Table of Contents
Overview
Definition and Scope
Neurovirology is an interdisciplinary field that integrates clinical neuroscience, virology, immunology, and molecular biology, with a primary focus on studying viruses capable of infecting the nervous system.[3.1] Established within the past 30 years, neurovirology has emerged as a significant discipline relevant to human disease and various aspects of neuroscience.[4.1] This field was founded upon the discovery that numerous viruses can invade and establish latent infections in nervous tissue, leading to slow, chronic, or progressive diseases of the nervous system.[1.1] As new viruses and viral infections of the nervous system continue to emerge, neurovirology must expand to address these evolving challenges.[1.1] The field of neurovirology has emerged over the past 30 years, focusing on the study of viral infections that affect the central nervous system (CNS) and incorporating elements from virology, neuroscience, and clinical neurology.[2.1] This discipline was established upon the recognition that numerous viruses can invade and establish latent infections in nervous tissue, leading to slow, chronic, or progressive diseases of the nervous system.[1.1] Neurovirology employs a range of techniques that have evolved from classical methods, such as tissue culture and virus isolation, to more modern approaches.[2.1] As the field continues to grow, it is crucial to adapt to the emergence of new viruses and viral infections, ensuring that neurovirology remains relevant to human disease and various aspects of neuroscience.[4.1]Importance in Neuroscience
Neurovirology plays a crucial role in understanding the interactions between viral infections and the nervous system, highlighting the significance of these interactions in both acute and chronic neurological conditions. Viral infections of the central nervous system (CNS) can lead to a spectrum of outcomes, ranging from acute conditions such as encephalitis to chronic neuropsychiatric disorders, including mood disorders and neurodegenerative diseases.[19.1] The mechanisms by which viruses disrupt the structural and functional integrity of the nervous system are of particular interest, as they can elucidate pathways leading to neuronal dysfunction and degeneration.[19.1] The central nervous system (CNS) is an immunologically specialized organ characterized by restrictive barrier structures that protect its parenchyma from inflammation and infection, which is crucial for preserving non-renewable resident cell populations such as neurons.[15.1] Despite significant advancements in the management of infectious diseases, CNS infections continue to pose major challenges, as they are often difficult to diagnose and treatments remain inadequate or nonexistent.[13.1] Existing and emerging viral CNS infections are significant sources of human morbidity and mortality, with effective treatments primarily limited to herpesviruses and human immunodeficiency virus (HIV).[11.1] Furthermore, aberrant immune system activities can lead to pathologies associated with altered nervous activities, including Alzheimer's disease and multiple sclerosis, highlighting the complex interplay between the immune response and neurological function.[9.1] Recent advancements in the diagnosis and treatment of central nervous system (CNS) infections have been notable, particularly as the past decade has seen considerable challenges, including the emergence of novel pathogens that complicate treatment efforts.[14.1] The immune response in the CNS is characterized by the presence of resident macrophages (microglia) and mast cells, along with other glial cells and neurons, which serve as the primary immune cells.[10.1] Furthermore, it has become increasingly evident that the CNS is not immune-privileged as once thought, highlighting the importance of the peripheral immune system and the key interactions between central and peripheral immune cells in neurological disorders.[8.1] Understanding these interactions is essential for developing effective therapeutic strategies to address viral infections that impact neurological function. Host genetic factors play a crucial role in determining susceptibility to severe viral infections, particularly within the nervous system. Specifically, inborn errors of immunity, which are characterized by single genetic mutations, can predispose individuals to specific types of viral infections. This relationship highlights the importance of understanding these genetic influences, as they are documented in the International Union of Immunological Societies (IUIS) list of human inborn errors of immunity (Tangye et al., 2020).[24.1] Recognizing these genetic predispositions can inform the development of personalized treatment strategies in neurovirology, ultimately enhancing patient outcomes in conditions associated with viral infections.In this section:
History
Early Discoveries
The early discoveries in neurovirology were pivotal in establishing the field and understanding the interactions between viruses and the nervous system. In 1901, yellow fever was identified as the first human disease caused by a “filterable virus,” marking a significant milestone in virology. This was followed by the recognition of rabies in 1903 as the first viral disease affecting the nervous system, with polio soon thereafter being classified as viral in nature. These early findings laid the groundwork for the study of viral infections of the central nervous system (CNS) and highlighted the importance of understanding viral pathogenesis and its implications for human health.[44.1] The early developments in neurovirology were marked by significant discoveries regarding the viral nature of diseases affecting the central nervous system (CNS). Within a decade, the viral nature of aseptic meningitis and herpes simplex sporadic encephalitis was demonstrated, which contributed to a growing interest in "slow viral diseases" as potential models for chronic neurological conditions from the 1950s through the 1970s.[45.1] This period laid the groundwork for the field of neurovirology, which has evolved over the past 30 years, founded on the understanding that numerous viruses can invade and establish latent infections in nervous tissue, leading to slow, chronic, or progressive diseases of the nervous system.[46.1] As the field continues to expand, it incorporates various disciplines, including virology, neuroscience, neurology, immunology, and molecular biology, reflecting the increasing interest in viral infections of the nervous system.[46.1] The identification of the rabies virus, particularly its inferred relationships to animal bites and the characteristic neurological signs it produces, had a major influence on scientific thought and applications toward a crucial understanding of viral pathogenesis, diagnosis, epidemiology, prevention, and control throughout the 19th and 20th centuries.[65.1] The inevitability of death associated with rabies further emphasized the urgency of these scientific advancements, highlighting the need for effective strategies to combat viral infections affecting the nervous system.[65.1] The yellow fever vaccine, specifically the attenuated YF 17D/17DD strain, exemplifies the impact of early viral discoveries on vaccine development. This vaccine is the only licensed protection against yellow fever in the United States and is recognized as one of the most successful vaccines ever produced. Its development underscores the importance of vaccination as a strategy to combat flaviviral diseases, which continue to pose significant health risks in tropical regions.[67.1]Evolution of the Field
The evolution of neurovirology as a distinct field of study has been marked by significant milestones and technological advancements. The term "neurovirology" itself is relatively recent, having been coined only a few decades ago, despite evidence of viral infections affecting the nervous system dating back millennia. Notably, the term was devised by Elizabeth Hartmann, an administrator at the National Institutes of Health, highlighting the field's administrative and organizational roots.[41.1] The foundation of neurovirology was laid within the last 30 years, driven by the discovery that numerous viruses can invade and establish latent infections in nervous tissue, leading to chronic or progressive diseases of the nervous system.[42.1] This understanding has been pivotal, as it has expanded the scope of research to include various related disciplines such as virology, neuroscience, neurology, immunology, and molecular biology.[42.1] Historically, key milestones in the field include the identification of yellow fever in 1901 as the first human disease caused by a filterable virus, followed by rabies in 1903, which was the first viral disease of the nervous system to be recognized.[43.1] These early discoveries opened the door to understanding the virology of the central nervous system (CNS) and set the stage for future research and advancements. In recent years, the field has benefited from remarkable technological advances, particularly in molecular diagnostics and imaging techniques. The introduction of polymerase chain reaction (PCR) technology has revolutionized the identification of infectious agents, while magnetic resonance imaging (MRI) has enhanced the ability to visualize the nervous system and diagnose infections.[40.1] These advancements have not only improved the accuracy and speed of diagnoses but have also facilitated the development of targeted antiviral therapies, thereby improving patient management and outcomes.[52.1] The field of neurovirology has developed significantly over the past 30 years, emerging from the understanding that numerous viruses can invade and establish latent infections in nervous tissue, leading to slow, chronic, or progressive diseases of the nervous system.[42.1] This discipline integrates various related fields, including virology, neuroscience, neurology, immunology, and molecular biology, reflecting the complexity of viral infections affecting the nervous system.[42.1] However, the diagnosis of viral central nervous system infections remains a considerable challenge, primarily due to the difficulty in obtaining brain tissue, where pathogen concentrations are likely highest, and the lack of sensitive molecular and serological detection methods in most clinical laboratories.[47.1] As new viruses and viral infections continue to emerge, the field of neurovirology must adapt and expand to address these evolving challenges and the increasing interest in researching viruses that infect the nervous system.[42.1]Techniques In Neurovirology
Classical Methods
