Iron Accumulation Is Not Homogenous among Patients with Parkinson’s Disease

Background. Iron is considered to lead to neurodegeneration and has been hypothesized as a possible cause of Parkinson’s disease (PD). Susceptibility-weighted imaging (SWI) is a powerful tool to measure phase related iron content of brain.Methods. Twelve de novo patients with PD were recruited from the Movement Disorders Clinic, Department of Neurology, Loma Linda University. Twelve age- and sex-matched non-PD subjects were recruited from neurology clinic as controls. Using SWI, the phase related iron content was estimated from different brain regions of interest (ROIs).Results. There was a trend between increasing age and iron accumulation in the globus pallidus and putamen in all subjects. Iron accumulation was not significant in different ROIs in PD patients compared to controls after adjustment for age. Our data revealed heterogeneity of phase values in different brain ROIs among all subjects with an exaggerated trend at SN in PD patients.Conclusions. Our data suggest a nonhomogeneous pattern of iron accumulation in different brain regions among PD patients. Further studies are needed to explore whether this may correlate to the progression of PD. To our knowledge, this is the first study demonstrating the heterogeneity of iron accumulation in the brain, among patients with PD.

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

Cortical Thinning Associated with Age and CSF Biomarkers in Early Parkinson’s Disease Is Modified by the SNCA rs356181 Polymorphism

Neurodegenerative Diseases ◽

10.1159/000493103 ◽

2018 ◽

Vol 18 (5-6) ◽

pp. 233-238

Author(s):

Frederic Sampedro ◽

Juan Marín-Lahoz ◽

Saul Martínez-Horta ◽

Javier Pagonabarraga ◽

Jaime Kulisevsky

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Decline ◽

De Novo ◽

Brain Regions ◽

Cortical Atrophy ◽

Csf Biomarkers ◽

Gene Encoding ◽

Cortical Thinning ◽

Age Related

The role of cerebrospinal fluid (CSF) biomarkers such as CSF α-synuclein and CSF tau in predicting cognitive decline in Parkinson’s disease (PD) continues to be inconsistent. Here, using a cohort of de novo PD patients with preserved cognition from the Parkinson’s Progression Markers Initiative (PPMI), we show that the SNCA rs356181 single nucleotide polymorphism (SNP) modulates the effect of these CSF biomarkers on cortical thinning. Depending on this SNP’s genotype, cortical atrophy was associated with either higher or lower CSF biomarker levels. Additionally, this SNP modified age-related atrophy. Importantly, the integrity of the brain regions where this phenomenon was observed correlated with cognitive measures. These results suggest that this genetic variation of the gene encoding the α-synuclein protein, known to be involved in the development of PD, also interferes in its subsequent neurodegeneration. Overall, our findings could shed light on the so far incongruent association of common CSF biomarkers with cognitive decline in PD.

Download Full-text

Microglial exosomes facilitate α-synuclein transmission in Parkinson’s disease

Brain ◽

10.1093/brain/awaa090 ◽

2020 ◽

Vol 143 (5) ◽

pp. 1476-1497 ◽

Cited By ~ 12

Author(s):

Min Guo ◽

Jian Wang ◽

Yanxin Zhao ◽

Yiwei Feng ◽

Sida Han ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Protein Aggregation ◽

