An attempt to dissect a peripheral marker based on cell pathology in Parkinson's disease.
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ABSTRACT:
SUBMITTER: Biagioni F
PROVIDER: S-EPMC8528800 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of motor control due to a wide loss of dopaminergic neurons along the nigro-striatal pathway. Some of the mechanisms that contribute to this cell death are inflammation, oxidative stress, and misfolded alpha-synuclein-induced toxicity. Current treatments are effective at managing the early motor symptoms of the disease, but they become ineffective over time and lead to adverse effects. Previous research using intracerebral stem cell therapy for treatment of PD has provided promising results; however, this method is very invasive and is often associated with unacceptable side effects. In this study, we used an MPTP-injected mouse model of PD and intravenously administered neural precursors (NPs) obtained from mouse embryonic and mesenchymal stem cells. Clinical signs and neuropathology were assessed. Female mice treated with NPs had improved motor function and reduction in the neuroinflammatory response. In terms of safety, there were no tumorigenic formations or any detectable adverse effect after treatment. Our results suggest that peripheral administration of stem cell-derived NPs may be a promising and safe therapy for the recovery of impaired motor function and amelioration of brain pathology in PD.
| S-EPMC6912680 | biostudies-literature
Project description:The diagnosis of Parkinson's disease (PD) is challenging at all stages due to variable symptomatology, comorbidities, and mimicking conditions. Postmortem assessment remains the gold standard for a definitive diagnosis. While it is well recognized that PD manifests pathologically in the central nervous system with aggregation of α-synuclein as Lewy bodies and neurites, similar Lewy-type synucleinopathy (LTS) is additionally found in the peripheral nervous system that may be useful as an antemortem biomarker. We have previously found that detection of LTS in submandibular gland (SMG) biopsies is sensitive and specific for advanced PD; however, the sensitivity is suboptimal especially for early-stage disease. Further, visual microscopic assessment of biopsies by a neuropathologist to identify LTS is impractical for large-scale adoption. Here, we trained and validated a convolutional neural network (CNN) for detection of LTS on 283 digital whole slide images (WSI) from 95 unique SMG biopsies. A total of 8,450 LTS and 35,066 background objects were annotated following an inter-rater reliability study with Fleiss Kappa = 0.72. We used transfer learning to train a CNN model to classify image patches (151 × 151 pixels at 20× magnification) with and without the presence of LTS objects. The trained CNN model showed the following performance on image patches: sensitivity: 0.99, specificity: 0.99, precision: 0.81, accuracy: 0.99, and F-1 score: 0.89. We further tested the trained network on 1230 naïve WSI from the same cohort of research subjects comprising 42 PD patients and 14 controls. Logistic regression models trained on features engineered from the CNN predictions on the WSI resulted in sensitivity: 0.71, specificity: 0.65, precision: 0.86, accuracy: 0.69, and F-1 score: 0.76 in predicting clinical PD status, and 0.64 accuracy in predicting PD stage, outperforming expert neuropathologist LTS density scoring in terms of sensitivity but not specificity. These findings demonstrate the practical utility of a CNN detector in screening for LTS, which can translate into a computational tool to facilitate the antemortem tissue-based diagnosis of PD in clinical settings.
| S-EPMC8842941 | biostudies-literature
Project description:Tau protein-a member of the microtubule-associated protein family-is a key protein involved in many neurodegenerative diseases. Tau pathology in neurodegenerative diseases is characterized by pathological tau aggregation in neurofibrillary tangles (NFTs). Diseases with this typical pathological feature are called tauopathies. Parkinson's disease (PD) was not initially considered to be a typical tauopathy. However, recent studies have demonstrated increasing evidence of tau pathology in PD. A genome-wide association (GWA) study indicated a potential association between tauopathy and sporadic PD. The aggregation and deposition of tau were also observed in ~50% of PD brains, and it seems to be transported from neuron to neuron. The aggregation of NFTs, the abnormal hyperphosphorylation of tau protein, and the interaction between tau and alpha-synuclein may all contribute to the cell death and poor axonal transport observed in PD and Parkinsonism.
