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Progressive supranuclear palsy: high-field-strength MR microscopy in the human substantia nigra and globus pallidus.

ABSTRACT: To characterize changes in the magnetic resonance (MR) relaxation properties of progressive supranuclear palsy (PSP) and tissue from neurologically normal brains by using high-resolution (21.1-T, 900-MHz) MR microscopy of postmortem human midbrain and basal ganglia.This HIPAA-compliant study was approved by the institutional review board at the Mayo Clinic and informed consent was obtained. Postmortem tissue from age-matched PSP (n = 6) and control (n = 3) brains was imaged by using three-dimensional fast low-angle shot MR imaging with isotropic resolution of 50 μm. Relaxation times and parametric relaxation maps were generated from spin-echo and gradient-recalled-echo sequences. MR findings were correlated with histologic features by evaluating the presence of iron by using Prussian blue and ferritin and microglia burden as determined by a custom-designed color deconvolution algorithm. T2 and T2*, signal intensities, percent pixels (that could not be fitted in a pixel-by-pixel regression analysis due to severe hypointensity), and histologic data (total iron, ferritin, and microglia burden) were statistically analyzed by using independent sample t tests (P < .05).PSP specimens showed higher iron burden in the cerebral peduncles and substantia nigra than did controls. However, only the putamen was significantly different, and it correlated with a decrease of T2* compared with controls (-48%; P = .043). Similarly, substantia nigra showed a significant decrease of T2* signal in PSP compared with controls (-57%; P = .028). Compared with controls, cerebral peduncles showed increased T2 (38%; P = .026) and T2* (34%; P = .014), as well as higher T2 signal intensity (57%; P = .049). Ferritin immunoreactivity was the opposite from iron burden and was significantly lower compared with controls in the putamen (-74%; P = .025), red nucleus (-61%; P = .018), and entire basal ganglia section (-63%; P = .016).High-field-strength MR microscopy yielded pronounced differences in substantia nigra and globus pallidus of PSP compared with control brains. Histologic data also suggested that the predominant iron in PSP is hemosiderin, not ferritin. Iron in the brain is a contrast enhancer and potential biomarker for PSP.

SUBMITTER: Foroutan P

PROVIDER: S-EPMC3528969 | biostudies-other | 2013 Jan

REPOSITORIES: biostudies-other

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Project description:BackgroundProgressive supranuclear palsy (PSP) is a neurodegenerative disorder clinically characterized by progressive postural instability, supranuclear gaze palsy, parkinsonism, and cognitive decline caused by degeneration in specific areas of the brain including globus pallidus (GP), substantia nigra, and subthalamic nucleus. However, the pathogenetic mechanism of PSP remains unclear to date.Unbiased global proteome analysis of patients' brain samples is an important step toward understanding PSP pathogenesis, as proteins serve as workhorses and building blocks of the cell.MethodsIn this study, we conducted unbiased mass spectrometry-based global proteome analysis of GP samples from 15 PSP patients, 15 Parkinson disease (PD) patients, and 15 healthy control (HC) individuals. To analyze 45 samples, we conducted 5 batches of 11-plex isobaric tandem mass tag (TMT)-based multiplexing experiments. The identified proteins were subjected to statistical analysis, such as a permutation-based statistical analysis in the significance analysis of microarray (SAM) method and bootstrap receiver operating characteristic curve (ROC)-based statistical analysis. Subsequently, we conducted bioinformatics analyses using gene set enrichment analysis, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) protein-protein interaction (PPI) analysis, and weighted gene co-expression network analysis (WGCNA).ResultsWe have identified 10,231 proteins with ∼1,000 differentially expressed proteins. The gene set enrichment analysis results showed that the PD pathway was the most highly enriched, followed by pathways for oxidative phosphorylation, Alzheimer disease, Huntington disease, and non-alcoholic fatty liver disease (NAFLD) when PSP was compared to HC or PD. Most of the proteins enriched in the gene set enrichment analysis were mitochondrial proteins such as cytochrome c oxidase, NADH dehydrogenase, acyl carrier protein, succinate dehydrogenase, ADP/ATP translocase, cytochrome b-c1 complex, and/or ATP synthase. Strikingly, all of the enriched mitochondrial proteins in the PD pathway were downregulated in PSP compared to both HC and PD. The subsequent STRING PPI analysis and the WGCNA further supported that the mitochondrial proteins were the most highly enriched in PSP.ConclusionOur study showed that the mitochondrial respiratory electron transport chain complex was the key proteins that were dysregulated in GP of PSP, suggesting that the mitochondrial respiratory electron transport chain complex could potentially be involved in the pathogenesis of PSP. This is the first global proteome analysis of human GP from PSP patients, and this study paves the way to understanding the mechanistic pathogenesis of PSP.

Project description:Progressive supranuclear palsy (PSP) is a neurodegenerative disorder clinically characterized by progressive postural instability, supranuclear gaze palsy, parkinsonism, and cognitive decline caused by degeneration in specific areas of the brain including globus pallidus (GP), substantia nigra, and subthalamic nucleus. However, the pathogenetic mechanism of PSP remains unclear to date. Unbiased global proteome analysis of patients’ brain samples is an important step toward understanding PSP pathogenesis, as proteins serve as workhorses and building blocks of the cell. In this study, we conducted unbiased mass spectrometry-based global proteome analysis of GP samples from 15 PSP patients, 15 Parkinson disease (PD) patients, and 15 healthy control (HC) individuals. To analyze 45 samples, we conducted 5 batches of 11-plex isobaric tandem mass tag (TMT)-based multiplexing experiments, identifying 10,231 proteins. The gene set enrichment analysis results showed that the PD pathway was the most highly enriched, followed by pathways for oxidative phosphorylation, Alzheimer disease, Huntington disease, and non-alcoholic fatty liver disease (NAFLD) when PSP was compared to HC or PD. Most of the proteins enriched in the gene set enrichment analysis were mitochondrial proteins such as cytochrome c oxidase, NADH dehydrogenase, acyl carrier protein, succinate dehydrogenase, ADP/ATP translocase, cytochrome b-c1 complex, and/or ATP synthase. Strikingly, all of the enriched mitochondrial proteins in the PD pathway were downregulated in PSP compared to both HC and PD. The subsequent Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) protein-protein interaction (PPI) analysis and the weighted gene co-expression network analysis (WGCNA) further supported that the mitochondrial proteins were the most highly enriched in PSP. This is the first global proteome analysis of human GP from PSP patients, and this study paves the way to understanding the pathogenesis mechanism of PSP.

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Progressive supranuclear palsy: high-field-strength MR microscopy in the human substantia nigra and globus pallidus.

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