Neuroinflammatory Disorders Research Articles

Tackling Neuroinflammation in Cognitive Disorders with Single-targeted and Multi-targeted Histamine H3 Receptor Modulators.

Neuroinflammation is a process involved in a variety of central nervous system (CNS) diseases and is being increasingly recognized as a key mediator of cognitive impairments. Neuroinflammatory responses including glial activation, increased production of proinflammatory cytokines, and aberrant neuronal signaling, contribute to cognitive dysfunctions. Histamine is a key peripheral inflammatory mediator, but plays an important role in neuroinflammatory processes as well. The unique localization of histamine H3 receptor (H3R) in the CNS along with the modulation of the release of other neurotransmitters via its action on heteroreceptors on non-histaminergic neurons have led to the development of several H3R ligands for various brain diseases. H3R antagonists/ inverse agonists have revealed potential to treat diverse neuroinflammatory CNS disorders, including neurodegenerative diseases, attention-deficit hyperactivity syndrome and schizophrenia. In this mini review, we provide a brief overview on the crucial involvement of the histaminergic transmission in the neuroinflammatory processes underlying these cognitive disorders, with a special focus on H3R involvement. The anti-neuroinflammatory potential of single-targeted and multi-targeted H3R antagonists/inverse agonists for the treatment of these conditions is discussed here.

Microglial and Macrophage Plasticity and Regional Cerebral Blood Flow in the Prenatal Brain and Gut Under Vagus Nerve Stimulation.

An intricate relationship exists between the vagus nerve and systemic immune cell regulation, specifically during fetal development. Little is known about the connection between the vagus nerve and the brain's regional circulatory control. In this chapter, we present a methodology for studying the impact of vagus nerve signaling on these connections in the developing fetus using the sheep model for human fetal physiology. First, we present the protocol to study the connection between the vagus nerve physiology and the regional cerebral blood flow (rCBF). Next, we detail the protocol for measuring how vagal signaling alters microglial cell plasticity in gut and brain. In previous work, our team showed that vagotomy results in amplified redistribution of rCBF toward subcortical structures in the fetal brain. Conversely, efferent VNS reduces rCBF to cortical structures while afferent VNS diminishes the rise of rCBF to subcortical structures (independent of cortical rCBF) when compared to controls in the fetal brain. Additionally, our team showed that Iba-1 expression, a marker for microglial cellular signaling activation, rises in a dose-dependent relationship with systemic inflammatory activation in the setting of vagotomy. The findings support existing preclinical and clinical evidence in adult human physiology that vagotomy is neuroprotective for neurodegenerative diseases such as Parkinson's likely via a glial cell-mediated mechanism. Vagus nerve stimulation (VNS) has also been shown to alter rCBF patterns in adults with treatment-resistant depression, underscoring the importance of further investigation of the relationship between the vagus nerve and rCBF as early as in utero. Together, the body of evidence emphasizes that the vagal pathway is an important player in the programming of microglial cell phenotypes within the developing brain. Further study is needed to better understand the significance of these relationships for the development and treatment of early susceptibility to neuroinflammatory and neurodegenerative disorders in later life. Therefore, we present a methodology for assessing rCBF and morphometric features of microglial and macrophage cell activation to allow future teams to expand on the existing body of work and further examine these relationships at a cellular and systems' levels.

Unraveling neuroprotection with Kv1.3 potassium channel blockade by a scorpion venom peptide

Voltage-gated potassium channels play a crucial role in cellular repolarization and are potential therapeutic targets in neuroinflammatory disorders and neurodegenerative diseases. This study explores Tityus bahiensis scorpion venom for neuroactive peptides. We identified the αKtx12 peptide as a potent neuroprotective agent. In SH-SY5Y cells, αKtx12 significantly enhances viability, validating its pharmacological potential. And in the animal model, we elucidate central nervous system (CNS) mechanism of αKtx12 through neuroproteomic analyses highlighting αKtx12 as a valuable tool for characterizing neuroplasticity and neurotropism, revealing its ability to elicit more physiological responses. The peptide’s potential to promote cell proliferation and neuroprotection suggests a role in functional recovery from nervous system injury or disease. This research unveils the neuroactive potential of scorpion venom-derived αKtx12’s, offering insights into its pharmacological utility. The peptide’s impact on neuronal processes suggests a promising avenue for therapeutic development, particularly in neurodegenerative conditions.

