Regional Metal Concentrations in Parkinson's Disease, Other Chronic Neurological Diseases, and Control Brains

ABSTRACT:Metal deficiency or toxicity states have been recognized as a cause of several neurological disorders and are suspected in others. We analyzed four brain regions (frontal cortex, caudate nucleus, substantia nigra, and cerebellum) in 36 human brains for concentrations of 24 metals (Ag, Al, As, B, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Pb, Mg, Mn, Mo, Na, Ni, P, Se, Ti, V, W, Zn). Regional metal concentrations, measured using atomic absorption and atomic emission spectroscopy, were compared between 9 Parkinson's disease (PD) brains, 15 brains from patients with other chronic neurological diseases, and 12 control brains. No significant metal concentration differences were noted between brains from PD and other chronic neurologic disease. However, parkinsonian brains (PD and parkinsonism secondary to neurofibrillary tangle disease) showed lower concentrations of magnesium in the caudate nucleus and copper in the substantia nigra than control brains. These findings may represent an etiologically important clue to parkinsonism.

Download Full-text

Neuroinflammation and protein pathology in Parkinson’s disease dementia

Acta Neuropathologica Communications ◽

10.1186/s40478-020-01083-5 ◽

2020 ◽

Vol 8 (1) ◽

Cited By ~ 1

Author(s):

Antonina Kouli ◽

Marta Camacho ◽

Kieren Allinson ◽

Caroline H. Williams-Gray

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

T Lymphocytes ◽

Substantia Nigra ◽

Amyloid Β ◽

Brain Regions ◽

Parkinson’S Disease Dementia ◽

Activated Microglia ◽

Cell Counts ◽

The Brain

AbstractParkinson’s disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer’s disease-type pathology. Whilst immune activation is well-described in Parkinson’s disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4+ T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4+ T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain.

Download Full-text

A pH-eQTL interaction at the RIT2-SYT4 Parkinson's disease risk locus in the substantia nigra

10.1101/2020.12.16.423140 ◽

2020 ◽

Author(s):

Sejal Patel ◽

Derek Howard ◽

Leon French

Keyword(s):

Gene Expression ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Human Brain ◽

Disease Risk ◽

Brain Regions ◽

Dopamine Neurons ◽

Postmortem Human Brain ◽

Increased Risk

BACKGROUND: Parkinson's disease (PD) causes severe motor and cognitive disabilities that result from the progressive loss of dopamine neurons in the substantia nigra. The rs12456492 variant in the RIT2 gene has been repeatedly associated with increased risk for Parkinson's disease. From a transcriptomic perspective, a meta-analysis found that RIT2 gene expression is correlated with pH in the human brain. OBJECTIVE: To assess pH associations at the RIT2-SYT4 locus. METHODS: Linear models to examine two datasets that assayed rs12456492, gene expression, and pH in the postmortem human brain. RESULTS: Using the BrainEAC dataset, we replicate the positive correlation between RIT2 gene expression and pH in the human brain. Furthermore, we found that the relationship between expression and pH is influenced by rs12456492. When tested across ten brain regions, this interaction is specifically found in the substantia nigra. A similar association was found for the co-localized SYT4 gene. In addition, SYT4 associations are stronger in a combined model with both genes, and the SYT4 interaction appears to be specific to males. In the GTEx dataset, the pH associations involving rs12456492 and expression of either SYT4 and RIT2 was not seen. This null finding may be due to the short postmortem intervals (PMI) of the GTEx tissue samples. In the BrainEAC data, we tested the effect of PMI and only observed the interactions in the longer PMI samples. CONCLUSIONS: These previously unknown associations suggest novel mechanistic roles for rs12456492, RIT2, and SYT4 in the regulation of pH in the substantia nigra.

Download Full-text

Mössbauer spectroscopy and ELISA studies reveal differences between Parkinson's disease and control substantia nigra

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2003.11.005 ◽

2004 ◽

Vol 1688 (2) ◽

pp. 130-136 ◽

Cited By ~ 37

Author(s):

Jolanta Galazka-Friedman ◽

Erika R. Bauminger ◽

Dariusz Koziorowski ◽

Andrzej Friedman

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mössbauer Spectroscopy ◽

Substantia Nigra ◽

Mossbauer Spectroscopy ◽

Mößbauer Spectroscopy ◽

And Control

Download Full-text

Polyomic Analyses of Dopaminergic Neurons Isolated From Human Substantia Nigra in Parkinson’s Disease: An Exploratory Study.

