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Environmental Research May 2022Air pollution is one of the most serious environmental problems that afflict our planet and one of the greatest risk factors for human health. In particular, PM is able...
Air pollution is one of the most serious environmental problems that afflict our planet and one of the greatest risk factors for human health. In particular, PM is able to cross the blood-alveolar and blood-brain barriers, thus increasing the onset of respiratory, cardiovascular and neurodegenerative diseases. Neurodegenerative disease is a progressive neuronal dysfunction that leads to neuronal lesions in both structure and function, and includes several diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), vascular dementia (VaD), multiple sclerosis (MS), and others. We carried out a systematic review using PRISMA approach to investigate on the possible association between exposure to PM and neurodegenerative diseases. The international databases (PubMed, Science Direct, Web of Sciences) were used to find published studies on the topic. The search period was between January 2011 and June 2021. About 2000 full research articles were selected, and finally, we included 20 full-research articles. Selected studies have highlighted how PM exposure can be associated with the onset of neurodegenerative diseases (AD, PD, MS, VaD). This association depends not only on age, PM levels and exposure time, but also on exposure to other air pollutants, proximity to areas with high vehicular traffic, and the presence of comorbidities. Exposure to PM promotes neuroinflammation processes, because through breathing the particles can reach the nasal epithelial mucosa and transferred to the brain through the olfactory bulb. Furthermore, exposure to PM has been associated with an increased expression of markers of neurodegenerative diseases (e.g. alpha-synuclein or beta-amyloid), which can contribute to the etiopathogenesis of neurodegenerative diseases. Although many studies have revealed the pathological relationship between PM exposure and cognitive impairment, the potential cellular and molecular mechanisms of PM leading to neurodegenerative disease remain not entirely clear, and then, further studies need to be carried out on the topic.
Topics: Air Pollutants; Air Pollution; Alzheimer Disease; Environmental Exposure; Humans; Neurodegenerative Diseases; Particulate Matter
PubMed: 34979121
DOI: 10.1016/j.envres.2021.112581 -
Geriatrie Et Psychologie... Dec 2021Cognitive diseases with Lewy bodies occur in two forms: dementia with Lewy bodies (DLB) and Parkinsonian dementia (PD), which follows the evolution of Parkinson disease....
BACKGROUND
Cognitive diseases with Lewy bodies occur in two forms: dementia with Lewy bodies (DLB) and Parkinsonian dementia (PD), which follows the evolution of Parkinson disease. There is currently no curative treatment for these cognitive diseases with Lewy bodies. Therapeutic trials in DLB are rare, due to the fact that the disease has only recently been described and the first international diagnostic criteria have only recently been published (1996).
METHOD
This article proposes a synthesis of the therapeutic trials carried out into DLB in the last five years, including PD patients, using the Clinicaltrials.gov and Pubmed.gov databases.
RESULTS
We identified 35 therapeutic trials on ClinicalTrials.gov and 14 on PubMed. In line with our temporal criteria, 21 trials were analysed. Of the 11 completed trials with reported results, two drugs showed positive results: two trials with zonisamide (phases 2 and 3) showed improvements in Parkinsonian syndrome and one trial with neflamapimod (phase 2) showed improvements in cognition and walking.
CONCLUSION
In recent years, there has been an increase in therapeutic research into DLB, which is consistent with the prevalence of this disease - approximately 200,000 patients in France. Compared to other cognitive neurodegenerative diseases, therapeutic research is largely insufficient, although the proportion of positive trials is significant. Effective treatment to modify the course of the disease would have significant consequences for patients and their relatives.
PubMed: 34933841
DOI: 10.1684/pnv.2021.0981 -
Geriatrie Et Psychologie... Sep 2021Cognitive diseases with Lewy bodies occur in two forms: dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which follows the progression of...
BACKGROUND
Cognitive diseases with Lewy bodies occur in two forms: dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which follows the progression of Parkinson's disease. There is currently no curative treatment for these cognitive diseases with Lewy bodies. Therapeutic trials in DLB are rare, due to the recent description of the disease as well as its first international diagnostic criteria (1996).
METHOD
This article proposes a synthesis of the therapeutic trials carried out in DLB in the last 5 years, including PDD patients with DLB patients, using the Clinicaltrials.gov and Pubmed.gov databases.
RESULTS
We identified 35 therapeutic trials on Clinical Trials and 14 on PubMed. According to our temporal criteria, 21 trials were analyzed. Among the 11 completed trials with reported results, two molecules showed positive results: two trials with zonisamide (phase 2 and 3) showed a gain on parkinsonism and one trial with neflamapimod (phase 2) a gain on cognition and walking.
CONCLUSION
In recent years, there has been an increase in the therapeutic research effort in DLB, which is consistent with the prevalence of this disease - approximately 200,000 patients in France. Compared to other cognitive neurodegenerative diseases, therapeutic research is largely insufficient, whereas the proportion of positive trials is important. An effective disease modifying would have strong consequences for the patient and the relatives.
