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Physiological Reviews Oct 2019The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the... (Review)
Review
The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.
Topics: Age Factors; Aging; Animals; Bacteria; Behavior; Brain; Brain Diseases; Dysbiosis; Enteric Nervous System; Gastrointestinal Microbiome; Host-Pathogen Interactions; Humans; Intestines; Neuroimmunomodulation; Neuronal Plasticity; Risk Factors
PubMed: 31460832
DOI: 10.1152/physrev.00018.2018 -
Nature Reviews. Disease Primers May 2021Alzheimer disease (AD) is biologically defined by the presence of β-amyloid-containing plaques and tau-containing neurofibrillary tangles. AD is a genetic and sporadic... (Review)
Review
Alzheimer disease (AD) is biologically defined by the presence of β-amyloid-containing plaques and tau-containing neurofibrillary tangles. AD is a genetic and sporadic neurodegenerative disease that causes an amnestic cognitive impairment in its prototypical presentation and non-amnestic cognitive impairment in its less common variants. AD is a common cause of cognitive impairment acquired in midlife and late-life but its clinical impact is modified by other neurodegenerative and cerebrovascular conditions. This Primer conceives of AD biology as the brain disorder that results from a complex interplay of loss of synaptic homeostasis and dysfunction in the highly interrelated endosomal/lysosomal clearance pathways in which the precursors, aggregated species and post-translationally modified products of Aβ and tau play important roles. Therapeutic endeavours are still struggling to find targets within this framework that substantially change the clinical course in persons with AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; Humans; Neurodegenerative Diseases; Neurofibrillary Tangles
PubMed: 33986301
DOI: 10.1038/s41572-021-00269-y -
Frontiers in Immunology 2020The human microbiota has a fundamental role in host physiology and pathology. Gut microbial alteration, also known as dysbiosis, is a condition associated not only with... (Review)
Review
The human microbiota has a fundamental role in host physiology and pathology. Gut microbial alteration, also known as dysbiosis, is a condition associated not only with gastrointestinal disorders but also with diseases affecting other distal organs. Recently it became evident that the intestinal bacteria can affect the central nervous system (CNS) physiology and inflammation. The nervous system and the gastrointestinal tract are communicating through a bidirectional network of signaling pathways called the gut-brain axis, which consists of multiple connections, including the vagus nerve, the immune system, and bacterial metabolites and products. During dysbiosis, these pathways are dysregulated and associated with altered permeability of the blood-brain barrier (BBB) and neuroinflammation. However, numerous mechanisms behind the impact of the gut microbiota in neuro-development and -pathogenesis remain poorly understood. There are several immune pathways involved in CNS homeostasis and inflammation. Among those, the inflammasome pathway has been linked to neuroinflammatory conditions such as multiple sclerosis, Alzheimer's and Parkinson's diseases, but also anxiety and depressive-like disorders. The inflammasome complex assembles upon cell activation due to exposure to microbes, danger signals, or stress and lead to the production of pro-inflammatory cytokines (interleukin-1β and interleukin-18) and to pyroptosis. Evidences suggest that there is a reciprocal influence of microbiota and inflammasome activation in the brain. However, how this influence is precisely working is yet to be discovered. Herein, we discuss the status of the knowledge and the open questions in the field focusing on the function of intestinal microbial metabolites or products on CNS cells during healthy and inflammatory conditions, such as multiple sclerosis, Alzheimer's and Parkinson's diseases, and also neuropsychiatric disorders. In particular, we focus on the innate inflammasome pathway as immune mechanism that can be involved in several of these conditions, upon exposure to certain microbes.
Topics: Animals; Bacteria; Brain; Brain Diseases; Dysbiosis; Gastrointestinal Microbiome; Host-Pathogen Interactions; Humans; Inflammasomes; Intestines; Mental Disorders
PubMed: 33362788
DOI: 10.3389/fimmu.2020.604179 -
Fluids and Barriers of the CNS Nov 2020The blood-brain barrier is playing a critical role in controlling the influx and efflux of biological substances essential for the brain's metabolic activity as well as... (Review)
Review
The blood-brain barrier is playing a critical role in controlling the influx and efflux of biological substances essential for the brain's metabolic activity as well as neuronal function. Thus, the functional and structural integrity of the BBB is pivotal to maintain the homeostasis of the brain microenvironment. The different cells and structures contributing to developing this barrier are summarized along with the different functions that BBB plays at the brain-blood interface. We also explained the role of shear stress in maintaining BBB integrity. Furthermore, we elaborated on the clinical aspects that correlate between BBB disruption and different neurological and pathological conditions. Finally, we discussed several biomarkers that can help to assess the BBB permeability and integrity in-vitro or in-vivo and briefly explain their advantages and disadvantages.
