Neurosarcoidosis: Clinical, biological, and MRI presentation of central nervous system disease in a national multicenter cohort.

INTRODUCTION: Neurosarcoidosis (NS) is a systemic inflammatory granulomatous disease affecting of patients with sarcoidosis. Its diagnosis is difficult as there is no specific test for it. Because of its rarity, the management of NS has so far only been described in case series and short retrospective cohorts. The objective of this study is description of the clinical, paraclinical presentation and the therapeutic management of central nervous system (CNS) involvement in NS patients in France. METHODS: This multicenter, retrospective, observational study involved patients hospitalized between 2010 and 2019 with a diagnosis of sarcoidosis and CNS involvement. RESULTS: We included 118 patients (38 with isolated NS, 80 with NS associated with systemic sarcoidosis). NS was the initial presentation in 78% of patients, with cranial nerve involvement (36%), medullary symptoms (23%), and seizures (21%). Twenty-one percent of the patients had already been diagnosed with systemic sarcoidosis. The most frequent biological abnormality was lymphopenia (62.5%), while angiotensin-converting enzyme was increased in 21%. Meningitis was present in 45% and hyperproteinorachia in 69.5% of cases. MRI mainly revealed white matter abnormalities and leptomeningeal enhancement (34%). Corticosteroids were the most useful treatment, and immunosuppressive agents were used in steroid-resistant patients and to limit side effects. Methotrexate, cyclophosphamide, and anti-TNFα were also used, exhibiting good efficacy. CONCLUSIONS: This cohort contributes to a better understanding of the clinical phenotype and associated imaging and biological abnormalities. Sharing of clinical, biological, and imaging data, as well as the therapeutic responses, of patients with NS helps to better understand and manage this disease that affects a small number of patients per center. A database project could be implemented in the future to enable this.

Gastrodin, a Promising Natural Small Molecule for the Treatment of Central Nervous System Disorders, and Its Recent Progress in Synthesis, Pharmacology and Pharmacokinetics.

Gastrodia elata Blume is a traditional medicinal and food homology substance that has been used for thousands of years, is mainly distributed in China and other Asian countries, and has always been distinguished as a superior class of herbs. Gastrodin is the main active ingredient of G. elata Blume and has attracted increasing attention because of its extensive pharmacological activities. In addition to extraction and isolation from the original plant, gastrodin can also be obtained via chemical synthesis and biosynthesis. Gastrodin has significant pharmacological effects on the central nervous system, such as sedation and improvement of sleep. It can also improve epilepsy, neurodegenerative diseases, emotional disorders and cognitive impairment to a certain extent. Gastrodin is rapidly absorbed and widely distributed in the body and can also penetrate the blood-brain barrier. In brief, gastrodin is a promising natural small molecule with significant potential in the treatment of brain diseases. In this review, we summarised studies on the synthesis, pharmacological effects and pharmacokinetic characteristics of gastrodin, with emphasis on its effects on central nervous system disorders and the possible mechanisms, in order to find potential therapeutic applications and provide favourable information for the research and development of gastodin.

HLA-transgenic mouse models to study autoimmune central nervous system diseases.

It is known that certain human leukocyte antigen (HLA) genes are associated with autoimmune central nervous system (CNS) diseases, such as multiple sclerosis (MS), but their exact role in disease susceptibility and etiopathogenesis remains unclear. The best studied HLA-associated autoimmune CNS disease is MS, and thus will be the primary focus of this review. Other HLA-associated autoimmune CNS diseases, such as autoimmune encephalitis and neuromyelitis optica will be discussed. The lack of animal models to accurately capture the complex human autoimmune response remains a major challenge. HLA transgenic (tg) mice provide researchers with powerful tools to investigate the underlying mechanisms promoting susceptibility and progression of HLA-associated autoimmune CNS diseases, as well as for elucidating the myelin epitopes potentially targeted by T cells in autoimmune disease patients. We will discuss the potential role(s) of autoimmune disease-associated HLA alleles in autoimmune CNS diseases and highlight information provided by studies using HLA tg mice to investigate the underlying pathological mechanisms and opportunities to use these models for development of novel therapies.

Therapeutic potential of fucoidan in central nervous system disorders: A systematic review.

