Blood-brain Barrier Disturbance Research Articles

Understanding the Importance of Blood-Brain Barrier Alterations in Brain Arteriovenous Malformations and Implications for Treatment: A Dynamic Contrast-Enhanced-MRI-Based Prospective Study.

The major clinical implication of brain arteriovenous malformations (bAVMs) is spontaneous intracranial hemorrhage. There is a growing body of experimental evidence proving that inflammation and blood-brain barrier (BBB) dysfunction are involved in both the clinical course of the disease and the risk of bleeding. However, how bAVM treatment affects perilesional BBB disturbances is yet unclear. We assessed the permeability changes of the BBB using dynamic contrast-enhanced MRI (DCE-MRI) in a series of bAVMs (n = 35), before and at a mean of 5 (±2) days after treatment. A set of cerebral cavernous malformations (CCMs) (n = 16) was used as a control group for the assessment of the surgical-related collateral changes. The extended Tofts pharmacokinetic model was used to extract permeability (Ktrans) values in the lesional, perilesional, and normal brain tissues. In patients with bAVM, the permeability of BBB was higher in the perilesional of bAVM tissue compared with the rest of the brain parenchyma (mean Ktrans 0.145 ± 0.104 vs 0.084 ± 0.035, P = .004). Meanwhile, no significant changes were seen in the perilesional brain of CCM cases (mean Ktrans 0.055 ± 0.056 vs 0.061 ± 0.026, P = .96). A significant decrease in BBB permeability was evident in the perilesional area of bAVM after surgical resection (mean Ktrans 0.145 ± 0.104 vs 0.096 ± 0.059, P = .037). This benefit in BBB permeability reduction after surgery seemed to surpass the relative increase in permeability inherent to the surgical manipulation. In contrast to CCMs, BBB permeability in patients with bAVM is increased in the perilesional parenchyma, as assessed using DCE-MRI. However, bAVM surgical resection seems to reduce BBB permeability in the perilesional tissue. No evidence of the so-called breakthrough phenomenon was detected in our series. DCE-MRI could become a valuable tool to follow the longitudinal course of BBB damage throughout the natural history and clinical course of bAVMs.

H2S prevents the disruption of the blood-brain barrier in rats with prenatal hyperhomocysteinemia

Elevation of the homocysteine concentration in the plasma called hyperhomocysteinemia (hHCY) during pregnancy causes a number of pre- and postnatal developmental disorders. The aim of our study was to analyze the effects of H2S donors –NaHS and N-acetylcysteine (NAC) on blood-brain barrier (BBB) permeability in rats with prenatal hHCY. In rats with mild hHCY BBB permeability assessed by Evans Blue extravasation in brain increased markedly throughout life. Administration of NaHS or NAC during pregnancy attenuated hHCY-associated damage and increased endogenous concentrations of sulfides in brain tissues. Acute application of dl-homocysteine thiolactone induced BBB leakage, which was prevented by the NMDA receptor antagonist MK-801 or H2S donors. Rats with hHCY demonstrated high levels of NO metabolite – nitrites and proinflammatory cytokines (IL-1β, TNF-α, IL-6) in brain. Lactate dehydrogenase (LDH) activity in the serum was higher in rats with hHCY. Mitochondrial complex-I activity was lower in brain of hHCY rats. NaHS treatment during pregnancy restored levels of proinflammatory cytokines, nitrites and activity of the respiratory chain complex in brain as well as the LDH activity in serum. Our data suggest that H2S has neuroprotective effects against prenatal hHCY-associated BBB disturbance providing a potential strategy for the prevention of developmental impairments in newborns.

Postoperative cognitive dysfunction: spotlight on light, circadian rhythms, and sleep.

Postoperative cognitive dysfunction (POCD) is a neurological disorder characterized by the emergence of cognitive impairment after surgery. A growing body of literature suggests that the onset of POCD is closely tied to circadian rhythm disruption (CRD). Circadian rhythms are patterns of behavioral and physiological change that repeat themselves at approximately, but not exactly, every 24 h. They are entrained to the 24 h day by the daily light-dark cycle. Postoperative CRD affects cognitive function likely by disrupting sleep architecture, which in turn provokes a host of pathological processes including neuroinflammation, blood-brain barrier disturbances, and glymphatic pathway dysfunction. Therefore, to address the pathogenesis of POCD it is first necessary to correct the dysregulated circadian rhythms that often occur in surgical patients. This narrative review summarizes the evidence for CRD as a key contributor to POCD and concludes with a brief discussion of how circadian-effective hospital lighting can be employed to re-entrain stable and robust circadian rhythms in surgical patients.

Dynamic contrast-enhanced MRI shows altered blood–brain barrier function of deep gray matter structures in neuroborreliosis: a case–control study