Topics: Biological Transport; Biomarkers; Blood-Brain Barrier; Brain Diseases; Humans
PubMed: 33208141
DOI: 10.1186/s12987-020-00230-3 -
Psychological Medicine Nov 2020Cognition is commonly affected in brain disorders. Non-invasive brain stimulation (NIBS) may have procognitive effects, with high tolerability. This meta-analysis... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cognition is commonly affected in brain disorders. Non-invasive brain stimulation (NIBS) may have procognitive effects, with high tolerability. This meta-analysis evaluates the efficacy of transcranial magnetic stimulation (TMS) and transcranial Direct Current Stimulation (tDCS) in improving cognition, in schizophrenia, depression, dementia, Parkinson's disease, stroke, traumatic brain injury, and multiple sclerosis.
METHODS
A PRISMA systematic search was conducted for randomized controlled trials. Hedges' g was used to quantify effect sizes (ES) for changes in cognition after TMS/tDCS v. sham. As different cognitive functions may have unequal susceptibility to TMS/tDCS, we separately evaluated the effects on: attention/vigilance, working memory, executive functioning, processing speed, verbal fluency, verbal learning, and social cognition.
RESULTS
We included 82 studies (n = 2784). For working memory, both TMS (ES = 0.17, p = 0.015) and tDCS (ES = 0.17, p = 0.021) showed small but significant effects. Age positively moderated the effect of TMS. TDCS was superior to sham for attention/vigilance (ES = 0.20, p = 0.020). These significant effects did not differ across the type of brain disorder. Results were not significant for the other five cognitive domains.
CONCLUSIONS
Our results revealed that both TMS and tDCS elicit a small trans-diagnostic effect on working memory, tDCS also improved attention/vigilance across diagnoses. Effects on the other domains were not significant. Observed ES were small, yet even slight cognitive improvements may facilitate daily functioning. While NIBS can be a well-tolerated treatment, its effects appear domain specific and should be applied only for realistic indications (i.e. to induce a small improvement in working memory or attention).
Topics: Attention; Brain Diseases; Cognition; Humans; Memory, Short-Term; Randomized Controlled Trials as Topic; Transcranial Direct Current Stimulation; Transcranial Magnetic Stimulation
PubMed: 33070785
DOI: 10.1017/S0033291720003670 -
Seminars in Pediatric Neurology Dec 2019This review includes the congenital infections best known by the acronym TORCH (Toxoplasma gondii, rubella virus, cytomegalovirus, and herpes virus), as well as Zika... (Review)
Review
This review includes the congenital infections best known by the acronym TORCH (Toxoplasma gondii, rubella virus, cytomegalovirus, and herpes virus), as well as Zika virus infection and perinatally acquired infections (enterovirus, parechovirus, rotavirus, parvovirus). Congenital infections are due to pathogens that can cross the placenta and are more likely to injure the brain when the infection occurs early in pregnancy. There are many similarities, with regards to brain lesions, for congenital Zika syndrome and congenital cytomegalovirus infection. Perinatally acquired viral infections tend to injure the white matter, with cystic evolution being more likely in the (late) preterm infant compared to the full-term infant. Congenital and perinatally acquired viral infections can be associated with adverse neurological outcomes. Prevention is important, especially as therapeutic options are limited. In this review both congenital as well as perinatally acquired viral infections will be discussed with a focus on neuro-imaging findings.
Topics: Brain; Brain Diseases; Humans; Infant, Newborn; Infections
PubMed: 31813517
DOI: 10.1016/j.spen.2019.08.005 -
Developmental Medicine and Child... Nov 2020In this paper we reframe febrile seizures, which are viewed as a symptom of an underlying brain disorder. The general observation is that a small cohort of children will... (Review)
Review
In this paper we reframe febrile seizures, which are viewed as a symptom of an underlying brain disorder. The general observation is that a small cohort of children will develop febrile seizures (2-5% in the West), while the greater majority will not. This suggests that the brain that generates a seizure, in an often-mild febrile context, differs in some ways from the brain that does not. While the underlying brain disorder appears to have no significant adverse implication in the majority of children with febrile seizures, serious long-term outcomes (cognitive and neuropsychiatric) have been recently reported, including sudden death. These adverse events likely reflect the underlying intrinsic brain pathology, as yet undefined, of which febrile seizures are purely a manifestation and not the primary cause. A complex interaction between brain-genetics-epigenetics-early environment is likely at play. In view of this emerging data, it is time to review whether febrile seizures are a single entity, with a new and multidimensional approach needed to help with predicting outcome. WHAT THIS PAPER ADDS: A febrile seizure is due to a brain's aberrant response to high temperature. Problems in a small group of children are now being identified later in life. There is no clear correlation between duration or other characteristics of febrile seizures and subsequent mesial temporal sclerosis.
