scholarly journals Vascular Dementia and Crosstalk Between the Complement and Coagulation Systems

2021 ◽  
Vol 8 ◽  
Author(s):  
Milad Mossanen Parsi ◽  
Cédric Duval ◽  
Robert A. S. Ariëns
Keyword(s):  
Vascular Dementia ◽  
Neurological Disorders ◽  
Tissue Injury ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Common Type ◽  
Neurocognitive Disorder ◽  
Defence Mechanisms ◽  
Acute Tissue Injury ◽  
The Brain

Vascular Dementia (VaD) is a neurocognitive disorder caused by reduced blood flow to the brain tissue, resulting in infarction, and is the second most common type of dementia. The complement and coagulation systems are evolutionary host defence mechanisms activated by acute tissue injury to induce inflammation, clot formation and lysis; recent studies have revealed that these systems are closely interlinked. Overactivation of these systems has been recognised to play a key role in the pathogenesis of neurological disorders such as Alzheimer's disease and multiple sclerosis, however their role in VaD has not yet been extensively reviewed. This review aims to bridge the gap in knowledge by collating current understanding of VaD to enable identification of complement and coagulation components involved in the pathogenesis of this disorder that may have their effects amplified or supressed by crosstalk. Exploration of these mechanisms may unveil novel therapeutic targets or biomarkers that would improve current treatment strategies for VaD.

Lipidomics and cognitive dysfunction – A Narrative review

2020 ◽  
Vol 45 (2) ◽  
Author(s):  
Arpita Chakraborty ◽  
Samir Kumar Praharaj ◽  
R. V. Krishnananda Prabhu ◽  
M. Mukhyaprana Prabhu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Vascular Dementia ◽  
Cognitive Dysfunction ◽  
Neurological Disorders ◽  
Brain Lipids ◽  
Complex Lipids ◽  
Functional Components ◽  
The Brain

AbstractBackgroundMore than half portion of the brain is formed by lipids. They play critical roles in maintaining the brain's structural and functional components. Any dysregulation in these brain lipids can lead to cognitive dysfunction which are associated with neurological disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia, vascular dementia etc. Studies have linked lipids with cognitive impairment. But not much has been studied about the complex brain lipids which might play a pivotal role in cognitive impairment. This review aims to highlight the lipidomic profiles in patients with cognitive dysfunction.ResultsForty-five articles were reviewed. These studies show alterations in complex lipids such as sphingolipids, phospholipids, glycolipids and sterols in brain in various neurological disorders such as vascular dementia, Parkinson's and Alzheimer's disease. However, the classes of fatty acids in these lipids involved are different across studies.ConclusionsThere is a need for targeted lipidomics analysis, specifically including sphingolipids in patients with neurodegenerative disorders so as to improve diagnostics as well as management of these disorders.

scholarly journals Molecular mechanisms of cell death in neurological diseases

2021 ◽  
Author(s):  
Diane Moujalled ◽  
Andreas Strasser ◽  
Jeffrey R. Liddell
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Neurological Diseases ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Response To Therapy ◽  
Signalling Cascades ◽  
The Brain

AbstractTightly orchestrated programmed cell death (PCD) signalling events occur during normal neuronal development in a spatially and temporally restricted manner to establish the neural architecture and shaping the CNS. Abnormalities in PCD signalling cascades, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death associated with autophagy as well as in unprogrammed necrosis can be observed in the pathogenesis of various neurological diseases. These cell deaths can be activated in response to various forms of cellular stress (exerted by intracellular or extracellular stimuli) and inflammatory processes. Aberrant activation of PCD pathways is a common feature in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, resulting in unwanted loss of neuronal cells and function. Conversely, inactivation of PCD is thought to contribute to the development of brain cancers and to impact their response to therapy. For many neurodegenerative diseases and brain cancers current treatment strategies have only modest effect, engendering the need for investigations into the origins of these diseases. With many diseases of the brain displaying aberrations in PCD pathways, it appears that agents that can either inhibit or induce PCD may be critical components of future therapeutic strategies. The development of such therapies will have to be guided by preclinical studies in animal models that faithfully mimic the human disease. In this review, we briefly describe PCD and unprogrammed cell death processes and the roles they play in contributing to neurodegenerative diseases or tumorigenesis in the brain. We also discuss the interplay between distinct cell death signalling cascades and disease pathogenesis and describe pharmacological agents targeting key players in the cell death signalling pathways that have progressed through to clinical trials.

