Toxoplasma gondii Infection of Alzheimer's Disease Mice Reduces Brain Amyloid Density Globally and Regionally.

BACKGROUND: Toxoplasma gondii infection of Alzheimer's disease model mice decreases amyloid ß plaques. We aimed to determine if there is a brain regional difference in amyloid ß reduction in the brains of T. gondii-infected compared to control mice. METHOD: Three-month-old 5xFAD (AD model) mice were injected with T. gondii or with phosphate-buffered saline as a control. Intact brains were harvested at 6 weeks postinfection, optically cleared using iDISCO+, and brain-wide amyloid burden was visualized using volumetric light-sheet imaging. Amyloid signal was quantified across each brain and computationally mapped to the Allen Institute Brain Reference Atlas to determine amyloid density in each region. RESULTS: A brain-wide analysis of amyloid in control and T. gondii-infected 5xFAD mice revealed that T. gondii infection decreased amyloid burden in the brain globally as well as in the cortex and hippocampus, and many daughter regions. Daughter regions that showed reduced amyloid burden included the prelimbic cortex, visual cortex, and retrosplenial cortex. The olfactory tubercle, a region known to have increased monocytes following T. gondii infection, also showed reduced amyloid after infection. CONCLUSIONS: T. gondii infection of AD mice reduces amyloid burden in a brain region-specific manner that overlaps with known regions of T. gondii infection and peripheral immune cell infiltration.

Association Between Clinical Severity, Neuroimaging, and Electroencephalographic Findings in Children with Subacute Sclerosing Panencephalitis.

BACKGROUND: Children diagnosed with subacute sclerosing panencephalitis (SSPE) display a range of neuroimaging abnormalities during different stages of the disease, but their exact clinical significance remains unclear. METHODS: In this retrospective cohort study, our objective was to examine magnetic resonance imaging (MRI) abnormalities in the brains of patients aged 18 years or younger with subacute sclerosing panencephalitis. We aimed to correlate these MRI abnormalities with clinical severity, sociodemographic variables, electroencephalographic (EEG) abnormalities, and cerebrospinal anti-measles antibody titers. RESULTS: The study included 112 cases of subacute sclerosing panencephalitis (mean age at onset: 8.9 ± 2.6 years). MRI analysis at the time of presentation revealed the following abnormalities: subcortical white matter signal changes (n = 95), periventricular white matter signal changes (n = 76), splenium of corpus callosum involvement (n = 39), diffuse corpus callosum involvement (n = 27), cerebral atrophy (n = 35), basal ganglia involvement (n = 10), and brain stem involvement (n = 2). Notably, subcortical white matter involvement, periventricular white matter involvement, diffuse corpus callosum involvement, and basal ganglia involvement were more prevalent in patients with stage III and IV subacute sclerosing panencephalitis (P < .05 for all). Cerebral atrophy was also significantly more common in patients with stage III compared to those with stage IV subacute sclerosing panencephalitis (P < .0001). However, no substantial positive or negative associations were found between MRI findings and EEG abnormalities, other sociodemographic/clinical variables, and cerebrospinal fluid measles-specific antibody titers (P > .05). CONCLUSION: Early in the disease progression of subacute sclerosing panencephalitis, the temporoparietal and parietooccipital regions of the subcortical white matter are affected. Neuroimaging abnormalities exhibit a stronger association with Jabbour's clinical staging, but do not show significant associations with other clinical, sociodemographic, and EEG features.

Clinical Management and Neurosurgical Approach of Pott's Puffy Tumor: A Case Report.

Pott's puffy tumors are assumed to be infrequent concomitant intra- and extracranial abscesses, mainly secondary to complicated frontal sinusitis during infancy. Due to the close proximity to the superior sagittal sinus, there is a risk of developing venous infections, thrombosis, and morbidity. In this case report, we present a case of an 11-year-old girl who presented with headache and face edema. After recognizing the Pott's puffy tumor pattern on the CT scan and brain MRI, the neurosurgical approach involved pus evacuation and frontal sinus blockage, and the patient received antibiotic therapy and was evaluated for total recovery. To our knowledge, the prompt diagnosis and treatment of such conditions are paramount to avoid complications, and differential diagnosis should be encouraged in medical practice.