Classical methods in neurovirology are essential for understanding viral infections that impact the central nervous system (CNS). This field integrates aspects of virology, neuroscience, and clinical neurology, underscoring its significance in relation to human disease and various facets of neuroscience.[79.1] Over the past 30 years, neurovirology has developed into a prominent discipline, demonstrating considerable relevance to both human health and numerous aspects of neuroscience.[80.1] This overview aims to succinctly define the major neurovirological techniques, encompassing both classical methods and more recent advancements, thereby providing insight into their applications in the study and diagnosis of CNS viral infections.[80.1] One of the foundational techniques in classical neurovirology is viral culture, which, although less frequently used today due to advancements in molecular techniques, was once a primary method for diagnosing CNS infections. For instance, herpes simplex virus (HSV) is only cultured from cerebrospinal fluid (CSF) in less than 5% of cases of HSV encephalitis, highlighting the limitations of this method.[97.1] The diagnosis of central nervous system (CNS) viral infections presents significant challenges; however, notable advancements have been made in laboratory diagnostic techniques for these infections. Among these advancements, polymerase chain reaction (PCR) has emerged as a powerful diagnostic tool, particularly in the field of neurovirology.[95.1] Following nucleic acid amplification (NAA), various molecular techniques can be employed to analyze the amplified nucleic acids, enhancing the accuracy of diagnosis in cases where traditional methods may fall short.[95.1] The diagnosis of central nervous system (CNS) viral infections presents significant challenges; however, advancements in laboratory diagnostics have been noteworthy. Polymerase chain reaction (PCR) has emerged as a powerful diagnostic tool in neurovirology, proving invaluable for the rapid and specific diagnosis of CNS viral infections, including herpes simplex virus type 1 (HSV-1), cytomegalovirus, varicella-zoster virus, and enteroviruses.[83.1] This technique is now recognized as the viral diagnostic method of choice in the field.[83.1] Additionally, PCR is utilized in other molecular techniques relevant to neurovirology, such as DNA sequencing and the cloning of genomic DNA, further enhancing its applicability in diagnosing CNS infections.[83.1]Recent Innovations
Recent advancements in neurovirology have been significantly influenced by the development of molecular diagnostic techniques, particularly those involving nucleic acid amplification, such as polymerase chain reaction (PCR). These techniques have revolutionized the diagnosis of central nervous system (CNS) infections, especially viral ones, due to their extraordinary sensitivity and rapidity, which have made them indispensable in clinical settings.[102.1] The integration of high-throughput sequencing technologies has further enhanced our understanding of viral pathogenesis in the nervous system. For instance, high-throughput sequencing allows for the detection of both known and unknown pathogenic viruses through the analysis of small RNA populations, thereby broadening the spectrum of viral agents that can be identified.[85.1] The evolution of diagnostic tools has been marked by the introduction of advanced platforms such as the PacBio sequencer, which is capable of producing full-length gene sequences. This capability is crucial for the structural analysis of complex microbial communities, thereby aiding in the understanding of host-pathogen interactions and the dynamics of viral diseases.[89.1] Moreover, the advent of next-generation sequencing has facilitated the development of streamlined protocols for whole-genome sequencing, exemplified by a SARS-CoV-2 sequencing protocol that incorporates one-step RT-PCR amplification and microfluidic technology.[87.1] Recent innovations in molecular diagnostics have introduced various techniques, including isothermal amplification methods and nucleic acid hybridization techniques, which are widely used in clinical settings. Among these, microarray technology holds significant promise due to its exceptional sensitivity and capacity to detect multiple pathogens simultaneously. However, the high costs associated with microarrays currently hinder their adaptation for routine use.[103.1] Molecular diagnostic methods play a crucial role in identifying different causative pathogens of viral infections, although the efficacy and specificity of these methods can vary depending on the pathogen involved. Notably, in a substantial number of patients, no identifiable pathogen is found in cerebrospinal fluid (CSF) samples, highlighting the challenges faced in diagnosing these infections.[104.1] Recent innovations in neurovirology have resulted in significant advancements in therapeutic options for the treatment of neurotropic infectious diseases over the past two decades. These advancements include the development of new therapeutic agents and the repurposing of existing agents, particularly immunomodulatory treatments.[90.1] Furthermore, the integration of molecular techniques with digital imaging and serological assays is anticipated to improve our understanding of viral infections in the central nervous system. To support this interdisciplinary approach, it is essential to develop training programs that educate staff on both digital imaging techniques and molecular diagnostic methods. Collaborative workshops and interdisciplinary meetings can facilitate the bridging of knowledge gaps and foster a culture of innovation, ensuring that all team members comprehend the benefits and limitations of these methodologies.[106.1]In this section:
Viral Infections And Neurological Disorders
Neurotropic Viruses
Neurotropic viruses are a subset of viruses that have the ability to infect the central nervous system (CNS) and can lead to various neurological disorders. The initial interaction between host and virus occurs in peripheral tissues, where viruses can replicate and spread among different cell types, including those at mucosal surfaces and within the immune and nervous systems. This complexity is crucial as it sets the stage for potential CNS invasion.[124.1] Viruses typically begin their infection in peripheral tissues before invading the mammalian nervous system, which includes both the peripheral nervous system (PNS) and, less frequently, the central nervous system (CNS). The CNS is generally protected from most viral infections due to effective immune responses and physical barriers. However, certain viruses can efficiently breach these defenses, either through the bloodstream or by directly infecting nerve endings.[126.1] For instance, herpes simplex virus type 1 (HSV-1) can enter the CNS via distal axons of trigeminal neurons, leading to nonproductive, silent infections that may later reactivate.[126.1] The impact of neurotropic viruses on neurological health is significant, as they can induce a range of diseases such as meningitis, encephalitis, and myelitis. Viruses that remain localized within the meninges or ventricular lining typically cause meningitis, while those that infect the CNS parenchyma can lead to more severe conditions like meningoencephalitis or encephalitis, characterized by intense inflammation and neurological dysfunction.[127.1] The immune response to infections, such as that caused by HSV-1, can exacerbate CNS pathology, resulting in severe outcomes like fatal encephalitis.[127.1] Emerging evidence suggests that a substantial proportion of viral infections may lead to severe neurological illness. Studies indicate that approximately 39% of emerging viral infections are associated with significant neurological complications, highlighting the public health burden posed by these diseases.[132.1] Neurological disorders, which affect a significant portion of the global population, are often linked to viral infections that may trigger immune responses leading to pathological symptoms.[135.1] Furthermore, the relationship between viral infections and neurological disorders can be complex, with some symptoms manifesting long after the initial infection. For example, viral encephalitis has been associated with an increased risk of developing dementia years later.[136.1] This underscores the importance of understanding the mechanisms by which neurotropic viruses operate, as they can directly damage neuronal cells or indirectly affect neural pathways through host immune responses.[137.1]Impact on Neurological Diseases
Viral infections have been increasingly recognized as significant contributors to the onset and progression of various neurological disorders. Research indicates that viral infections can lead to both transient and permanent neurological or psychiatric disorders, with evidence suggesting a potential link between viral infections and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.[120.1] The mechanisms by which viral infections induce neurological complications are complex and multifaceted, involving direct infection of central nervous system (CNS) cells as well as indirect effects mediated by the host's immune response.[122.1] The global burden of neurological disorders is substantial, with over 276 million cases reported worldwide, making them a leading cause of disability-adjusted life years (DALYs).[153.1] The chronic dysfunction of neuronal cells, which is characteristic of many neurological disorders, may arise from irreversible damage and cell death caused by viral infections.[121.1] Recent studies have highlighted the long-term consequences of viral infections, particularly in the context of COVID-19, where approximately 30% of survivors report enduring neurological symptoms such as cognitive impairment and fatigue, collectively referred to as long-COVID-19.[156.1] Emerging viral infections of the nervous system pose a significant global public health challenge in the 21st century. Over the past five decades, vector-borne viruses, primarily transmitted by arthropods, have been linked to epidemics that result in a considerable burden of neurological disease. For instance, one study estimated that approximately 39% of emerging viral infections may lead to severe neurological illness, while an additional 10% do so on a less frequent basis.[119.1] These diseases impose a substantial burden on affected communities, contributing not only to acute mortality but also to long-term disabilities.[119.1] This underscores the importance of developing effective public health strategies to address the impact of these viral infections on neurological disorders.[119.1] Public health initiatives are increasingly recognizing the long-term neurological effects associated with viral infections, necessitating a proactive approach to mitigate these impacts on societal health.[141.1] The past two decades have witnessed a rise in significant outbreaks, with COVID-19 being the most recent and devastating, resulting in over 5 million deaths and approximately 30% of survivors reporting persistent neurological symptoms.[142.1] Recent studies have established a connection between viral infections and the onset of neurological disorders, indicating that these infections may either directly cause neurological symptoms or provoke immune responses that lead to such conditions.[152.1] Understanding the pathogenesis of these diseases is essential, as it may facilitate the development of new diagnostic and therapeutic strategies.[152.1]In this section:
Recent Advancements
New Diagnostic Tools