Topics: Brain Diseases; Child, Preschool; Cognitive Dysfunction; Epilepsy; Humans; Infant; Mental Disorders; Seizures, Febrile
PubMed: 32748466
DOI: 10.1111/dmcn.14642 -
Science Advances Sep 2022Lipids are crucial components of cellular function owing to their role in membrane formation, intercellular signaling, energy storage, and homeostasis maintenance. In... (Review)
Review
Lipids are crucial components of cellular function owing to their role in membrane formation, intercellular signaling, energy storage, and homeostasis maintenance. In the brain, lipid dysregulations have been associated with the etiology and progression of neurodegeneration and other neurological pathologies. Hence, brain lipids are emerging as important potential targets for the early diagnosis and prognosis of neurological diseases. This review aims to highlight the significance and usefulness of lipidomics in diagnosing and treating brain diseases. We explored lipid alterations associated with brain diseases, paying attention to organ-specific characteristics and the functions of brain lipids. As the recent advances in brain lipidomics would have been impossible without advances in analytical techniques, we provide up-to-date information on mass spectrometric approaches and integrative analysis with other omic approaches. Last, we present the potential applications of lipidomics combined with artificial intelligence techniques and interdisciplinary collaborative research for treating brain diseases with clinical heterogeneities.
Topics: Artificial Intelligence; Brain; Brain Diseases; Humans; Lipid Metabolism; Lipidomics; Lipids
PubMed: 36112688
DOI: 10.1126/sciadv.adc9317 -
Cells Jul 2019Accumulating evidence indicates that exercise can enhance brain function and attenuate neurodegeneration. Besides improving neuroplasticity by altering the synaptic... (Review)
Review
Accumulating evidence indicates that exercise can enhance brain function and attenuate neurodegeneration. Besides improving neuroplasticity by altering the synaptic structure and function in various brain regions, exercise also modulates multiple systems that are known to regulate neuroinflammation and glial activation. Activated microglia and several pro-inflammatory cytokines play active roles in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. The purpose of this review is to highlight the impacts of exercise on microglial activation. Possible mechanisms involved in exercise-modulated microglial activation are also discussed. Undoubtedly, more studies are needed in order to disclose the detailed mechanisms, but this approach offers therapeutic potential for improving the brain health of millions of aging people where pharmacological intervention has failed.
Topics: Animals; Brain Diseases; Cytokines; Exercise Therapy; Humans; Microglia; Motor Activity; Toll-Like Receptors
PubMed: 31324021
DOI: 10.3390/cells8070691 -
Clinical Neurophysiology : Official... Jul 2019Stroke has long been regarded as focal disease with circumscribed damage leading to neurological deficits. However, advances in methods for assessing the human brain and... (Review)
Review
Stroke has long been regarded as focal disease with circumscribed damage leading to neurological deficits. However, advances in methods for assessing the human brain and in statistics have enabled new tools for the examination of the consequences of stroke on brain structure and function. Thereby, it has become evident that stroke has impact on the entire brain and its network properties and can therefore be considered as a network disease. The present review first gives an overview of current methodological opportunities and pitfalls for assessing stroke-induced changes and reorganization in the human brain. We then summarize principles of plasticity after stroke that have emerged from the assessment of networks. Thereby, it is shown that neurological deficits do not only arise from focal tissue damage but also from local and remote changes in white-matter tracts and in neural interactions among wide-spread networks. Similarly, plasticity and clinical improvements are associated with specific compensatory structural and functional patterns of neural network interactions. Innovative treatment approaches have started to target such network patterns to enhance recovery. Network assessments to predict treatment response and to individualize rehabilitation is a promising way to enhance specific treatment effects and overall outcome after stroke.
Topics: Brain Diseases; Connectome; Diffusion Magnetic Resonance Imaging; Diffusion Tensor Imaging; Electric Stimulation; Electroencephalography; Humans; Magnetoencephalography; Nerve Net; Neuronal Plasticity; Organ Motion; Stroke; Stroke Rehabilitation
PubMed: 31082786
DOI: 10.1016/j.clinph.2019.04.004