Neuroinflammation plays a crucial role in traumatic brain injury (TBI), contributing to both damage and recovery, yet no effective therapy exists to mitigate central nervous system (CNS) injury and promote recovery after TBI. In the present study, we found that nasal administration of an anti-CD3 monoclonal antibody ameliorated CNS damage and behavioral deficits in a mouse model of contusional TBI. Nasal anti-CD3 induced a population of interleukin (IL)-10-producing regulatory T cells (T-reg cells) that migrated to the brain and closely contacted microglia. T-reg cells directly reduced chronic microglia inflammation and regulated their phagocytic function in an IL-10-dependent manner. Blocking the IL-10 receptor globally or specifically on microglia in vivo abrogated the beneficial effects of nasal anti-CD3. However, the adoptive transfer of IL-10-producing T-reg cells to TBI-injured mice restored these beneficial effects by enhancing microglial phagocytic capacity and reducing microglia-induced neuroinflammation. These findings suggest that nasal anti-CD3 represents a promising new therapeutic approach for treating TBI and potentially other forms of acute brain injury.

Traumatic brain injury (TBI) remains a leading cause of chronic neurological impairment, yet the cellular mechanisms underlying long-term neurodegeneration in TBI remain incompletely understood. Astrocytes, the most abundant glial cell type, are central to maintaining neuroglial and neurovascular homeostasis. Following TBI, however, astrocytic activation contributes to sustained inflammation and neurotoxicity. In this study, we employed immunohistochemistry and RNA sequencing to longitudinally profile astrocyte morphology and transcriptional states at acute (2 days), subacute (2 weeks), and chronic (1 year) stages after controlled cortical impact in mice. We identified a temporally evolving astrocyte response—beginning with a pro-inflammatory profile acutely, transitioning through a profile suggestive of mixed inflammatory and neurodegenerative signatures subacutely, and culminating in a chronic state marked generally by expression of Alzheimer’s and Parkinson’s disease-associated genes. Notably, a subset of astrocyte-derived progenitor cells also was found up to one-year post-injury, expressing markers associated with neurogenesis. These findings reveal that astrocyte activation is not transient but persists chronically, undergoing a dynamic shift from inflammation to degeneration. The observed parallels between astrocyte states in chronic TBI and neurodegenerative disorders underscore their potential role in post-traumatic cognitive decline and highlight astrocyte-targeted interventions as a promising avenue for therapeutic development. Transcriptomic analysis of astrocytes in the acute, subacute, and chronic phases after traumatic brain injury reveal an evolving dynamic shift from neuroinflammation to neurodegeneration, and to a limited extent, regeneration.

Intracranial subdural empyema is a loculated collection of pus in the subdural space between the dura mater and the arachnoid that can be life-threatening. Here, we present a case of a 22-year-old man hospitalized for management of sepsis due to right orbital cellulitis who experienced sudden-onset right-sided hemiplegia and was found to have a holohemispheric intracranial subdural empyema requiring emergent neurosurgical intervention. Subdural empyemas are commonly caused by maxillofacial infections, including orbital infections. We demonstrate that orbital cellulitis may cause an intracranial subdural empyema that can present with sudden-onset neurological deficits warranting prompt neurosurgical intervention.

Lambl’s excrescences (LEs) are thin, filiform and hypermobile strands that develop at the valvular coaptation sites of the heart. Since first described in 1856 by Vilém Dušan Lambl, there has been an increasing number of reports of central and peripheral emboli arising from cardiac LEs. LEs have been linked to ischemic strokes irrespective of age and comorbidities. We report one of the youngest reported cases in literature of an embolic stroke in a 25-year-old woman caused by a LE. A comprehensive workup was performed that revealed a large aortic valve LE. The patient was discharged on dual anti-platelet therapy with outpatient cardiology follow-up for surveillance echocardiograms. We then surveyed the literature and reviewed case reports and observational studies of LEs linked to systemic emboli. We found that most LEs are present on left-sided high-pressure valves especially the ventricular aspect of the aortic valves and that most reported cases of cerebral embolism had aortic valve LEs. The management of cardioembolic stroke secondary to LEs remains unclear. LEs have not been identified as a definite etiology of cardioembolic strokes warranting the need for large-scale studies to help guide the management of cardiac LEs in the setting of ischemic stroke.

