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Acta Neuropathologica Communications Jun 2021Traumatic brain injury (TBI) constitutes one of the strongest environmental risk factors for several progressive neurodegenerative disorders of cognitive impairment and...
Mouse closed head traumatic brain injury replicates the histological tau pathology pattern of human disease: characterization of a novel model and systematic review of the literature.
Traumatic brain injury (TBI) constitutes one of the strongest environmental risk factors for several progressive neurodegenerative disorders of cognitive impairment and dementia that are characterized by the pathological accumulation of hyperphosphorylated tau (p-Tau). It has been questioned whether mouse closed-head TBI models can replicate human TBI-associated tauopathy. We conducted longitudinal histopathological characterization of a mouse closed head TBI model, with a focus on pathological features reported in human TBI-associated tauopathy. Male C57BL/6 J mice were subjected to once daily TBI for 5 consecutive days using a weight drop paradigm. Histological analyses (AT8, TDP-43, pTDP-43, NeuN, GFAP, Iba-1, MBP, SMI-312, Prussian blue, IgG, βAPP, alpha-synuclein) were conducted at 1 week, 4 weeks, and 24 weeks after rTBI and compared to sham operated controls. We conducted a systematic review of the literature for mouse models of closed-head injury focusing on studies referencing tau protein assessment. At 1-week post rTBI, p-Tau accumulation was restricted to the corpus callosum and perivascular spaces adjacent to the superior longitudinal fissure. Progressive p-Tau accumulation was observed in the superficial layers of the cerebral cortex, as well as in mammillary bodies and cortical perivascular, subpial, and periventricular locations at 4 to 24 weeks after rTBI. Associated cortical histopathologies included microvascular injury, neuroaxonal rarefaction, astroglial and microglial activation, and cytoplasmatic localization of TDP-43 and pTDP-43. In our systematic review, less than 1% of mouse studies (25/3756) reported p-Tau using immunostaining, of which only 3 (0.08%) reported perivascular p-Tau, which is considered a defining feature of chronic traumatic encephalopathy. Commonly reported associated pathologies included neuronal loss (23%), axonal loss (43%), microglial activation and astrogliosis (50%, each), and beta amyloid deposition (29%). Our novel model, supported by systematic review of the literature, indicates progressive tau pathology after closed head murine TBI, highlighting the suitability of mouse models to replicate pertinent human histopathology.
Topics: Animals; Brain Injuries, Traumatic; Chronic Traumatic Encephalopathy; Disease Models, Animal; Head Injuries, Closed; Humans; Male; Mice; Mice, Inbred C57BL; Tauopathies
PubMed: 34187585
DOI: 10.1186/s40478-021-01220-8 -
Nihon Rinsho. Japanese Journal of... Sep 2004There has been lots of progress in Parkinson's disease. First of all, in Japan, a guideline for the treatment of Parkinson's disease was published. This guideline... (Review)
Review
There has been lots of progress in Parkinson's disease. First of all, in Japan, a guideline for the treatment of Parkinson's disease was published. This guideline contains both EBM based systematic review of every drugs being used in the treatment of Parkinson's disease including those drugs for the management of side effects and other problems arising during the course of the treatment and an algorithm of the practical treatment of Parkinson's disease patients. This is an official publication of Japanese Neurological Society. In the diagnosis of Parkinson's disease, many specialists in Parkinson's disease have recognized the usefulness of MIBG SPECT of the cardiac sympathetic endings. MIBG uptake shows remarkable decrease in Lewy body positive Parkinson's disease patients from the early stage except for some of the stage I patients. In the basic aspect, studies on familial forms of Parkinson's disease have contributed a lot to the understanding of the pathogenesis of sporadic Parkinson's disease. Mutations of alpha-synuclein cause autosomal dominant Parkinson's disease. Recently, triplication of one of the alpha-synuclein genes was found as the third mutation of PARK1. Thus just overproduction of normal alpha-synuclein is toxic to nigral neurons. In this form and sporadic Parkinson's disease, oxidative damage plays an important role in nigral neurodegeneration. PARK2 is caused by mutations of the parkin gene. Parkin protein is an ubiquitin-protein ligase. In this form also, oxidative damage appears to be operating in neurodegeneration. Thus a common mechanism appears to be present in different forms of Parkinson's disease. Future investigation to find neuroprotective drugs should take this concept of common mechanism into their research strategies.