Recent advancements in neurovirology have significantly transformed the diagnostic landscape through the integration of high-throughput technologies and artificial intelligence. The introduction of polymerase chain reaction (PCR) arrays, virus-specific cDNA and DNA microarrays, and large-scale DNA sequencing has enhanced the complexity and range of viral agents that can be detected, leading to improved diagnostic capabilities for viral infections affecting the nervous system.[184.1] Historically, diagnosis often relied on invasive methods such as brain biopsies, which could delay treatment and carry risks of morbidity and mortality. However, the combination of MRI lesion detection and PCR technology has enabled a more sensitive, rapid, and less invasive approach to diagnosis, resulting in better patient outcomes.[185.1] For instance, a positive PCR result significantly increases the likelihood of a definitive diagnosis of viral infection in the central nervous system (CNS), with patients being 88 times more likely to receive a correct diagnosis compared to those with negative results. This underscores the potential of PCR to become the first-line diagnostic test for conditions such as viral meningitis and encephalitis.[186.1] Moreover, the integration of artificial intelligence (AI) and machine learning (ML) into neurovirology diagnostics is emerging as a critical advancement. These technologies facilitate the analysis of high-throughput sequencing data, allowing for a more comprehensive understanding of viral diseases. AI tools can enhance treatment optimization and personalization by curating treatment plans based on genomic data, thereby predicting patient responses and guiding drug discovery.[196.1] Additionally, AI's capabilities in data analytics and automation are improving diagnostic precision and streamlining treatment planning, which is essential for enhancing care quality and reducing costs in healthcare.[197.1] The integration of high-throughput sequencing technologies and machine learning has facilitated a more comprehensive analysis of genetic-level biological inquiries, which includes diagnosis and patient management in the field of neurovirology.[198.1] This amalgamation of advanced technologies is expected to significantly impact the future of neurovirology diagnostics by enhancing the ability to analyze complex genetic data, thereby improving diagnostic accuracy and patient outcomes.[198.1]Emerging Therapeutics
Recent advancements in neurovirology have been significantly influenced by the evolution of more virulent agents, such as enterovirus 71 and chikungunya virus, as well as the emergence of drug-resistant microbes. Additionally, geographic relocation of viral agents, exemplified by Dengue type 3 in Sri Lanka and West Nile virus in North America, has contributed to the changing landscape of viral infections affecting the central nervous system (CNS).[168.1] The advent of new high-throughput technologies, including polymerase chain reaction (PCR) arrays and virus-specific cDNA and DNA microarrays, has enhanced diagnostic capabilities, allowing for the rapid detection of various neurotropic viruses and the identification of newly discovered viral agents.[168.1] This progress is crucial for improving therapeutic interventions, particularly in response to outbreaks, such as the West Nile virus infection that occurred in the New York City area in 1999, which underscored the need for effective response strategies.[168.1] Recent advancements in stem cell technology, particularly the generation of human induced pluripotent stem cells (hiPSCs) and their differentiation into various cell types and organoids, have significantly enhanced our ability to model neurotropic viral infections. These developments have facilitated the establishment of versatile, non-invasive, ethically sustainable, and patient-specific models for investigating the mechanisms of human diseases, including viral infections and host-pathogen interactions.[181.1] Traditional two-dimensional culture systems have posed challenges in studying neurotropic viral infections due to their lack of a multicellular composition of central nervous system (CNS) cell networks.[183.1] In contrast, recent advances in 3D brain organoid modeling have provided a better understanding of cell-to-cell interactions during disease progression, particularly with neurotropic viral infections.[182.1] Consequently, these innovative models have proven invaluable for elucidating the complexities of neurotropic viral infections and informing future therapeutic strategies. Emerging therapeutics for central nervous system (CNS) diseases require a thorough understanding of neuropathogenesis, which refers to the mechanisms of origin, development, and progression of CNS diseases, including both neuroinvasion and neurovirulence.[187.1] Neurotropic viruses, which are capable of inducing neuropathogenesis, enter the CNS through peripheral nerves or by crossing the blood-brain barrier following hematogenous dissemination.[189.1] These viruses target various cell types within the nervous system, leading to a spectrum of clinical manifestations, from seizures to paralysis or even death.[189.1] The primary families of neurotropic viruses include picornaviruses, arboviruses, paramyxoviruses, arenaviruses, and herpesviruses, each exhibiting distinct mechanisms of neuropathogenesis.[188.1] For example, the neuroinflammatory disorders induced by the West Nile virus (WNV), a mosquito-borne RNA virus, illustrate how viral infections can result in CNS neurodegeneration, specifically viral encephalitis.[191.1] Recent advancements in understanding these neurotropic viruses have highlighted the similarities and distinctions in their mechanisms of entry, replication, and evolution within the CNS, as well as their neuropathogenesis and treatment strategies.[190.1] This knowledge is essential for developing targeted therapeutic approaches that can effectively address the unique challenges posed by different neurotropic viruses.In this section:
Challenges In Neurovirology
Identification of Biomarkers
The identification of biomarkers in neurovirology is a critical area of research that aims to enhance the understanding and management of neurological disorders. The arsenal of biomarkers in neurology is expected to expand as advancements in measuring multiple biological variables improve and as knowledge about the pathophysiology of neurological diseases increases. Biomarkers serve various purposes, including guiding clinical diagnosis, estimating disease risk or prognosis, and evaluating treatment responses.[227.1] Recent advancements in neuroimaging techniques have significantly contributed to the early detection of neurological disorders. Technologies such as resting-state functional MRI, diffusion tensor imaging, and magnetoencephalography have provided unprecedented insights into the brain's structure and function, facilitating earlier and more accurate diagnoses of conditions like Alzheimer's disease and other neurodegenerative disorders.[225.1] Furthermore, quantitative neuroimaging methods are being developed to evaluate the brain as an integrated structural and functional network. These approaches are crucial for deciphering brain circuitry and understanding the dysfunction of brain network connectivity that occurs during the progression of various neurological and psychiatric disorders.[226.1] In the context of clinical trials, genetic factors play a significant role in the progression and success of drug discovery projects. Research indicates that human genetics support for therapeutic hypotheses can increase the likelihood of trial progression, highlighting the importance of genetic considerations in the design and implementation of clinical trials in neurovirology.[221.1] However, challenges such as the rarity and sporadic nature of certain diagnoses complicate clinical trials, making them complex and costly. Factors such as limited sample sizes and the need for specific regional and temporal outbreak scenarios further complicate the landscape of neurovirology research.[220.1]Management of Viral Infections
Clinical trials in the management of viral infections associated with neurovirological diseases face significant challenges due to the unique characteristics of these conditions. Many neurovirological diseases are classified as rare, with a prevalence of fewer than 200,000 cases at any given time in the USA, which complicates the design of clinical trials due to limited sample sizes that may restrict statistical power.[208.1] Additionally, the clinical presentations of these diseases can vary widely, often stemming from life-threatening conditions, which further complicates trial design and the reliability of outcomes.[207.1] To address these challenges, innovative strategies are being employed in clinical trial design. For instance, the use of adaptive designs allows for modifications to trial characteristics based on accumulating data, enhancing the flexibility and efficiency of the trials.[218.1] Such designs can improve statistical efficiency and ethical considerations, such as the ability to stop a trial early if safety concerns arise or to enrich the trial with participants expected to benefit from the intervention.[217.1] Moreover, the integration of technology, including wearable devices and remote monitoring, is being explored to make clinical trials more patient-focused.[211.1] This approach not only facilitates better data collection but also enhances patient engagement in the research process. The precise definition of research questions and strategic planning are also critical elements in navigating the complexities of clinical research in this field.[210.1] The management of viral infections in neurovirology is increasingly focused on the use of biomarkers as outcomes in clinical trials. Many neurovirological trials utilize biomarkers, which can serve as surrogate endpoints if they are responsive to treatment interventions, such as viral load.[209.1] However, current pharmacological treatments often provide only temporary symptomatic relief without addressing the underlying causes of neuroviral infections. In contrast, virus-mediated gene therapy has emerged as a viable long-term strategy for the disease-modifying treatment of several neurological and neurodegenerative disorders.[212.1] This evolving landscape highlights the importance of adaptive trial designs and innovative technologies aimed at improving the reliability and effectiveness of clinical trials in neurovirology.Future Directions
Integration with Molecular Biology