PU-H71 (NSC 750424): a molecular masterpiece that targets HSP90 in cancer and beyond.

Heat shock protein 90 (HSP90) is a pivotal molecular chaperone with multifaceted roles in cellular health and disease. Herein, we explore how HSP90 orchestrates cellular stress responses, particularly through its partnership with heat shock factor 1 (HSF-1). PU-H71, a selective inhibitor of HSP90, demonstrates significant potential in cancer therapy by targeting a wide array of oncogenic pathways. By inducing the degradation of multiple client proteins, PU-H71 disrupts critical signaling pathways such as MAPK, PI3K/Akt, JAK/STAT, EGFR, and mTOR, which are essential for cancer cell survival, proliferation, and metastasis. We examined its impact on combating triple-negative breast cancer and enhancing the effectiveness of carbon-ion beam therapy, offering new avenues for cancer treatment. Furthermore, the dual inhibition of HSP90A and HSP90B1 by PU-H71 proves highly effective in the context of myeloma, providing fresh hope for patients with this challenging malignancy. We delve into its potential to induce apoptosis in B-cell lymphomas that rely on Bcl6 for survival, highlighting its relevance in the realm of hematologic cancers. Shifting our focus to hepatocellular carcinoma, we explore innovative approaches to chemotherapy. Moreover, the current review elucidates the potential capacity of PU-H71 to suppress glial cell activation paving the way for developing novel therapeutic strategies for neuroinflammatory disorders. Additionally, the present report also suggests the promising role of PU-H71 in JAK2-dependent myeloproliferative neoplasms. Eventually, our report sheds more light on the multiple functions of HSP90 protein as well as the potential therapeutic benefit of its selective inhibitor PU-H71 in the context of an array of diseases, laying the foundations for the development of novel therapeutic approaches that could achieve better treatment outcomes.

Border-Associated Macrophages: From Embryogenesis to Immune Regulation.

Border-associated macrophages (BAMs) play a pivotal role in maintaining brain homeostasis and responding to pathological conditions. Understanding their origins, characteristics, and roles in both healthy and diseased brains is crucial for advancing our knowledge of neuroinflammatory and neurodegenerative diseases. This review addresses the ontogeny, replenishment, microenvironmental regulation, and transcriptomic heterogeneity of BAMs, highlighting recent advancements in lineage tracing and fate-mapping studies. Furthermore, we examine the roles of BAMs in maintaining brain homeostasis, immune surveillance, and responses to injury and neurodegenerative diseases. Further research is crucial to clarify the dynamic interplay between BAMs and the brain's microenvironment in health and disease. This effort will not only resolve existing controversies but also reveal new therapeutic targets for neuroinflammatory and neurodegenerative disorders, pushing the boundaries of neuroscience.

An initial investigation of transcutaneous delivery of plasmid DNA encoding interleukin-10 for the treatment of psoriatic skin conditions

Psoriasis is a chronic immune-mediated skin disorder characterized by intense local inflammation, epidermal hyperplasia, and leukocyte infiltration. Current treatment approaches for psoriasis aim to alleviate symptoms and prevent disease progression, including systemically administered drugs with whole body side effects. Despite some advances in psoriasis treatment, success has been quite limited. To begin to address this challenge, we undertook an initial investigation of whether transcutaneous delivery of an endogenous anti-inflammatory cytokine could provide an effective, local treatment of psoriatic-like skin conditions. To do this, we utilized a previously documented rodent model of psoriasis, induced via a single topical application of Imiquimod (IMQ) to the shaved back of rats. The therapeutic approach used for this initial investigation was delivery of plasmid DNA encoding rat interleukin-10 (pDNA-rIL10), a non-viral gene therapy approach previously shown to be effective in suppressing neuroinflammatory disorders after localized delivery either intracerebrally or intrathecally. Translation of this CNS therapeutic for use in psoriatic-like skin disorders required reformulation to enable transcutaneous delivery. Toward that end, pDNA-rIL10 was topically applied in Lipoderm HMW, a base explicitly designed to deliver higher molecular weight compounds into skin. Here we show that a single topical application of pDNA-rIL10 in Lipoderm HMW was effective in decreasing mRNA levels of pro-inflammatory cytokines as well as reducing the recruitment of T-cells to IMQ-treated skin. Furthermore, this transcutaneous IL-10 gene therapy decreased signs of skin inflammation, reflected by reduced erythema. Moreover, the results provide an initial indication that IL10 may stimulate hair regrowth in psoriatic-like skin.

