Advancing Neurological Health: Insights into Aging, Immunity, and Vascular Dynamics.

This editorial provides an overview of recent advancements in the understanding and treatment of neurological disorders, focusing on aging, immunity, and blood flow, as featured in this special issue. The first section explores the importance of identifying biomarkers of aging and aging-related diseases, such as Alzheimer's Disease, highlighting the emerging role of saliva-based biomarkers and the gut-brain axis in disease diagnosis and management. In the subsequent section, the dysregulated immune systems associated with aging are discussed, emphasizing the intricate landscape of the immune system during aging and its bidirectional relationship with neuroinflammation. Additionally, insights into the involvement of Myeloid-Derived Suppressor Cells (MDSCs) in Multiple Sclerosis (MS) pathogenesis are presented. The third section examines the role of microglia in neuroinflammation and various neurological diseases, including age-related macular degeneration (AMD) and Tuberculous Meningitis (TBM). Furthermore, the therapeutic potential of stem cell and extracellular vesicle-based therapies for stroke is explored, along with molecular mechanism of how inflammation regulates cerebral and myocardial ischemia. Finally, the importance of blood flow in maintaining vascular health and its impact on neurological disorders are discussed, highlighting the potential of novel assessment methods for optimizing patient care. Overall, this special issue offers valuable insights into the complex mechanisms underlying neurological disorders and identifies potential avenues for therapeutic intervention.

An overview of the co-transcription factor NACC1: Beyond its pro-tumor effects.

Nucleus accumbens-associated protein 1 (NACC1) is a member of the broad complex, tramtrack, bric-a-brac/poxvirus and zinc finger (BTB/POZ) protein families, mainly exerting its biological functions as a transcription co-regulator. NACC1 forms homo- or hetero-dimers through the BTB/POZ or BANP, E5R, and NACC1 (BEN) domain with other transcriptional regulators to regulate downstream signals. Recently, the overexpression of NACC1 has been observed in various tumors and is positively associated with tumor progression, high recurrence rate, indicating poor prognosis. NACC1 also regulates biological processes such as embryonic development, stem cell pluripotency, innate immunity, and related diseases. Our review combines recent research to summarize advancements in the structure, biological functions, and relative molecular mechanisms of NACC1. The future development of NACC1 clinical appliances is also discussed.

Metal-induced autoimmunity in neurological disorders: A review of current understanding and future directions.

Autoimmunity is a multifaceted disorder influenced by both genetic and environmental factors, and metal exposure has been implicated as a potential catalyst, especially in autoimmune diseases affecting the central nervous system. Notably, metals like mercury, lead, and aluminum exhibit well-established neurotoxic effects, yet the precise mechanisms by which they elicit autoimmune responses in susceptible individuals remain unclear. Recent studies propose that metal-induced autoimmunity may arise from direct toxic effects on immune cells and tissues, coupled with indirect impacts on the gut microbiome and the blood-brain barrier. These effects can activate self-reactive T cells, prompting the production of autoantibodies, inflammatory responses, and tissue damage. Diagnosing metal-induced autoimmunity proves challenging due to nonspecific symptoms and a lack of reliable biomarkers. Treatment typically involves chelation therapy to eliminate excess metals and immunomodulatory agents to suppress autoimmune responses. Prevention strategies include lifestyle adjustments to reduce metal exposure and avoiding occupational and environmental risks. Prognosis is generally favorable with proper treatment; however, untreated cases may lead to autoimmune disorder progression and irreversible organ damage, particularly in the brain. Future research aims to identify genetic and environmental risk factors, enhance diagnostic precision, and explore novel treatment approaches for improved prevention and management of this intricate and debilitating disease.

Brain borders at the central stage of neuroimmunology.

The concept of immune privilege suggests that the central nervous system is isolated from the immune system. However, recent studies have highlighted the borders of the central nervous system as central sites of neuro-immune interactions. Although the nervous and immune systems both function to maintain homeostasis, under rare circumstances, they can develop pathological interactions that lead to neurological or psychiatric diseases. Here we discuss recent findings that dissect the key anatomical, cellular and molecular mechanisms that enable neuro-immune responses at the borders of the brain and spinal cord and the implications of these interactions for diseases of the central nervous system.

Animal Model of Neonatal Immune Challenge by Lipopolysaccharide: A Study of Sex Influence in Behavioral and Immune/Neurotrophic Alterations in Juvenile Mice.

