Brain Iron in Prodromal and Early Parkinson’s Disease: A 4-year Longitudinal QSM and R2* Study
Poster No:
150
Submission Type:
Abstract Submission
Authors:
Rahul Gaurav1, François-Xavier Lejeune1, Mathieu Santin1, romain valabregue1, Jean-Baptiste Pérot1, Nadya Pyatigorskaya1,2, Graziella Mangone1,2, Smaranda Leu-Semenescu2, Isabelle Arnulf2,1, Marie Vidailhet2,1, Jean-Christophe Corvol2,1, Stéphane Lehéricy2,1
Institutions:
1Sorbonne Université, Paris Brain Institute (ICM), Paris, France, 2Pitié-Salpêtrière Hospital, AP-HP, Paris, France
First Author:
Co-Author(s):
Nadya Pyatigorskaya, MD, PhD
Sorbonne Université, Paris Brain Institute (ICM)|Pitié-Salpêtrière Hospital, AP-HP
Paris, France|Paris, France
Sorbonne Université, Paris Brain Institute (ICM)|Pitié-Salpêtrière Hospital, AP-HP
Paris, France|Paris, France
Graziella Mangone, MD, PhD
Sorbonne Université, Paris Brain Institute (ICM)|Pitié-Salpêtrière Hospital, AP-HP
Paris, France|Paris, France
Sorbonne Université, Paris Brain Institute (ICM)|Pitié-Salpêtrière Hospital, AP-HP
Paris, France|Paris, France
Isabelle Arnulf, MD, PhD
Pitié-Salpêtrière Hospital, AP-HP|Sorbonne Université, Paris Brain Institute (ICM)
Paris, France|Paris, France
Pitié-Salpêtrière Hospital, AP-HP|Sorbonne Université, Paris Brain Institute (ICM)
Paris, France|Paris, France
Marie Vidailhet, MD
Pitié-Salpêtrière Hospital, AP-HP|Sorbonne Université, Paris Brain Institute (ICM)
Paris, France|Paris, France
Pitié-Salpêtrière Hospital, AP-HP|Sorbonne Université, Paris Brain Institute (ICM)
Paris, France|Paris, France
Jean-Christophe Corvol, MD, PhD
Pitié-Salpêtrière Hospital, AP-HP|Sorbonne Université, Paris Brain Institute (ICM)
Paris, France|Paris, France
Pitié-Salpêtrière Hospital, AP-HP|Sorbonne Université, Paris Brain Institute (ICM)
Paris, France|Paris, France
Stéphane Lehéricy
Pitié-Salpêtrière Hospital, AP-HP|Sorbonne Université, Paris Brain Institute (ICM)
Paris, France|Paris, France
Pitié-Salpêtrière Hospital, AP-HP|Sorbonne Université, Paris Brain Institute (ICM)
Paris, France|Paris, France
Introduction:
Parkinson's disease (PD) demonstrates a progressive depletion of neuromelanin (NM)-containing dopaminergic neurons in the substantia nigra pars compacta (SNc)1 and a high nigral iron concentration that can be quantified using quantitative susceptibility mapping (QSM) or R2*maps 2,3. Rapid eye movement (REM) Sleep Behavior Disorder (RBD) is characterized by abnormal behaviors during REM sleep4. Isolated RBD (iRBD) is considered a prodromal parkinsonian condition as most patients convert to α-synucleinopathies5.
Regional brain iron progression in prodromal and early PD is partially understood6.
Regional brain iron progression in prodromal and early PD is partially understood6.
Methods:
Participants: We included polysomnography-confirmed early PD with (PDRBD+) and without RBD (PDRBD-), iRBD, and healthy volunteers (HVs) scanned at 3T and evaluated at baseline (V1), 2-(V2) and 4-year (V3) follow-ups.
Image Analysis: QSM images were computed using MEDI toolbox7. The reconstructed images were used to construct a QSM template using Advanced Normalization Tools (ANTs)8. R2* maps were obtained using a nonlinear fit over echo times. NM-sensitive images were acquired using a T1-weighted (T1w) 2D axial turbo spin echo protocol.
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 raters9. Subject-wise regions were obtained using inverse transformation.
We automatically segmented the caudate nucleus, putamen, globus pallidus and thalamus on the 3D T1w images and coregistered to the QSM images using NiftyReg10.
Statistical Analyses: Baseline between-group differences were tested using multivariate linear regression models with age and sex as covariates. Longitudinal analyses were performed on subjects with at least two visits using linear mixed-effects models (LMM). Each LMM took the groups and the visit intervals with interaction as fixed effects, and the subject identifiers as a random (intercept) effect. Significance effects of the main or interaction effects were tested by Type II Wald Chi-square tests.