The associations between human concussions and subsequent sequelae of chronic neuropsychiatric and cardiovascular diseases such as hypertension have been reported; however, little is known about the underlying biological processes. We hypothesized that dietary changes, including a high-salt diet, disrupt the bidirectional gut-brain axis, resulting in worsening neuroinflammation and emergence of cardiovascular and behavioural phenotypes in the chronic period after repetitive closed head injury in adolescent mice. Adolescent mice were subjected to three daily closed head injuries, recovered for 12 weeks and then maintained on a high-salt diet or a normal diet for an additional 12 weeks. Experimental endpoints were haemodynamics, behaviour, microglial gene expression (bulk RNA sequencing), brain inflammation (brain tissue quantitative PCR) and microbiome diversity (16S RNA sequencing). High-salt diet did not affect systemic blood pressure or heart rate in sham or injured mice. High-salt diet increased anxiety-like behaviour in injured mice compared to sham mice fed with high-salt diet and injured mice fed with normal diet. Increased anxiety in injured mice that received a high-salt diet was associated with microgliosis and a proinflammatory microglial transcriptomic signature, including upregulation in interferon-gamma, interferon-beta and oxidative stress-related pathways. Accordingly, we found upregulation of tumour necrosis factor-alpha and interferon-gamma mRNA in the brain tissue of high salt diet-fed injured mice. High-salt diet had a larger effect on the gut microbiome composition than repetitive closed head injury. Increases in gut microbes in the families Lachnospiraceae, Erysipelotrichaceae and Clostridiaceae were positively correlated with anxiety-like behaviours. In contrast, Muribaculaceae, Acholeplasmataceae and Lactobacillaceae were negatively correlated with anxiety in injured mice that received a high-salt diet, a time-dependent effect. The findings suggest that high-salt diet, administered after a recovery period, may affect neurologic outcomes following mild repetitive head injury, including the development of anxiety. This effect was linked to microbiome dysregulation and an exacerbation of microglial inflammation, which may be physiological targets to prevent behavioural sequelae in the chronic period after mild repetitive head injury. The data suggest an important contribution of diet in determining long-term outcomes after mild repetitive head injury. Izzy et al. studied the impact of a high-salt diet (HSD) on long-term cardiovascular and neuropsychiatric outcomes after repetitive closed head injury. They identified that a HSD disrupted the gut-brain axis, causing microbiome dysregulation, worsening microglial inflammation and triggering chronic anxiety-like behaviour post-repetitive head injury in adolescent mice. Graphical Abstract

Moyamoya disease (MMD) is a rare occlusive cerebrovascular disease that is characterized by progressive stenosis of the terminal portion of the internal carotid artery and its main branches with compensatory development of dilated and fragile collateral vasculature at the base of the brain. MMD has a bimodal age distribution commonly affecting children and adults, whereas onset in the elderly population is a rare occurrence. Here, we present a case of a 78-year-old patient of Indonesian descent who was incidentally found to have moyamoya arteriopathy after presenting with acute ischemic stroke in the left pons. The patient underwent diagnostic cerebral angiogram that showed right middle cerebral artery stenosis with pathognomonic collateral moyamoya vessels. The patient was discharged on antiplatelet therapy. We report a rare case of an elderly patient with MMD. The role of medical or surgical management in asymptomatic MMD in elderly patients remains largely unknown.

Cerebral venous sinus thrombosis (CVST) is a rare condition that can result in severe neurological complications when left untreated. Disease pathology results from thrombus development within the superficial cortical veins or the dural sinuses. Thrombosis impedes cerebral drainage leading to venous congestion and consequent increase in cerebral pressure, parenchymal damage, and blood-brain barrier disruption. Headache is the most common presenting symptom; other symptoms include focal neurological signs, seizures, papilledema, and altered sensorium. Diagnosis is typically made with visualization of obstructed flow in the cerebral venous system using one of three imaging modalities: computed tomography-venography (CTV), magnetic resonance imaging with venography (MRV), and diagnostic cerebral angiography. First-line therapy for CVST is anticoagulation, and the prognosis is generally favorable with early detection and prompt treatment. In this case report, we discuss a singular case of a patient presenting with loss of consciousness who was found to have CVST and treated with anticoagulation therapy in the setting of an intraparenchymal hemorrhage.