Recent advancements in neuroimaging techniques have significantly enhanced our understanding of viral interactions with neurons, which is crucial for developing targeted therapies for chronic neurological diseases. Multiple pathways of viral neuroinvasion have been proposed, including transsynaptic transfer across infected neurons and intracranial entry via the olfactory nerve. Advanced neuroimaging techniques have focused on these findings in the olfactory bulb and have expanded the region of interest to brain regions involved in the olfactory system.[245.1] Moreover, the introduction of novel viral tracers, such as PRV-290, has improved transneuronal tracing of neural circuitry, marking an important advance in the technology used to study these interactions.[246.1] Techniques like resting-state functional MRI, diffusion tensor imaging, and magnetoencephalography have provided unprecedented insights into the brain's structure and function, allowing for earlier and more accurate detection of diseases like Alzheimer’s and other neurodegenerative conditions.[247.1] The integration of artificial intelligence (AI) and machine learning (ML) into neuroimaging workflows is revolutionizing the management of neurological disorders. AI-powered algorithms analyze diverse patient data, including medical history, imaging results, and genetic profiles, to identify subtle markers of neurological disorders that may not be readily observable by human clinicians.[250.1] This technological advancement not only enhances diagnostic capabilities but also facilitates the development of personalized treatment plans, which are crucial for optimizing patient care.[250.1] Furthermore, the intersection of clinical virology with AI and ML is essential for improving our understanding of viral diseases. These technologies can be employed alongside other AI techniques, such as Natural Language Processing (NLP), to extract valuable insights from clinical notes and research articles, thereby contributing to a more comprehensive understanding of viral infections.[249.1] AI tools also provide frameworks for continuous monitoring, ensuring rapid responses during public health emergencies and aiding in the identification of potential outbreaks.[249.1] By leveraging genomic data, AI can curate treatment plans that predict patient responses to specific therapies, laying the groundwork for precision medicine.[249.1] Overall, the integration of AI into neuroimaging and virology signifies a transformative shift in the approach to managing neurological disorders and viral infections. High-throughput DNA sequencing technologies have significantly transformed genomics by enabling rapid and cost-effective analysis of genetic material, which is crucial for identifying novel viral agents in the central nervous system.[261.1] These advancements support a wide range of applications, including personalized medicine and the exploration of complex viral interactions.[261.1] In neurovirology, high-throughput sequencing (HTS) has emerged as a promising diagnostic approach, particularly since up to 60% of meningoencephalitis cases remain undiagnosed after routine clinical testing.[260.1] The ability of HTS to test for multiple pathogens in a single assay, without the need for specific targeted primers, enhances its utility in diagnosing neurological infections.[260.1] Furthermore, advances in next-generation sequencing (NGS) have revolutionized virus identification techniques, making them more accessible and cost-effective.[263.1] The integration of NGS with other diagnostic methods, such as MRI and PCR technology, allows for sensitive, rapid, and less invasive detection of viral infections, thereby facilitating the development of personalized therapeutic approaches in neurovirology.[259.1]Potential for Gene Therapy
The potential for gene therapy in neurovirology is increasingly recognized as a promising avenue for addressing viral infections of the nervous system. The recent advancements in quantifying and localizing the interaction of antigen-specific T cells within the central nervous system during infectious and autoimmune diseases are expected to significantly enhance the understanding of the molecular and biological mechanisms underlying virus-induced diseases. This understanding is crucial for developing targeted gene therapies that can effectively combat these infections.[242.1] The field of neurovirology has emerged over the past 30 years, founded on the discovery that numerous viruses can invade and establish latent infections in nervous tissue, leading to slow, chronic, or progressive diseases.[243.1] As new viruses and viral infections affecting the nervous system continue to arise, the field must adapt to meet these evolving challenges.[243.1] Factors contributing to the emergence of these infections include the evolution of more virulent agents, such as enterovirus 71 and chikungunya virus, geographic relocation of viruses like Dengue type 3 and West Nile virus, and interactions with animals that cross species barriers, exemplified by bovine spongiform encephalopathy and Nipah virus.[244.1] The advancement of high-throughput technologies, including polymerase chain reaction (PCR) arrays and large-scale DNA sequencing, has significantly improved diagnostic tools for viral infections, enabling the detection of a wider range of agents.[244.1] As the field of neurovirology continues to expand, it is essential to explore innovative approaches to address the challenges posed by these emerging viral infections.[243.1] Moreover, the advent of high-throughput technologies, such as polymerase chain reaction (PCR) arrays and large-scale DNA sequencing, has expanded the diagnostic capabilities for viral infections. These advancements not only enhance the detection of known viruses but also facilitate the discovery of new viral agents. Consequently, gene therapy strategies can be tailored based on the specific viral profiles identified in patients, potentially leading to more effective therapeutic interventions.[244.1]In this section:
References
[1] Neurovirology - Wikipedia — The field of neurovirology was formed within the past 30 years. It was founded upon the discovery that a large number of viruses are capable of invading and establishing latent infections in nervous tissue. Such viruses have been shown to produce slow, chronic, or progressive nervous system diseases.: v Neurovirology incorporates the related fields of virology, neuroscience, neurology, immunology, and molecular biology. New viruses and viral infections of the nervous system will continue to emerge and the field of neurovirology must constantly expand to meet these growing needs.: v While the interest in researching viruses that infect the nervous system has increased dramatically over the past 40 years, there are three key components vital for the continued advancement of the field:
[2] Neurovirological methods and their applications - Academia.edu — This overview explores the field of neurovirology, which encompasses the study of viral infections affecting the central nervous system (CNS), combining aspects of virology, neuroscience, and clinical neurology. It highlights the evolution of neurovirological techniques, from classical methods like tissue culture and virus isolation to modern
[3] Neurovirology - Wikipedia — Neurovirology is an interdisciplinary field which represents a melding of clinical neuroscience, virology, immunology, and molecular biology. The main focus of the field is to study viruses capable of infecting the nervous system. ... Overview. The field of neurovirology was formed within the past 30 years.
[4] Neurovirological methods and their applications | Journal of Neurology ... — Over the last 30 years neurovirology has emerged as a major discipline which has much relevance to both human disease and many aspects of neuroscience. This overview of the field aims to define briefly most of the major neurovirological techniques, both "classical" and more recent, and to indicate how these have been used to gain knowledge about the pathogenesis, clinical investigation
[8] Immune Response in Neurological Pathology: Emerging Role of Central and ... — More recently, the impact of the peripheral immune system is being recognized, since it has become evident that the central nervous system is not immune-privileged, as once thought. In this review, we highlight key interactions between central and peripheral immune cells in neurological disorders.
[9] Central/peripheral nervous system and immune responses — Inversely, aberrant immune system activities could lead to pathologies associated with altered nervous activities, such as Alzheimer's disease, chronic fatigue, or multiple sclerosis. The nervous, endocrine and immune circuitry is multi-directional, and a chemical, physical or emotional stress could upset the homeostasis.
[10] Immune Response in Neurological Pathology: Emerging Role of Central and ... — The Immune Response in the Central Nervous System: Key Effectors Innate Immune System. The central immune system, also known as the neuroimmune system, is comprised of resident macrophages (microglia) and mast cells, as well as other glial cells and neurons . Microglia, resident macrophages of the CNS, serve as the primary immune cells in the
[11] Novel approaches and challenges to treatment of central nervous system ... — Existing and emerging viral central nervous system (CNS) infections are major sources of human morbidity and mortality. Treatments of proven efficacy are currently limited predominantly to herpesviruses and human immunodeficiency virus (HIV). Development of new therapies has been hampered by the lac …
[13] Neuroinfectious Diseases: A Crisis in Neurology and a Call for Action — Despite significant advancements in the management of infectious diseases, central nervous system (CNS) infections remain a major challenge. They are often difficult to diagnose, and treatments are inadequate or nonexistent. ... immunomodulatory therapy in neurological diseases. Curr Treat Options Neurol. 2012;14(3):241-255. doi: 10.1007
[14] Major advances against a moving target of CNS infections — The past decade has seen some considerable advances in the diagnosis and treatment of CNS infections, despite some major challenges, such as the emergence of novel pathogens, the spread of
[15] New advances in CNS immunity against viral infection — The central nervous system (CNS) is an immunologically specialized organ where restrictive barrier structures protect the parenchyma from inflammation and infection. This protection is important in preventing damage to non-renewable resident cell populations, such as neurons, responsible for functions ranging from executive to autonomic.
[19] Shared interactions of six neurotropic viruses with 38 human proteins ... — Introduction Viral infections may disrupt the structural and functional integrity of the nervous system, leading to acute conditions such as encephalitis, and neuropsychiatric conditions as mood disorders, schizophrenia, and neurodegenerative diseases. Investigating viral interactions of human proteins may reveal mechanisms underlying these effects and offer insights for therapeutic
[24] The role of host genetics in susceptibility to severe viral infections ... — Host genetic factors predisposing to severe viral infection include inborn errors of immunity which involve a single genetic mutation that predisposes to a certain type of infection, e.g., single viral infection as reported in the International Union of Immunological Societies (IUIS) list of human inborn errors of immunity (Tangye et al., 2020
[40] A history of viral infections of the central nervous system — The era of modern neurovirology has been characterized by two principal features. The first is the remarkable advances in technology - witness the use of polymerase chain reaction (PCR) for identifying infectious agents, magnetic resonance imaging (MRI) to image the nervous system, and the advance in therapeutics based on molecular medicine.
[41] A history of viral infections of the central nervous system ... — "Neurovirology" is a term of relatively recent vintage, no more than decades old. Yet evidence of viral infections of the nervous system is ancient - millennia old. Richard Johnson has recounted a charming anecdote of how the term neurovirology was devised by Elizabeth Hartmann, an administrator at the National Institutes of Health.
