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Cells Dec 2023The greatest risk factor for neurodegeneration is the aging of the multiple cell types of human CNS, among which microglia are important because they are the "sentinels"... (Review)
Review
The greatest risk factor for neurodegeneration is the aging of the multiple cell types of human CNS, among which microglia are important because they are the "sentinels" of internal and external perturbations and have long lifespans. We aim to emphasize microglial signatures in physiologic brain aging and Alzheimer's disease (AD). A systematic literature search of all published articles about microglial senescence in human healthy aging and AD was performed, searching for PubMed and Scopus online databases. Among 1947 articles screened, a total of 289 articles were assessed for full-text eligibility. Microglial transcriptomic, phenotypic, and neuropathological profiles were analyzed comprising healthy aging and AD. Our review highlights that studies on animal models only partially clarify what happens in humans. Human and mice microglia are hugely heterogeneous. Like a two-sided coin, microglia can be protective or harmful, depending on the context. Brain health depends upon a balance between the actions and reactions of microglia maintaining brain homeostasis in cooperation with other cell types (especially astrocytes and oligodendrocytes). During aging, accumulating oxidative stress and mitochondrial dysfunction weaken microglia leading to dystrophic/senescent, otherwise over-reactive, phenotype-enhancing neurodegenerative phenomena. Microglia are crucial for managing Aβ, pTAU, and damaged synapses, being pivotal in AD pathogenesis.
Topics: Humans; Mice; Animals; Alzheimer Disease; Microglia; Healthy Aging; Aging; Brain
PubMed: 38132144
DOI: 10.3390/cells12242824 -
Biomedicine & Pharmacotherapy =... Sep 2023Neurodegenerative diseases (NDDs) encompass a range of conditions that involve progressive deterioration and dysfunction of the nervous system. Some of the common NDDs... (Review)
Review
Neurodegenerative diseases (NDDs) encompass a range of conditions that involve progressive deterioration and dysfunction of the nervous system. Some of the common NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Although significant progress has been made in understanding the pathological mechanisms of NDDs in recent years, the development of targeted and effective drugs for their treatment remains challenging. Kaempferol is a flavonoid whose derivatives include kaempferol-O-rhamnoside, 3-O-β-rutinoside/6-hydroxykaempferol 3,6-di-O-β-d-glucoside, and kaempferide. Emerging studies have suggested that kaempferol and its derivatives possess neuroprotective properties and may have potential therapeutic benefits in NDDs. Here, we aimed to provide a theoretical basis for the use of kaempferol and its derivatives in the clinical treatment of NDDs. We systematically reviewed the literature in the PubMed, Web of Science, and Science Direct databases until June 2022 using the search terms "kaempferol," "kaempferol derivatives," "NDDs," "pharmacokinetics," and "biosynthesis" according to the reporting items for systematic review (PRISMA) standard. Based on combined results of in vivo and in vitro studies, we summarize the basic mechanisms and targets of kaempferol and its derivatives in the management of AD, PD, HD, and ALS. Kaempferol and its derivatives exert a neuroprotective role mainly by preventing the deposition of amyloid fibrils (such as Aβ, tau, and α-synuclein), inhibiting microglia activation, reducing the release of inflammatory factors, restoring the mitochondrial membrane to prevent oxidative stress, protecting the blood-brain barrier, and inhibiting specific enzyme activities (such as cholinesterase). Kaempferol and its derivatives are promising natural neuroprotective agents. By determining their pharmacological mechanism, kaempferol and its derivatives may be new candidate drugs for the treatment of NDDs.