INTRODUCTION: The prenatal/perinatal exposure to infections may trigger neurodevelopmental alterations that lead to neuropsychiatric disorders such as autism spectrum disorder (ASD). Previous evidence points to long-term behavioral consequences, such as autistic-like behaviors in rodents induced by lipopolysaccharide (LPS) pre- and postnatal (PN) exposure during critical neurodevelopmental periods. Additionally, sex influences the prevalence and symptoms of ASD. Despite this, the mechanisms underlying this influence are poorly understood. We aim to study sex influences in behavioral and neurotrophic/inflammatory alterations triggered by LPS neonatal exposure in juvenile mice at an approximate age of ASD diagnosis in humans. METHODS: Swiss male and female mice on PN days 5 and 7 received a single daily injection of 500 µg/kg LPS from Escherichia coli or sterile saline (control group). We conducted behavioral determinations of locomotor activity, repetitive behavior, anxiety-like behavior, social interaction, and working memory in animals on PN25 (equivalent to 3-5 years old of the human). To determine BDNF levels in the prefrontal cortex and hippocampus, we used animals on PN8 (equivalent to a human term infant) and PN25. In addition, we evaluated iba-1 (microglia marker), TNFα, and parvalbumin expression on PN25. RESULTS: Male juvenile mice presented repetitive behavior, anxiety, and working memory deficits. Females showed social impairment and working memory deficits. In the neurochemical analysis, we detected lower BDNF levels in brain areas of female mice that were more evident in juvenile mice. Only LPS-challenged females presented a marked hippocampal expression of the microglial activation marker, iba-1, and increased TNFα levels, accompanied by a lower parvalbumin expression. DISCUSSION/CONCLUSION: Male and female mice presented distinct behavioral alterations. However, LPS-challenged juvenile females showed the most prominent neurobiological alterations related to autism, such as increased microglial activation and parvalbumin impairment. Since these sex-sensitive alterations seem to be age-dependent, a better understanding of changes induced by the exposure to specific risk factors throughout life represents essential targets for developing strategies for autism prevention and precision therapy.

Negative Regulation of the IL-1 System by IL-1R2 and IL-1R8: Relevance in Pathophysiology and Disease.

Interleukin-1 (IL-1) is a primary cytokine of innate immunity and inflammation. IL-1 belongs to a complex family including ligands with agonist activity, receptor antagonists, and an anti-inflammatory cytokine. The receptors for these ligands, the IL-1 Receptor (IL-1R) family, include signaling receptor complexes, decoy receptors, and negative regulators. Agonists and regulatory molecules co-evolved, suggesting the evolutionary relevance of a tight control of inflammatory responses, which ensures a balance between amplification of innate immunity and uncontrolled inflammation. IL-1 family members interact with innate immunity cells promoting innate immunity, as well as with innate and adaptive lymphoid cells, contributing to their differentiation and functional polarization and plasticity. Here we will review the properties of two key regulatory receptors of the IL-1 system, IL-1R2, the first decoy receptor identified, and IL-1R8, a pleiotropic regulator of different IL-1 family members and co-receptor for IL-37, the anti-inflammatory member of the IL-1 family. Their complex impact in pathology, ranging from infections and inflammatory responses, to cancer and neurologic disorders, as well as clinical implications and potential therapeutic exploitation will be presented.

Nervous system consequences of COVID-19.

Neurological symptoms highlight the need to understand pathophysiologic mechanisms.

Retinal nerve fibre layer and ganglion cell layer changes in children who recovered from COVID-19: a cohort study.

OBJECTIVE: To investigate the optic nerve and macular parameters of children who recovered from COVID-19 compared with healthy children using optical coherence tomography (OCT). DESIGN: Cohort study. SETTING: Hospital Clinico San Carlos, Madrid. PATIENTS: Children between 6 and 18 years old who recovered from COVID-19 with laboratory-confirmed SARS-CoV-2 infection and historical controls were included. INTERVENTIONS: All patients underwent an ophthalmological examination, including macular and optic nerve OCT. Demographic data, medical history and COVID-19 symptoms were noted. MAIN OUTCOME MEASURES: Peripapillary retinal nerve fibre layer thickness, macular retinal nerve fibre layer thickness, macular ganglion cell layer thickness and retinal thickness. RESULTS: 90 patients were included: 29 children who recovered from COVID-19 and 61 controls. Patients with COVID-19 presented an increase in global peripapillary retinal nerve fibre layer thickness (mean difference 7.7; 95% CI 3.4 to 12.1), temporal superior (mean difference 11.0; 95% CI 3.3 to 18.6), temporal inferior (mean difference 15.6; 95% CI 6.5 to 24.7) and nasal (mean difference 9.8; 95% CI 2.9 to 16.7) sectors. Macular retinal nerve fibre layer analysis showed decreased thickness in the nasal outer (p=0.011) and temporal inner (p=0.036) sectors in patients with COVID-19, while macular ganglion cell layer thickness increased in these sectors (p=0.001 and p=0.015, respectively). No differences in retinal thickness were noted. CONCLUSIONS: Children with recent history of COVID-19 present significant changes in peripapillary and macular OCT analyses.