| S-EPMC6176019 | biostudies-other
Project description:Parkinson's disease is delayed in clinical onset, asymmetric in initial appearance, and slow in progression. One explanation for these characteristics may be a boost in natural defenses after early exposure to mild cellular stress. As the patient ages and resilience recedes, however, stress levels may become sufficiently high that toxic cellular responses can no longer be curbed, culminating in inverted U-shaped stress-response curves as a function of disease duration. If dopaminergic systems are indeed capable of responding to mild stress with effective natural defenses, experimental models of Parkinson's disease should adhere to the principles of preconditioning, whereby stress exposure fortifies cells and tempers the toxic sequelae of subsequent stressors. Here, I review evidence favoring the efficacy of preconditioning in dopaminergic systems. Recent animal work also raises the possibility that cross-hemispheric preconditioning may arrest the spread of asymmetric Parkinson's pathology to the other side of the brain. Indeed, compensatory homeostatic systems have long been hypothesized to maintain neurological function until a threshold of cell loss is exceeded and are often displayed as inverted U-shaped curves. However, some stress responses assume an exponential or sigmoidal profile as a function of disease severity, suggesting end-stage deceleration of disease processes. Thus, surviving dopaminergic neurons may become progressively harder to kill, with the dorsal nigral tier dying slower due to superior baseline defenses, inducible conditioning capacity, or delayed dorsomedial nigral spread of disease. In addition, compensatory processes may be useful as biomarkers to distinguish "responder patients" from "nonresponders" before clinical trials. However, another possibility is that defenses are already maximally conditioned in most patients and no further boost is possible. A third alternative is that genuinely diseased human cells cannot be conditioned, in contrast to preclinical models, none of which faithfully recapitulate age-related human conditions. Disease-related "conditioning deficiencies" would then explain how Parkinson's pathology takes root, progressively shrinks defenses, and eventually kills the patient.
| S-EPMC6200356 | biostudies-other
Project description:IntroductionPatients with Parkinson's disease (PD) frequently experience disrupted sleep, and several sleep abnormalities are associated with an increased risk of incident PD. However, there are few data concerning the relationship between objectively quantified sleep disruption and the cardinal histopathological features of PD, especially in individuals without clinical PD.MethodsWe studied 269 older adults without PD who had participated in the Rush Memory and Aging Project and undergone uniform structured neuropathologic evaluations upon death. Sleep fragmentation was measured using actigraphy. Logistic regression models examined the associations of sleep fragmentation proximate to death with the burden of Lewy body pathology and substantia nigra neuron loss.ResultsGreater sleep fragmentation was associated with the presence of Lewy body pathology (odds ratio 1.40; 95% confidence interval 1.05-1.86; P = .02) and substantia nigra neuron loss (odds ratio 1.43; 95% confidence interval 1.10-1.88; P = .008) and a higher odds of a pathological diagnosis of PD (odds ratio 2.04; 95% confidence interval 1.34-3.16; P = .0009). These associations were independent of motor features of parkinsonism, demographic characteristics, and a wide range of medical co-morbidities.ConclusionsSleep fragmentation is associated with PD pathology in older adults without PD. These results suggest that sleep fragmentation may be a marker of or risk factor for PD pathology in older adults without PD. © 2017 International Parkinson and Movement Disorder Society.
| S-EPMC5778902 | biostudies-literature
Project description:Parkinson's Disease (PD) and Non-Demented Control (NDC) human sera were probed onto human protein microarrays in order to identify differentially expressed autoantibody biomarkers that could be used as diagnostic indicators. In the study presented here, 29 PD and 40 NDC human serum samples were probed onto human protein microarrays in order to identify differentially expressed autoantibodies. Microarray data was analyzed using several statistical significance algorithms, and autoantibodies that demonstrated significant group prevelance were selected as biomarkers of disease. Prediction classification analysis tested the diagnostic efficacy of the identified biomarkers; and differentiation of PD samples from other neurodegeneratively-diseased and non-neurodegeneratively-diseased controls (Alzheimer's disease, multiple sclerosis, and breast cancer) confirmed their specificity.