Clinical Applications of Micro/Nanobubble Technology in Neurological Diseases.

Nanomedicine, leveraging the unique properties of nanoparticles, has revolutionized the diagnosis and treatment of neurological diseases. Among various nanotechnological advancements, ultrasound-mediated drug delivery using micro- and nanobubbles offers promising solutions to overcome the blood-brain barrier (BBB), enhancing the precision and efficacy of therapeutic interventions. This review explores the principles, current clinical applications, challenges, and future directions of ultrasound-mediated drug delivery systems in treating stroke, brain tumors, neurodegenerative diseases, and neuroinflammatory disorders. Additionally, ongoing clinical trials and potential advancements in this field are discussed, providing a comprehensive overview of the impact of nanomedicine on neurological diseases.

Is vagus nerve-mediated regulation of immunity an etiological target for therapeutic intervention in endometriosis?

Endometriosis is a complex chronic neuro-inflammatory disorder, affecting roughly 10% of reproductive-age women. It is characterized by the presence of endometrial-like tissue outside the uterus, which induces a chronic inflammatory reaction. This disease can present a wide range of symptoms, including chronic pain and infertility. Despite extensive research, the exact pathogenesis of endometriosis remains incompletely understood. New strategies and paradigms on pathogenesis and treatment are needed. Schematic factors contributing to the development of endometriosis lesions include genetic, hormonal, and immunological factors. Although genetics may contribute to the epidemiologically suggested heritability of endometriosis, epigenetics has gained an increasing consideration in research. Remarkably, microbiota dysbiosis, acting as a catalyst for the main acknowledged epigenetic etiologies (locally produced estradiol, pro-inflammatory cytokines, and hypoxic stress) demands further attention. Indeed, over the past 10 years, it has become clear that the vagus nerve, the fastest component of the microbiota-gut-brain axis, can efficiently control inflammation through the cholinergic anti-inflammatory pathway. Therefore, stimulation of the vagus nerve could be a good candidate for modulating the severity of endometriosis. The detrimental consequences of microbiome dysbiosis and the estrobolome activity on the initiation of the disease as well as counterpart dysfunctions in the central nervous system will be focused on, both supporting a key role of the vagus nerve since the early stage of endometriosis. Consequently, the rationale for using non-invasive vagus nerve stimulation will be discussed, introducing a fruitful shift of paradigm in this still enigmatic disease.

Human Umbilical Cord-Mesenchymal Stem Cells Promote Extracellular Matrix Remodeling in Microglia.

Human mesenchymal stem cells modulate the immune response and are good candidates for cell therapy in neuroinflammatory brain disorders affecting both adult and premature infants. Recent evidence indicates that through their secretome, mesenchymal stem cells direct microglia, brain-resident immune cells, toward pro-regenerative functions, but the mechanisms underlying microglial phenotypic transition are still under investigation. Using an in vitro coculture approach combined with transcriptomic analysis, we identified the extracellular matrix as the most relevant pathway altered by the human mesenchymal stem cell secretome in the response of microglia to inflammatory cytokines. We confirmed extracellular matrix remodeling in microglia exposed to the mesenchymal stem cell secretome via immunofluorescence analysis of the matrix component fibronectin and the extracellular crosslinking enzyme transglutaminase-2. Furthermore, an analysis of hallmark microglial functions revealed that changes in the extracellular matrix enhance ruffle formation by microglia and cell motility. These findings point to extracellular matrix changes, associated plasma membrane remodeling, and enhanced microglial migration as novel mechanisms by which mesenchymal stem cells contribute to the pro-regenerative microglial transition.

Genetic analysis of the X-linked Adrenoleukodystrophy ABCD1 gene in Drosophila uncovers a role in Peroxisomal dynamics.