Central nervous system (CNS) disorders have a complicated pathogenesis, and to date, no single mechanism can fully explain them. Most drugs used for CNS disorders primarily aim to manage symptoms and delay disease progression, and none have demonstrated any pathological reversal. Fucoidan is a safe, sulfated polysaccharide from seaweed that exhibits multiple pharmacological effects, and it is anticipated to be a novel treatment for CNS disorders. To assess the possible clinical uses of fucoidan, this review aims to provide an overview of its neuroprotective mechanism in both in vivo and in vitro CNS disease models, as well as its pharmacokinetics and safety. We included 39 articles on the pharmacology of fucoidan in CNS disorders. In vitro and in vivo experiments demonstrate that fucoidan has important roles in regulating lipid metabolism, enhancing the cholinergic system, maintaining the functional integrity of the blood-brain barrier and mitochondria, inhibiting inflammation, and attenuating oxidative stress and apoptosis, highlighting its potential for CNS disease treatment. Fucoidan has a protective effect against CNS disorders. With ongoing research on fucoidan, it is expected that a natural, highly effective, less toxic, and highly potent fucoidan-based drug or nutritional supplement targeting CNS diseases will be developed.

Drug Repurposing for COVID-19 by Constructing a Comorbidity Network with Central Nervous System Disorders.

In the post-COVID-19 era, treatment options for potential SARS-CoV-2 outbreaks remain limited. An increased incidence of central nervous system (CNS) disorders has been observed in long-term COVID-19 patients. Understanding the shared molecular mechanisms between these conditions may provide new insights for developing effective therapies. This study developed an integrative drug-repurposing framework for COVID-19, leveraging comorbidity data with CNS disorders, network-based modular analysis, and dynamic perturbation analysis to identify potential drug targets and candidates against SARS-CoV-2. We constructed a comorbidity network based on the literature and data collection, including COVID-19-related proteins and genes associated with Alzheimer's disease, Parkinson's disease, multiple sclerosis, and autism spectrum disorder. Functional module detection and annotation identified a module primarily involved in protein synthesis as a key target module, utilizing connectivity map drug perturbation data. Through the construction of a weighted drug-target network and dynamic network-based drug-repurposing analysis, ubiquitin-carboxy-terminal hydrolase L1 emerged as a potential drug target. Molecular dynamics simulations suggested pregnenolone and BRD-K87426499 as two drug candidates for COVID-19. This study introduces a dynamic-perturbation-network-based drug-repurposing approach to identify COVID-19 drug targets and candidates by incorporating the comorbidity conditions of CNS disorders.

The Role of RNA m5C Modification in Central Nervous System Diseases.

As advances in RNA modification research progress, the significance of 5-methylcytosine (m5C) modification is being increasingly acknowledged. m5C undergoes modification by the methyltransferase NOP2/Sun domain (NSUN) family/DNA methyltransferase (DNMT) family (writer) and is removed by demethylases (eraser), including the ten-eleven translocation (TET) family and Alkb homolog 1 (ALKBH1). Moreover, m5C interacts with RNA-binding proteins (reader), such as Y-box-binding protein 1 (YBX1) and Aly/REF export factor (ALYREF). Expanding on this structural framework, m5C modification possesses the capacity to regulate various physiological and pathological processes. Recent studies indicate that m5C plays a pivotal regulatory role in the central nervous system, and its dysregulation may correlate with the onset and progression of various central nervous system diseases. In this review, we summarize recent research on m5C components and delve into the potential mechanisms of m5C involvement in central nervous system disorders, such as Alzheimer's disease, brain tumors, epilepsy, and stroke.

The Role of Astrocytes in CNS Disorders: Historic and Contemporary Views.

This Special Issue of Cells presents a collection of 22 published, peer-reviewed articles on the theme of "Astrocytes in CNS Disorders," including 9 reviews of the evidence implicating astrocytes in the etiology of specific disorders, and 13 original research papers providing such evidence [...].

[Multidisciplinary consensus on the use of Cereton drug in treatment of central nervous system diseases with cognitive impairments of congenital and acquired origin in children. Resolution of the multidisciplinary panel of experts]. / Mezhdistsiplinarnyi konsensus po primeneniyu preparata Tsereton v terapii zabolevanii tsentral'noi nervnoi sistemy s kognitivnymi narusheniyami vrozhdennogo i priobretennogo geneza u detei. Rezolyutsiya mezhdistsiplinarnogo soveta ekspertov.