scholarly journals Dysfunction of the Glymphatic System as a Potential Mechanism of Perioperative Neurocognitive Disorders

2021 ◽  
Vol 13 ◽  
Author(s):  
Xuli Ren ◽  
Shan Liu ◽  
Chuang Lian ◽  
Haixia Li ◽  
Kai Li ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
The Elderly ◽  
Brain Dysfunction ◽  
Neurocognitive Disorder ◽  
Potential Mechanism ◽  
Lymphatic Function ◽  
Cognitive Domains ◽  
Glymphatic System ◽  
The Brain

Perioperative neurocognitive disorder (PND) frequently occurs in the elderly as a severe postoperative complication and is characterized by a decline in cognitive function that impairs memory, attention, and other cognitive domains. Currently, the exact pathogenic mechanism of PND is multifaceted and remains unclear. The glymphatic system is a newly discovered glial-dependent perivascular network that subserves a pseudo-lymphatic function in the brain. Recent studies have highlighted the significant role of the glymphatic system in the removal of harmful metabolites in the brain. Dysfunction of the glymphatic system can reduce metabolic waste removal, leading to neuroinflammation and neurological disorders. We speculate that there is a causal relationship between the glymphatic system and symptomatic progression in PND. This paper reviews the current literature on the glymphatic system and some perioperative factors to discuss the role of the glymphatic system in PND.

Multiple Sclerosis

2017 ◽  
Author(s):  
Pavan Bhargava ◽  
Peter A. Calabresi
Keyword(s):  
Multiple Sclerosis ◽  
Immunosuppressive Agents ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Phase 2 ◽  
Future Directions ◽  
Disease Modifying Therapies ◽  
Future Challenges ◽  
Brain And Spinal Cord ◽  
The Brain

Multiple sclerosis is a chronic demyelinating neurological disorder of the brain and spinal cord, with both inflammatory and degenerative components. Current treatment strategies utilize immunomodulatory and immunosuppressive agents to reduce the inflammatory disease activity and retard accumulation of disability. Future challenges for treatment include identifying agents that will promote remyelination and axonal protection to help impact progressive forms of multiple sclerosis. This chapter discusses currently available disease modifying therapies, agents currently in phase 2/3 trials, and future directions in the treatment of multiple sclerosis.

scholarly journals Clinical Management of Moyamoya Patients

2021 ◽  
Vol 10 (16) ◽  
pp. 3628
Author(s):  
Isabella Canavero ◽  
Ignazio Gaspare Vetrano ◽  
Marialuisa Zedde ◽  
Rosario Pascarella ◽  
Laura Gatti ◽  
...  
Keyword(s):  
Randomized Clinical Trials ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Long Term Outcomes ◽  
Hemorrhagic Risk ◽  
Collateral Vessels ◽  
Hereditary Conditions ◽  
The Brain ◽  
Internal Carotid Arteries