Topics: Humans; Parkinson Disease; Research
PubMed: 15462371
DOI: No ID Found -
Neurologia I Neurochirurgia Polska 2020The identification of reliable biomarkers of Parkinson's disease (PD) is a pivotal step in the introduction of causal therapies. Saliva is a biofluid which may be... (Review)
Review
The identification of reliable biomarkers of Parkinson's disease (PD) is a pivotal step in the introduction of causal therapies. Saliva is a biofluid which may be involved in synuclein pathology in PD. We have reviewed current studies on salivary proteins and compounds in PD patients and healthy controls, and their potential application as biomarkers. A systematic literature search of the Pubmed and Scopus databases was performed. A total of 198 studies were screened, of which 20 were included in our qualitative analysis. We conclude that the oligomeric form of salivary alpha synuclein is higher in PD patients, and that this may serve as a potential biomarker of PD. Salivary DJ-1 concentrations fail to differentiate PD patients from controls. Other enzymes and substances (heme oxygenase-1, nitric oxide, acetylcholinesterase) have been assessed in single studies. Salivary cortisol levels are higher in PD than in healthy subjects. Further validation of these findings is needed. Saliva may be a promising source of biomarkers in PD.
Topics: Biomarkers; Humans; Mouth; Parkinson Disease; Saliva; alpha-Synuclein
PubMed: 32003440
DOI: 10.5603/PJNNS.a2020.0011 -
Journal of Neurology, Neurosurgery, and... Nov 2019Dementia is a common, debilitating feature of late Parkinson's disease (PD). PD dementia (PDD) is associated with α-synuclein propagation, but coexistent Alzheimer's...
BACKGROUND
Dementia is a common, debilitating feature of late Parkinson's disease (PD). PD dementia (PDD) is associated with α-synuclein propagation, but coexistent Alzheimer's disease (AD) pathology may coexist. Other pathologies (cerebrovascular, transactive response DNA-binding protein 43 (TDP-43)) may also influence cognition. We aimed to describe the neuropathology underlying dementia in PD.
METHODS
Systematic review of autopsy studies published in English involving PD cases with dementia. Comparison groups included PD without dementia, AD, dementia with Lewy bodies (DLB) and healthy controls.
RESULTS
44 reports involving 2002 cases, 57.2% with dementia, met inclusion criteria. While limbic and neocortical α-synuclein pathology had the strongest association with dementia, between a fifth and a third of all PD cases in the largest studies had comorbid AD. In PD cases with dementia, tau pathology was moderate or severe in around a third, and amyloid-β pathology was moderate or severe in over half. Amyloid-β was associated with a more rapid cognitive decline and earlier mortality, and in the striatum, distinguished PDD from DLB. Positive correlations between multiple measures of α-synuclein, tau and amyloid-β were found. Cerebrovascular and TDP-43 pathologies did not generally contribute to dementia in PD. TDP-43 and amyloid angiopathy correlated with coexistent Alzheimer pathology.
CONCLUSIONS
While significant α-synuclein pathology is the main substrate of dementia in PD, coexistent pathologies are common. In particular, tau and amyloid-β pathologies independently contribute to the development and pattern of cognitive decline in PD. Their presence should be assessed in future clinical trials where dementia is a key outcome measure.
TRIAL REGISTRATION NUMBER
CRD42018088691.
Topics: Alzheimer Disease; Autopsy; Brain; Comorbidity; Dementia; Humans; Parkinson Disease
PubMed: 31444276
DOI: 10.1136/jnnp-2019-321111 -
Acta Neuropsychiatrica Dec 2020Lewy body dementia (LBD) is the second most prevalent neurodegenerative dementia and it causes more morbidity and mortality than Alzheimer's disease. Several genetic...
OBJECTIVES
Lewy body dementia (LBD) is the second most prevalent neurodegenerative dementia and it causes more morbidity and mortality than Alzheimer's disease. Several genetic associations of LBD have been reported and their functional implications remain uncertain. Hence, we aimed to do a systematic review of all gene expression studies that investigated people with LBD for improving our understanding of LBD molecular pathology and for facilitating discovery of novel biomarkers and therapeutic targets for LBD.
METHODS
We systematically reviewed five online databases (PROSPERO protocol: CRD42017080647) and assessed the functional implications of all reported differentially expressed genes (DEGs) using Ingenuity Pathway Analyses.
RESULTS
We screened 3,809 articles and identified 31 eligible studies. In that, 1,242 statistically significant (p < 0.05) DEGs including 70 microRNAs have been reported in people with LBD. Expression levels of alternatively spliced transcripts of SNCA, SNCB, PRKN, APP, RELA, and ATXN2 significantly differ in LBD. Several mitochondrial genes and genes involved in ubiquitin proteasome system and autophagy-lysosomal pathway were significantly downregulated in LBD. Evidence supporting chronic neuroinflammation in LBD was inconsistent. Our functional analyses highlighted the importance of ribonucleic acid (RNA)-mediated gene silencing, neuregulin signalling, and neurotrophic factors in the molecular pathology of LBD.
