Longitudinal Iron and Neuromelanin in Restless Legs Syndrome associated with Parkinson’s Disease
Poster No:
176
Submission Type:
Abstract Submission
Authors:
Rahul Gaurav1, Pauline Dodet1,2, François-Xavier Lejeune1, Mathieu Santin1, Smaranda Leu-Semenescu2, Romain Valabrègue1, Nadya Pyatigorskaya1,2, Graziella Mangone1,2, Jean-Christophe Corvol1,2, Marie Vidailhet1,2, Stéphane Lehéricy1,2, Isabelle Arnulf1,2
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
Nadya Pyatigorskaya, 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
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
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
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
Introduction:
Restless legs syndrome (RLS) is a sensorimotor disorder demonstrated by an urge to move the legs with an unpleasant sensation during rest1. RLS can be idiopathic or manifest with Parkinson disease (PD)1,2..
PD is characterized by neuromelanin (NM) loss and elevated iron in the substantia nigra (SN)3. Isolated REM sleep behavior disorder (iRBD), a prodromal parkinsonism stage, is characterized by abnormal violent behaviors during REM sleep4. Unlike PD, RLS patients often demonstrate nigral iron deficiency5,6,7. Neuropathological studies suggested that the iron scarcity might come from the damage in iron acquisition by the nigral neuromelanin cells6,7. Some patients with idiopathic RLS also demonstrate dopaminergic abnormality8.
Nonetheless, the longitudinal regional iron changes in RLS associated with PD are still debated.
PD is characterized by neuromelanin (NM) loss and elevated iron in the substantia nigra (SN)3. Isolated REM sleep behavior disorder (iRBD), a prodromal parkinsonism stage, is characterized by abnormal violent behaviors during REM sleep4. Unlike PD, RLS patients often demonstrate nigral iron deficiency5,6,7. Neuropathological studies suggested that the iron scarcity might come from the damage in iron acquisition by the nigral neuromelanin cells6,7. Some patients with idiopathic RLS also demonstrate dopaminergic abnormality8.
Nonetheless, the longitudinal regional iron changes in RLS associated with PD are still debated.
Methods:
Participants: Early PD with (PDRLS+) and without RLS (PDRLS-), iRBD and HVs were scanned using 3T MRI and assessed thrice (V1/V2/V3) with a 2-year interval between the visits.
Image analysis: QSM images were computed using MEDI toolbox9 and were used to construct a QSM template using Advanced Normalization Tools (ANTs). R2* maps were obtained using a nonlinear fit over echo times. The subthalamic nucleus, entire SN and its subdivisions (anterior and posterior territories of dorsal and ventral SN) were manually segmented on the template by experienced raters. Subject wise regions were obtained automatically using inverse transformation.
NM images were aligned to an average brain template. Contrast to noise ratio (CNR) was computed using an SN mask partitioned into sensorimotor, associative and limbic territories and a background region10.
Statistical analyses: Baseline between-group differences were tested using multivariate linear regression models including age and sex as covariates. Longitudinal analyses were performed on 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 were tested by Type II Wald Chi-square tests.
Pearson's correlations corrected for multiple tests were performed to test iron with clinical variables, REM without atonia (RWA), periodic limb movements (PLM) and CNR.
Image analysis: QSM images were computed using MEDI toolbox9 and were used to construct a QSM template using Advanced Normalization Tools (ANTs). R2* maps were obtained using a nonlinear fit over echo times. The subthalamic nucleus, entire SN and its subdivisions (anterior and posterior territories of dorsal and ventral SN) were manually segmented on the template by experienced raters. Subject wise regions were obtained automatically using inverse transformation.
NM images were aligned to an average brain template. Contrast to noise ratio (CNR) was computed using an SN mask partitioned into sensorimotor, associative and limbic territories and a background region10.
Statistical analyses: Baseline between-group differences were tested using multivariate linear regression models including age and sex as covariates. Longitudinal analyses were performed on 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 were tested by Type II Wald Chi-square tests.
Pearson's correlations corrected for multiple tests were performed to test iron with clinical variables, REM without atonia (RWA), periodic limb movements (PLM) and CNR.
Results:
Clinical characteristics: At V1/V2/V3, 60/52/41 HVs, 58/43/33 iRBD, 148/145/96 PD were included respectively. Age, sex, MDS-UPDRS-OFF score and RWA differed between groups and there was a trend for PLM.
IRBD had the highest rate of RWA and PLM. PDRLS+ were older and had longer disease duration (2.4 ± 1.0 years) compared to PDRLS- (1.3 ± 0.9 years).
Baseline: Groups were different in QSM and R2* (p=0.04). QSM and R2* increased in the posteroventral SN only and not in any other regions. We found that PDRBD- had +17.8% elevated posteroventral SN iron (p= 0.03) vs. HV, but there was no evidence for a difference of PDRLS- with PDRRLS+ or with iRBD. Regional SN CNRs were also different.
Longitudinal: We observed group and visit effects for posteroventral SN iron for QSM, R2* and CNRs in all regional SN territories (p<0.001). Only CNR in the sensorimotor region showed group X visit interaction effect (p=0.02).
Correlations: In PDRLS-, posteroventral SN iron increased with the decrease in CNR in the sensorimotor region (r=-0.21, p=0.04) and with the increase in disease duration (r=0.27, p =0.04) and PLM (r=0.36, p=0.002).
IRBD had the highest rate of RWA and PLM. PDRLS+ were older and had longer disease duration (2.4 ± 1.0 years) compared to PDRLS- (1.3 ± 0.9 years).
Baseline: Groups were different in QSM and R2* (p=0.04). QSM and R2* increased in the posteroventral SN only and not in any other regions. We found that PDRBD- had +17.8% elevated posteroventral SN iron (p= 0.03) vs. HV, but there was no evidence for a difference of PDRLS- with PDRRLS+ or with iRBD. Regional SN CNRs were also different.
Longitudinal: We observed group and visit effects for posteroventral SN iron for QSM, R2* and CNRs in all regional SN territories (p<0.001). Only CNR in the sensorimotor region showed group X visit interaction effect (p=0.02).
Correlations: In PDRLS-, posteroventral SN iron increased with the decrease in CNR in the sensorimotor region (r=-0.21, p=0.04) and with the increase in disease duration (r=0.27, p =0.04) and PLM (r=0.36, p=0.002).
·Figure 1
·Figure 2
Conclusions:
PD patients without RLS had a greater longitudinal iron increase in the posteroventral SN region and CNR decrease in the sensorimotor SN region.
These iron changes were related to the disease duration and the decreased in NM signal.
Nonetheless, further studies including patients with idiopathic RLS are warranted.
These iron changes were related to the disease duration and the decreased in NM signal.
Nonetheless, further studies including patients with idiopathic RLS are warranted.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Modeling and Analysis Methods:
Image Registration and Computational Anatomy
Segmentation and Parcellation
Novel Imaging Acquisition Methods:
Multi-Modal Imaging 2
Keywords:
Basal Ganglia
Brainstem
Degenerative Disease
Segmentation
STRUCTURAL MRI
Other - Neuromelanin
1|2Indicates the priority used for review
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