Topics: Humans; Neurodegenerative Diseases; Neuroprotective Agents; Amyotrophic Lateral Sclerosis; Kaempferols; Alzheimer Disease; Parkinson Disease; Huntington Disease
PubMed: 37494786
DOI: 10.1016/j.biopha.2023.115215 -
International Journal of Molecular... Jul 2023Inflammatory mechanisms are increasingly recognized as important contributors to the pathogenesis of neurodegenerative diseases, including Lewy body dementia (LBD). Our... (Review)
Review
Inflammatory mechanisms are increasingly recognized as important contributors to the pathogenesis of neurodegenerative diseases, including Lewy body dementia (LBD). Our objectives were to, firstly, review inflammation investigation methods in LBD (dementia with Lewy bodies and Parkinson's disease dementia) and, secondly, identify alterations in inflammatory signals in LBD compared to people without neurodegenerative disease and other neurodegenerative diseases. A systematic scoping review was performed by searching major electronic databases (MEDLINE, Embase, Web of Science, and PSYCHInfo) to identify relevant human studies. Of the 2509 results screened, 80 studies were included. Thirty-six studies analyzed postmortem brain tissue, and 44 investigated living subjects with cerebrospinal fluid, blood, and/or brain imaging assessments. Largely cross-sectional data were available, although two longitudinal clinical studies investigated prodromal Lewy body disease. Investigations were focused on inflammatory immune cell activity (microglia, astrocytes, and lymphocytes) and inflammatory molecules (cytokines, etc.). Results of the included studies identified innate and adaptive immune system contributions to inflammation associated with Lewy body pathology and clinical disease features. Different signals in early and late-stage disease, with possible late immune senescence and dystrophic glial cell populations, were identified. The strength of these associations is limited by the varying methodologies, small study sizes, and cross-sectional nature of the data. Longitudinal studies investigating associations with clinical and other biomarker outcomes are needed to improve understanding of inflammatory activity over the course of LBD. This could identify markers of disease activity and support therapeutic development.
Topics: Humans; Lewy Body Disease; Dementia; Neurodegenerative Diseases; Cross-Sectional Studies; Parkinson Disease; Inflammation; alpha-Synuclein
PubMed: 37569491
DOI: 10.3390/ijms241512116 -
Frontiers in Immunology 2023Neuropathic pain is caused by a neurological injury or disease and can have a significant impact on people's daily lives. Studies have shown that neuropathic pain is...
BACKGROUND
Neuropathic pain is caused by a neurological injury or disease and can have a significant impact on people's daily lives. Studies have shown that neuropathic pain is commonly associated with neurodegenerative diseases. In recent years, there has been a lot of literature on the relationship between neuropathic pain and neurodegenerative diseases. However, bibliometrics is rarely used in analyzing the general aspects of studies on neuropathic pain in neurodegenerative diseases.
METHODS
The bibliometric analysis software CiteSpace and VOSviewer were used to analyze the knowledge graph of 387 studies in the Science Citation Index Expanded of the Web of Science Core Collection Database.
RESULTS
We obtained 2,036 documents through the search, leaving 387 documents after culling. 387 documents were used for the data analysis. The data analysis showed that 330 papers related to neuropathic pain in neurodegenerative diseases were published from 2007-2022, accounting for 85.27% of all published literature. In terms of contributions to the scientific study of neuropathic pain, the United States is in the top tier, with the highest number of publications, citations, and H-indexes.
CONCLUSION
The findings in our study may provide researchers with useful information about research trends, frontiers, and cooperative institutions. Multiple sclerosis, Parkinson's disease, and Alzheimer's disease are the three most studied neurodegenerative diseases. Among the pathological basis of neurodegenerative diseases, microglia-regulated neuroinflammation is a hot research topic. Deep brain stimulation and gamma knife radiosurgery are two popular treatments.
Topics: Humans; Neurodegenerative Diseases; Neuralgia; Alzheimer Disease; Parkinson Disease; Bibliometrics
PubMed: 37503342
DOI: 10.3389/fimmu.2023.1182411 -
Brain, Behavior, and Immunity Oct 2023The 18-kDa translocator protein (TSPO) is increasingly recognized as a molecular target for PET imaging of inflammatory responses in various central nervous system (CNS)...
INTRODUCTION
The 18-kDa translocator protein (TSPO) is increasingly recognized as a molecular target for PET imaging of inflammatory responses in various central nervous system (CNS) disorders. However, the reported sensitivity and specificity of TSPO PET to identify brain inflammatory processes appears to vary greatly across disorders, disease stages, and applied quantification methods. To advance TSPO PET as a potential biomarker to evaluate brain inflammation and anti-inflammatory therapies, a better understanding of its applicability across disorders is needed. We conducted a transdiagnostic systematic review and meta-analysis of all in vivo human TSPO PET imaging case-control studies in the CNS. Specifically, we investigated the direction, strength, and heterogeneity associated with the TSPO PET signal across disorders in pre-specified brain regions, and explored the demographic and methodological sources of heterogeneity.