Interdisciplinary consensus on the use of Cereton in the treatment of central nervous system diseases with cognitive impairment of congenital and acquired genesis in children. Resolution of the interdisciplinary council of expertsXXIII All-Russian Forum "Zdravnitsa-2024".

The Glycocalyx: The Importance of Sugar Coating the Blood-Brain Barrier.

The endothelial glycocalyx (GCX), located on the luminal surface of vascular endothelial cells, is composed of glycoproteins, proteoglycans, and glycosaminoglycans. It plays a pivotal role in maintaining blood-brain barrier (BBB) integrity and vascular health within the central nervous system (CNS), influencing critical processes such as blood flow regulation, inflammation modulation, and vascular permeability. While the GCX is ubiquitously expressed on the surface of every cell in the body, the GCX at the BBB is highly specialized, with a distinct composition of glycans, physical structure, and surface charge when compared to GCX elsewhere in the body. There is evidence that the GCX at the BBB is disrupted and partially shed in many diseases that impact the CNS. Despite this, the GCX has yet to be a major focus of therapeutic targeting for CNS diseases. This review examines diverse model systems used in cerebrovascular GCX-related research, emphasizing the importance of selecting appropriate models to ensure clinical relevance and translational potential. This review aims to highlight the importance of the GCX in disease and how targeting the GCX at the BBB specifically may be an effective approach for brain specific targeting for therapeutics.

Inflammatory Role of CCR1 in the Central Nervous System.

BACKGROUND: Chemokine ligands and their corresponding receptors are essential for regulating inflammatory responses. Chemokine receptors can stimulate immune activation or inhibit/promote signaling pathways by binding to specific chemokine ligands. Among these receptors, CC chemokine receptor 1 (CCR1) is extensively studied as a G protein-linked receptor target, predominantly expressed in various leukocytes, and is considered a promising target for anti-inflammatory therapy. Furthermore, CCR1 is essential for monocyte extravasation and transportation in inflammatory conditions. Its involvement in inflammatory diseases of the central nervous system (CNS), including multiple sclerosis, Alzheimer's disease, and stroke, has been extensively studied along with its ligands. Animal models have demonstrated the beneficial effects resulting from inhibiting CCR1 or its ligands. SUMMARY: This review demonstrates the significance of CCR1 in CNS inflammatory diseases, the molecules implicated in the inflammatory pathway, and potential drugs or molecules for treating CNS diseases. This evidence may offer new targets or strategies for treating inflammatory CNS diseases.

Advanced Noninvasive Strategies for the Brain Delivery of Therapeutic Proteins and Peptides.

Recent years have witnessed rapid progress in the discovery of therapeutic proteins and peptides for the treatment of central nervous system (CNS) diseases. However, their clinical applications have been considerably hindered by challenges such as low biomembrane permeability, poor stability, short circulation time, and the formidable blood-brain barrier (BBB). Recently, substantial improvements have been made in understanding the dynamics of the BBB and developing efficient approaches for delivering proteins and peptides to the CNS, especially by using various nanoparticles. Herein, we present an overview of the up-to-date understanding of the BBB under physiological and pathological conditions, emphasizing their effects on brain drug delivery. We summarize advanced strategies and elucidate the underlying mechanisms for delivering proteins and peptides to the brain. We highlight the developments and applications of nanocarriers in treating CNS diseases via BBB crossing. We also provide critical opinions on the limitations and obstacles of the current strategies and put forward prospects for future research.

Tailored Borneol-Modified Lipid Nanoparticles Nasal Spray for Enhanced Nose-to-Brain Delivery to Central Nervous System Diseases.