Mitochondrial DNA Heteroplasmy as an Informational Reservoir Dynamically Linked to Metabolic and Immunological Processes Associated with COVID-19 Neurological Disorders.

Mitochondrial DNA (mtDNA) heteroplasmy is the dynamically determined co-expression of wild type (WT) inherited polymorphisms and collective time-dependent somatic mutations within individual mtDNA genomes. The temporal expression and distribution of cell-specific and tissue-specific mtDNA heteroplasmy in healthy individuals may be functionally associated with intracellular mitochondrial signaling pathways and nuclear DNA gene expression. The maintenance of endogenously regulated tissue-specific copy numbers of heteroplasmic mtDNA may represent a sensitive biomarker of homeostasis of mitochondrial dynamics, metabolic integrity, and immune competence. Myeloid cells, monocytes, macrophages, and antigen-presenting dendritic cells undergo programmed changes in mitochondrial metabolism according to innate and adaptive immunological processes. In the central nervous system (CNS), the polarization of activated microglial cells is dependent on strategically programmed changes in mitochondrial function. Therefore, variations in heteroplasmic mtDNA copy numbers may have functional consequences in metabolically competent mitochondria in innate and adaptive immune processes involving the CNS. Recently, altered mitochondrial function has been demonstrated in the progression of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Accordingly, our review is organized to present convergent lines of empirical evidence that potentially link expression of mtDNA heteroplasmy by functionally interactive CNS cell types to the extent and severity of acute and chronic post-COVID-19 neurological disorders.

Performance, clinical effectiveness, and safety of immunoadsorption in a wide range of indications.

Immunoadsorption is well known to selectively remove immunoglobulins and immune complexes from plasma and is applied in a variety of autoimmune diseases and for desensitization before, or at acute rejection after organ transplantation. Performance, safety, and clinical effectiveness of immunoadsorption were the aim of this study. This prospective, noninterventional, multicentre cohort study included patients treated with immunoadsorption (Immunosorba or GLOBAFFIN adsorbers) for any indication. Clinical effectiveness was assessed after termination of the patient's individual treatment schedule. Eighty-one patients were included, 69 were treated with Immunosorba, 11 with GLOBAFFIN, one patient with both adsorbers. A majority of patients was treated for neurological indications, dilated cardiomyopathy, and before or after kidney or heart transplantation. Mean IgG reduction from pre- to post-treatment was 69.9% ± 11.5% for Immunosorba and 74.1% ± 5.0% for GLOBAFFIN, respectively. The overall IgG reduction over a complete treatment block was 68%-93% with Immunosorba and 62%-90% with GLOBAFFIN depending on the duration of the overall treatment. After termination of the immunoadsorption therapy, an improvement of clinical status was observed in 63.0%, stabilization of symptoms in 29.6%, and a deterioration in 4.9% of patients. Changes in fibrinogen, thrombocytes, and albumin were mostly classified as noncritical. Overall, the treatments were well tolerated. Immunoadsorption in routine clinical practice with both GLOBAFFIN and Immunosorba has been safely performed, was well tolerated by patients, and effective in lowering immunoglobulins with an improvement or maintenance of clinical status, thus represents an additional therapeutic option for therapy refractory immune disorders.

Impact of COVID-19 in Immunosuppressed Children With Neuroimmunologic Disorders.

BACKGROUND AND OBJECTIVES: To investigate whether children receiving immunosuppressive therapies for neuroimmunologic disorders had (1) increased susceptibility to SARS-CoV2 infection or to develop more severe forms of COVID-19; (2) increased relapses or autoimmune complications if infected; and (3) changes in health care delivery during the pandemic. METHODS: Patients with and without immunosuppressive treatment were recruited to participate in a retrospective survey evaluating the period from March 14, 2020, to March 30, 2021. Demographics, clinical features, type of immunosuppressive treatment, suspected or confirmed COVID-19 in the patients or cohabitants, and changes in care delivery were recorded. RESULTS: One hundred fifty-three children were included: 84 (55%) female, median age 13 years (interquartile range [8-16] years), 79 (52%) on immunosuppressive treatment. COVID-19 was suspected or confirmed in 17 (11%) (all mild), with a frequency similar in patients with and without immunosuppressive treatment (11/79 [14%] vs 6/74 [8%], p = 0.3085). The frequency of neurologic relapses was similar in patients with (18%) and without (21%) COVID-19. Factors associated with COVID-19 included having cohabitants with COVID-19 (p < 0.001) and lower blood levels of vitamin D (p = 0.039). Return to face-to-face schooling or mask type did not influence the risk of infection, although 43(28%) children had contact with a classmate with COVID-19. Clinic visits changed from face to face to remote for 120 (79%) patients; 110 (92%) were satisfied with the change. DISCUSSION: In this cohort of children with neuroimmunologic disorders, the frequency of COVID-19 was low and not affected by immunosuppressive therapies. The main risk factors for developing COVID-19 were having cohabitants with COVID-19 and low vitamin D levels.