Emerging evidence suggests that dysregulation of neuroinflammation, particularly that orchestrated by microglia, plays a significant role in the pathogenesis of Alzheimer’s disease (AD). Danger signals including dead neurons, dystrophic axons, phosphorylated tau, and amyloid plaques alter the functional phenotype of microglia from a homeostatic (M0) to a neurodegenerative or disease-associated phenotype, which in turn drives neuroinflammation and promotes disease. Thus, therapies that target microglia activation constitute a unique approach for treating AD. Here, we report that nasally administered anti-CD3 monoclonal antibody in the 3xTg AD mouse model reduced microglial activation and improved cognition independent of amyloid beta deposition. In addition, gene expression analysis demonstrated decreased oxidative stress, increased axogenesis and synaptic organization, and metabolic changes in the hippocampus and cortex of nasal anti-CD3 treated animals. The beneficial effect of nasal anti-CD3 was associated with the accumulation of T cells in the brain where they were in close contact with microglial cells. Taken together, our findings identify nasal anti-CD3 as a unique form of immunotherapy to treat Alzheimer’s disease independent of amyloid beta targeting.

The association between myasthenia gravis (MG) and thymomas is well-documented. Thymomas are rare epithelial cell tumors that arise from the thymus gland and occur in the mediastinum. Myasthenia gravis is a neuromuscular disorder that causes skeletal muscle weakness due to the presence of anti-acetylcholinesterase antibodies. Roughly 60% of thymomas are associated with MG, while only 10% of MG patients have thymomas. We present an atypical presentation of myasthenia gravis with an associated unusual metastatic thymoma. This case is of a young, previously healthy 26-year-old male with no previous medical history who presented with non-specific symptoms of fatigue, diarrhea, abdominal pain, back pain, blurry vision, and unintended weight loss. He underwent treatment with intravenous immunoglobulins (IVIG), had two surgical resections of the thymoma, and ultimately received radiotherapy. Based on our experience with this case, diagnosing myasthenia gravis by testing for specific muscle antibodies for patients with ptosis in the setting of non-specific complaints, including fatigue, vomiting, diarrhea, and abdominal or back pain, should be considered. Routine imaging should follow with a chest computed tomography to screen for thymomas if the specific anti-titin and anti-ryanodine receptor (anti-RyR) muscle antibodies are positive and myasthenia gravis is suspected. If a thymoma is confirmed, it is best to confirm; and mass characterizes with chest magnetic resonance imaging. A treatment approach of IVIG followed by surgical resection and possible debulking if the lesion is deemed metastatic could also be considered thereafter, especially in young patients with few comorbidities. Treatment with Pyridostigmine 30 mg twice daily for 25 days post-surgically and radiation for treatment of any remaining unresectable tumor should also be considered.