Moyamoya angiopathy (MMA) is a peculiar cerebrovascular condition characterized by progressive steno-occlusion of the terminal part of the internal carotid arteries (ICAs) and their proximal branches, associated with the development of a network of fragile collateral vessels at the base of the brain. The diagnosis is essentially made by radiological angiographic techniques. MMA is often idiopathic (moyamoya disease-MMD); conversely, it can be associated with acquired or hereditary conditions (moyamoya Syndrome-MMS); however, the pathophysiology underlying either MMD or MMS has not been fully elucidated to date, and this poor knowledge reflects uncertainties and heterogeneity in patient management. MMD and MMS also have similar clinical expressions, including, above all, ischemic and hemorrhagic strokes, then headaches, seizures, cognitive impairment, and movement disorders. The available treatment strategies are currently shared between idiopathic MMD and MMS, including pharmacological and surgical stroke prevention treatments and symptomatic drugs. No pharmacological treatment able to reverse the progressive disappearance of the ICAs has been found to date in both idiopathic and syndromic cases. Antithrombotic agents are usually prescribed in ischemic MMA, although the coexisting hemorrhagic risk should be considered. Surgical revascularization techniques, which are currently the best available treatment in symptomatic MMA, are associated with good long-term outcomes and reduced ischemic and hemorrhagic risks. Given the lack of dedicated randomized clinical trials, current treatment is mainly based on observational studies and physicians’ and surgeons’ expertise.

scholarly journals Interferon Beta Contributes to Astrocyte Activation in the Brain following Reovirus Infection

2019 ◽  
Vol 93 (10) ◽  
Author(s):  
Penny Clarke ◽  
Yonghua Zhuang ◽  
Heather M. Berens ◽  
J. Smith Leser ◽  
Kenneth L. Tyler
Keyword(s):  
Interferon Beta ◽  
Viral Encephalitis ◽  
Prolonged Exposure ◽  
Tissue Injury ◽  
Ex Vivo ◽  
Treatment Strategies ◽  
Astrocyte Activation ◽  
Reovirus Infection ◽  
Primary Astrocytes ◽  
The Brain

ABSTRACTReovirus encephalitis in mice was used as a model system to investigate astrocyte activation (astrogliosis) following viral infection of the brain. Reovirus infection resulted in astrogliosis, as evidenced by increased expression of glial fibrillary acidic protein (GFAP), and the upregulation of genes that have been previously associated with astrocyte activation. Astrocyte activation occurred in regions of the brain that are targeted by reovirus but extended beyond areas of active infection. Astrogliosis also occurred following reovirus infection ofex vivobrain slice cultures (BSCs), demonstrating that factors intrinsic to the brain are sufficient to activate astrocytes and that this process can occur in the absence of any contribution from the peripheral immune response. In agreement with previous reports, reovirus antigen did not colocalize with GFAP in infected brains, suggesting that reovirus does not infect astrocytes. Reovirus-infected neurons produce interferon beta (IFN-β). IFN-β treatment of primary astrocytes resulted in both the upregulation of GFAP and cytokines that are associated with astrocyte activation. In addition, the ability of media from reovirus-infected BSCs to activate primary astrocytes was blocked by anti-IFN-β antibodies. These results suggest that IFN-β, likely released from reovirus-infected neurons, results in the activation of astrocytes during reovirus encephalitis. In areas where infection and injury were pronounced, an absence of GFAP staining was consistent with activation-induced cell death as a mechanism of inflammation control. In support of this, activated Bak and cleaved caspase 3 were detected in astrocytes within reovirus-infected brains, indicating that activated astrocytes undergo apoptosis.IMPORTANCEViral encephalitis is a significant cause of worldwide morbidity and mortality, and specific treatments are extremely limited. Virus infection of the brain triggers neuroinflammation; however, the role of neuroinflammation in the pathogenesis of viral encephalitis is unclear. Initial neuroinflammatory responses likely contribute to viral clearance, but prolonged exposure to proinflammatory cytokines released during neuroinflammation may be deleterious and contribute to neuronal death and tissue injury. Activation of astrocytes is a hallmark of neuroinflammation. Here, we show that reovirus infection of the brain results in the activation of astrocytes via an IFN-β-mediated process and that these astrocytes later die by Bak-mediated apoptosis. A better understanding of neuroinflammatory responses during viral encephalitis may facilitate the development of new treatment strategies for these diseases.

scholarly journals IL-1β-mediated macrophage infiltration into the brain after peripheral tissue injury