10.21203/rs.3.rs-182873/v1 ◽

2021 ◽

Author(s):

Affif ZACCARIA ◽

Paola Antinori Malaspina ◽

Virginie Licker ◽

Enikö Kovari ◽

Johannes A Lobrinus ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Protein Expression ◽

Differential Expression ◽

Exploratory Study ◽

Substantia Nigra Pars Compacta ◽

Control Group ◽

Gene And Protein Expression ◽

And Control

Abstract Background Dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc) selectively and progressively degenerate in Parkinson’s disease (PD). Until now, molecular analyses of DA neurons in PD have been limited to genomic and transcriptomic approaches, whereas, to the best of our knowledge, no proteomic or combined polyomic study examining the protein profile of these neurons, is currently available. Methods In this exploratory study, we used laser microdissection to extract DA neurons from 10 human SNpc samples obtained at autopsy in PD patients and control subjects. Extracted RNA and proteins were identified by RNA sequencing and nano-LC-MS/MS, respectively, and the differential expression between the PD and control group was assessed. Results Qualitative analyses confirmed that the microdissection protocol preserves the integrity of our samples and offers access to specific molecular pathways. This polyomic analysis highlighted differential expression of 52 genes and 33 proteins, including molecules of interest already known to be dysregulated in PD, such as LRP2, PNMT, CXCR4, MAOA and CBLN1 genes, or the Aldehyde dehydrogenase 1 protein. On the other hand, despite the same samples were used for both analyses, correlation between RNA and protein expression was low, as exemplified by the CST3 gene encoding for the cystatin C protein. Conclusion This is the first exploratory study analyzing both gene and protein expression of LMD-dissected DA neurons from SNpc in PD. Although correlation between RNA and protein expressions was limited, this polyomic study provides an extensive and integrated overview of molecular changes identified in the PD SNpc and may offer novel insights into specific pathological processes at work in PD degeneration.

Download Full-text

Susceptibility-weighted MR imaging (SWI) of basal ganglia iron deposition in the early and advanced stages of Parkinson's disease

Neurology neuropsychiatry Psychosomatics ◽

10.14412/2074-2711-2019-2-30-36 ◽

2019 ◽

Vol 11 (2) ◽

pp. 30-36

Author(s):

A. G. Trufanov ◽

A. A. Yurin ◽

A. B. Buriak ◽

S. A. Sandalov ◽

M. M. Odinak ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Basal Ganglia ◽

Substantia Nigra ◽

Caudate Nucleus ◽

Globus Pallidus ◽

Red Nucleus ◽

Regions Of Interest ◽

Iron Deposition ◽

Left Caudate

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease and the first one among the nosological entities of parkinsonism. Susceptibility-weighted imaging (SWI), magnetic resonance imaging (MRI) pulse sequence, which allows the in vivo estimation of the values of iron deposition in different areas of the brain, is a potential technique for the early diagnosis of PD and for the study of the pathogenesis of its complications.Objective: to compare the values of iron deposition in the basal ganglia in Stages II and III PD and to determine the relationship of clinical findings to the level of iron deposition according to the SWI findings.Patients and methods. Twenty-four patients with Hoehn and Yahr Stages II (n=24) and III (n=12) PD were examined. All the patients underwent brain MRI on a Siemens TrioTim (3T) MRI scanner by using pulse sequences T1, T2, SWI and subsequently quantifying the iron deposition (SPIN software). The accumulation of iron is visualized as an area of reduced signal intensity on SWI, and its estimation in accordance with the SPIN program has accordingly a smaller value. The regions of interest on both sides were the dentate nucleus, substantia nigra, red nucleus, putamen, globus pallidus, and head of the caudate nucleus. The examination protocol also included tests using the following scales: the Unified Parkinson's Disease Rating Scale (UPDRS), the Mini-Mental State Examination (MMSE), Frontal Assessment Batter (FAB), Freezing of Gait (FOG), Gait and Balance Scale (GABS), the Epworth Daytime Sleepiness Scale, the Parkinson's Disease Quality of Life Questionnaire (PDQ), the Beck Depression Inventory, and the Clock-Drawing Test.Results and discussion. The investigators found significant (p<0.05) correlations between the clinical picture and the level of iron deposition in the regions of interest in patients with Stage II PD: FOG – left caudate nucleus (r=-0.94); GABS – left caudate nucleus (r=-0.94); and in patients with stage III of the disease: UPDRS (full) – left red nucleus (r=-0.82), right globus pallidus (r=-0,80), left putamen (r=-0,96); UPDRS (Section 2) – left red nucleus (r=-0.77), left globus pallidus (r=-0.84); UPDRS (Section 3) – right putamen (r=-0,85), right globus pallidus (r=-0.78), left globus pallidus (r=-0,92); FOG – left globus pallidus (r=-0.81); GABS – left red nucleus (r=-0.96), left putamen (r=0.82), right putamen (r=-0.89), left globus pallidus (r=-0.82), right globus pallidus (r=-0.85), left caudate nucleus (r=-0.82), right caudate nucleus (r=-0.89); Beck Depression Inventory – right substantia nigra (r=-0.82).Conclusion. SWI measurement of the values of iron deposition in the structures of the extrapyramidal system in PD provides an additional insight into the pathological processes occurring in them.

Download Full-text