The neuroimmunology of traumatic brain injury (TBI) has recently gained recognition as a crucial element in the secondary pathophysiological consequences that occur following neurotrauma. Both immune cells residing within the central nervous system (CNS) and those migrating from the periphery play significant roles in the development of secondary brain injury. However, the precise mechanisms governing communication between innate and adaptive immune cells remain incompletely understood, partly due to a limited utilization of relevant experimental models and techniques. Therefore, in this discussion, we outline current methodologies that can aid in the exploration of TBI neuroimmunology, with a particular emphasis on the interactions between resident neuroglial cells and recruited lymphocytes. These techniques encompass adoptive cell transfer, intra-CNS injection(s), selective cellular depletion, genetic manipulation, molecular neuroimaging, as well as in vitro co-culture systems and the utilization of organoid models. By incorporating key elements of both innate and adaptive immunity, these methods facilitate the examination of clinically relevant interactions. In addition to these preclinical approaches, we also detail an emerging avenue of research that seeks to leverage human biofluids. This approach enables the investigation of how resident and infiltrating immune cells modulate neuroglial responses after TBI. Considering the growing significance of neuroinflammation in TBI, the introduction and application of advanced methodologies will be pivotal in advancing translational research in this field.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality. The innate and adaptive immune responses play an important role in the pathogenesis of TBI. Gamma-delta (γδ) T cells have been shown to affect brain immunopathology in multiple different conditions, however, their role in acute and chronic TBI is largely unknown. Here, we show that γδ T cells affect the pathophysiology of TBI as early as one day and up to one year following injury in a mouse model. TCRδ-/- mice are characterized by reduced inflammation in acute TBI and improved neurocognitive functions in chronic TBI. We find that the Vγ1 and Vγ4 γδ T cell subsets play opposing roles in TBI. Vγ4 γδ T cells infiltrate the brain and secrete IFN-γ and IL-17 that activate microglia and induce neuroinflammation. Vγ1 γδ T cells, however, secrete TGF-β that maintains microglial homeostasis and dampens TBI upon infiltrating the brain. These findings provide new insights on the role of different γδ T cell subsets after brain injury and lay down the principles for the development of targeted γδ T-cell-based therapy for TBI.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by a pathologic immune response in the setting of infection, malignancy, acute illness, or any immunological stimulus. Infection is the most common etiology of HLH. HLH involves aberrant activation of lymphocytes and macrophages with resultant hypercytokinemia due to an inappropriately stimulated and ineffective immune response. Here, we present the case of a previously healthy 19-year-old male presenting with hiccups and scleral icterus, who was found to have HLH due to a severe Epstein-Barr virus infection. Despite a morphologically normal bone marrow biopsy, the patient met the diagnostic criteria for HLH, including a low natural killer cell count and elevated soluble interleukin-2 receptor. Notably, ferritin was severely elevated at 85,810 ng/mL. The patient was treated with an induction course of dexamethasone intravenously for eight weeks. Since HLH can progress into multi-organ failure, timely diagnosis and prompt initiation of treatment are critical. Novel disease-modifying therapies and further clinical trials are warranted to treat this potentially fatal immunological disease with multisystem ramifications.

To investigate the effect of decompressive craniectomy on survival in rapidly deteriorating patients with severe cerebral venous sinus thrombosis (CVST).

Abstract Traumatic brain injury (TBI) results in both morbidity and mortality in which both innate and adaptive immune responses play an important role in the pathogenesis of TBI. Nonetheless, the role of gamma-delta (γδ) T cells in acute and chronic TBI is unknown. Here, we show that γδ T cells affect the pathophysiology of TBI as early as one day and up to one year after injury. TCRδ−/− mice exhibited reduced inflammation in acute TBI and improved neurocognitive functions in chronic TBI. We found that Vγ1 and Vγ4 γδ T cell subsets played opposing roles in TBI. Vγ4 γδ T cells infiltrate the brain and secrete IFN-γ and IL-17 that activate microglia and induce neuroinflammation, whereas Vγ1 γδ T cells infiltrate the brain and secrete TGF-β that maintains microglial homeostasis and dampens TBI. These findings provide new insights on the role of different γδ T cell subsets after brain injury and provide novel avenues for the development of targeted γδ T-cell-based therapy for the treatment of TBI.

To examine the association between multisystem morbidities developing after traumatic brain injury (TBI) and the risk of dementia.

The purpose of our study is to investigate the association between comorbidities developing after traumatic brain injury (TBI) and risk of ischemic stroke (IS)

To compare the risk of dementia in young patients with traumatic versus spontaneous intracerebral hemorrhage (ICH).

Myeloid suppressor cells promote tumor growth by a variety of mechanisms which are not fully characterized. We identified myeloid cells (MCs) expressing the latency-associated peptide (LAP) of TGF-beta on their surface and LAP(Hi) MCs that stimulate Foxp3(+) Tregs while inhibiting effector T cell proliferation and function. Blocking TGF-beta inhibits the tolerogenic ability of LAP(Hi) MCs. Furthermore, adoptive transfer of LAP(Hi) MCs promotes Treg accumulation and tumor growth in vivo. Conversely, anti-LAP antibody, which reduces LAP(Hi) MCs, slows cancer progression.. Single-cell RNA-Seq analysis on tumor-derived immune cells reveal LAP(Hi) dominated cell subsets v ! -h distinct immunosuppressive signatures, including those with high levels of MHCII and PD-L1 genes. Analogous to mice, LAP is expressed on myeloid suppressor cells in humans, and these cells are increased in glioma patients. Thus, our results identify a previously unknown function by which LAP(Hi) MCs promote tumor growth and offer therapeutic intervention to target these cells in cancer.