3D Spheroid and Organoid Models to Study Neuroinfection of RNA Viruses.

Three-dimensional culture models of the brain enable the study of neuroinfection in the context of a complex interconnected cell matrix. Depending on the differentiation status of the neural cells, two models exist: 3D spheroids also called neurospheres and cerebral organoids. Here, we describe the preparation of 3D spheroids and cerebral organoids and give an outlook on their usage to study Rift Valley fever virus and other neurotropic viruses.

The rapidly progressing and fatal outcome of rhombencephalitis by listeriosis in a 61-year-old male.

Listeria monocytogenes is a Gram-positive facultative anaerobic bacterium that is ubiquitous in the environment and can cause severe infections in immunocompromised individuals, pregnant women, and newborns. Listeriosis can manifest as meningitis, encephalitis, or sepsis, and its diagnosis requires a high index of suspicion. The case is reported of a rare presentation of rhombencephalitis by listeriosis in a 61-year-old male who initially suffered from subacute gastric disturbances and fever. Neurological consultation showed abnormal functions of cranial nerves and meningeal signs were observed. MRI revealed a poorly demarcated focus of approximately 45 × 16 × 15mm, indicating possible inflammatory processes, necessitating a lumbar puncture. Assessment of the CSF indicated infection with the bacterium- Listeria Monocytogenes, with the final diagnosis of Listeriosis encephalitis. Despite antibiotic therapy of Ceftazidine and Ampicillin, the patient's condition deteriorated, followed by death.

Long-term neurological and neurocognitive impairments after tick-borne encephalitis in Lithuania - a prospective study.

BACKGROUND: The aim of this study was to characterise long-term neurological and neurocognitive sequelae after tick-borne encephalitis (TBE) in adults. METHODS: 98 prospective consecutive TBE patients, classified by disease severity, were included. Immediate outcomes were evaluated with Glasgow Outcome Scale (GOS) and Rankin Scale (RS). After 6 and 18 months, long-term disability was evaluated using Modified Rankin Scale (MRS) and neurocognitive assessment was performed with Matrics Consensus Cognitive Battery (MCCB), measuring processing speed, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving and social cognition. The MCCB results were compared to healthy age, gender and education-matched controls. RESULTS: Mild, moderate, and severe TBE was diagnosed in 53.1%, 38.8%, and 8.2% of cases, respectively. At discharge, 25.5% of the patients had major or moderate impairments (GOS) and various levels of disability in 34.7% (RS). Up to 18 months from the onset of TBE, over 20% remained with slight to moderate disability (MRS). GOS, RS and MRS scores correlated with disease severity. At 6 months after the onset, TBE patients scored significantly lower than controls in processing speed, verbal, and visual learning. Two latter domains were significantly more impaired in patients with mild TBE. Patients aged 18-39 performed significantly worse in attention/vigilance and working memory, whereas aged 60+ in verbal learning. A year later, significant improvement was observed in six of seven cognitive domains. CONCLUSIONS: Long-term neurological sequelae persist in a substantial proportion of TBE patients with significant impairment in several cognitive domains, especially in younger patients and even after mild TBE.

Herpes simplex virus type 1 modifies the protein composition of extracellular vesicles to promote neurite outgrowth and neuroinfection.