Brain Regions ◽

Dependent Manner ◽

Nigrostriatal Pathway ◽

Stereotaxic Injection ◽

Promising Therapeutic Target ◽

The Brain

Abstract Accumulation of neuronal α-synuclein is a prominent feature in Parkinson’s disease. More recently, such abnormal protein aggregation has been reported to spread from cell to cell and exosomes are considered as important mediators. The focus of such research, however, has been primarily in neurons. Given the increasing recognition of the importance of non-cell autonomous-mediated neurotoxicity, it is critical to investigate the contribution of glia to α-synuclein aggregation and spread. Microglia are the primary phagocytes in the brain and have been well-documented as inducers of neuroinflammation. How and to what extent microglia and their exosomes impact α-synuclein pathology has not been well delineated. We report here that when treated with human α-synuclein preformed fibrils, exosomes containing α-synuclein released by microglia are fully capable of inducing protein aggregation in the recipient neurons. Additionally, when combined with microglial proinflammatory cytokines, these exosomes further increased protein aggregation in neurons. Inhibition of exosome synthesis in microglia reduced α-synuclein transmission. The in vivo significance of these exosomes was demonstrated by stereotaxic injection of exosomes isolated from α-synuclein preformed fibrils treated microglia into the mouse striatum. Phosphorylated α-synuclein was observed in multiple brain regions consistent with their neuronal connectivity. These animals also exhibited neurodegeneration in the nigrostriatal pathway in a time-dependent manner. Depleting microglia in vivo dramatically suppressed the transmission of α-synuclein after stereotaxic injection of preformed fibrils. Mechanistically, we report here that α-synuclein preformed fibrils impaired autophagy flux by upregulating PELI1, which in turn, resulted in degradation of LAMP2 in activated microglia. More importantly, by purifying microglia/macrophage derived exosomes in the CSF of Parkinson’s disease patients, we confirmed the presence of α-synuclein oligomer in CD11b+ exosomes, which were able to induce α-synuclein aggregation in neurons, further supporting the translational aspect of this study. Taken together, our study supports the view that microglial exosomes contribute to the progression of α-synuclein pathology and therefore, they may serve as a promising therapeutic target for Parkinson’s disease.

Download Full-text

The Efficacy of Iron Chelators for Removing Iron from Specific Brain Regions and the Pituitary—Ironing out the Brain

Pharmaceuticals ◽

10.3390/ph12030138 ◽

2019 ◽

Vol 12 (3) ◽

pp. 138 ◽

Cited By ~ 5

Author(s):

Robert R. Crichton ◽

Roberta J. Ward ◽

Robert C. Hider

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Iron Chelation ◽

Brain Regions ◽

Beta Thalassemia ◽

Excess Iron ◽

New Class ◽

Clinical Conditions ◽

The Brain

Iron chelation therapy, either subcutaneous or orally administered, has been used successfully in various clinical conditions. The removal of excess iron from various tissues, e.g., the liver spleen, heart, and the pituitary, in beta thalassemia patients, has become an essential therapy to prolong life. More recently, the use of deferiprone to chelate iron from various brain regions in Parkinson’s Disease and Friederich’s Ataxia has yielded encouraging results, although the side effects, in <2% of Parkinson’s Disease(PD) patients, have limited its long-term use. A new class of hydroxpyridinones has recently been synthesised, which showed no adverse effects in preliminary trials. A vital question remaining is whether inflammation may influence chelation efficacy, with a recent study suggesting that high levels of inflammation may diminish the ability of the chelator to bind the excess iron.

Download Full-text

Systemic α-synuclein injection triggers selective neuronal pathology as seen in patients with Parkinson’s disease

Molecular Psychiatry ◽

10.1038/s41380-019-0608-9 ◽

2019 ◽

Cited By ~ 3

Author(s):

Wei-Li Kuan ◽

Katherine Stott ◽

Xiaoling He ◽

Tobias C. Wood ◽

Sujeong Yang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Brain Regions ◽

Neuronal Populations ◽

Novel Approach ◽

Quaternary Structures ◽

Cellular Pathology ◽

First Time ◽

The Brain ◽

Delivery Approach

AbstractParkinson’s disease (PD) is an α-synucleinopathy characterized by the progressive loss of specific neuronal populations. Here, we develop a novel approach to transvascularly deliver proteins of complex quaternary structures, including α-synuclein preformed fibrils (pff). We show that a single systemic administration of α-synuclein pff triggers pathological transformation of endogenous α-synuclein in non-transgenic rats, which leads to neurodegeneration in discrete brain regions. Specifically, pff-exposed animals displayed a progressive deterioration in gastrointestinal and olfactory functions, which corresponded with the presence of cellular pathology in the central and enteric nervous systems. The α-synuclein pathology generated was both time dependent and region specific. Interestingly, the most significant neuropathological changes were observed in those brain regions affected in the early stages of PD. Our data therefore demonstrate for the first time that a single, transvascular administration of α-synuclein pff can lead to selective regional neuropathology resembling the premotor stage of idiopathic PD. Furthermore, this novel delivery approach could also be used to deliver a range of other pathogenic, as well as therapeutic, protein cargos transvascularly to the brain.