X-linked adrenoleukodystrophy (X-ALD) is a progressive neurodegenerative disorder caused by a loss-of-function (LOF) mutation in the ATP-binding cassette subfamily D member 1 (ABCD1) gene, leading to the accumulation of very long-chain fatty acids (VLCFAs). This disorder exhibits striking heterogeneity; some male patients develop an early childhood neuroinflammatory demyelination disorder, while other patients, including adult males and most affected female carriers, experience a chronic progressive myelopathy. Adrenocortical failure is observed in almost all male patients, with age of onset varying sometimes being the first diagnostic finding. The gene underlying this spectrum of disease encodes an ATP-binding cassette (ABC) transporter that localizes to peroxisomes and facilitates VLCFA transport. X-ALD is considered a single peroxisomal component defect and does not play a direct role in peroxisome assembly. Drosophila models of other peroxisomal genes have provided mechanistic insight into some of the neurodegenerative mechanisms with reduced lifespan, retinal degeneration, and VLCFA accumulation. Here, we perform a genetic analysis of the fly ABCD1 ortholog Abcd1 (CG2316). Knockdown or deficiency of Abcd1 leads to VLCFA accumulation, salivary gland defects, locomotor impairment and retinal lipid abnormalities. Interestingly, there is also evidence of reduced peroxisomal numbers. Flies overexpressing the human cDNA for ABCD1 display a wing crumpling phenotype characteristic of the pex2 loss-of-function. Surprisingly, overexpression of human ABCD1 appears to inhibit or overwhelm peroxisomal biogenesis to levels similar to null mutations in fly pex2, pex16 and pex3. Drosophila Abcd1 is therefore implicated in peroxisomal number, and overexpression of the human ABCD1 gene acts a potent inhibitor of peroxisomal biogenesis in flies.

Cerebral Cortical Encephalitis and Other Meningocortical Manifestations of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease in Children: Case Series and Review of the Literature.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease is a neuroinflammatory disorder (MOGAD) with heterogeneous phenotype including paroxysms of optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, brainstem demyelination, and encephalitis. Fluid-attenuated inversion recovery hyperintense cortical lesions in MOG-associated encephalitis with seizures, or FLAMES, is a manifestation of cerebral cortical encephalitis seen less frequently than other typical MOG antibody-associated disease presentations. Cases of FLAMES are rarer in children, and frequently initially misdiagnosed with infectious meningoencephalitis. Other meningocortical manifestations of MOG antibody-associated disease have been described and likely exist along a continuum. In this retrospective single-center case series, we describe the demographic, clinical, radiographic, laboratory, and electroencephalographic features of 5 children with clinicoradiographic features consistent with the spectrum of MOG-IgG-positive meningocortical syndromes.

Esketamine improves cognitive function in sepsis-associated encephalopathy by inhibiting microglia-mediated neuroinflammation

Microglia-mediated neuroinflammation is critical in the pathogenesis of sepsis-associated encephalopathy(SAE). Identifying the key factors that inhibit microglia-mediated neuroinflammation holds promise as a potential target for preventing and treating SAE. Esketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been proposed to possess protective and therapeutic properties against neuroinflammatory disorders. This study provides evidence that the administration of Esketamine in SAE mice improves cognitive impairments and alleviates neuronal damage by inhibiting the microglia-mediated neuroinflammation. The BDNF receptor antagonist K252a was employed in both vivo and in vitro experiments. The findings indicate that K252a successfully counteracted the beneficial effects of Esketamine on microglia and cognitive behavior in mice with SAE. Consequently, these results suggest that Esketamine inhibits microglia-mediated neuroinflammation by activating the BDNF pathway, and mitigating neuronal damage and cognitive dysfunction associated with SAE.

Neuroinflammatory Disorders of the Central Nervous System Associated with Monkeypox Virus Infection: A Systematic Review and Call to Action.

The Monkeypox virus, a zoonotic pathogen of the Orthopoxvirus genus, has shown a marked global spread, resulting in cases of neuroinflammatory disorders. This systematic review aims to summarize the central nervous system manifestations linked to monkeypox virus infection. We conducted a systematic review according to PRISMA guidelines. Databases such as PubMed, EMBASE, Cochrane Library, and Web of Science were searched up to September 2024. Inclusion criteria focused on monkeypox virus-positive patients with confirmed central nervous system inflammatory disorders, including encephalitis, meningitis, myelitis, and related neuroimmune diseases. From 770 screened articles, 38 studies were included. Of the 20 reported monkeypox virus-infected cases with central nervous system involvement, the most common manifestations were encephalitis (40%), encephalomyelitis (30%), and meningoencephalitis (10%). Additional rarer presentations included Guillain-Barré syndrome (5%) and transverse myelitis (5%). The mean age of affected individuals was 27.9±13.69 years, and 75% were male. Fever, fatigue, and myalgia were the predominant systemic symptoms, with neurological complications often appearing within 4.6±2.5 days post-infection. Diagnoses were confirmed by quantitative reverse transcription polymerase chain reaction, magnetic resonance imaging, and cerebrospinal fluid analysis. Treatment strategies varied, with antivirals (e.g., tecovirimat) and immunomodulatory therapies (e.g., methylprednisolone, immunoglobulins, and rituximab) utilized. Monkeypox virus infection is associated with severe neuroinflammatory disorders, with varying outcomes from complete recovery to mortality. Increased awareness, comprehensive diagnostic approaches, and targeted therapeutic interventions are critical in managing these cases. Further research is required to elucidate the mechanisms of neuroinflammation in the monkeypox virus and establish standardized treatment protocols.