[42] Neurovirology - Wikipedia — The field of neurovirology was formed within the past 30 years. It was founded upon the discovery that a large number of viruses are capable of invading and establishing latent infections in nervous tissue. Such viruses have been shown to produce slow, chronic, or progressive nervous system diseases.: v Neurovirology incorporates the related fields of virology, neuroscience, neurology, immunology, and molecular biology. New viruses and viral infections of the nervous system will continue to emerge and the field of neurovirology must constantly expand to meet these growing needs.: v While the interest in researching viruses that infect the nervous system has increased dramatically over the past 40 years, there are three key components vital for the continued advancement of the field:
[43] A history of viral infections of the central nervous system ... — In 1901 yellow fever was shown to be the first human disease to be caused by a “filterable virus.” In 1903 rabies would be the first disease of the nervous system to be determined to be viral in nature, and polio followed soon thereafter. Given the three to four millennia between the first recognition of neurologic diseases shown ultimately to be of viral origin to the naming of neurovirology as a field of explicit study, how does one tell the story of viral infections of the nervous system? Two viral diseases of the nervous system, rabies and polio, were among the first human diseases to be shown to be viral in nature and serve to open up the history of the virology of the central nervous system (CNS).
[44] A history of viral infections of the central nervous system ... — In 1901 yellow fever was shown to be the first human disease to be caused by a “filterable virus.” In 1903 rabies would be the first disease of the nervous system to be determined to be viral in nature, and polio followed soon thereafter. Given the three to four millennia between the first recognition of neurologic diseases shown ultimately to be of viral origin to the naming of neurovirology as a field of explicit study, how does one tell the story of viral infections of the nervous system? Two viral diseases of the nervous system, rabies and polio, were among the first human diseases to be shown to be viral in nature and serve to open up the history of the virology of the central nervous system (CNS).
[45] A history of viral infections of the central nervous system — Within a decade, the viral nature of aseptic meningitis and herpes simplex sporadic encephalitis was demonstrated. From the 1950s through the 1970s great interest in "slow viral diseases" arose as potential models for chronic diseases of the nervous system. The era of modern neurovirology has been characterized by two principal features.
[46] Neurovirology - Wikipedia — The field of neurovirology was formed within the past 30 years. It was founded upon the discovery that a large number of viruses are capable of invading and establishing latent infections in nervous tissue. Such viruses have been shown to produce slow, chronic, or progressive nervous system diseases.: v Neurovirology incorporates the related fields of virology, neuroscience, neurology, immunology, and molecular biology. New viruses and viral infections of the nervous system will continue to emerge and the field of neurovirology must constantly expand to meet these growing needs.: v While the interest in researching viruses that infect the nervous system has increased dramatically over the past 40 years, there are three key components vital for the continued advancement of the field:
[47] Diagnostics and Discovery in Viral Central Nervous System Infections — Diagnosis of viral central nervous system infections is challenging in that brain tissue, where the pathogen concentration is likely to be highest, is not readily obtained and sensitive methods for molecular and serological detection of infection are not available in most clinical microbiology laboratories.
[52] Molecular Diagnosis of CNS Viral Infections - ScienceDirect — A CNS infection is extremely serious and life threatening with unpredictable neurological disorders. The confident diagnoses of neuroviral infections will help to improve the management of infected people and facilitate the development of specific antiviral compounds while aiding the development of methods to control disease.
[65] A history of rabies—The foundation for global canine rabies elimination — Inferred relationships of rabies to animal bites, the characteristic neurological signs and inevitability of death had a major influence on scientific thought and applications toward a crucial understanding of viral pathogenesis, diagnosis, epidemiology, prevention, and control throughout the 19th-20th centuries.
[67] Identification of Novel Yellow Fever Class II Epitopes in YF-17D ... — The yellow fever 17D-based vaccine (YF-17D) is a live attenuated vaccine produced by Sanofi Pasteur under the tradename YF-VAX® and is the only YF vaccine licensed in the United States . Vaccination is an important strategy to combat flaviviral diseases, and the YF vaccine is amongst the most successful vaccines ever produced [ 5 ].
[79] Neurovirological methods and their applications - Academia.edu — This overview explores the field of neurovirology, which encompasses the study of viral infections affecting the central nervous system (CNS), combining aspects of virology, neuroscience, and clinical neurology. ... Published by group.bmj.com Neurovirology for neurologists 1021 Table 4 Possible major applications of techniques in neurovirology
[80] Neurovirological methods and their applications - PubMed — Over the last 30 years neurovirology has emerged as a major discipline which has much relevance to both human disease and many aspects of neuroscience. This overview of the field aims to define briefly most of the major neurovirological techniques, both "classical" and more recent, and to indicate h …
[83] Neurovirological methods and their applications - Academia.edu — PCR is also used in other molecular techniques relevant to neurovirology, such as DNA sequencing and cloning of genomic DNA.22 PCR has proved very valuable in the rapid and specific diagnosis of CNS viral infections such as HSV-1, cytomegalovirus, varicella-zoster virus, and enteroviruses, and is now the viral diagnostic method of choice in
[85] Pathogenic viruses: Molecular detection and characterization — Apart from PCR-based detection, known and unknown pathogenic viruses in circulation can also be detected by high-throughput sequencing of small RNAs populations followed by bioinformatics analysis (Massart et al., 2019).
[87] Rapid High-Throughput Whole-Genome Sequencing of SARS-CoV-2 by Using ... — In conclusion, our study demonstrates a convenient SARS-CoV-2 whole-genome sequencing protocol by incorporating one-step RT-PCR amplification, microfluidic technology, and next-generation sequencing to achieve a simple and fast workflow with consistent and high-quality data.
[89] From Tradition to Innovation: Diverse Molecular Techniques in ... - MDPI — A high-throughput platform, the PacBio sequencer stands out from other sequencing platforms due to its capacity to produce full-length gene sequences . Being able to completely identify and structurally analyze complex microbial communities makes PacBio a useful tool.
[90] Therapeutic advances in neuroinfectious diseases - PMC — Despite these challenges, there have been several important advances in therapeutic options for the treatment of neurotropic infectious diseases over the past two decades. These include the development of new therapeutic agents and repurposing of existing agents, particularly immunomodulatory treatments.
[95] Molecular Diagnosis of CNS Viral Infections - ScienceDirect — The diagnosis of CNS viral infections is challenging, yet significant progress in laboratory diagnosis of CNS infections has been made. ... PCR has become a powerful diagnostic tool, especially in neurovirology. 26. Following NAA, several molecular techniques may be used to analyze amplified nucleic acids, some of which are only applied in
[97] Diagnostic Testing of Neurologic Infections - PMC - PubMed Central (PMC) — Herpes simplex virus (HSV) is only cultured from CSF in less than 5% of HSV encephalitis cases. 15 Fortunately, with the advent of advanced molecular techniques, the need for viral cultures as a diagnostic tool for CNS infections has diminished. 16. Fungal cultures can be performed on specific fungal mediums.
[102] Molecular analysis of cerebrospinal fluid in viral diseases of the ... — Over the last decade, nucleic acid (NA) amplification-based techniques, primarily the polymerase chain reaction (PCR), have revolutionised the diagnosis of CNS infections, especially those caused by viruses (Fredricks and Relman, 1999).Their advantages, accounting for their success in diagnostic neurovirology, have been the extraordinary sensitivity and rapidity.
[103] Molecular diagnostic techniques - PMC — Other widely used molecular diagnostic techniques are isothermal amplification methods and nucleic acid hybridization techniques. Microarray is a technique which holds promise and has an exceptional sensitivity and the capacity to detect several pathogens simultaneously. However, microarrays are currently too expensive to be adapted for routine
[104] Molecular diagnostics in cerebrospinal fluid for the diagnosis of ... — Molecular diagnostic methods are pivotal for identifying the different causative pathogens of these infections in clinical settings. The efficacy and specificity of these methods can vary per pathogen involved, and in a substantial part of patients, no pathogen is identified in the cerebrospinal fluid (CSF).
[106] 5 Ways Molecular Digital Integration Transforms Pathology — Training programs should be developed to educate staff on both digital imaging techniques and molecular diagnostic methods. Collaborative workshops and interdisciplinary meetings can help bridge knowledge gaps and promote a culture of innovation, ensuring that all team members understand the benefits and limitations of Molecular Digital
[119] Can viral infections lead to neurological disorders? — Can viral infections lead to neurological disorders? We've known that viral infections can be associated with neurological disorders for years. The development of neurological disorders related to viral infections still occurs, however. In addition to MS, cases of Epstein-Barr that progress to mono, are also associated with other inflammatory neurologic disorders in children and adults such as Guillain-Barré syndrome, transverse myelitis, encephalitis, meningitis and cranial nerve palsies such as Bell's palsy, notes Dr. Zabad. There are several mechanisms that occur during a viral infection that may be associated with progression to neurological disorders. "The scientific community is one step forward in understanding one of the many, yet important factors that might associate neurological disorders with viral infections," says Dr. Zabad.