CONCLUSIONS
α-synuclein aggregation, mitochondrial dysfunction, defects in molecular networks clearing misfolded proteins, and RNA-mediated gene silencing contribute to neurodegeneration in LBD. Larger longitudinal transcriptomic studies investigating biological fluids of people living with LBD are needed for molecular subtyping and staging of LBD. Diagnostic biomarker potential and therapeutic promise of identified DEGs warrant further research.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Protein Precursor; Ataxin-2; Autophagy; Biomarkers; Brain; Databases, Factual; Down-Regulation; Gene Expression; Genes, Mitochondrial; Humans; Lewy Body Disease; MicroRNAs; Proteasome Endopeptidase Complex; Proteins; Transcription Factor RelA; Ubiquitin; Ubiquitin-Protein Ligases; alpha-Synuclein; beta-Synuclein
PubMed: 32178745
DOI: 10.1017/neu.2020.13 -
Frontiers in Neural Circuits 2019An imbalance of iron metabolism with consecutive aggregation of α-synuclein and axonal degeneration of neurons has been postulated as the main pathological feature in...
An imbalance of iron metabolism with consecutive aggregation of α-synuclein and axonal degeneration of neurons has been postulated as the main pathological feature in the development of Parkinson's disease (PD). Quantitative susceptibility mapping (QSM) is a new imaging technique, which enables to measure structural changes caused by defective iron deposition in parkinsonian brains. Due to its novelty, its potential as a new imaging technique remains elusive for disease-specific characterization of motor and non-motor symptoms (characterizing the individual parkinsonian phenotype). Functional network changes associated with these symptoms are however frequently described for both magnetoencephalography (MEG) and resting state functional magnetic imaging (rs-fMRI). Here, we performed a systematic review of the current literature about QSM imaging, MEG and rs-fMRI in order to collect existing data about structural and functional changes caused by motor and non-motor symptoms in PD. Whereas all three techniques provide an effect in the motor domain, the understanding of network changes caused by non-motor symptoms is much more lacking for MEG and rs-fMRI, and does not yet really exist for QSM imaging. In order to better understand the influence of pathological iron distribution onto the functional outcome, whole-brain QSM analyses should be integrated in functional analyses (especially for the non-motor domain), to enable a proper pathophysiological interpretation of MEG and rs-fMRI network changes in PD. Herewith, a better understanding of the relationship between neuropathological changes, functional network changes and clinical phenotype might become possible.
Topics: Animals; Brain; Brain Mapping; Humans; Nerve Net; Parkinsonian Disorders; Phenotype; Rest
PubMed: 31447651
DOI: 10.3389/fncir.2019.00050 -
Neuropsychology Review Dec 2015Many patients with Parkinson's disease (PD) will develop cognitive impairment. Cross-sectional studies have shown that certain protein levels are altered in the... (Review)
Review
Many patients with Parkinson's disease (PD) will develop cognitive impairment. Cross-sectional studies have shown that certain protein levels are altered in the cerebrospinal fluid (CSF) of PD patients with dementia and are thought to represent potential biomarkers of underlying pathogenesis. Recent studies suggest that CSF biomarker levels may be predictive of future risk of cognitive decline in non-demented PD patients. However, the strength of this evidence and difference between specific CSF biomarkers is not well delineated. We therefore performed a systematic review to assess if levels of specific CSF protein biomarkers are predictive of progression to cognitive impairment. Nine articles were identified that met inclusion criteria for the review. Findings from the review suggest a convergence of evidence that a low baseline Aβ42 in the CSF of non-demented PD patients predicts development of cognitive impairment over time. Conversely, there is limited evidence that CSF levels of tau, either total tau or phosphorylated tau, is a useful predictive biomarker. There are mixed results for other CSF biomarkers such as α-synuclein, Neurofilament light chain, and Heart fatty acid-binding protein. Overall the results of this review show that certain CSF biomarkers have better predictive ability to identify PD patients who are at risk for developing cognitive impairment. Given the interest in developing disease-modifying therapies, identifying this group will be important for clinical trials as initiation of therapy prior to the onset of cognitive decline is likely to be more efficacious.
Topics: Biomarkers; Cognition; Cognition Disorders; Humans; Parkinson Disease; Prognosis
PubMed: 26626621
DOI: 10.1007/s11065-015-9307-8 -
International Journal of Geriatric... May 2020Lewy body dementia (LBD) causes more morbidity, disability, and earlier mortality than Alzheimer disease. Molecular mechanisms underlying neurodegeneration in LBD are...
OBJECTIVES
Lewy body dementia (LBD) causes more morbidity, disability, and earlier mortality than Alzheimer disease. Molecular mechanisms underlying neurodegeneration in LBD are poorly understood. We aimed to do a systematic review of all genetic association studies that investigated people with LBD for improving our understanding of LBD molecular genetics and for facilitating discovery of novel biomarkers and therapeutic targets for LBD.