AN OVERLAP OF GUILLAIN-BARRÉ SYNDROME, MILLER-FISHER SYNDROME, AND BICKERSTAFF BRAINSTEM ENCEPHALITIS PRESENTING AS CLINICAL BRAIN DEATH, A CASE SERIES

Guillain-Barré Syndrome (GBS), Miller-Fisher Syndrome (MFS), and Bickerstaff Brainstem Encephalitis (BBE) are neuroinflammatory disorders that share common immunopathogenic mechanisms. Although overlapping presentations of these conditions are rare, they pose significant diagnostic challenges, especially when mimicking clinical brain death. Objective: To present a case series of three patients who demonstrated an overlap of GBS, MFS, and BBE, with all patients exhibiting profound neurological impairments, including clinical signs of brain death. Methods: A retrospective review of three cases admitted to the ICU over the last three years was conducted. Detailed clinical profiles, cerebrospinal fluid (CSF) analysis, nerve conduction studies (NCS), and electromyography (EMG) results were reviewed. All patients were treated with intravenous immunoglobulins (IVIG) and therapeutic plasma exchange (TPE). Results: All three patients had a history of preceding infections and were presented with ophthalmoplegia, ataxia, and altered levels of consciousness, progressing to coma. CSF analysis revealed albuminocytological dissociation, and NCS/EMG indicated severe polyneuropathy. Two patients responded positively to IVIG and plasmapheresis, showing significant neurological recovery, while the third patient demonstrated a delayed but spontaneous recovery. All patients eventually achieved full or near-full neurological recovery. Conclusions: This case series highlights the clinical continuum and diagnostic complexity of overlapping GBS, MFS, and BBE, particularly in presentations mimicking brain death. Early recognition and prompt immunomodulatory therapy are crucial in improving patient outcomes, even in cases with severe neurological deficits. Further research is warranted to elucidate pathophysiology and optimize treatment strategies for overlapping neuroinflammatory syndromes.

Unveiling citicoline's mechanisms and clinical relevance in the treatment of neuroinflammatory disorders.

Citicoline, a compound produced naturally in small amounts in the human body, assumes a pivotal role in phosphatidylcholine synthesis, a dynamic constituent of membranes of neurons. Across diverse models of brain injury and neurodegeneration, citicoline has demonstrated its potential through neuroprotective and anti-inflammatory effects. This review aims to elucidate citicoline's anti-inflammatory mechanism and its clinical implications in conditions such as ischemic stroke, head trauma, glaucoma, and age-associated memory impairment. Citicoline's anti-inflammatory prowess is rooted in its ability to stabilize cellular membranes, thereby curbing the excessive release of glutamate-a pro-inflammatory neurotransmitter. Moreover, it actively diminishes free radicals and inflammatory cytokines productions, which could otherwise harm neurons and incite neuroinflammation. It also exhibits the potential to modulate microglia activity, the brain's resident immune cells, and hinder the activation of NF-κB, a transcription factor governing inflammatory genes. Clinical trials have subjected citicoline to rigorous scrutiny in patients grappling with acute ischemic stroke, head trauma, glaucoma, and age-related memory impairment. While findings from these trials are mixed, numerous studies suggest that citicoline could confer improvements in neurological function, disability reduction, expedited recovery, and cognitive decline prevention within these cohorts. Additionally, citicoline boasts a favorable safety profile and high tolerability. In summary, citicoline stands as a promising agent, wielding both neuroprotective and anti-inflammatory potential across a spectrum of neurological conditions. However, further research is imperative to delineate the optimal dosage, treatment duration, and underlying mechanisms. Moreover, identifying specific patient subgroups most likely to reap the benefits of citicoline as a new therapy remains a critical avenue for exploration.

Erdheim-Chester Disease Masquerading as CLIPPERS.