The highly prevalent herpes simplex virus type 1 (HSV-1) causes a range of diseases, including cold sores, blinding keratitis, and life-threatening encephalitis. HSV-1 initially replicates in epithelial cells, enters the peripheral nervous system via neurites, and establishes lifelong infection in the neuronal cell bodies. Neurites are highly dynamic structures that grow or retract in response to attractive or repulsive cues, respectively. Here, we show that infection with HSV-1, but not with a mutant virus lacking glycoprotein G (gG), reduced the repulsive effect of epithelial cells on neurite outgrowth and facilitated HSV-1 invasion of neurons. HSV-1 gG was required and sufficient to induce neurite outgrowth by modifying the protein composition of extracellular vesicles, increasing the amount of neurotrophic and neuroprotective proteins, including galectin-1. Antibodies directed against galectin-1 neutralized the capacity of extracellular vesicles released from HSV-1-infected cells to promote neurite outgrowth. Our study provides new insights into the neurotropism of HSV-1 and identifies a viral protein that modifies the protein composition of extracellular vesicles to stimulate neurite outgrowth and invasion of the nervous system.IMPORTANCEHerpes simplex virus type 1 (HSV-1) must infect neurites (or nerve endings) to establish a chronic infection in neurons. Neurites are highly dynamic structures that retract or grow in the presence of repulsive or attractive proteins. Some of these proteins are released by epithelial cells in extracellular vesicles and act upon interaction with their receptor present on neurites. We show here that HSV-1 infection of epithelial cells modulated their effect on neurites, increasing neurite growth. Mechanistically, HSV-1 glycoprotein G (gG) modifies the protein composition of extracellular vesicles released by epithelial cells, increasing the amount of attractive proteins that enhance neurite outgrowth and facilitate neuronal infection. These results could inform of therapeutic strategies to block HSV-1 induction of neurite outgrowth and, thereby, neuronal infection.

Kocuria kristinae neuroinfection in an immunocompetent patient: a case report and review of the literature.

Few cases of disease by Kocuria kristinae have been reported, some in immunocompetent patients but mainly in immunocompromised. The current case report describes a 28-year-old female with an initial diagnosis of pituitary macroadenoma. After the initial surgery, the patient was readmitted due to tension pneumocephalus and cerebrospinal fluid (CSF) fistula. Cultures showed K. kristinae in the CSF and Candida albicans in the urine. The patient died after multiple complications. This is the first case of neuroinfection by K. kristinae in the American continent as reviewed. It was not determined as the main cause of death due to the sudden herniation, however, with active infection derived from the identification in two different samples, for this reason, we consider that it could be useful to take it as a cause of disease and a probable cause when the studies for detection of the most common pathogens have been negative.

Bacterial Brain Abscesses in a Patient With Transposition of the Great Arteries and Interventricular Communication.

Brain abscesses are localized infections in the brain's parenchyma, characterized by inflammation, pus formation, and the development of a surrounding capsule. These lesions typically occur due to underlying factors such as immunosuppression, ear and sinus infections, and contamination during neurosurgery. While brain abscesses are a life-threatening complication of cyanotic heart defects, they are rarely reported, with only sporadic cases previously documented. This article presents the case of an eight-year-old male patient with an uncorrected transposition of the great arteries, who was evaluated for symptoms including headache, fever, and neurological focalization. Diagnostic imaging revealed three lesions consistent with brain abscesses. Furthermore, the causal agents were identified as Streptococcus intermedius and Fusobacterium spp., representing oral microorganisms. Additionally, the patient exhibited poor oral hygiene and dental caries in multiple teeth. This article discusses and integrates the possible pathophysiological mechanisms that allowed a localized dental infection to spread hematogenously and cause brain abscesses in this patient. Prompt management of the infectious source is crucial to prevent a poor prognosis associated with brain abscesses. Therefore, this case emphasizes the importance of regular dental assessments and thromboprophylaxis for patients with underlying cardiomyopathies that cause right-to-left shunting to prevent potential complications.

Development and validation of a predictive model assessing the risk of seizure recurrence in children with neurocysticercosis.