2020 ◽  
Author(s):  
Xiang Ke Chen ◽  
Joseph Shiu-Kwong Kwan ◽  
Gordon Tin-Chun Wong ◽  
Kazi Md. Mahmudul H ◽  
Zhen-Ni Yi ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Fluorescent Protein ◽  
Tissue Injury ◽  
Interleukin 1 ◽  
Macrophage Infiltration ◽  
Peripheral Tissue ◽  
Transgenic Zebrafish ◽  
Peripheral Inflammation ◽  
Hyperactive Behavior ◽  
The Brain

Abstract Background: Infiltration of macrophages into the central nervous system (CNS) is involved in many neurological disorders, such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and autism. Despite extensive studies into neuroinflammation associated macrophage infiltration into the CNS, its underlying mechanisms and pathological roles remain unclear, especially when triggered by peripheral inflammation. Methods: To further elucidate the role and mechanism of peripheral inflammation in neurological disorders, we exploited interleukin 1 beta (il1b) mutant transgenic zebrafish (Danio rerio) with fluorescent protein expression restricted to macrophages to track the macrophage migration under peripheral inflammation following tail amputation.Results: We found that macrophage infiltration into the brain of zebrafish embryo following peripheral tissue injury can be alleviated via genetically targeting il1b. In addition, through circulation-independent migration, macrophages infiltrate brains with evidence of increased apoptosis. We further identified the expression of camk2g1 in the brains of zebrafish with hyperactive behavior following peripheral tissue injury. This il1b-regulated protein is associated with neuropsychiatry disorders. Conclusion: These findings demonstrated that peripheral tissue injury induces il1b-mediated macrophage infiltration into the brain and a hyperactive behavior.

scholarly journals Innate and Adaptive Cell Populations Driving Inflammation in Dry Eye Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
José L. Reyes ◽  
Danielle T. Vannan ◽  
Bertus Eksteen ◽  
Imelda Juárez Avelar ◽  
Tonathiu Rodríguez ◽  
...  
Keyword(s):  
Dry Eye ◽  
Immune Cell ◽  
Tissue Injury ◽  
Treatment Strategies ◽  
Tear Film ◽  
Current Treatment ◽  
Dry Eye Disease ◽  
Eye Disease ◽  
Cell Populations ◽  
Secondary Form

Dry eye disease (DED) is the most common ocular disease and affects millions of individuals worldwide. DED encompasses a heterogeneous group of diseases that can be generally divided into two forms including aqueous-deficient and evaporative DED. Evidence suggests that these conditions arise from either failure of lacrimal gland secretion or low tear film quality. In its secondary form, DED is often associated with autoimmune diseases such as Sjögren’s syndrome and rheumatoid arthritis. Current treatment strategies for DED are limited to anti-inflammatory medications that target the immune system as the source of deleterious inflammation and tissue injury. However, there is a lack of understanding of the underlying pathogenesis of DED, and subsequently, there are very few effective treatment strategies. The gap in our knowledge of the etiology of primary DED is in part because the majority of research in DED focused on secondary autoimmune causes. This review focuses on what is currently understood about the contribution of innate and adaptive immune cell populations in the pathogenesis of DED and highlights the need to continue investigating the central role of immunity driving DED.

scholarly journals RVG-functionalized reduction sensitive micelles for the effective accumulation of doxorubicin in brain

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jiangkang Xu ◽  
Xiaoye Yang ◽  
Jianbo Ji ◽  
Yuan Gao ◽  
Na Qiu ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Glioma Cells ◽  
Current Treatment ◽  
Chemotherapeutic Agents ◽  
Brain Targeting ◽  
Hydrophobic Core ◽  
Rat Glioma ◽  
Novel Treatment Strategies ◽  
The Brain