METHODS
We searched for English peer-reviewed articles that reported in vivo human case-control TSPO PET differences. We extracted the demographic details, TSPO PET outcomes, and technical variables of the PET procedure. A random-effects meta-analysis was applied to estimate case-control standardized mean differences (SMD) of the TSPO PET signal in the lobar/whole-brain cortical grey matter (cGM), thalamus, and cortico-limbic circuitry between different illness categories. Heterogeneity was evaluated with the I statistic and explored using subgroup and meta-regression analyses for radioligand generation, PET quantification method, age, sex, and publication year. Significance was set at the False Discovery Rate (FDR)-corrected P < 0.05.
RESULTS
156 individual case-control studies were included in the systematic review, incorporating data for 2381 healthy controls and 2626 patients. 139 studies documented meta-analysable data and were grouped into 11 illness categories. Across all the illness categories, we observed a significantly higher TSPO PET signal in cases compared to controls for the cGM (n = 121 studies, SMD = 0.358, P < 0.001, I = 68%), with a significant difference between the illness categories (P = 0.004). cGM increases were only significant for Alzheimer's disease (SMD = 0.693, P < 0.001, I = 64%) and other neurodegenerative disorders (SMD = 0.929, P < 0.001, I = 73%). Cortico-limbic increases (n = 97 studies, SMD = 0.541, P < 0.001, I = 67%) were most prominent for Alzheimer's disease, mild cognitive impairment, other neurodegenerative disorders, mood disorders and multiple sclerosis. Thalamic involvement (n = 79 studies, SMD = 0.393, P < 0.001, I = 71%) was observed for Alzheimer's disease, other neurodegenerative disorders, multiple sclerosis, and chronic pain and functional disorders (all P < 0.05). Main outcomes for systemic immunological disorders, viral infections, substance use disorders, schizophrenia and traumatic brain injury were not significant. We identified multiple sources of between-study variance to the TSPO PET signal including a strong transdiagnostic effect of the quantification method (explaining 25% of between-study variance; V-based SMD = 0.000 versus reference tissue-based studies SMD = 0.630; F = 20.49, df = 1;103, P < 0.001), patient age (9% of variance), and radioligand generation (5% of variance).
CONCLUSION
This study is the first overarching transdiagnostic meta-analysis of case-control TSPO PET findings in humans across several brain regions. We observed robust increases in the TSPO signal for specific types of disorders, which were widespread or focal depending on illness category. We also found a large and transdiagnostic horizontal (positive) shift of the effect estimates of reference tissue-based compared to V-based studies. Our results can support future studies to optimize experimental design and power calculations, by taking into account the type of disorder, brain region-of-interest, radioligand, and quantification method.
PubMed: 37543251
DOI: 10.1016/j.bbi.2023.07.023 -
Frontiers in Neurology 2023Spinal cord injury (SCI) triggers motor, sensory, and autonomic impairments that adversely damage patients' quality of life. Its pathophysiological processes include...
BACKGROUND
Spinal cord injury (SCI) triggers motor, sensory, and autonomic impairments that adversely damage patients' quality of life. Its pathophysiological processes include inflammation, oxidative stress, and apoptosis, although existing treatment options have little success. Macrophages have a vital function in controlling inflammation in SCI, with their M1-type and M2-type macrophages dominating early inflammatory effects and late brain tissue repair and regeneration, respectively. However, there is a dearth of rigorous bibliometric study in this sector to explore its dynamics and trends. This study intends to examine the current status and trends of macrophage usage in SCI using bibliometric methodologies, which may drive novel therapeutic options.
METHODS
In this study, the Web of Science Core Collection (WOSCC) was utilized to collect publications and reviews on macrophages in SCI from 2002 to 2023. Bibliometrics and visualization analyses were performed by VOSviewer, CiteSpace, the R package "bibliometrix", and online analytic platforms. These analyses covered a variety of aspects, including countries and institutions, authors and co-cited authors, journals and co-cited journals, subject categories, co-cited references, and keyword co-occurrences, in order to provide insights into the research trends and hotspots in this field.