INTRODUCTION: Neurocysticercosis (NCC) is a significant factor contributing to the incidence of seizures in developing countries. While numerous studies have investigated the recurrence of seizures in NCC, their reliability is often limited. METHODS: We assessed the socio-demographic, clinical, and neuroimaging details of 161 children with seizures caused by NCC. We monitored them for seizure recurrence over a 6-month follow-up period. We divided the children into two groups: those with seizure recurrence and those without. Subsequently, we identified predictive factors associated with seizure recurrence through univariate analysis, followed by multivariate binary logistic regression. We evaluated the prognostic model for discrimination and calibration and then internally validated it using the bootstrap method. RESULTS: A total of 23 children experienced breakthrough seizures. In multivariate analysis, the presence of epileptiform abnormalities in electroencephalogram (EEG), more than 5 NCC lesions, the presence of perilesional edema greater than 2 cm in maximum dimension, and a cluster of seizures before presentation were significantly associated with seizure recurrence (p < 0.05). These factors were included in the final NEPC (Number of NCC lesions, Epileptiform EEG abnormality, Perilesional edema, and Cluster of seizures) score. The final model exhibited good discrimination (AUC = 89.1 %; 95 % CI=80.5-95.3 %, p < 0.001) and calibration (p = 0.54). A score of 4 appeared to be the optimal threshold for discriminating between individuals with and without seizure recurrence, with sensitivity and specificity values of 85 % and 87 %, respectively. Interrater reliability was very strong between two pediatric neurologists and strong between a pediatric neurologist and a pediatric neurology trainee resident (k = 0.92 and 0.86, respectively). CONCLUSION: The NEPC score demonstrates good sensitivity and specificity in predicting seizure recurrence in pediatric children with NCC.

Cytokine profile in patients with acute bacterial meningitis.

BACKGROUND: Bacterial meningitis is a life-threatening disease with high mortality and common long-term sequelae. The inflammatory response in the subarachnoid space, modulated by different cytokines, plays a major role in the pathogenesis of acute central nervous system infections. We aimed to examine correlations of interleukin (IL)-6, IL-8, IL-10, IL-12(p40), and tumor necrosis factor (TNF)-α levels with disease severity, complications, and outcome in patients with acute bacterial meningitis. METHODS: The study involved 30 patients with bacterial meningitis/meningoencephalitis admitted to the University Hospital St. George, Plovdiv over a period of 4 years. Patients were selected based on clinical presentation and laboratory abnormalities, consistent with a neuroinfection. Enzyme-linked immunosorbent assay was used to measure the studied cytokines in both cerebrospinal fluid (CSF) and serum in parallel. For microbiological diagnosis multiplex, polymerase chain reaction, and CSF culture were used. RESULTS: In patients with acute bacterial meningitis CSF levels of IL-6, IL-8, IL-10, and TNF-α are significantly increased than in serum. CSF TNF-α, CSF IL-8, and CSF IL-10 had a moderate negative correlation to CSF glucose. It was found that serum IL-8 is significantly elevated in patients who experienced neurological complications, have severe clinical course, and in deceased patients. CSF IL-10 is increased only in patients with severe acute bacterial meningitis. CONCLUSION: Among patients with acute bacterial meningitis serum IL-8 could delineate these with increased risk of neurological complications, severe clinical course, and fatal outcome. Serum IL-8 and CSF IL-10 could be used as indicators of disease severity.

Tick-borne encephalitis in pregnancy.

A case report describing the case of a young and healthy pregnant patient who manifested tick-borne encephalitis in her peripartal period. This neuroinfection is rare in pregnant women. A more severe encephalomyelitic form of the disease, resulting in lasting consequences, occurred in the patient even though she had recently undergone a proper vaccination. In the course of 11-month observation, her newborn showed no symptoms of the disease nor psychomotor developmental disorders.

Viral-induced neuroinflammation: Different mechanisms converging to similar exacerbated glial responses.