Dendritic Cell-Targeted Therapies to Treat Neurological Disorders.

Dendritic cells (DCs) are the immune system's highly specialized antigen-presenting cells. When DCs are sluggish and mature, self-antigen presentation results in tolerance; however, when pathogen-associated molecular patterns stimulate mature DCs, antigen presentation results in the development of antigen-specific immunity. DCs have been identified in various vital organs of mammals (e.g., the skin, heart, lungs, intestines, and spleen), but the brain has long been thought to be devoid of DCs in the absence of neuroinflammation. However, neuroinflammation is becoming more recognized as a factor in a variety of brain illnesses. DCs are present in the brain parenchyma in trace amounts under healthy circumstances, but their numbers rise during neuroinflammation. New therapeutics are being developed that can reduce dendritic cell immunogenicity by inhibiting pro-inflammatory cytokine production and T cell co-stimulatory pathways. Additionally, innovative ways of regulating dendritic cell growth and differentiation and harnessing their tolerogenic capability are being explored. Herein, we described the function of dendritic cells in neurological disorders and discussed the potential for future therapeutic techniques that target dendritic cells and dendritic cell-related targets in the treatment of neurological disorders.

Neurological Immune-Related Adverse Events After COVID-19 Vaccination: A Systematic Review.

The coronavirus disease 2019 (COVID-19) pandemic has affected millions of individuals worldwide. The global scientific effort to design an effective vaccine against this virus has led to the development of several vaccine candidates. The expedited rollout of these vaccines has created some public distrust regarding the safety of these new vaccines. This review compiles clinical data from reports of diagnosed immune-related neurological events that have occurred after COVID-19 vaccine administration with the exception of those secondary to hematological abnormalities. A systematic literature search was performed, using several databases, to identify reports of postvaccination adverse neurological events. The search resulted in 18 studies that met our criteria. These studies included 61 patients who had received COVID-19 vaccines and experienced at least 1 neurological adverse effect. The most common neurological event was facial nerve palsy (50% of all events). Other less frequently reported events included the reactivation of herpes zoster, Guillain-Barre syndrome, other demyelinating diseases, and neuropathy. The underlying mechanism was hypothesized to be related to vaccine-induced type 1 interferon production leading to decreased tolerance of the myelin sheath antigens. Other hypotheses include vaccine-induced transient lymphopenia and immune dysregulation. Most of the reported events were time limited and resolved spontaneously. Given the rarity of reported neurological events compared to the total number of vaccines administered, and the similarity in the incidence of events between COVID-19 vaccines and other more common vaccines, there is little evidence to support a causal relationship between COVID-19 vaccines and adverse neurological events.

Fisetin, potential flavonoid with multifarious targets for treating neurological disorders: An updated review.

Neurodegenerative disorders pose a significant health burden and imprint a debilitative impact on the quality of life. Importantly, aging is intricately intertwined with the progression of these disorders, and their prevalence increases with a rise in the aging population worldwide. In recent times, fisetin emerged as one of the potential miracle molecules to address neurobehavioral and cognitive abnormalities. These effects were attributed to its actions on several macromolecules and multiple molecular mechanisms. Fisetin belongs to a class of flavonoids, which is found abundantly in several fruits and vegetables. Fisetin has manifested several health benefits in preclinical models of neurodegenerative diseases such as Alzheimer's disease, Vascular dementia, and Schizophrenia. Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Stroke, Traumatic Brain Injury (TBI), and age-associated changes. This review aimed to evaluate the potential mechanisms and pharmacological effects of fisetin in treating several neurological diseases. This review also provides comprehensive data on up-to-date recent literature and highlights the various mechanistic pathways pertaining to fisetin's neuroprotective role.

Acute and chronic neurological disorders in COVID-19: potential mechanisms of disease.