Download Full-text

Faculty Opinions recommendation of The coenzyme Q10 status of the brain regions of Parkinson's disease patients.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1146888.603980 ◽

2009 ◽

Author(s):

David Williams

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Coenzyme Q10 ◽

Brain Regions ◽

The Brain

Download Full-text

Application of Functional Magnetic Resonance Imaging in the Diagnosis of Parkinson’s Disease: A Histogram Analysis

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.624731 ◽

2021 ◽

Vol 13 ◽

Author(s):

Dafa Shi ◽

Haoran Zhang ◽

Siyuan Wang ◽

Guangsong Wang ◽

Ke Ren

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Feature Selection ◽

Model Performance ◽

Area Under The Curve ◽

Low Frequency ◽

Brain Regions ◽

Histogram Analysis ◽

Validation Set ◽

The Brain

This study aimed to investigate the value of amplitude of low-frequency fluctuation (ALFF)-based histogram analysis in the diagnosis of Parkinson’s disease (PD) and to investigate the regions of the most important discriminative features and their contribution to classification discrimination. Patients with PD (n = 59) and healthy controls (HCs; n = 41) were identified and divided into a primary set (80 cases, including 48 patients with PD and 32 HCs) and a validation set (20 cases, including 11 patients with PD and nine HCs). The Automated Anatomical Labeling (AAL) 116 atlas was used to extract the histogram features of the regions of interest in the brain. Machine learning methods were used in the primary set for data dimensionality reduction, feature selection, model construction, and model performance evaluation. The model performance was further validated in the validation set. After feature data dimension reduction and feature selection, 23 of a total of 1,276 features were entered in the model. The brain regions of the selected features included the frontal, temporal, parietal, occipital, and limbic lobes, as well as the cerebellum and the thalamus. In the primary set, the area under the curve (AUC) of the model was 0.974, the sensitivity was 93.8%, the specificity was 90.6%, and the accuracy was 93.8%. In the validation set, the AUC, sensitivity, specificity, and accuracy were 0.980, 90.9%, 88.9%, and 90.0%, respectively. ALFF-based histogram analysis can be used to classify patients with PD and HCs and to effectively identify abnormal brain function regions in PD patients.

Download Full-text

Brain atrophy progression in Parkinson's disease is shaped by connectivity and local vulnerability

10.1101/2021.06.08.21258321 ◽

2021 ◽

Author(s):

Christina Tremblay ◽

Shady Rahayel ◽

Andrew Vo ◽

Filip Morys ◽

Golia Shafiei ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Brain Atrophy ◽

De Novo ◽

Brain Connectivity ◽

Brain Regions ◽

Posterior Cingulate Cortex ◽

Alpha Synuclein ◽

Cell Type ◽

Expression Of Genes

Atrophy in multiple brain regions has been reported in the early stages of Parkinson's Disease, but there have been few longitudinal studies. How intrinsic properties of the brain, such as anatomical connectivity, local cell type distribution and gene expression combine to determine the pattern of disease progression remains unknown. One hypothesis proposes that the disease stems from prion-like propagation of misfolded alpha-synuclein via the connectome that might cause varying degrees of tissue damage based on local properties. Here we used MRI data from the Parkinson Progression Markers Initiative to test this model by mapping the progression of brain atrophy over one, two and four years and relating it to brain structural and functional connectivity, cell type expression and gene ontology enrichment analyses. In this longitudinal study, we derived atrophy progression maps for the three time points using deformation-based morphometry applied to T1-weighted MRI from 74 de novo Parkinson's Disease patients (50 Men: 24 Women) and 157 healthy control participants (115 Men: 42 Women). After regressing out the expected age and sex effects associated with normal aging, we found that atrophy significantly progressed over two and four years in the caudate, nucleus accumbens, hippocampus, and the temporal, parietal, occipital and posterior cingulate cortex. This progression was shaped by both structural and functional brain connectivity. Also, the progression of atrophy was more pronounced in regions with a higher expression of genes related to synapses and was related to the prevalence of oligodendrocytes and endothelial cells. In sum, we demonstrate that the progression of atrophy in Parkinson's Disease is in line with the prion-like propagation hypothesis of alpha-synuclein and provide evidence that synapses may be especially vulnerable to synucleinopathy. In addition to identifying vulnerable brain regions, this study reveals different factors that may be implicated in the neurotoxic mechanisms leading to progression in Parkinson's Disease.

Download Full-text