[120] Editorial: Viral infection and brain diseases - PMC — In fact, virus infections of the brain have long been reported to result in either transient or permanent neurological or psychiatric disorders (van den Pol, 2009). Recent studies also hypothesized that the pathogenesis of neurodegenerative diseases including Alzheimer's disease might be relevant to virus infection (Limongi and Baldelli, 2016
[121] Viral infections and their relationship to neurological disorders — The chronic dysfunction of neuronal cells, both central and peripheral, a characteristic of neurological disorders, may be caused by irreversible damage and cell death. In 2016, more than 276 million cases of neurological disorders were reported worldwide. Moreover, neurological disorders are the second leading cause of death. Generally, the etiology of neurological diseases is not fully
[122] Viral Infections And Their Neurological Complications — The way that viral infections induce neurological complications is often complex and multi-faceted. Damage to cells and neural pathways may be caused directly by infection of the CNS or indirectly, through the host response to the infection. 22 . Direct pathway Some viral infections can directly infect neurons and other cells in the CNS.
[124] Five Questions about Viral Trafficking in Neurons - PMC — The initial interaction of host and virus particles in peripheral tissue prior to nervous system infection can be complex, often involving significant productive replication and spread among a variety of cell types, including those present at mucosal surfaces as well as those of the immune and nervous systems. On the other hand, some viruses (e
[126] Virus Infections in the Nervous System - PMC - PubMed Central (PMC) — In contrast to the dangerous zoonotic CNS infections described above, some human-adapted viruses gain access to the CNS as a result of diminished host defenses that fail to limit peripheral infections (e.g. Epstein-Barr virus, human cytomegalovirus, JC virus). Virus infections that leave the periphery and find their way into the PNS or CNS do so either by direct infection of nerve endings in the tissues, or by infecting cells of the circulatory system that ultimately carry the infection through the BBB into the CNS (Table 1, Figure 2). Entry of herpes simplex virus type 1 (HSV-1) into the distal axons of trigeminal neurons favors the onset of nonproductive, silent infection. Alpha and gamma interferons inhibit herpes simplex virus type 1 infection and spread in epidermal cells after axonal transmission.
[127] Viral Diseases of the Central Nervous System - PMC — This review highlights a selection of neurotropic viruses that infect the CNS and explores the means by which they induce neurological diseases such as meningitis, encephalitis, and myelitis. Viruses that remain within cells of the meninges or ventricular lining often induce meningitis, whereas those that infect the CNS parenchyma give rise to meningoencephalitis, encephalitis, or myelitis (Figures 1, 2). Viruses that infect neurons within the CNS can induce intense inflammation of the parenchyma (encephalitis) as well as the meninges (meningoencephalitis), leading to headache, fever, and neurological dysfunction (Figures 1, 2). The immune response to herpes simplex virus type 1 infection in susceptible mice is a major cause of central nervous system pathology resulting in fatal encephalitis.
[132] Public health trends in neurologically relevant infections: a global ... — Focusing on emerging viruses, one study estimated that 39% of emerging viral infections may cause severe neurological illness, while another 10% do so on a more infrequent basis. 5 These diseases inflict a significant burden on the communities they affect, both in terms of acute mortality but also with respect to the long-term, disabling
[135] Viral infections and their relationship to neurological disorders — Moreover, neurological disorders are the second leading cause of death. Generally, the etiology of neurological diseases is not fully understood. Recent studies have related the onset of neurological disorders to viral infections, which may cause neurological symptoms or lead to immune responses that trigger these pathological signs.
[136] Chronic and delayed neurological manifestations of persistent infections — Delayed onset of neurological issues due to infections can occur months or years after the initial infectious insult as highlighted by the recent striking finding that viral encephalitis is associated with significant risk of later development of dementia [4 ] and that vaccination against some viruses can decrease the risk of developing
[137] Viral Infections And Their Neurological Complications — The way that viral infections induce neurological complications is often complex and multi-faceted. Damage to cells and neural pathways may be caused directly by infection of the CNS or indirectly, through the host response to the infection. 22 . Direct pathway Some viral infections can directly infect neurons and other cells in the CNS.
[141] Neurological Manifestations of Infectious Diseases: Insights From ... — The discussion focuses on the public health implications of preventive efforts against infectious infections, including their neurological consequences. The story emphasizes the link between infectious diseases and overall societal health, advocating for a proactive strategy to reduce the impact of neurological complications.
[142] Major advances in neuroinfectious diseases in the past two decades — The past two decades have seen an increasing number of outbreaks of public health importance, of which the most recent and devastating is COVID-19, with a death toll of more than 5 million people and around 30% of survivors reporting long-term neurological symptoms. Other recent outbreaks include Zika virus infection, mainly affecting populations in South America and Central America, Ebola
[152] Viral infections and their relationship to neurological disorders — Recent studies have related the onset of neurological disorders to viral infections, which may cause neurological symptoms or lead to immune responses that trigger these pathological signs. ... Comprehending the pathogenesis of these diseases and exploring novel theories may favor the development of new strategies for diagnosis and therapy in
[153] Viral infections and their relationship to neurological disorders — Neurological disorders (NDs) are among the most significant public health challenges in today's society, and they are mainly associated with the aging of the population [].NDs are the leading cause of disability-adjusted life years (DALYs), with approximately 276 million cases [].The continuous dysfunction provoked by NDs triggers degeneration and consequent cell death in the nervous system [].
[156] Major advances in neuroinfectious diseases in the past two decades — Conditions such as community-acquired bacterial meningitis and tropical neurological infections remain major drivers of death and disability-adjusted life-years (DALYs) worldwide.1 Infections like neurocysticercosis, HIV, and Zika virus not only cause neurological injury in the acute setting, but also contribute substantially to long-term sequelae, such as neurodevelopmental disorders, cerebrovascular disease, epilepsy, or cognitive impairment. Although SARS-CoV-2 is identified as a primary respiratory pathogen, many neurological complications (ie, encephalopathy, stroke, and neuromuscular disorders) manifest during the acute phase of COVID-19.4 Furthermore, impaired concentration, headache, and sensory disturbances can persist for months after infection, as part of a constellation of symptoms termed long-COVID-19 or post-acute sequelae of COVID-19.4 The effects of such outbreaks are enormous, not only for individual patients, but also because of their large-scale socioeconomic consequences.5, 6 These global threats have highlighted our need to invest in lasting research projects into the pathogenesis, enhanced diagnostics, and treatments of neurological infections.
[168] Emerging Issues in Neurovirology: New Viruses, Diagnostic Tools, and ... — Some have been due to the evolution of more virulent agents (eg, enterovirus 71, chikunqunya virus, and drug-resistant microbes), some to geographic relocation of agents (eg, Dengue type 3 in Sri Lanka and West Nile virus in North America), and some to contact with animals and crossing of species barriers (eg, bovine spongiform encephalopathy, variant Creutzfeldt-Jakob disease, Nipah virus, and the severe acute respiratory syndrome [SARS] virus). With the advent of new high-throughput technologies including polymerase chain reaction (PCR) arrays, virus-specific cDNA and DNA microarrays, and the capacity to perform large-scale DNA sequencing , diagnostic tools for viral infections are rapidly advancing in complexity and in the spectrum of agents that can be detected or newly discovered. The outbreak of West Nile virus infection in the New York City area in 1999.
[181] Modelling Neurotropic Flavivirus Infection in Human Induced ... - PubMed — Generation of human induced pluripotent stem cells (hiPSCs) and their differentiation into a variety of cells and organoids have allowed setting up versatile, non-invasive, ethically sustainable, and patient-specific models for the investigation of the mechanisms of human diseases, including viral infections and host-pathogen interactions.
[182] iPSC-derived three-dimensional brain organoid models and neurotropic ... — Recent advances in 3D brain organoid modeling have provided access to a better understanding of cell-to-cell interactions in disease progression, particularly with neurotropic viral infections. Neurotropic viral infections have been difficult to study in two-dimensional culture systems in vitro due to the lack of a multicellular composition of
[183] iPSC-derived three-dimensional brain organoid models and neurotropic ... — Neurotropic viral infections have been difficult to study in two-dimensional culture systems in vitro due to the lack of a multicellular composition of CNS cell networks. In recent years, 3D brain organoids have been preferred for modeling neurotropic viral diseases and have provided invaluable information for better understanding the molecular
[184] Emerging Issues in Neurovirology: New Viruses ... - ScienceDirect — With the advent of new high-throughput technologies including polymerase chain reaction (PCR) arrays, virus-specific cDNA and DNA microarrays, and the capacity to perform large-scale DNA sequencing , diagnostic tools for viral infections are rapidly advancing in complexity and in the spectrum of agents that can be detected or newly discovered.
