Dataset Information

Parkinson's disease related signal change in the nigrosomes 1-5 and the substantia nigra using T2* weighted 7T MRI.

ABSTRACT: Improved markers for the progression of Parkinson's disease (PD) are required. Previous work has proven that iron dependent MRI scans can detect the largest Nigrosome (N1) within the substantia nigra (SN) pars compacta and changes in PD. Histopathological studies have shown that N1 is particularly affected in early PD whereas the other nigrosomes (N2-N5) and the surrounding iron-rich SN are affected later. In this study we aimed to determine whether MRI can detect the smaller nigrosomes (N2-N5) and whether graded signal alterations can be detected on T2*-weighted MRI at different disease stages consistent with histopathological changes. An observational prospective study was performed within the research imaging centre at the University of Nottingham, UK. Altogether 26 individuals with confirmed PD (median Hoehn&Yahr stage?=?1, Unified PD Rating Scale [UPDRS]?=?12.5) and 15 healthy controls participated. High resolution T2*weighted 7T MRI of the brain was performed and visibility of N1-N5 within the SN was qualitatively rated. Normalised T2*weighted signal intensities in manually segmented N1-N5 regions and iron-rich SN were calculated. We performed group comparisons and correlations with severity based on UPDRS. Qualitative measures were a nigrosome visibility score and a confidence score for identification. Quantitative measures were T2*weighted contrast of N1-5 and iron-rich SN relative to white matter. We found that visual assessment of the SN for N1-N5 revealed normal range visibility scores in 14 of 15 controls. N1 was identified with the highest confidence and visibility was in abnormal range in all 26 PD patients. The other nigrosomes were less well visible and less confidently identified. There was a larger PD induced signal reduction in all nigrosomes than in the iron-rich SN (median signal difference N1-5 PD compared to controls: 19.4% [IQR?=?24%], iron-rich SN 11% [IQR?=?24%, p?=?0.017]). The largest PD induced signal reduction was in N1: 37.2% [IQR?=?19%] which inversely correlated with UPDRS in PD (R²?=?0.19). All nigrosomes can be detected using 7T MRI, and PD induced T2*weighted signal reduction was greatest in the nigrosomes (especially N1). The graded T2*weighted signal alterations in the nigrosomes match previously described differential histopathological effects of PD. N1 was identified with the highest confidence and T2*weighted signal in N1 correlated with UPDRS confirming N1 as the most promising SN marker of PD pathology.

SUBMITTER: Schwarz ST

PROVIDER: S-EPMC5986169 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Parkinson's disease related signal change in the nigrosomes 1-5 and the substantia nigra using T2* weighted 7T MRI.

Schwarz Stefan Theodor ST Mougin Olivier O Xing Yue Y Blazejewska Anna A Bajaj Nin N Auer Dorothee P DP Gowland Penny P

NeuroImage. Clinical 20180524

Improved markers for the progression of Parkinson's disease (PD) are required. Previous work has proven that iron dependent MRI scans can detect the largest Nigrosome (N1) within the substantia nigra (SN) pars compacta and changes in PD. Histopathological studies have shown that N1 is particularly affected in early PD whereas the other nigrosomes (N2-N5) and the surrounding iron-rich SN are affected later. In this study we aimed to determine whether MRI can detect the smaller nigrosomes (N2-N5) ...[more]

PMID: 29872633

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Project description:BACKGROUND:Susceptibility MRI may capture Parkinson's disease-related pathology. This study delineated longitudinal changes in different substantia nigra regions. METHODS:Seventy-two PD patients and 62 controls were studied at both baseline and after 18 months with MRI. R2* and quantitative susceptibility mapping values from the substantia nigra pars compacta and substantia nigra pars reticulata were calculated. Mixed-effects models compared controls with PD or PD subgroups having different disease durations: early (<1 year), middle (<5 years, middle-stage PD), and late (>5 years, late-stage PD). Pearson's correlation assessed associations between imaging and clinical measures. RESULTS:At baseline, R2* and quantitative susceptibility mapping were higher in both the substantia nigra pars compacta and substantia nigra pars reticulata in all PD patients (group effect, P???0.003). Longitudinally, the substantia nigra pars compacta R2* showed a faster increase in PD compared with controls (time?×?group, P?=?0.002), whereas quantitative susceptibility mapping did not (P?=?0.668). The substantia nigra pars reticulata R2* and quantitative susceptibility mapping did not differ between PD and controls (time?×?group, P???0.084), although both decreased longitudinally (time effect, P???0.004). Baseline substantia nigra pars compacta R2* was higher in all PD subgroups (group, P???0.006), but showed a significantly faster increase only in later-stage PD (time?×?group, P?<?0.0001) that correlated with changes in nonmotor symptoms (r?=?0.746, P?=?0.002). Baseline substantia nigra pars reticulata quantitative susceptibility mapping was higher in middle-stage PD and later-stage PD (group, P???0.002), but showed a longitudinal decrease (time?×?group, P?=?0.004) only in later-stage PD that correlated with changes in motor signs (r?=?0.837, P?<?0.001). CONCLUSION:Susceptibility MRI revealed distinct patterns of PD progression in the substantia nigra pars compacta and substantia nigra pars reticulata. The different patterns are particularly clear in later-stage patients. These findings may resolve past controversies and have implications in the pathophysiological processes during PD progression. © 2018 International Parkinson and Movement Disorder Society.