METHODS
We systematically reviewed five online databases (PROSPERO protocol: CRD42018087114) and completed the quality assessment using the quality of genetic association studies tool.
RESULTS
Eight thousand five hundred twenty-one articles were screened, and 75 articles were eligible to be included. Genetic associations of LBD with APOE, GBA, and SNCA variants have been replicated by two or more good quality studies. Our meta-analyses confirmed that APOE-ε4 is significantly associated with dementia with Lewy bodies (pooled odds ratio [POR] = 2.70; 95% CI, 2.37-3.07; P < .001) and Parkinson's disease dementia (POR = 1.60; 95% CI, 1.21-2.11; P = .001). Other reported genetic associations that need further replication include variants in A2M, BCHE-K, BCL7C, CHRFAM7A, CNTN1, ESR1, GABRB3, MAPT, mitochondrial DNA (mtDNA) haplogroup H, NOS2A, PSEN1, SCARB2, TFAM, TREM2, and UCHL1.
CONCLUSIONS
The reported genetic associations and their potential interactions indicate the importance of α-synuclein, amyloid, and tau pathology, autophagy lysosomal pathway, ubiquitin proteasome system, oxidative stress, and mitochondrial dysfunction in LBD. There is a need for larger genome-wide association study (GWAS) for identifying more LBD-associated genes. Future hypothesis-driven studies should aim to replicate reported genetic associations of LBD and to explore their functional implications.
Topics: Aged, 80 and over; Alzheimer Disease; Biomarkers; Female; Genome-Wide Association Study; Humans; Lewy Bodies; Lewy Body Disease; Lysosomal Membrane Proteins; Male; Membrane Glycoproteins; Receptors, Immunologic; Receptors, Scavenger; alpha-Synuclein
PubMed: 31898332
DOI: 10.1002/gps.5260 -
Journal of Parkinson's Disease 2019Gut microbiota have been studied in relation to the pathophysiology of Parkinson's disease (PD) due to the early gastrointestinal symptomatology and presence of...
Gut microbiota have been studied in relation to the pathophysiology of Parkinson's disease (PD) due to the early gastrointestinal symptomatology and presence of alpha-synuclein pathology in the enteric nervous system, hypothesized to ascend via the vagal nerve to the central nervous system. Accordingly, sixteen human case-control studies have published gut microbiome composition changes in PD and reported over 100 differentially abundant taxa covering all taxonomic levels from phylum to genus or species, depending on methodology. While certain findings were replicated across several studies, various contradictory findings were reported. Here, differences in methodologies and the presence of possible confounders in the study populations are assessed for their potential to confound the results of gut microbiome studies in PD. Gut microbiome studies in PD exhibited considerable variability with respect to the study population, sample transport conditions, laboratory protocols and sequencing, bioinformatics pipelines, and biostatistical methods. To move from the current heterogeneous dataset towards clinically relevant biomarkers and the identification of putative therapeutic targets, recommendations are derived from the limitations of the available studies to increase the future comparability of microbiome studies in PD. In addition, integration of currently available data on the gut microbiome in PD is proposed to identify robust gut microbiome profiles in PD. Furthermore, expansion of the current dataset with atypical parkinsonism cohorts, prodromal and treatment-naïve de novo PD subjects, measurements of fecal microbial concentrations and multi-omics assessments are required to provide clinically relevant biomarkers and reveal therapeutic targets within the gut microbiome of PD.
Topics: Gastrointestinal Microbiome; Humans; Parkinson Disease
PubMed: 31498131
DOI: 10.3233/JPD-191711 -
Frontiers in Aging Neuroscience 2022Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by neuroinflammation, formation of Lewy bodies, and progressive loss of...
Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by neuroinflammation, formation of Lewy bodies, and progressive loss of dopaminergic neurons in the substantia nigra of the brain. In this review, we summarize evidence obtained by animal studies demonstrating neuroinflammation as one of the central pathogenetic mechanisms of PD. We also focus on the protein factors that initiate the development of PD and other neurodegenerative diseases. Our targeted literature search identified 40 pre-clinical and studies written in English. Nuclear factor B (NF-kB) pathway is demonstrated as a common mechanism engaged by neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6hydroxydopamine (6-OHDA), as well as the bacterial lipopolysaccharide (LPS). The α-synuclein protein, which plays a prominent role in PD neuropathology, may also contribute to neuroinflammation by activating mast cells. Meanwhile, 6-OHDA models of PD identify microsomal prostaglandin E synthase-1 (mPGES-1) as one of the contributors to neuroinflammatory processes in this model. Immune responses are used by the central nervous system to fight and remove pathogens; however, hyperactivated and prolonged immune responses can lead to a harmful neuroinflammatory state, which is one of the key mechanisms in the pathogenesis of PD.
PubMed: 35912090
DOI: 10.3389/fnagi.2022.855776