Evolution was tracked with respect to the age of the non-PD subjects. PD was added by aligning all individual ages at onset to the baseline mean age of the HVs. During the study, 7 iRBDs converted to PD.
Correlations were studied with clinical variables and nigral NM normalized signal intensity (NSI) computed using a template.
Image Analysis: QSM images were computed using MEDI toolbox7. The reconstructed images were used to construct a QSM template using Advanced Normalization Tools (ANTs)8. R2* maps were obtained using a nonlinear fit over echo times. NM-sensitive images were acquired using a T1-weighted (T1w) 2D axial turbo spin echo protocol.
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 raters9. Subject-wise regions were obtained using inverse transformation.
We automatically segmented the caudate nucleus, putamen, globus pallidus and thalamus on the 3D T1w images and coregistered to the QSM images using NiftyReg10.
Statistical Analyses: Baseline between-group differences were tested using multivariate linear regression models with age and sex as covariates. Longitudinal analyses were performed on subjects with at least two visits using linear mixed-effects models (LMM). Each LMM took the groups and the visit intervals with interaction as fixed effects, and the subject identifiers as a random (intercept) effect. Significance effects of the main or interaction effects were tested by Type II Wald Chi-square tests.
Evolution was tracked with respect to the age of the non-PD subjects. PD was added by aligning all individual ages at onset to the baseline mean age of the HVs. During the study, 7 iRBDs converted to PD.
Correlations were studied with clinical variables and nigral NM normalized signal intensity (NSI) computed using a template.
Results:
At V1/V2/V3, 47/31/13 HV, 36/19/7 iRBD, 25/11/6 PDRBD+ and 80/40/12 PDRBD- were included.
Baseline: QSM was increased in the posteroventral SN only and not in any other regions. PDRBD- had +17.8% elevated iron in the posteroventral SN (p= 0.03) vs. HV, while iron changes did not reach significance in PDRBD+ (+15.9%) and iRBD (+10.3%). No differences were found in the other regions. Results were similar for R2*.
Longitudinal: Overall group and time effects were observed only in the posteroventral SN iron for both QSM and R2* along with an interaction in R2* but not in QSM. Posteroventral SN iron in PDRBD- showed 26.2% significantly higher rate of increase at V3 compared to HV.
Progression model: Our modeling suggested that the iron increase at age of onset (60.6 years) would be approximately +10.7% compared to the mean HV level. Among the iRBD converters, the prediction suggested a greater increase in this group at age of onset (66.4 years) reaching +27.6%.
Correlations: Posteroventral nigral iron showed positive correlations (r=0.31; p adjusted=0.025) with disease duration for PDRBD-. Negative correlations were found with NSI for HV and PDRBD-, and a trend for PDRBD+.
Baseline: QSM was increased in the posteroventral SN only and not in any other regions. PDRBD- had +17.8% elevated iron in the posteroventral SN (p= 0.03) vs. HV, while iron changes did not reach significance in PDRBD+ (+15.9%) and iRBD (+10.3%). No differences were found in the other regions. Results were similar for R2*.
Longitudinal: Overall group and time effects were observed only in the posteroventral SN iron for both QSM and R2* along with an interaction in R2* but not in QSM. Posteroventral SN iron in PDRBD- showed 26.2% significantly higher rate of increase at V3 compared to HV.
Progression model: Our modeling suggested that the iron increase at age of onset (60.6 years) would be approximately +10.7% compared to the mean HV level. Among the iRBD converters, the prediction suggested a greater increase in this group at age of onset (66.4 years) reaching +27.6%.
Correlations: Posteroventral nigral iron showed positive correlations (r=0.31; p adjusted=0.025) with disease duration for PDRBD-. Negative correlations were found with NSI for HV and PDRBD-, and a trend for PDRBD+.
·Box plot (A) of baseline changes using QSM. Line plots (B) of longitudinal changes using QSM over the years.
Conclusions:
PDRBD- had increased iron only in the posteroventral nigral region, which was related to disease duration and decreased NM signal.
Iron deposition also increased in iRBD and PDRBD- although not significantly probably because of the lower number of subjects in these groups.
Iron deposition also increased in iRBD and PDRBD- although not significantly probably because of the lower number of subjects in these groups.
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:
Anatomical MRI
Multi-Modal Imaging 2
Keywords:
Basal Ganglia
Brainstem
Data analysis
Degenerative Disease
Movement Disorder
MRI
Neurological
Segmentation
Statistical Methods
STRUCTURAL MRI
1|2Indicates the priority used for review
·Scatter plot showing significant negative correlations between iron using QSM and nigral neuromelanin normalized signal intensity (NSI).
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3. Langkammer, C., Pirpamer, L., Seiler, et al. (2016), ‘Quantitative susceptibility mapping in Parkinson’s disease’, PLoS One, 11(9), e0162460.
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