To present 4 patients with Erdheim-Chester disease (ECD) based on clinical, radiologic, histopathologic, and molecular genetic findings who had enhancing brainstem lesions and were initially believed to have chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Case series. Although patients with ECD can demonstrate clinical and imaging features similar to CLIPPERS, refractoriness to corticosteroids, lack of fulfillment of specific MRI criteria (i.e., enhancing lesions >3 mm, T2 abnormalities that exceed areas of T1 postgadolinium enhancement), and systemic findings such as "hairy kidney" appearance and metadiaphyseal osteosclerosis on 18F-fluorodeoxyglucose PET-CT help discriminate it from CLIPPERS. ECD is a histiocytic neoplasm characterized by multiorgan infiltration of clonal histiocytes carrying activating variants of the MAPK-ERK pathway. Neurologic involvement occurs in up to 40% of ECD with frequent brainstem lesions that can mimic acquired neuroinflammatory disorders, such as CLIPPERS. ECD is an important CLIPPERS mimic with distinct pathophysiology and targeted treatments. We highlight the need to consider histiocytic disorders among other alternate diagnoses when findings are not classic for CLIPPERS.

IRF3 regulates neuroinflammatory responses and the expression of genes associated with Alzheimer’s disease

The pathological role of interferon signaling is emerging in neuroinflammatory disorders, yet, the specific role of Interferon Regulatory Factor 3 (IRF3) in neuroinflammation remains poorly understood. Here, we show that global IRF3 deficiency delays TLR4-mediated signaling in microglia and attenuates the hallmark features of LPS-induced inflammation such as cytokine release, microglial reactivity, astrocyte activation, myeloid cell infiltration, and inflammasome activation. Moreover, expression of a constitutively active IRF3 (S388D/S390D: IRF3-2D) in microglia induces a transcriptional program reminiscent of the Activated Response Microglia and the expression of genes associated with Alzheimer’s disease, notably apolipoprotein-e. Using bulk-RNAseq of IRF3-2D brain myeloid cells, we identified Z-DNA binding protein-1 (ZBP1) as a target of IRF3 that is relevant across various neuroinflammatory disorders. Lastly, we show IRF3 phosphorylation and IRF3-dependent ZBP1 induction in response to Aβ in primary microglia cultures. Together, our results identify IRF3 as an important regulator of LPS and Aβ -mediated neuroinflammatory responses and highlight IRF3 as a central regulator of disease-specific gene activation in different neuroinflammatory diseases.

Hyperreflective choroidal foci in diabetic eyes with and without macular edema: Novel insights on diabetic choroidopathy

Histopathologic studies of diabetic choroid suggest that diabetic choroidopathy is a key aspect secondary to diabetes. Recently, hyperreflective choroidal foci (HCF) have been introduced as novel optical coherence tomography (OCT) parameter. The aim of this study was to identify and quantify HCF in diabetic subjects with retinopathy, with or without diabetic macular edema (DME). Eighty-five diabetic subjects with different degrees of DR were enrolled: 37 without DME and 48 with DME. All subjects underwent full ophthalmologic examination including spectral domain optical coherence tomography (OCT). OCT images were analyzed to quantify and localize HCF. Each image was analyzed by two independent, masked examiners. OCT images showed that all subjects (100%) had HCF in the different layers of the choroid. The number of HCF was significantly higher in diabetics with DME versus those without DME (p < 0.0001). HCF showed variable size, shape and location inside the choroid. They were mainly located in choriocapillaris and Sattler's layer, on the edges of blood vessels. The intraobserver and interobserver agreement was almost perfect (ICC >0.9). This study suggests that hyperreflective foci in the choroid of subjects with DR may be accurately identified with structural OCT. Their number significantly increases with the progression of DME. These HCF may represent, as in the retina, a sign of infiltration of inflammatory cells (mainly migrating microglia) into the choroid, according to the hypothesis raised by Jerry Lutty. HCF may confirm in vivo the histopathologic findings suggesting that diabetic choroidopathy may be primarily a neuroinflammatory disorder.

Ex-Vivo 13C NMR Spectroscopy of Rodent Brain: TNF Restricts Neuronal Utilization of Astrocyte-Derived Metabolites.

