (ICM)|Pitié-Salpêtrière Hospital, AP-HP
Paris, France|Paris, France
Paris Brain Institute (ICM)|Pitié-Salpêtrière Hospital, AP-HP
Paris, France|Paris, France
Jean-Christophe Corvol, MD, PhD
Paris Brain Institute (ICM)|Pitié-Salpêtrière Hospital, AP-HP
Paris, France|Paris, France
Paris Brain Institute (ICM)|Pitié-Salpêtrière Hospital, AP-HP
Paris, France|Paris, France
Marie Vidailhet, MD
Paris Brain Institute (ICM)|Pitié-Salpêtrière Hospital, AP-HP
Paris, France|Paris, France
Paris Brain Institute (ICM)|Pitié-Salpêtrière Hospital, AP-HP
Paris, France|Paris, France
Isabelle Arnulf, MD, PhD
Paris Brain Institute (ICM)|Pitié-Salpêtrière Hospital, AP-HP
Paris, France|Paris, France
Paris Brain Institute (ICM)|Pitié-Salpêtrière Hospital, AP-HP
Paris, France|Paris, France
Stéphane Lehéricy
Paris Brain Institute (ICM)|Pitié-Salpêtrière Hospital, AP-HP
Paris, France|Paris, France
Paris Brain Institute (ICM)|Pitié-Salpêtrière Hospital, AP-HP
Paris, France|Paris, France
Introduction:
The locus coeruleus (LC) and the locus subcoeruleus (LsC) are brainstem nuclei that are affected in neurodegenerative parkinsonism1. The LC is the main source of noradrenergic innervation in the human brain2. The LsC contains neurons driving muscle atonia during REM sleep3. The LsC damage is known to be associated with rapid eye movement (REM) sleep behavior disorder (RBD), that is characterized by abnormal violent behaviors during REM sleep3,4,5. The LC/LsC complex contain catecholaminergic neurons that exhibit high neuromelanin (NM) concentrations, and can be visualized using NM-MRI6.
Parkinson's disease (PD) and isolated RBD (iRBD), a prodromal parkinsonism stage7,8, demonstrate LC/LsC neurodegeneration9. Longitudinal changes over years in the LC/LsC complex in these conditions remain unclear.
Parkinson's disease (PD) and isolated RBD (iRBD), a prodromal parkinsonism stage7,8, demonstrate LC/LsC neurodegeneration9. Longitudinal changes over years in the LC/LsC complex in these conditions remain unclear.
Methods:
Participants: Polysomnography-confirmed early PD with (PDRBD+) and without RBD (PDRBD-), iRBD and healthy volunteers (HVs) were scanned using 3T MRI and assessed three times (V1/V2/V3) with an interval of 2.0 ± 0.2 years between the visits.
Image analysis: LC/LsC was automatically analyzed blindly to the clinical status of the participants. Firstly, for signal intensity standardization, we defined three anatomical regions of interest (ROIs) in a brain template comprising left and right LC/LsC and a background region. Secondly, we resampled these ROIs onto NM-MRI using rigid and nonlinear transformations. Thirdly, we obtained the 10 connected voxels with the brightest intensities in both left and right LC/LsC. Lastly, we computed the ratio between the average signal intensities inside LC/LsC and the background ROI.
Statistical analyses: Baseline between-group differences were tested using multivariate linear regression models including age and sex as covariates. Longitudinal analyses were performed in subjects with at least two visits using linear mixed-effects models (LMMs). In each LMM, the group, the visit interval and their interaction term were considered as fixed effects, while a random (intercept) effect was applied on subject identifiers. Significance effects of the main or interaction effects was tested by Type II Wald Chi-square tests.
Pearson's correlations corrected for multiple testing were performed to test baseline LC/LsC signal with clinical variables, REM without atonia, nigral NM contrast to noise ratio (CNR)10, ventral nigral iron using QSM, and striatal DaT specific binding ratios (SBR).
Image analysis: LC/LsC was automatically analyzed blindly to the clinical status of the participants. Firstly, for signal intensity standardization, we defined three anatomical regions of interest (ROIs) in a brain template comprising left and right LC/LsC and a background region. Secondly, we resampled these ROIs onto NM-MRI using rigid and nonlinear transformations. Thirdly, we obtained the 10 connected voxels with the brightest intensities in both left and right LC/LsC. Lastly, we computed the ratio between the average signal intensities inside LC/LsC and the background ROI.