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by SARS-CoV-2 infection and is associated with both acute and chronic disorders affecting the nervous system. Acute neurological disorders affecting patients with COVID-19 range widely from anosmia, stroke, encephalopathy/encephalitis, and seizures to Guillain-Barré syndrome. Chronic neurological sequelae are less well defined although exercise intolerance, dysautonomia, pain, as well as neurocognitive and psychiatric dysfunctions are commonly reported. Molecular analyses of CSF and neuropathological studies highlight both vascular and immunologic perturbations. Low levels of viral RNA have been detected in the brains of few acutely ill individuals. Potential pathogenic mechanisms in the acute phase include coagulopathies with associated cerebral hypoxic-ischaemic injury, blood-brain barrier abnormalities with endotheliopathy and possibly viral neuroinvasion accompanied by neuro-immune responses. Established diagnostic tools are limited by a lack of clearly defined COVID-19 specific neurological syndromes. Future interventions will require delineation of specific neurological syndromes, diagnostic algorithm development and uncovering the underlying disease mechanisms that will guide effective therapies.

COVID-19 Vaccination in Fragile Patients: Current Evidence and an Harmonized Transdisease Trial.

Patients diagnosed with malignancy, neurological and immunological disorders, i.e., fragile patients, have been excluded from COVID-19 vaccine trials. However, this population may present immune response abnormalities, and relative reduced vaccine responsiveness. Here we review the limited current evidence on the immune responses to vaccination of patients with different underlying diseases. To address open questions we present the VAX4FRAIL study aimed at assessing immune responses to vaccination in a large transdisease cohort of patients with cancer, neurological and rheumatological diseases.

A monoclonal antibody neutralizes pesudorabies virus by blocking gD binding to the receptor nectin-1.

Pseudorabies virus (PRV) was isolated from some human cases recently and the infected patients manifested respiratory dysfunction and acute neurological symptoms. However, no effective drug or vaccine, preventing the progression of PRV infection, is available. Nectin-1 was the only reported receptor for PRV cell entry both swine and human origin, representing an excellent target to block PRV infection, and especially its transmission from pigs to humans. A PRV-gD specific mAbs (10B6) was isolated from hybridomas and its neutralizing activities in vitro and in vivo were determined. 10B6 exhibited effective neutralizing activities in vitro with IC50 = 2.514 µg/ml and 4.297 µg/ml in the presence and absence of complement. And in vivo, 10B6 provided 100% protection against PRV lethal challenge with a dose of 15 mg/kg. Further, 10B6 could bind to a conserved epitope, 316QPAEPFP322, locating in gD pro-fusion domain, and finally blocks the binding of PRV-gD to nectin-1. Moreover, 10B6 showed an effective inhibition on PRV cell-attachment in a cell type-independent manner and could also block the virus spreading among cells. 10B6 exhibited effectively neutralizing activities to Chinese PRV variant strain in vitro and in vivo by blocking gD binding to nectin-1, implied both prophylactic and therapeutic interventions against PRV infections.

Neurological manifestations of COVID-19: A comprehensive literature review and discussion of mechanisms.

Several neurological symptoms and complications have been described in association with COVID-19, such as anosmia, ageusia, encephalitis and Guillain-Barré syndrome. Here, we review the literature describing SARS-CoV-2-induced neurological manifestations and provide a comprehensive discussion of proposed mechanisms underlying the neurological pathophysiology. First, we analyse the neuroinvasiveness potential of the coronavirus family based on previous SARS-CoV-1 studies. Then, we describe the current evidence on COVID-19-induced nervous tissue damage, including processes behind brain vasculopathy and cytokine storm. We also discuss in detail anosmia and Guillain-Barré syndrome. Finally, we provide a summarised timeline of the main findings in the field. Future perspectives are presented, and suggestions of further investigations to clarify how SARS-COV-2 can affect the CNS.

Emerging neurotropic features of SARS-CoV-2.

The prevailing coronavirus disease-19 (COVID-19) caused by a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has presented some neurological manifestations including hyposmia, hypogeusia, headache, stroke, encephalitis, Guillain-Barre syndrome, and some neuropsychiatric disorders. Although several cell types in the brain express angiotensin-converting enzyme-2 (ACE2), the main SARS-CoV-2 receptor, and other related proteins, it remains unclear whether the observed neurological manifestations are attributed to virus invasion into the brain or just comorbidities caused by dysregulation of systemic factors. Here, we briefly review the neurological manifestations of SARS-CoV-2, summarize recent evidence for the potential neurotropism of SARS-CoV-2, and discuss the potential mechanisms of COVID-19-associated neurological diseases.