Abstract Background Glioblastoma is a lethal neoplasm with few effective therapy options. As a mainstay in the current treatment of glioma at present, chemotherapeutic agents usually show inadequate therapeutic efficiency due to their low blood brain barrier traversal and brain targeting, together with tumor multidrug resistance. Novel treatment strategies are thus urgently needed to improve chemotherapy outcomes. Results Here, we report that nanomedicines developed by functionalizing the neurotropic rabies virus-derived polypeptide, RVG, and loading reduction-sensitive nanomicelles (polymer and doxorubicin) enable a highly specific and efficacious drug accumulation in the brain. Interestingly, curcumin serves as the hydrophobic core of the polymer, while suppressing the major efflux proteins in doxorubicin-resistant glioma cells. Studies on doxorubicin-resistant rat glioma cells demonstrate that the RVG-modified micelles exhibit superior cell entry and antitumor activity. In vivo research further showed that RVG modified nanomicelles significantly enhanced brain accumulation and tumor inhibition rate in mice, leading to a higher survival rate with negligible systemic toxicity. Moreover, effective suppression of recurrence and pulmonary metastatic nodules were also determined after the RVG-modified nanomicelles treatment. Conclusions The potential of RVG-modified nanomicelles for glioma was demonstrated. Brain accumulation was markedly enhanced after intravenous administration. This unique drug delivery nanoplatform to the brain provides a novel and powerful therapeutic strategy for the treatment of central nervous system disorders including glioma. Graphic abstract

Ultradeep HIV-1 proviral envelope sequencing reveals complex population structure within and between brain and splenic tissues

2021 ◽  
Author(s):  
Rebecca Rose ◽  
Maria Paz Gonzalez-Perez ◽  
David J Nolan ◽  
Sissy Cross ◽  
Susanna L Lamers ◽  
...  
Keyword(s):  
Population Structure ◽  
High Throughput ◽  
Neurological Disorders ◽  
Treatment Strategies ◽  
Viral Population ◽  
Variable Regions ◽  
Functional Differences ◽  
The Brain ◽  
Hiv 1 ◽  
Brain Tissues

Understanding tissue-based HIV-1 proviral population structure is important for improving treatment strategies for individuals with HIV-associated neurological disorders (HAND). Prior analyses have revealed HIV-1 envelope ( env ) population structure between brain and peripheral tissues, as well as Env functional differences, especially in individuals with HAND. Furthermore, population structure has been detected among different anatomical locations in the brain itself, although such patterns are inconsistent across individuals and less strongly associated with the presence/absence of HAND. Here we utilized the Pacific Biosciences single molecule real-time (SMRT) high-throughput technology to generate thousands of sequences for each tissue, along with phylogenetic and distance-based analyses, to investigate env sequences from paired brain and spleen samples from eight individuals with/without HAND. To account for the high error rate associated with SMRT sequencing, we used a clustering approach to identify high quality consensus sequences representative of ≥10 reads (“HQCS10”). In parallel, we characterized variable regions from non-clustered sequences to identify potential functional differences. We found evidence for significant population structure between brain and spleen tissues, as well as among brain tissues and within the same brain tissue, in individuals both with and without HAND. Variable region analysis showed differences in length and charge among brain and non-brain tissues, as well as within the brain, suggesting possible functional differences. Our results demonstrate the complexity of HIV-1 env structure/gene flow among tissues and support the concept that selective pressures in different tissue microenvironments drive viral evolution and adaptation. IMPORTANCE Understanding the evolution of HIV-1 in the brain compared to other tissues is important for improving treatment strategies for individuals with HIV-associated neurological disorders (HAND). We utilized a high-throughput sequencing technology to generate thousands of full-length env sequences from paired brain and spleen samples from eight individuals with/without HAND. We found significant viral population structure for participants both with and without HAND, providing robust evidence for the brain as a compartmentalized tissue and potentially a viral reservoir. We also found striking genetic differences between virus populations, even from the same tissue, suggesting the potential for functional differences and the possibility for multiple evolutionary pathways that result in similar tropism and/or other tissue-adapted characteristics. Our results demonstrate the complexity of viral population structure within the brain and suggest that analysis of peripheral blood samples alone may not be fully informative with respect to improving strategies to treat or eradicate HIV-1.

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