Project description:Ferroptosis is an iron-dependent, lipid peroxidation-driven cell death pathway, while Parkinson's disease (PD) patients exhibit iron deposition and lipid peroxidation in the brain. Thus, the features of ferroptosis highly overlap with the pathophysiological features of PD. Despite this superficial connection, the possible role(s) of ferroptosis-related (Fr) proteins in dopaminergic neurons and/or glial cells in the substantia nigra (SN) in PD have not been examined in depth. To explore the correlations between the different SN cell types and ferroptosis at the single-cell level in PD patients, and to explore genes that may affect the sensitivity of dopaminergic neurons to ferroptosis, we performed in silico analysis of a single cell RNA sequence (RNA-seq) set (GSE178265) from the Gene Expression Omnibus (GEO) database. We identified differentially expressed genes (DEGs) in the different cell types in the human SN, and proceeded to perform enrichment analysis, constructing a protein-protein interaction network from the DEGs of dopaminergic neurons with the Metascape database. We examined the intersection of Fr genes present in the FerrDb database with DEGs from the GSE178265 set to identify Fr-DEGs in the different brain cells. Further, we identified Fr-DEGs encoding secreted proteins to implicate cell-cell interactions in the potential stimulation of ferroptosis in PD. The Fr-DEGs we identified were verified using the bulk RNA-seq sets (GSE49036 and GSE20164). The number of dopaminergic neurons decreased in the SN of PD patients. Interestingly, non-dopaminergic neurons possessed the fewest DEGs. Enrichment analysis of dopaminergic neurons' DEGs revealed changes in transmission across chemical synapses and ATP metabolic process in PD. The secreted Fr-DEGs identified were ceruloplasmin (CP), high mobility group box 1 (HMGB1) and transferrin (TF). The bulk RNA-seq set from the GEO database demonstrates that CP expression is increased in the PD brain. In conclusion, our results identify CP as a potential therapeutic target to protect dopaminergic neurons by reducing neurons' sensitivity to ferroptosis.

Project description:BackgroundParkinson's disease (PD) is the most common neurodegenerative disorder involving the motor system. Although not being the only region involved in PD, affection of the substantia nigra and its projections is responsible for some of the most debilitating features of the disease. To further advance a comprehensive understanding of nigral pathology, we conducted a tissue based comparative proteome study of healthy and diseased human substantia nigra.ResultsThe gross number of differentially regulated proteins in PD was 221. In total, we identified 37 proteins, of which 16 were differentially expressed. Identified differential proteins comprised elements of iron metabolism (H-ferritin) and glutathione-related redox metabolism (GST M3, GST P1, GST O1), including novel redox proteins (SH3BGRL). Additionally, many glial or related proteins were found to be differentially regulated in PD (GFAP, GMFB, galectin-1, sorcin), as well as proteins belonging to metabolic pathways sparsely described in PD, such as adenosyl homocysteinase (methylation), aldehyde dehydrogenase 1 and cellular retinol-binding protein 1 (aldehyde metabolism). Further differentially regulated proteins included annexin V, beta-tubulin cofactor A, coactosin-like protein and V-type ATPase subunit 1. Proteins that were similarly expressed in healthy or diseased substantia nigra comprised housekeeping proteins such as COX5A, Rho GDI alpha, actin gamma 1, creatin-kinase B, lactate dehydrogenase B, disulfide isomerase ER-60, Rab GDI beta, methyl glyoxalase 1 (AGE metabolism) and glutamine synthetase. Interestingly, also DJ-1 and UCH-L1 were expressed similarly. Furthermore, proteins believed to serve as internal standards were found to be expressed in a constant manner, such as 14-3-3 epsilon and hCRMP-2, thus lending further validity to our results.ConclusionUsing an approach encompassing high sensitivity and high resolution, we show that alterations of SN in PD include many more proteins than previously thought. The results point towards a heterogeneous aetiopathogenesis of the disease, including alterations of GSH-related proteins as well as alterations of proteins involved in retinoid metabolism, and they indicate that proteins involved in familial PD may not be differentially regulated in idiopathic Parkinson's disease.

Dataset Information

Parkinson's disease related signal change in the nigrosomes 1-5 and the substantia nigra using T2* weighted 7T MRI.

Publications

Parkinson's disease related signal change in the nigrosomes 1-5 and the substantia nigra using T2* weighted 7T MRI.

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