The nanodrug delivery system-based nasal spray (NDDS-NS) can bypass the blood-brain barrier and deliver drugs directly to the brain, offering unparalleled advantages in the treatment of central nervous system (CNS) diseases. However, the current design of NNDS-NS is excessively focused on mucosal absorption while neglecting the impact of nasal deposition on nose-to-brain drug delivery, resulting in an unsatisfactory nose-to-brain delivery efficiency. In this study, the effect of the dispersion medium viscosity on nasal drug deposition and nose-to-brain delivery in NDDS-NS was elucidated. The optimized formulation F5 (39.36 mPa·s) demonstrated significantly higher olfactory deposition fraction (ODF) of 23.58%, and a strong correlation between ODF and intracerebral drug delivery (R2 = 0.7755) was observed. Building upon this understanding, a borneol-modified lipid nanoparticle nasal spray (BLNP-NS) that combined both nasal deposition and mucosal absorption was designed for efficient nose-to-brain delivery. BLNP-NS exhibited an accelerated onset of action and enhanced brain targeting efficiency, which could be attributed to borneol modification facilitating the opening of tight junction channels. Furthermore, BLNP-NS showed superiority in a chronic migraine rat model. It not only provided rapid relief of migraine symptoms but also reversed neuroinflammation-induced hyperalgesia. The results revealed that borneol modification could induce the polarization of microglia, regulate the neuroinflammatory microenvironment, and repair the neuronal damage caused by neuroinflammation. This study highlights the impact of dispersion medium viscosity on the nose-to-brain delivery process of NDDS-NS and serves as a bridge between the formulation development and clinical transformation of NDDS-NS for the treatment of CNS diseases.

Aseptic meningitis with recurrent headache episodes, vomiting, and central fever as first manifestation of isolated neurosarcoidosis: a case report.

BACKGROUND: Neurosarcoidosis is a rare entity, usually within the context of systematic sarcoidosis. Isolated neurosarcoidosis and especially a manifestation with pachymeningitis is a notable rarity. CASE REPORT: A 26-year-old patient presented to the emergency department with acute onset, recurrent episodes of occipital headaches spreading over the whole cranium and vomiting without food consumption, for three days. The clinical examination did not reveal any neurological deficits. The laboratory exams showed no pathological findings. A CT examination with angiography did not detect any acute intracranial or vessel pathology. A lumbar puncture was performed to rule out subarachnoid hemorrhage. The results showed a lymphocytic pleocytosis of 400/µL, elevated protein levels of 1077 mg/dL and reduced glucose levels (CSF: 55 mg/dL, Serum: 118 mg/dL). Extensive infectiological examinations did not reveal any signs of infection, including Borrelia spp. and M. tuberculosis. No positive auto-antibodies or vasculitis-related auto-antibodies were detected. The CSF analysis showed negative oligoclonal bands but an isolated increase in ß2-microglobulin, neopterin, and IL-2R levels. The MRI examination revealed a dural gadolinium-enhancement, pronounced in the basal cerebral structures and the upper segment of the cervical spine, consistent with neurosarcoidosis. Corticosteroid treatment rapidly led to a significant improvement of the symptoms. No systemic manifestations of sarcoidosis were found. CONCLUSIONS: This case report aims to highlight aseptic meningitis with atypical, acute onset headache attacks as a possible manifestation of isolated neurosarcoidosis. Neurosarcoidosis is a clinical entity that requires prompt treatment to avoid permanent neurological deficits.

Central nervous system manifestations in rheumatic diseases.

As the role of neurologists in managing patients with rheumatic diseases expands, collaboration between rheumatologists and neurologists becomes increasingly vital. This literature review provides an overview of the central nervous system (CNS) manifestations of major autoimmune rheumatic disorders, which may include parenchymal brain and meningeal disease (stroke, meningoencephalitis, meningitis), myelopathies, psychosis, chorea, seizure disorders, and various forms of cephalea. Novel findings linking specific autoimmune markers to CNS damage reveal a direct, previously underestimated link between systemic inflammation and neural injury. Besides, with the increasing use of biological therapies, it is crucial to recognize when neurological manifestations are related to adverse events of therapy, as this may significantly influence treatment decisions. Neurologists play a key role in this assessment, working closely with rheumatologists. Overall, addressing CNS involvement in rheumatic diseases is important for improving patient outcomes and advancing medical knowledge in this complex field. A thorough understanding of the neurologic aspects of rheumatic diseases is essential for optimal patient care, necessitating a multidisciplinary approach to management.

Metabolic Control of Microglia.

Microglia, immune sentinels of the central nervous system (CNS), play a critical role in maintaining its health and integrity. This chapter delves into the concept of immunometabolism, exploring how microglial metabolism shapes their diverse immune functions. It examines the impact of cell metabolism on microglia during various CNS states, including homeostasis, development, aging, and inflammation. Particularly in CNS inflammation, the chapter discusses how metabolic rewiring in microglia can initiate, resolve, or perpetuate inflammatory responses. The potential of targeting microglial metabolism as a therapeutic strategy for chronic CNS disorders with prominent innate immune cell activation is also explored.

Neurosarcoidosis as a rapidly progressive dementia associated with normal pressure hydrocephalus.