Tumor necrosis factor (TNF) has well-established roles in neuroinflammatory disorders, but the effect of TNF on the biochemistry of brain cells remains poorly understood. Here, we microinjected TNF into the brain to study its impact on glial and neuronal metabolism (glycolysis, pentose phosphate pathway, citric acid cycle, pyruvate dehydrogenase, and pyruvate carboxylase pathways) using 13C NMR spectroscopy on brain extracts following intravenous [1,2-13C]-glucose (to probe glia and neuron metabolism), [2-13C]-acetate (probing astrocyte-specific metabolites), or [3-13C]-lactate. An increase in [4,5-13C]-glutamine and [2,3-13C]-lactate coupled with a decrease in [4,5-13C]-glutamate was observed in the [1,2-13C]-glucose-infused animals treated with TNF. As glutamine is produced from glutamate by astrocyte-specific glutamine synthetase the increase in [4,5-13C]-glutamine reflects increased production of glutamine by astrocytes. This was confirmed by infusion with astrocyte substrate [2-13C]-acetate. As lactate is metabolized in the brain to produce glutamate, the simultaneous increase in [2,3-13C]-lactate and decrease in [4,5-13C]-glutamate suggests decreased lactate utilization, which was confirmed using [3-13C]-lactate as a metabolic precursor. These results suggest that TNF rearranges the metabolic network, disrupting the energy supply chain perturbing the glutamine-glutamate shuttle between astrocytes and the neurons. These insights pave the way for developing astrocyte-targeted therapeutic strategies aimed at modulating effects of TNF to restore metabolic homeostasis in neuroinflammatory disorders.

Development of Autoimmune Diseases Among Children With Pediatric Acute-Onset Neuropsychiatric Syndrome

Epidemiologic studies indicate a high rate of autoimmune conditions among patients with obsessive-complusive disorder and other psychiatric conditions. Furthering the understanding of the inflammatory diatheses of psychiatric conditions may open doors to new treatment paradigms for psychiatric disorders. To evaluate whether pediatric acute-onset neuropsychiatric syndrome (PANS) is associated with an inflammatory diathesis by assessing signs of immune activation and vasculopathy during a psychiatric symptom exacerbation (flare), estimating the risk of developing arthritis and other autoimmune diseases, and characterizing subtypes of arthritis. This retrospective cohort study used longitudinal clinical data on 193 consecutive patients with PANS followed up within the Stanford Immune Behavioral Health Clinic from September 1, 2012, to December 31, 2021. Medical records were reviewed, and a predefined set of immune markers that were measured during a flare and the features and imaging findings of arthritis and other autoimmune diseases were collected. Immune activation markers included (1) autoimmunity signs (antinuclear antibody, antihistone antibody, antithyroglobulin antibody, C1q binding assay, and complement levels [C3 and C4]); (2) immune dysregulation or inflammation signs (leukopenia, thrombocytosis, C-reactive protein, and erythrocyte sedimentation rate); and (3) vasculopathy signs (livedo reticularis, periungual redness and swelling, abnormally prominent onychodermal band, palatal petechiae, high von Willebrand factor antigen, and high d-dimer). Last, the cumulative risk of developing arthritis and autoimmune diseases was estimated using product limit (Kaplan-Meier) survival probability. The study included data from 193 children (112 boys [58.0%]) who had PANS at a mean (SD) age of 7.5 (3.5) years. They were followed up for a mean (SD) of 4.0 (2.1) years. Among those tested for immune activation markers, 54.2% (97 of 179) had nonspecific markers of autoimmunity, 12.0% (22 of 184) had nonspecific signs of immune dysregulation or inflammation, and 35.8% (69 of 193) had signs of vasculopathy. By 14 years of age, the estimated cumulative incidence of arthritis was 28.3% (95% CI, 20.8%-36.3%), and the estimated cumulative incidence of another autoimmune disease was 7.5% (95% CI, 4.0%-12.4%). Novel findings in the subgroup with arthritis include joint capsule thickening (55.0% [22 of 40]), distal interphalangeal joint tenderness (81.8% [45 of 55]), and spinous process tenderness (80.0% [44 of 55]). Among the 55 patients with arthritis, the most common subtypes of arthritis included enthesitis-related arthritis (37 [67.3%]), spondyloarthritis (27 [49.1%]), and psoriatic arthritis (10 [18.2%]). This study found that patients with PANS show signs of immune activation and vasculopathy during psychiatric symptom flares and have an increased risk of developing arthritis and other autoimmune diseases compared with the general pediatric population. The most common arthritis subtype was enthesitis-related arthritis. These findings suggest that PANS may be part of a multisystem inflammatory condition rather than an isolated psychiatric or neuroinflammatory disorder.