[185] Clinical Trials in Neurovirology: Successes, Challenges, and Pitfalls — Diagnosis in early trials depended on brain biopsy, which often delayed initiation of therapy, and had its own morbidity and mortality. The combination of MRI lesion detection and CSF demonstration of virus with PCR technology permits sensitive, rapid, and less invasive diagnosis, and better outcomes . However, the challenges of RCTs of PML are
[186] Diagnosis of viral infections of the central nervous system: clinical ... — A patient with a positive PCR result was 88 times as likely to have a definite diagnosis of viral infection of the CNS as a patient with a negative PCR result. A negative PCR result can be used with moderate confidence to rule out a diagnosis of viral infection of the CNS. We believe that PCR will become the first-line diagnostic test for viral meningitis and encephalitis.
[187] (PDF) Neuropathogenesis of Neurotropic Viruses - Academia.edu — Neuropathogenesis can simply be defined as the mechanisms of the origin, development and progression of the CNS disease which comprises both neuroinvasion and neurovirulence. Viruses that have the ability to induce neuropathogenesis are called neurotropic pathogens. The exact mechanisms of neuropathogenesis is still unknown, however, the following pathways have been proposed and include
[188] PDF — The main neurotropic viral families are picornaviruses, arboviruses, paramixoviruses, arenaviruses and herpes family viruses. In this review, the main mechanisms of neuropathogenesis of the neurotropic members of these viral families was discussed.
[189] Comparison of three neurotropic viruses reveals differences in viral ... — Neurotropic viruses enter the CNS through peripheral nerves or by crossing the blood-brain barrier following hematogenous dissemination. Different viruses target different cell types within the nervous system, causing symptoms ranging from seizures to paralysis or death.
[190] Reemerging Infectious Diseases and Neuroimmunologic Complications — Within the past decade, much knowledge has been gained about many neurotropic viruses. This review addresses knowledge of established and emerging infectious diseases affecting the nervous system over the past 10 years. Similarities and distinctions between what are known about mechanisms of virus entry, replication and evolution in the CNS, neuropathogenesis, and treatment strategies are
[191] Neuroinflammation and Infection: Molecular Mechanisms Associated with ... — The neuroinflammatory disorders induced by West Nile virus (WNV) is another example of a viral infection-mediated CNS neurodegeneration. WNV is a mosquito-borne RNA virus belonging to flaviviruses (Lindenbach and Rice, 2003). WNV is a major pathogen of the CNS neurons and causes viral encephalitis.
[196] Transforming clinical virology with AI, machine learning and deep ... — To address these challenges, the intersection of clinical virology with emerging technologies such as Artificial Intelligence (AI), Machine Learning (ML), and Deep Learning (DL) is not just promising but imperative. They can also be used in tandem with other AI techniques like Natural Language Processing (NLP) to mine valuable insights from clinical notes, research articles, and other textual data sources, contributing to a more holistic understanding of viral diseases. In addition to identifying potential outbreaks, AI tools provide frameworks for continuous monitoring, ensuring rapid response times during public health emergencies. Treatment optimization and personalization: AI’s ability to curate treatment plans based on genomic data provides the groundwork for precision medicine, predicting patient responses to specific treatments, and guiding drug discovery.
[197] The Impact of Artificial Intelligence on Healthcare: A Comprehensive ... — It examines the uses and effects of AI on healthcare by synthesizing recent literature and real‐world case studies, such as Google Health and IBM Watson Health, highlighting AI technologies, their useful applications, and the difficulties in putting them into practice, including problems with data security and resource limitations. Artificial Intelligence (AI) in healthcare, exploiting machine learning (ML) algorithms, data analytics, and automation, is enduring a paradigm transition by improving medical decision‐making, diagnosis, and treatment outcomes, with the potential to boost productivity, care quality, and ease costs . This in‐depth study looks at how AI is significantly impacting the healthcare sector, improving diagnostic precision through data analysis, streamlining treatment planning through predictive algorithms, and shedding light on how these advancements are challenging accepted wisdom and setting new benchmarks for quality .
[198] Integrating bioinformatics and machine learning for comprehensive ... — The amalgamation of high-throughput sequencing technologies and machine learning has facilitated a more comprehensive analysis of genetic-level biological inquiries, encompassing diagnosis and
[207] Clinical Trials in Neurovirology: Successes, Challenges ... - ResearchGate — Clinical trials in the setting of neurovirological diseases are characterized by specific challenges, which may include small sample sizes, clinical presentations from life-threatening conditions
[208] Clinical Trials in Neurovirology: Successes, Challenges, and Pitfalls — Many neurovirological diseases typically present with a low prevalence, fulfilling the criteria of rare diseases, that is, < 200,000 cases at any given time in the USA. Clinical trials in the rare disease setting are often challenging, as limited sample sizes may restrict the ability to design a clinical trial with adequate statistical power.
[209] Clinical Trials in Neurovirology: Successes, Challenges, and Pitfalls — Alternatively, time to progression can be used as outcome if the time point of progression can be clearly defined as event in a clinical trial. Many neurovirological trials will use biomarkers as outcomes. To qualify as a surrogate biomarker, the outcome (e.g., viral load) should be responsive to the treatment intervention and predict a
[210] 7 Essential Clinical Trial Design Strategies for Success — The landscape of clinical trials is undergoing a transformative shift as organizations embrace innovative strategies to enhance trial design and execution. Key elements such as the precise definition of research questions, strategic planning, and the integration of technology are essential for navigating the complexities of clinical research.
[211] Transforming Clinical Trials with Technology - Neuroscience Trials of ... — New technologies such as wearable devices, remote monitoring, and virtual clinical visits may help fulfill the goal of making clinical trials more patient focused (Kieburtz). Exploiting new technologies in the design of clinical trials will require the drug development community to apply the lessons learned from other industries, including an increasing focus on the consumer, said Schiller. Joynt Professor in Neurology and director of the Clinical and Translational Science Institute at the University of Rochester Medical Center, said that regardless of the changes brought about by the introduction of new technologies, three aspects of traditional drug development will endure: (1) enabling the participation of patients and families in meaningful research opportunities, (2) generating robust data, and (3) drawing valid inferences.
[212] Gene-Editing Technologies Paired With Viral Vectors for Translational ... — Unfortunately, current pharmacological treatments provide only temporary symptomatic relief (if that), without addressing the underlying causes. Virus-mediated gene therapy, on the other hand, is a viable long-term strategy for the disease-modifying treatment of several neurological and neurodegenerative disorders.
[217] Recent innovations in adaptive trial designs: A review of design ... — The FDA noted that adaptive designs may have multiple advantages over traditional, nonadaptive designs for improving statistical efficiency of trial operating characteristics (e.g., type I error rates and power), addressing ethical considerations (e.g., stopping a trial early if an intervention shows safety concerns or limited benefit, increasing randomization to better-performing arms), adding to our understanding of treatment effects (e.g., enriching a trial with more participants expected to benefit), and being more acceptable to stakeholders (e.g., increased flexibility to successfully complete the trial) . | Adaptations to treatment arm selection | Modification to the trial design that could add or terminate study arms, present in both early phase studies (e.g., dose-finding) and later phase studies (e.g., seamless designs and platform trials) |
[218] Adaptive designs in clinical trials: why use them, and how to run and ... — Adaptive designs in clinical trials: why use them, and how to run and report them | BMC Medicine | Full Text Skip to main content Advertisement Search Explore journals Get published About BMC My account Search all BMC articles Search BMC Medicine Home About Articles Submission Guidelines Collections Submit manuscript Adaptive designs in clinical trials: why use them, and how to run and report them Download PDF Download PDF Correspondence Open access Published: 28 February 2018 Adaptive designs in clinical trials: why use them, and how to run and report them Philip Pallmann ORCID: orcid.org/0000-0001-8274-96961, Alun W. Bedding2, Babak Choodari-Oskooei3, Munyaradzi Dimairo4, Laura Flight5, Lisa V. Hampson1,6, Jane Holmes7, Adrian P. Mander8, Lang’o Odondi7, Matthew R. Sydes3, Sofía S. Villar8, James M. S. Wason8,9, Christopher J. Weir10, Graham M. Wheeler8,11, Christina Yap12 & … Thomas Jaki1 Show authorsBMC Medicine volume 16, Article number: 29 (2018) Cite this article 164k Accesses 357 Altmetric Metrics details Abstract Adaptive designs can make clinical trials more flexible by utilising results accumulating in the trial to modify the trial’s course in accordance with pre-specified rules. Trials with an adaptive design are often more efficient, informative and ethical than trials with a traditional fixed design since they often make better use of resources such as time and money, and might require fewer participants. Adaptive designs can be applied across all phases of clinical research, from early-phase dose escalation to confirmatory trials. This tutorial paper provides guidance on key aspects of adaptive designs that are relevant to clinical triallists. We explain the basic rationale behind adaptive designs, clarify ambiguous terminology and summarise the utility and pitfalls of adaptive designs.