There is increasing evidence that viral infections are the source/origin of various types of encephalitis, encephalomyelitis, and other neurological and cognitive disorders. While the involvement of certain viruses, such as the Nipah virus and measles virus, is known, the mechanisms of neural invasion and the factors that trigger intense immune reactions are not fully understood. Based on recent publications, this review discusses the role of the immune response, interactions between viruses and glial cells, and cytokine mediators in the development of inflammatory diseases in the central nervous system. It also highlights the significant gaps in knowledge regarding these mechanisms.

Metabolic reprogramming and lipid droplets are involved in Zika virus replication in neural cells.

Zika virus (ZIKV) infection is a global public health concern linked to adult neurological disorders and congenital diseases in newborns. Host lipid metabolism, including lipid droplet (LD) biogenesis, has been associated with viral replication and pathogenesis of different viruses. However, the mechanisms of LD formation and their roles in ZIKV infection in neural cells are still unclear. Here, we demonstrate that ZIKV regulates the expression of pathways associated with lipid metabolism, including the upregulation and activation of lipogenesis-associated transcription factors and decreased expression of lipolysis-associated proteins, leading to significant LD accumulation in human neuroblastoma SH-SY5Y cells and in neural stem cells (NSCs). Pharmacological inhibition of DGAT-1 decreased LD accumulation and ZIKV replication in vitro in human cells and in an in vivo mouse model of infection. In accordance with the role of LDs in the regulation of inflammation and innate immunity, we show that blocking LD formation has major roles in inflammatory cytokine production in the brain. Moreover, we observed that inhibition of DGAT-1 inhibited the weight loss and mortality induced by ZIKV infection in vivo. Our results reveal that LD biogenesis triggered by ZIKV infection is a crucial step for ZIKV replication and pathogenesis in neural cells. Therefore, targeting lipid metabolism and LD biogenesis may represent potential strategies for anti-ZIKV treatment development.

Lyme neuroborreliosis with encephalitis: A rare case.

Encephalitis caused by Borrelia burgdorferi sensu lato is a rare clinical manifestation of Lyme neuroborreliosis and only in few cases have brain parenchymal inflammation been documented. Here, we present a case of Lyme neuroborreliosis with encephalitis with significant parenchymal inflammation on magnetic resonance imaging (MRI) in an immunosuppressed patient.

Immune Functions of Astrocytes in Viral Neuroinfections.

Neuroinfections of the central nervous system (CNS) can be triggered by various pathogens. Viruses are the most widespread and have the potential to induce long-term neurologic symptoms with potentially lethal outcomes. In addition to directly affecting their host cells and inducing immediate changes in a plethora of cellular processes, viral infections of the CNS also trigger an intense immune response. Regulation of the innate immune response in the CNS depends not only on microglia, which are fundamental immune cells of the CNS, but also on astrocytes. These cells align blood vessels and ventricle cavities, and consequently, they are one of the first cell types to become infected after the virus breaches the CNS. Moreover, astrocytes are increasingly recognized as a potential viral reservoir in the CNS; therefore, the immune response initiated by the presence of intracellular virus particles may have a profound effect on cellular and tissue physiology and morphology. These changes should be addressed in terms of persisting infections because they may contribute to recurring neurologic sequelae. To date, infections of astrocytes with different viruses originating from genetically distinct families, including Flaviviridae, Coronaviridae, Retroviridae, Togaviridae, Paramyxoviridae, Picomaviridae, Rhabdoviridae, and Herpesviridae, have been confirmed. Astrocytes express a plethora of receptors that detect viral particles and trigger signaling cascades, leading to an innate immune response. In this review, we summarize the current knowledge on virus receptors that initiate the release of inflammatory cytokines from astrocytes and depict the involvement of astrocytes in immune functions of the CNS.

Astrocytes in the pathophysiology of neuroinfection.