RESULTS
1,775 papers were included in the study, comprising 1,528 articles and 247 reviews. Our research analysis demonstrates that the number of relevant studies in this sector is expanding, specifically the number of publications in the United States and China has risen dramatically. However, there are fewer collaborations between institutions in different nations, and international cooperation needs to be reinforced. Among them, Popovich PG became the leader in the field, and significant journals include Experimental Neurology, Journal of Neurotrauma, and Journal of Neuroscience. Research hotspots involve macrophage polarization, microglia, astrocytes, signaling, cytokines, inflammation, and neuroprotection.
CONCLUSIONS
This analysis gives, for the first time, a comprehensive overview of bibliometric studies on macrophages in SCI over the past 20 years. This study not only gives an extensive picture of the knowledge structure but also indicates trends in the subject. The systematic summarization gives a complete and intuitive understanding of the link between spinal cord damage and macrophages and provides a great reference for future related studies.
PubMed: 38073628
DOI: 10.3389/fneur.2023.1285908 -
Frontiers in Cellular Neuroscience 2024Schizophrenia is a complex and severe mental disorder that affects approximately 1% of the global population. It is characterized by a wide range of symptoms, including...
Schizophrenia is a complex and severe mental disorder that affects approximately 1% of the global population. It is characterized by a wide range of symptoms, including delusions, hallucinations, disorganized speech and behavior, and cognitive impairment. Recent research has suggested that the immune system dysregulation may play a significant role in the pathogenesis of schizophrenia, and glial cells, such as astroglia and microglia known to be involved in neuroinflammation and immune regulation, have emerged as potential players in this process. The aim of this systematic review is to summarize the glial hallmarks of schizophrenia, choosing as cellular candidate the astroglia and microglia, and focusing also on disease-associated psychological (cognitive and emotional) changes. We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed, Scopus, and Web of Science for articles that investigated the differences in astroglia and microglia in patients with schizophrenia, published in the last 5 years. The present systematic review indicates that changes in the density, morphology, and functioning of astroglia and microglia may be involved in the development of schizophrenia. The glial alterations may contribute to the pathogenesis of schizophrenia by dysregulating neurotransmission and immune responses, worsening cognitive capabilities. The complex interplay of astroglial and microglial activation, genetic/epigenetic variations, and cognitive assessments underscores the intricate relationship between biological mechanisms, symptomatology, and cognitive functioning in schizophrenia.
PubMed: 38419655
DOI: 10.3389/fncel.2024.1358450 -
Frontiers in Immunology 2023The aim of this study was to systematically review the neuroimmunology literature to determine the average immune cell counts reported by flow cytometry in wild-type...
OBJECTIVE
The aim of this study was to systematically review the neuroimmunology literature to determine the average immune cell counts reported by flow cytometry in wild-type (WT) homogenized mouse brains.
BACKGROUND
Mouse models of gene dysfunction are widely used to study age-associated neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. The importance of the neuroimmune system in these multifactorial disorders has become increasingly evident, and methods to quantify resident and infiltrating immune cells in the brain, including flow cytometry, are necessary. However, there appears to be no consensus on the best approach to perform flow cytometry or quantify/report immune cell counts. The development of more standardized methods would accelerate neuroimmune discovery and validation by meta-analysis.
METHODS
There has not yet been a systematic review of 'neuroimmunology' by 'flow cytometry' via examination of the PROSPERO registry. A protocol for a systematic review was subsequently based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) using the Studies, Data, Methods, and Outcomes (SDMO) criteria. Literature searches were conducted in the Google Scholar and PubMed databases. From that search, 900 candidate studies were identified, and 437 studies were assessed for eligibility based on formal exclusion criteria.
RESULTS
Out of the 437 studies reviewed, 58 were eligible for inclusion and comparative analysis. Each study assessed immune cell subsets within homogenized mouse brains and used flow cytometry. Nonetheless, there was considerable variability in the methods, data analysis, reporting, and results. Descriptive statistics have been presented on the study designs and results, including medians with interquartile ranges (IQRs) and overall means with standard deviations (SD) for specific immune cell counts and their relative proportions, within and between studies. A total of 58 studies reported the most abundant immune cells within the brains were TMEM119 microglia, bulk CD4 T cells, and bulk CD8 T cells.
CONCLUSION
Experiments to conduct and report flow cytometry data, derived from WT homogenized mouse brains, would benefit from a more standardized approach. While within-study comparisons are valid, the variability in methods of counting of immune cell populations is too broad for meta-analysis. The inclusion of a minimal protocol with more detailed methods, controls, and standards could enable this nascent field to compare results across studies.