2012-02-27 | E-GEOD-29654 | biostudies-arrayexpress
Project description:Extensive loss of dopaminergic neurons and aggregation of the protein α-synuclein into ubiquitin-positive Lewy bodies represents a major neuropathological hallmark of Parkinson's disease (PD). At present, the generation of large nuclear-associated Lewy bodies from endogenous wild-type α-synuclein, translationally regulated under its own promoter in human cell culture models, requires costly and time-consuming protocols. Here, we demonstrate that fully differentiated human SH-SY5Y neuroblastoma cells grown in three-dimensional cell culture develop Lewy-body-like pathology upon exposure to exogenous α-synuclein species. In contrast to most cell- and rodent-based PD models, which exhibit multiple diffuse α-synuclein aggregates throughout the cytoplasm, a single large nuclear inclusion that is immunopositive for α-synuclein and ubiquitin is rapidly obtained in our model. This was achieved without the need for overexpression of α-synuclein or genetic modification of the cell line. However, phosphorylation of α-synuclein within these inclusions was not observed. The system described here provides an ideal tool to screen compounds to therapeutically intervene in Lewy body formation, and to investigate the mechanisms involved in disease progression in synucleinopathies.
| S-EPMC6505482 | biostudies-literature
Project description:Understanding the contribution of immune mechanisms to Parkinson's disease pathogenesis is an important challenge, potentially of major therapeutic implications. To further elucidate the involvement of peripheral immune cells, we studied epigenome-wide DNA methylation in isolated populations of CD14+ monocytes, CD19+ B cells, CD4+ T cells, and CD8+ T cells from Parkinson's disease patients and healthy control participants. We included 25 patients with a maximum five years of disease duration and 25 controls, and isolated four immune cell populations from each fresh blood sample. Epigenome-wide DNA methylation profiles were generated from 186 samples using the Illumina MethylationEpic array and association with disease status was tested using linear regression models. We identified six differentially methylated CpGs in CD14+ monocytes and one in CD8 + T cells. Four differentially methylated regions were identified in monocytes, including a region upstream of RAB32, a gene that has been linked to LRRK2. Methylation upstream of RAB32 correlated negatively with mRNA expression, and RAB32 expression was upregulated in Parkinson's disease both in our samples and in summary statistics from a previous study. Our epigenome-wide association study of early Parkinson's disease provides evidence for methylation changes across different peripheral immune cell types, highlighting monocytes and the RAB32 locus. The findings were predominantly cell-type-specific, demonstrating the value of isolating purified cell populations for genomic studies.
| S-EPMC10616224 | biostudies-literature
Project description:Parkinson'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.
| S-EPMC7713145 | biostudies-literature
Project description:While Parkinson's disease remains clinically defined by cardinal motor symptoms resulting from nigrostriatal degeneration, it is now appreciated that the disease commonly consists of multiple pathologies, but it is unclear where these co-pathologies occur early in disease and whether they are responsible for the nigrostriatal degeneration. For the past number of years, we have been studying a well-characterized cohort of subjects with motor impairment that we have termed mild motor deficits. Motor deficits were determined on a modified and validated Unified Parkinson's Disease Rating Scale III but were insufficient in degree to diagnose Parkinson's disease. However, in our past studies, cases in this cohort had a selection bias, as both a clinical syndrome in between no motor deficits and Parkinson's disease, plus nigral Lewy pathology as defined post-mortem, were required for inclusion. Therefore, in the current study, we only based inclusion on the presence of a clinical phenotype with mild motor impairment insufficient to diagnose Parkinson's disease. Then, we divided this group further based upon whether or not subjects had a synucleinopathy in the nigrostriatal system. Here we demonstrate that loss of nigral dopaminergic neurons, loss of putamenal dopaminergic innervation and loss of the tyrosine hydroxylase-phenotype in the substantia nigra and putamen occur equally in mild motor deficit groups with and without nigral alpha-synuclein aggregates. Indeed, the common feature of these two groups is that both have similar degrees of AT8 positive phosphorylated tau, a pathology not seen in the nigrostriatal system of age-matched controls. These findings were confirmed with early (tau Ser208 phosphorylation) and late (tau Ser396/Ser404 phosphorylation) tau markers. This suggests that the initiation of nigrostriatal dopaminergic neurodegeneration occurs independently of alpha-synuclein aggregation and can be tau mediated.
| S-EPMC10834249 | biostudies-literature