Key homeostasis providing cells in the central nervous system (CNS) are astrocytes, which belong to the class of cells known as atroglia, a highly heterogeneous type of neuroglia and a prominent element of the brain defence. Diseases evolve due to altered homeostatic state, associated with pathology-induced astroglia remodelling represented by reactive astrocytes, astroglial atrophy and astrodegeneration. These features are hallmarks of most infectious insults, mediated by bacteria, protozoa and viruses; they are also prominent in the systemic infection. The COVID-19 pandemic revived the focus into neurotropic viruses such as SARS-CoV2 (Coronaviridae) but also the Flaviviridae viruses including tick-borne encephalitis (TBEV) and Zika virus (ZIKV) causing the epidemic in South America prior to COVID-19. Astrocytes provide a key response to neurotropic infections in the CNS. Astrocytes form a parenchymal part of the blood-brain barrier, the site of virus entry into the CNS. Astrocytes exhibit aerobic glycolysis, a form of metabolism characteristic of highly morphologically plastic cells, like cancer cells, hence a suitable milieu for multiplication of infectious agent, including viral particles. However, why the protection afforded by astrocytes fails in some circumstances is an open question to be studied in the future.

Serum matrix metalloproteinase-9 (MMP-9) as a biomarker in paediatric and adult tick-borne encephalitis patients.

Matrix metalloproteinases (MMPs) play an important role in central nervous system infections. We analysed the levels of 8 different MMPs in the cerebrospinal fluid (CSF) of 89 adult patients infected with tick-borne encephalitis (TBE) virus and compared them with the levels in a control group. MMP-9 was the only MMP that showed significantly increased CSF levels in TBE patients. Serum MMP-9 levels were subsequently measured in 101 adult TBE patients at various time points during the neurological phase of TBE and at follow-up. In addition, serum MMP-9 was analysed in 37 paediatric TBE patients. Compared with control levels, both paediatric and adult TBE patients had significantly elevated serum MMP-9 levels. In most adult patients, serum MMP-9 levels peaked at hospital admission, with higher serum MMP-9 levels observed in patients with encephalitis than in patients with meningitis. Elevated serum MMP-9 levels were observed throughout hospitalisation but decreased to normal levels at follow-up. Serum MMP-9 levels correlated with clinical course, especially in patients heterozygous for the single-nucleotide polymorphism rs17576 (A/G; Gln279Arg) in the MMP9 gene. The results highlight the importance of MMP-9 in the pathogenesis of TBE and suggest that serum MMP-9 may serve as a promising bioindicator of TBE in both paediatric and adult TBE patients.

Management of cerebral abscess with large ventricular septal defect in rural area: a case report.

Cerebral abscess is an uncommon complication of cyanotic heart disease. However, it has a high case fatality rate, and its management requires a multidisciplinary approach. Earlier diagnosis would result in a better outcome. In this report, we presented a case of a 6-year-old boy with a cerebral abscess and a large ventricular septal defect, which was treated surgically in a rural area with a limited resources facility.

Lipid droplets in Zika neuroinfection: Potential targets for intervention?

Lipid droplets (LD) are evolutionarily conserved lipid-enriched organelles with a diverse array of cell- and stimulus-regulated proteins. Accumulating evidence demonstrates that intracellular pathogens exploit LD as energy sources, replication sites, and part of the mechanisms of immune evasion. Nevertheless, LD can also favor the host as part of the immune and inflammatory response to pathogens. The functions of LD in the central nervous system have gained great interest due to their presence in various cell types in the brain and for their suggested involvement in neurodevelopment and neurodegenerative diseases. Only recently have the roles of LD in neuroinfections begun to be explored. Recent findings reveal that lipid remodelling and increased LD biogenesis play important roles for Zika virus (ZIKV) replication and pathogenesis in neural cells. Moreover, blocking LD formation by targeting DGAT-1 in vivo inhibited virus replication and inflammation in the brain. Therefore, targeting lipid metabolism and LD biogenesis may represent potential strategies for anti-ZIKV treatment development. Here, we review the progress in understanding LD functions in the central nervous system in the context of the host response to Zika infection.