Topics: Animals; Mice; Brain; CD8-Positive T-Lymphocytes; Flow Cytometry; Research Design; Systematic Reviews as Topic
PubMed: 38022545
DOI: 10.3389/fimmu.2023.1281705 -
Cellular and Molecular Neurobiology Feb 2024It is well known that as part of their response to infectious agents such as viruses, microglia transition from a quiescent state to an activated state that includes... (Review)
Review
It is well known that as part of their response to infectious agents such as viruses, microglia transition from a quiescent state to an activated state that includes proinflammatory and anti-inflammatory phases; this behavior has been described through in vitro studies. However, recent in vivo studies on the function of microglia have questioned the two-phase paradigm; therefore, a change in the frequency of in vitro studies is expected. A systematic review was carried out to identify the microglial cytokine profile against viral infection that has been further evaluated through in vitro studies (pro-inflammatory or anti-inflammatory), along with analysis of its publication frequency over the years. For this review, 531 articles published in the English language were collected from PubMed, Web of Science, EBSCO and ResearchGate. Only 27 papers met the inclusion criteria for this systematic review. In total, 19 cytokines were evaluated in these studies, most of which are proinflammatory; the most common are IL-6, followed by TNF-α and IL-1β. It should be pointed out that half of the studies were published between 2015 and 2022 (raw data available in https://github.com/dadriba05/SystematicReview.git ). In this review, we identified that evaluation of pro-inflammatory cytokines released by microglia against viral infections has been performed more frequently than that of anti-inflammatory cytokines; additionally, a higher frequency of evaluation of the response of microglia cells to viral infection through in vitro studies from 2015 and beyond was noted.
Topics: Humans; Cytokines; Microglia; Virus Diseases; Tumor Necrosis Factor-alpha; Anti-Inflammatory Agents
PubMed: 38349562
DOI: 10.1007/s10571-024-01454-9 -
Neural Regeneration Research Jan 2024Repetitive transcranial magnetic stimulation has been increasingly studied in different neurological diseases, and although most studies focus on its effects on neuronal... (Review)
Review
Repetitive transcranial magnetic stimulation has been increasingly studied in different neurological diseases, and although most studies focus on its effects on neuronal cells, the contribution of non-neuronal cells to the improvement triggered by repetitive transcranial magnetic stimulation in these diseases has been increasingly suggested. To systematically review the effects of repetitive magnetic stimulation on non-neuronal cells two online databases, Web of Science and PubMed were searched for the effects of high-frequency-repetitive transcranial magnetic stimulation, low-frequency-repetitive transcranial magnetic stimulation, intermittent theta-burst stimulation, continuous theta-burst stimulation, or repetitive magnetic stimulation on non-neuronal cells in models of disease and in unlesioned animals or cells. A total of 52 studies were included. The protocol more frequently used was high-frequency-repetitive magnetic stimulation, and in models of disease, most studies report that high-frequency-repetitive magnetic stimulation led to a decrease in astrocyte and microglial reactivity, a decrease in the release of pro-inflammatory cytokines, and an increase of oligodendrocyte proliferation. The trend towards decreased microglial and astrocyte reactivity as well as increased oligodendrocyte proliferation occurred with intermittent theta-burst stimulation and continuous theta-burst stimulation. Few papers analyzed the low-frequency-repetitive transcranial magnetic stimulation protocol, and the parameters evaluated were restricted to the study of astrocyte reactivity and release of pro-inflammatory cytokines, reporting the absence of effects on these parameters. In what concerns the use of magnetic stimulation in unlesioned animals or cells, most articles on all four types of stimulation reported a lack of effects. It is also important to point out that the studies were developed mostly in male rodents, not evaluating possible differential effects of repetitive transcranial magnetic stimulation between sexes. This systematic review supports that through modulation of glial cells repetitive magnetic stimulation contributes to the neuroprotection or repair in various neurological disease models. However, it should be noted that there are still few articles focusing on the impact of repetitive magnetic stimulation on non-neuronal cells and most studies did not perform in-depth analyses of the effects, emphasizing the need for more studies in this field.
PubMed: 37488852
DOI: 10.4103/1673-5374.374140