Topics: Cognition; Cognition Disorders; France; Humans; Lewy Body Disease; Parkinson Disease
PubMed: 34609295
DOI: 10.1684/pnv.2021.0947 -
Cureus Aug 2021Parkinson's disease (PD) is a neurodegenerative disease caused due to the destruction of dopaminergic neurons and the deposition of α-synuclein proteins, known as Lewy... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disease caused due to the destruction of dopaminergic neurons and the deposition of α-synuclein proteins, known as Lewy bodies. Generally, the diagnosis of PD is centered around motor symptoms. However, the early recognition of non-motor symptoms such as autonomic dysfunction, sleep disturbances, and cognitive and psychiatric disturbances are gaining increased attention for the early diagnosis of PD. Rapid eye movement (REM) sleep behavior disorder or REM sleep behavior disorder (RBD) is described as parasomnia, which is a condition of loss of normal muscle atonia causing the person to act out vivid dreams and it has been seen to be associated with the misprocessing of intercellular α-synuclein leading to neurodegenerative diseases such as PD. This review's objective is to highlight the significance of RBD as a prodromal premotor marker for the early detection of PD. We used PubMed as our primary database to search for articles on May 2, 2021, and a total of 1849 articles were found in our initial search using keywords and medical subject heading (MeSH) keywords. Thereafter, we removed the duplicates, applied the inclusion/exclusion criteria, and did a quality appraisal to include 10 articles in this study. We concluded that the recognition and diagnosis of RBD are of paramount importance to detect early PD, and further longitudinal studies and clinical trials are of utmost importance to understand their correlation; also, treatment trials are needed to prevent the phenoconversion of RBD into PD.
PubMed: 34522507
DOI: 10.7759/cureus.17026 -
Brain Research Oct 2021Research has suggested a link between the gut microbiota and Parkinson's Disease (PD), and an early involvement of gastrointestinal dysfunction has been reported in...
INTRODUCTION
Research has suggested a link between the gut microbiota and Parkinson's Disease (PD), and an early involvement of gastrointestinal dysfunction has been reported in patients. A mechanism review was performed to investigate whether the neurodegenerative cascade begins in the gut; mediated by gut dysbiosis and retrograde transport of α-synuclein. This review provides a summary of microbiome composition associated with PD, and evaluates pathophysiological mechanisms from animal and in vitro models of PD.
METHOD
A systematic literature search was performed in PubMed; 82 of 299 papers met the inclusion criteria.
RESULTS
All twenty-two human case-control studies demonstrated an altered gut microbiota in PD compared to healthy controls, with results suggesting a proinflammatory phenotype present in PD. A germ-free animal study has demonstrated that gut microbiota are required for microglia activation, α-synuclein pathology and motor deficits. Accumulation of phosphorylated α-synuclein has been observed in the enteric nervous system prior to the onset of motor symptoms in animal models of PD, and there is data to support retrograde transport of α-synuclein from the gut to the brain. Different animal models of PD have demonstrated neuroinflammation, microglial activation and loss of dopaminergic neurons in the brain.
CONCLUSION
Evidence from this review supports the hypothesis that pathology spreads from the gut to the brain. Future animal studies using oral LPS or microbiota transplants from human PD cases could provide further insight into the entire mechanism. Prospective longitudinal microbiome studies and novel modelling approaches could help to identify functional dysbiosis and early biomarkers for PD.
Topics: Animals; Gastrointestinal Microbiome; Humans; Parkinson Disease; alpha-Synuclein
PubMed: 34371014
DOI: 10.1016/j.brainres.2021.147609 -
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 -
Journal of Neuromuscular Diseases 2021Parkinson's disease (PD) is a disabling neurological condition characterized by the loss of dopaminergic neurons. Currently, the treatment for PD is symptomatic and...
Parkinson's disease (PD) is a disabling neurological condition characterized by the loss of dopaminergic neurons. Currently, the treatment for PD is symptomatic and compensates for the endogenous loss of dopamine production. In cases where the pharmacological therapy is only partly beneficial or results in major wearing-off complications, surgical interventions such as deep brain stimulation may be an alternative treatment. The disease cause often remains unknown, but in some patients, a monogenic cause can be identified. Mutations in at least six genes, LRRK2, SNCA, and VPS35 (dominant forms) or Parkin/PRKN, PINK1, and DJ1/PARK7 (recessive forms) have been unequivocally linked to PD pathogenesis. We here systematically screened 8,576 publications on these monogenic PD forms. We identified 2,226 mutation carriers from 456 papers. Levodopa was the most widely applied treatment; only 34 patients were indicated to be untreated at the time of reporting. Notably, detailed treatment data was rarely mentioned including response quantification (good, moderate, minimal) in 951 and/or dose in 293 patients only. Based on available data, levodopa showed an overall good outcome, especially in LRRK2, VPS35, Parkin, and PINK1 mutation carriers ("good" response in 94.6-100%). Side effects of levodopa therapy were reported in ∼15-40%of levodopa-treated patients across genes with dyskinesias as the most frequent one. Non-levodopa medication was indicated to be administered to <200 patients with mainly good outcome. Only a few reports were available on outcomes of brain surgery. Here, most mutation carriers showed a good response. Importantly, none of the available treatments is harmful to one genetic form but effective in another one. In the light of different medication schemes, the progressive nature of PD, and side effects, an improvement of therapeutic options for PD is warranted including a treatabolome database to guide clinicians in treatment decisions. Further, novel disease-cause-modifying drugs are needed.