[220] Clinical Trials in Neurovirology: Successes, Challenges, and Pitfalls — Factors contributing to this include the rarity and sporadic nature of the diagnosis, leading to clinical trials being complex and costly. ... Clinical trials in neurovirology may have common challenges, including limited sample sizes, an emergency or intensive care setting, and regional and temporal outbreak scenarios, as well as settings in
[221] Genetic factors associated with reasons for clinical trial stoppage — Many drug discovery projects are started but few progress fully through clinical trials to approval. Previous work has shown that human genetics support for the therapeutic hypothesis increases the chance of trial progression. ... Genetic factors associated with reasons for clinical trial stoppage Nat Genet. 2024 Sep;56(9):1862-1867. doi: 10.
[225] PDF — https://www.eejournals.org Open Access Page | 5 Advancements in Neuroimaging for Early Detection of Neurological Disorders Kato Jumba K. This paper examines the most recent breakthroughs in neuroimaging, with a focus on resting-state functional MRI, presymptomatic detection in Alzheimer's research, diffusion tensor imaging for white matter analysis, and magnetoencephalography. Keywords: Neuroimaging, Early Detection, Alzheimer's Disease, Functional MRI, Diffusion Tensor Imaging INTRODUCTION Advancements in neuroimaging for early detection of neurological disorders. APPLICATIONS OF NEUROIMAGING IN EARLY DETECTION Neuroimaging is becoming increasingly useful in the early diagnosis and monitoring of neurological disorders. Technologies such as resting-state functional MRI, diffusion tensor imaging, and magnetoencephalography have provided unprecedented insights into the brain's structure and function, allowing for earlier and more accurate detection of diseases like Alzheimer’s and other neurodegenerative conditions. Advancements in Neuroimaging for Early Detection of Neurological Disorders.
[226] The vast potential and bright future of neuroimaging - PMC — Quantitative neuroimaging is well-suited for statistical modeling and systematic image analysis approaches that utilize canonical templates or brain atlases to measure changes in specific regions of interest.7 Quantitative methods are beginning to evaluate the brain as an integrated structural and functional network.8 These new approaches might be critical not only for deciphering brain circuitry but also for understanding the dysfunction of brain network connectivity that occurs during the progression of many neurological and psychiatric disorders.
[227] Biomarkers in neurological disorders: a fast-growing market — The arsenal of biomarkers in neurology is likely to keep growing as our ability to measure accurately multiple biological variables and our knowledge about the pathophysiology of the neurological diseases increase. Biomarkers can be used for several purposes: to guide clinical diagnosis, to estimate disease risk or prognosis, to evaluate
[242] Future trends in neurovirology: neuronal survival during virus ... — The recent ability to quantitate and localize the interaction of antigen-specific T cells in the central nervous system during infectious and autoimmune diseases will greatly enhance our understanding of the molecular and biologic basis of virus-induced diseases of the nervous and other systems.
[243] Neurovirology - Wikipedia — The field of neurovirology was formed within the past 30 years. It was founded upon the discovery that a large number of viruses are capable of invading and establishing latent infections in nervous tissue. Such viruses have been shown to produce slow, chronic, or progressive nervous system diseases.: v Neurovirology incorporates the related fields of virology, neuroscience, neurology, immunology, and molecular biology. New viruses and viral infections of the nervous system will continue to emerge and the field of neurovirology must constantly expand to meet these growing needs.: v While the interest in researching viruses that infect the nervous system has increased dramatically over the past 40 years, there are three key components vital for the continued advancement of the field:
[244] Emerging Issues in Neurovirology: New Viruses, Diagnostic Tools, and ... — Some have been due to the evolution of more virulent agents (eg, enterovirus 71, chikunqunya virus, and drug-resistant microbes), some to geographic relocation of agents (eg, Dengue type 3 in Sri Lanka and West Nile virus in North America), and some to contact with animals and crossing of species barriers (eg, bovine spongiform encephalopathy, variant Creutzfeldt-Jakob disease, Nipah virus, and the severe acute respiratory syndrome [SARS] virus). With the advent of new high-throughput technologies including polymerase chain reaction (PCR) arrays, virus-specific cDNA and DNA microarrays, and the capacity to perform large-scale DNA sequencing , diagnostic tools for viral infections are rapidly advancing in complexity and in the spectrum of agents that can be detected or newly discovered. The outbreak of West Nile virus infection in the New York City area in 1999.
[245] On the merits and potential of advanced neuroimaging techniques in ... — Multiple pathways of viral neuroinvasion have been proposed, including transsynaptic transfer across infected neurons, intracranial entry via the olfactory nerve, ... Advanced neuroimaging techniques have focused on these findings in the olfactory bulb and have expanded the region of interest to brain regions involved in the olfactory system.
[246] Interrogating autonomic peripheral nervous system neurons with viruses ... — The Hogue et al. (2018) study demonstrated that PRV-290 is a valuable addition to the viral tracer toolbox for transneuronal tracing of neural circuitry, suggesting that the novel demonstration of three recombinants infecting individual neurons represents an important advance in the technology.
[247] PDF — https://www.eejournals.org Open Access Page | 5 Advancements in Neuroimaging for Early Detection of Neurological Disorders Kato Jumba K. This paper examines the most recent breakthroughs in neuroimaging, with a focus on resting-state functional MRI, presymptomatic detection in Alzheimer's research, diffusion tensor imaging for white matter analysis, and magnetoencephalography. Keywords: Neuroimaging, Early Detection, Alzheimer's Disease, Functional MRI, Diffusion Tensor Imaging INTRODUCTION Advancements in neuroimaging for early detection of neurological disorders. APPLICATIONS OF NEUROIMAGING IN EARLY DETECTION Neuroimaging is becoming increasingly useful in the early diagnosis and monitoring of neurological disorders. Technologies such as resting-state functional MRI, diffusion tensor imaging, and magnetoencephalography have provided unprecedented insights into the brain's structure and function, allowing for earlier and more accurate detection of diseases like Alzheimer’s and other neurodegenerative conditions. Advancements in Neuroimaging for Early Detection of Neurological Disorders.
[249] Transforming clinical virology with AI, machine learning and deep ... — To address these challenges, the intersection of clinical virology with emerging technologies such as Artificial Intelligence (AI), Machine Learning (ML), and Deep Learning (DL) is not just promising but imperative. They can also be used in tandem with other AI techniques like Natural Language Processing (NLP) to mine valuable insights from clinical notes, research articles, and other textual data sources, contributing to a more holistic understanding of viral diseases. In addition to identifying potential outbreaks, AI tools provide frameworks for continuous monitoring, ensuring rapid response times during public health emergencies. Treatment optimization and personalization: AI’s ability to curate treatment plans based on genomic data provides the groundwork for precision medicine, predicting patient responses to specific treatments, and guiding drug discovery.
[250] Revolutionizing Neurology: The Role of Artificial Intelligence in ... — Keywords: ai algorithms, brain signals, neuroimaging, brain-computer interfaces, precision medicine, neurological disorders, artificial intelligence Integrating AI technologies into neurology has yielded many benefits, including early diagnosis, personalized treatment plans, neuroimaging analysis, treatment optimization, and groundbreaking research endeavors . AI-powered algorithms analyze diverse patient data - medical history, imaging results, genetic profiles - to identify subtle markers of neurological disorders that might evade human observation . AI can significantly enhance the quality and effectiveness of treatment plans for neurological disorders by leveraging data-driven insights and personalizing care for individual patients. From early diagnosis and personalized treatment to BCIs and drug discovery, AI drives transformative changes that enhance patient care and our understanding of neurological disorders.
[259] Clinical Trials in Neurovirology: Successes, Challenges, and Pitfalls — Seeking alternative antiviral drugs to address JCV has been attempted by using a high-throughput screening approach of approved drugs. ... The combination of MRI lesion detection and CSF demonstration of virus with PCR technology permits sensitive, rapid, and less invasive ... Clinical trials in neurovirology may have common challenges
[260] Application of VirCapSeq-VERT and BacCapSeq in the diagnosis of ... — High-throughput sequencing (HTS) is a promising approach in diagnosis of neurological infections, as up to 60% of meningoencephalitis cases remain undiagnosed after routine clinical testing (Glaser et al. 2006; Granerod et al. 2010).With the ability to test for a multitude of pathogens in a single assay without the need for specific targeted primers as used in consensus polymerase chain
[261] Advancements in High-Throughput DNA Sequencing Technologies — High-throughput DNA sequencing technologies have transformed genomics, enabling rapid and cost-effective analysis of genetic material. These advancements support a wide range of applications, from personalized medicine to biodiversity research. The ability to sequence vast amounts of DNA quickly has opened new avenues in understanding complex
[263] Next generation sequencing-based transcriptome data mining for virus ... — Advances in next-generation sequencing (NGS) which refers to modern sequencing technologies that allow for massively parallel sequencing and computational approaches, such as artificial intelligence (AI), have revolutionized virus identification techniques in recent years . NGS has emerged as a cost-effective and accessible method for large