Statistical analyses: Baseline between-group differences were tested using multivariate linear regression models including age and sex as covariates. Longitudinal analyses were performed in subjects with at least two visits using linear mixed-effects models (LMMs). In each LMM, the group, the visit interval and their interaction term were considered as fixed effects, while a random (intercept) effect was applied on subject identifiers. Significance effects of the main or interaction effects was tested by Type II Wald Chi-square tests.
Pearson's correlations corrected for multiple testing were performed to test baseline LC/LsC signal with clinical variables, REM without atonia, nigral NM contrast to noise ratio (CNR)10, ventral nigral iron using QSM, and striatal DaT specific binding ratios (SBR).
Results:
Clinical characteristics: At V1/V2/V3, 55/45/32 HVs, 46/31/21 iRBD, 32/30/20 PDRBD+ and 99/64/29 PDRBD- were included respectively. Age, sex, MDS-UPDRS-OFF and HY scores were different between groups.
Baseline: Groups were different with highest LC/LsC signal in the HVs, lowest in PDRBD+ (p=0.01), a trend in iRBD (p=0.06) and no change in PDRBD- (p=0.31). The right values were significantly lower than the left for all groups.
Longitudinal: Overall, we observed group, visit and group X visit interaction effects (p<0.01 for right and p=0.09 for bilateral LC/LsC). All groups showed progressive decrease over time with PDRBD- demonstrating most significant decrease as compared to HVs (p=0.03).
An annual decrease of 0.22% for HVs, 0.36% for iRBD, 0.32% for PDRBD+, and 0.58% for PDRBD- was observed.
Correlations: LC/LsC signal decreased with the increase in age (r=-0.44, p<0.01) for HVs and PDRBD- (r=-0.40, p<0.001). It also decreased with the increase in MDS-UPDRS-ON score for PDRBD+ (r=-0.48, p=0.03). Further, it decreased with the increase in REM without atonia in iRBD (r=-0.37, p=0.02), nigral CNR in PDRBD- (r=-0.28, p<0.01) and ventral nigral iron in PDRBD- (r=-0.23, p=0.04). No group showed correlations with the SBR.
Baseline: Groups were different with highest LC/LsC signal in the HVs, lowest in PDRBD+ (p=0.01), a trend in iRBD (p=0.06) and no change in PDRBD- (p=0.31). The right values were significantly lower than the left for all groups.
Longitudinal: Overall, we observed group, visit and group X visit interaction effects (p<0.01 for right and p=0.09 for bilateral LC/LsC). All groups showed progressive decrease over time with PDRBD- demonstrating most significant decrease as compared to HVs (p=0.03).
An annual decrease of 0.22% for HVs, 0.36% for iRBD, 0.32% for PDRBD+, and 0.58% for PDRBD- was observed.
Correlations: LC/LsC signal decreased with the increase in age (r=-0.44, p<0.01) for HVs and PDRBD- (r=-0.40, p<0.001). It also decreased with the increase in MDS-UPDRS-ON score for PDRBD+ (r=-0.48, p=0.03). Further, it decreased with the increase in REM without atonia in iRBD (r=-0.37, p=0.02), nigral CNR in PDRBD- (r=-0.28, p<0.01) and ventral nigral iron in PDRBD- (r=-0.23, p=0.04). No group showed correlations with the SBR.
·Baseline left (A) and right (B) side LC/LsC signal changes in groups using NM-MRI.
·Longitudinal left and right-side LC/LsC signal changes in groups using NM-MRI
Conclusions:
Taken together, we demonstrated an age-related progressive LC/LsC degeneration in all groups. PDRBD+ had the lowest baseline signal, but PDRBD- decreased more rapidly over time.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Modeling and Analysis Methods:
Segmentation and Parcellation 2
Novel Imaging Acquisition Methods:
Anatomical MRI
Multi-Modal Imaging
Keywords:
Basal Ganglia
Brainstem
Movement Disorder
MRI
Norpinephrine
Segmentation
STRUCTURAL MRI
Other - Neuromelanin
1|2Indicates the priority used for review
Provide references using author date format
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