Topics: Antiparkinson Agents; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Levodopa; Mutation; Parkinson Disease; Protein Deglycase DJ-1; Protein Kinases; Ubiquitin-Protein Ligases; Vesicular Transport Proteins; alpha-Synuclein
PubMed: 33459660
DOI: 10.3233/JND-200598 -
Journal of the Neurological Sciences Aug 2020Frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB) are two common forms of neurodegenerative dementia, subsequent to Alzheimer's disease (AD). AD is the... (Review)
Review
RATIONALE
Frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB) are two common forms of neurodegenerative dementia, subsequent to Alzheimer's disease (AD). AD is the only dementia that includes clinically validated cerebrospinal fluid (CSF) biomarkers in the diagnostic criteria. FTD and DLB often overlap with AD in their clinical and pathological features, making it challenging to differentiate between these conditions.
AIM
This systematic review aimed to identify if novel fluid biomarkers are useful in differentiating FTD and DLB from AD. Increasing the certainty of the differentiation between dementia subtypes would be advantageous clinically and in research.
METHODS
PubMed and Scopus were searched for studies that quantified and assessed diagnostic accuracy of novel fluid biomarkers in clinically diagnosed patients with FTD or DLB, in comparison to patients with AD. Meta-analyses were performed on biomarkers that were quantified in 3 studies or more.
RESULTS
The search strategy yielded 614 results, from which, 27 studies were included. When comparing bio-fluid levels in AD and FTD patients, neurofilament light chain (NfL) level was often higher in FTD, whilst brain soluble amyloid precursor protein β (sAPPβ) was higher in patients with AD. When comparing bio-fluid levels in AD and DLB patients, α-synuclein ensued heterogeneous findings, while the noradrenaline metabolite (MHPG) was found to be lower in DLB. Ratios of Aβ42/Aβ38 and Aβ42/Aβ40 were lower in AD than FTD and DLB and offered better diagnostic accuracy than raw amyloid-β (Aβ) concentrations.
CONCLUSIONS
Several promising novel biomarkers were highlighted in this review. Combinations of fluid biomarkers were more often useful than individual biomarkers in distinguishing subtypes of dementia. Considering the heterogeneity in methods and results between the studies, further validation, ideally with longitudinal prospective designs with large sample sizes and unified protocols, are fundamental before conclusions can be finalised.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Frontotemporal Dementia; Humans; Lewy Body Disease; Peptide Fragments; Prospective Studies; tau Proteins
PubMed: 32428759
DOI: 10.1016/j.jns.2020.116886 -
Brain Sciences Apr 2020The accumulation of abnormal protein aggregates represents a universal hallmark of neurodegenerative diseases (NDDs). Post-translational modifications (PTMs) regulate... (Review)
Review
The accumulation of abnormal protein aggregates represents a universal hallmark of neurodegenerative diseases (NDDs). Post-translational modifications (PTMs) regulate protein structure and function. Dysregulated PTMs may influence the propensity for protein aggregation in NDD-proteinopathies. To investigate this, we systematically reviewed the literature to evaluate effects of PTMs on aggregation propensity for major proteins linked to the pathogenesis and/or progression of NDDs. A search of PubMed, MEDLINE, EMBASE, and Web of Science Core Collection was conducted to retrieve studies that investigated an association between PTMs and protein aggregation in seven NDDs: Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxias, transmissible spongiform encephalopathy, and multiple sclerosis. Together, 1222 studies were identified, of which 69 met eligibility criteria. We identified that the following PTMs, in isolation or combination, potentially act as modulators of proteinopathy in NDDs: isoaspartate formation in Aβ, phosphorylation of Aβ or tau in AD; acetylation, 4-hydroxy-2-neonal modification, -GlcNAcylation or phosphorylation of α-synuclein in PD; acetylation or phosphorylation of TAR DNA-binding protein-43 in ALS, and SUMOylation of superoxide dismutase-1 in ALS; and phosphorylation of huntingtin in HD. The potential pharmacological manipulation of these aggregation-modulating PTMs represents an as-yet untapped source of therapy to treat NDDs.
PubMed: 32290481
DOI: 10.3390/brainsci10040232 -
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