Neurosarcoidosis (NS) is a rare subtype of sarcoidosis with a poor prognosis and diverse clinical presentations that often poses a diagnostic and therapeutic challenge. We describe the case of a 53-year-old male with an initial diagnosis of lingual sarcoidosis, who subsequently developed ataxia and rapidly progressive cognitive impairment. A lumbar puncture revealed hypoglycorrhachia, hyperproteinorrachia, lymphocytic pleocytosis, and elevated IL-6 levels (600 pg/ml). Cerebrospinal fluid flow cytometry showed an elevated CD4 lymphocyte concentration and a CD4+/CD8+ ratio of 3.91, indicative of NS. Brain MRI showed hyperintense periventricular and subcortical lesions on FLAIR/T2 resembling progressive multifocal leukoencephalopathy (PML), although negative PCR for JC virus ruled out the differential diagnosis. Following a favorable evolutionary course with corticosteroid pulses, the patient relapsed with normotensive hydrocephalus, treated with immunosuppressants and ventriculoperitoneal shunting with a good response to date. This case underscores the importance of maintaining a high index of suspicion for NS in individuals with sarcoidosis and neurologic symptoms. In these cases, cerebrospinal fluid biomarkers such as IL-6 and CD4+/CD8+ ratio are essential to guide the diagnosis. Furthermore, it highlights that hydrocephalus is a rare complication and requires a multidisciplinary approach, including medical and neurosurgical treatment.

La neurosarcoidosis es un subtipo raro de sarcoidosis con mal pronóstico y diversas presentaciones clínicas que a menudo plantea un reto diagnóstico y terapéutico. Describimos el caso de un varón de 53 años con diagnóstico inicial de sarcoidosis lingual, que posteriormente desarrolló ataxia y deterioro cognitivo de rápida evolución. Una punción lumbar reveló hipoglucorraquia, hiperproteinorraquia, pleocitosis linfocítica y niveles elevados de IL-6 (600 pg/ml). La citometría de flujo del líquido cefalorraquídeo mostró una concentración elevada de linfocitos CD4 y un cociente CD4+/CD8+ de 3.91, indicativo de neurosarcoidosis. La RM cerebral evidenció lesiones hiperintensas periventriculares y subcorticales en FLAIR/T2 que se asemejaban a una leucoencefalopatía multifocal progresiva (LMP), aunque la PCR negativa para el virus JC descartó el diagnóstico diferencial. Tras un curso evolutivo favorable con pulsos de corticoides, el paciente recayó con hidrocefalia normotensiva, tratada con inmunosupresores y derivación ventriculoperitoneal con buena respuesta hasta la fecha. Este caso subraya la importancia de mantener un alto índice de sospecha de neurosarcoidosis en individuos con sarcoidosis y síntomas neurológicos. En estos casos, los biomarcadores del líquido cefalorraquídeo tales como la IL-6 y el cociente CD4+/CD8+ son esenciales para orientar el diagnóstico. Además, destaca que la hidrocefalia es una complicación poco frecuente y requiere un abordaje multidisciplinario, que incluya tratamiento médico y neuroquirúrgico.

Neurologic Manifestations of Rheumatologic Disorders.

OBJECTIVE: This article provides an overview of the neurologic manifestations of sarcoidosis and select rheumatologic disorders. An approach to the assessment and differential diagnosis of characteristic clinical presentations, including meningitis and vasculitis, is also reviewed. A review of treatment options is included as well as discussion of distinct areas of overlap, including rheumatologic disease in the setting of neuromyelitis spectrum disorder and demyelinating disease in the setting of tumor necrosis factor-α inhibitors. LATEST DEVELOPMENTS: An increased understanding of the immune mechanisms involved in sarcoidosis and rheumatologic diseases has resulted in a greater diversity of therapeutic options for their treatment. Evidence directing the treatment of the central nervous system (CNS) manifestations of these same diseases is lacking, with a paucity of controlled trials. ESSENTIAL POINTS: It is important to have a basic knowledge of the common CNS manifestations of rheumatologic diseases and sarcoidosis so that they can be recognized when encountered. In the context of many systemic inflammatory diseases, including systemic lupus erythematosus, IgG4-related disease, and sarcoidosis, CNS disease may be a presenting feature or occur without systemic manifestations of the disease, making familiarity with these diseases even more important.