BackgroundMain aim was assessment of regional blood–brain barrier (BBB) function by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with neuroborreliosis. Secondary aim was to study the correlation of BBB function with biochemical, clinical, and cognitive parameters.MethodsRegional ethical committee approved this prospective single-center case–control study. Within 1 month after diagnosis of neuroborreliosis, 55 patients underwent DCE-MRI. The patient group consisted of 25 males and 30 females with mean age 58 years, and the controls were 8 males and 7 females with mean age 57 years. Pharmacokinetic compartment modelling with Patlak fit was applied, providing estimates for capillary leakage rate and blood volume fraction. Nine anatomical brain regions were sampled with auto-generated binary masks. Fatigue, severity of clinical symptoms and findings, and cognitive function were assessed in the acute phase and 6 months after treatment.ResultsLeakage rates and blood volume fractions were lower in patients compared to controls in the thalamus (p = 0.027 and p = 0.018, respectively), caudate nucleus (p = 0.009 for both), and hippocampus (p = 0.054 and p = 0.009). No correlation of leakage rates with fatigue, clinical disease severity or cognitive function was found.ConclusionsIn neuroborreliosis, leakage rate and blood volume fraction in the thalamus, caudate nucleus, and hippocampus were lower in patients compared to controls. DCE-MRI provided new insight to pathophysiology of neuroborreliosis, and can serve as biomarker of BBB function and regulatory mechanisms of the neurovascular unit in infection and inflammation.Relevance statementDCE-MRI provided new insight to pathophysiology of neuroborreliosis, and can serve as biomarker of blood–brain barrier function and regulatory mechanisms of the neurovascular unit in infection and inflammation.Key points• Neuroborreliosis is an infection with disturbed BBB function.• Microvessel leakage can be studied with DCE-MRI.• Prospective case–control study showed altered microvessel properties in thalamus, caudate, and hippocampus.Graphical

PET Imaging and Protein Expression of Prostate-Specific Membrane Antigen in Glioblastoma: A Multicenter Inventory Study.

Upregulation of prostate-specific membrane antigen (PSMA) in neovasculature has been described in glioblastoma multiforme (GBM), whereas vasculature in nonaffected brain shows hardly any expression of PSMA. It is unclear whether PSMA-targeting tracer uptake on PET is based on PSMA-specific binding to neovasculature or aspecific uptake in tumor. Here, we quantified uptake of various PSMA-targeting tracers in GBM and correlated this with PSMA expression in tumor biopsy samples from the same patients. Methods: Fourteen patients diagnosed with de novo (n = 8) or recurrent (n = 6) GBM underwent a preoperative PET scan after injection of 1.5 MBq/kg [68Ga]Ga-PSMA-11 (n = 7), 200 MBq of [18F]DCFpyl (n = 3), or 200 MBq of [18F]PSMA-1007 (n = 4). Uptake in tumor and tumor-to-background ratios, with contralateral nonaffected brain as background, were determined. In a subset of patients, PSMA expression levels from different regions in the tumor tissue samples (n = 40), determined using immunohistochemistry (n = 35) or RNA sequencing (n = 13), were correlated with tracer uptake on PET. Results: Moderate to high (SUVmax, 1.3-20.0) heterogeneous uptake was found in all tumors irrespective of the tracer type used. Uptake in nonaffected brain was low, resulting in high tumor-to-background ratios (6.1-359.0) calculated by dividing SUVmax of tumor by SUVmax of background. Immunohistochemistry showed variable PSMA expression on endothelial cells of tumor microvasculature, as well as on dispersed individual cells (of unknown origin), and granular staining of the neuropil. No correlation was found between invivo uptake and PSMA expression levels (for immunohistochemistry, r = -0.173, P = 0.320; for RNA, r = -0.033, P = 0.915). Conclusion: Our results indicate the potential use of various PSMA-targeting tracers in GBM. However, we found no correlation between PSMA expression levels on immunohistochemistry and uptake intensity on PET. Whether this may be explained by methodologic reasons, such as the inability to measure functionally active PSMA with immunohistochemistry, tracer pharmacokinetics, or the contribution of a disturbed blood-brain barrier to tracer retention, should still be investigated.

Intracerebral gadolinium deposition following blood–brain barrier disturbance in two different mouse models

To evaluate the influence of the blood–brain barrier on neuronal gadolinium deposition in a mouse model after multiple intravenous applications of the linear contrast agent gadodiamide. The prospective study held 54 mice divided into three groups: healthy mice (A), mice with iatrogenic induced disturbance of the blood–brain barrier by glioblastoma (B) or cerebral infarction (C). In each group 9 animals received 10 iv-injections of gadodiamide (1.2 mmol/kg) every 48 h followed by plain T1-weighted brain MRI. A final MRI was performed 5 days after the last contrast injection. Remaining mice underwent MRI in the same time intervals without contrast application (control group). Signal intensities of thalamus, pallidum, pons, dentate nucleus, and globus pallidus-to-thalamus and dentate nucleus-to-pons ratios, were determined. Gadodiamide complex and total gadolinium amount were quantified after the last MR examination via LC–MS/MS and ICP-MS. Dentate nucleus-to-pons and globus pallidus-to-thalamus SI ratios showed no significant increase over time within all mice groups receiving gadodiamide, as well as compared to the control groups at last MR examination. Comparing healthy mice with group B and C after repetitive contrast administration, a significant SI increase could only be detected for glioblastoma mice in globus pallidus-to-thalamus ratio (p = 0.033), infarction mice showed no significant SI alteration. Tissue analysis revealed significantly higher gadolinium levels in glioblastoma group compared to healthy (p = 0.013) and infarction mice (p = 0.029). Multiple application of the linear contrast agent gadodiamide leads to cerebral gadolinium deposition without imaging correlate in MRI.

Regional contribution of vascular dysfunction in white matter dementia: clinical and neuropathological insights.

The maintenance of adequate blood supply and vascular integrity is fundamental to ensure cerebral function. A wide range of studies report vascular dysfunction in white matter dementias, a group of cerebral disorders characterized by substantial white matter damage in the brain leading to cognitive impairment. Despite recent advances in imaging, the contribution of vascular-specific regional alterations in white matter dementia has been not extensively reviewed. First, we present an overview of the main components of the vascular system involved in the maintenance of brain function, modulation of cerebral blood flow and integrity of the blood-brain barrier in the healthy brain and during aging. Second, we review the regional contribution of cerebral blood flow and blood-brain barrier disturbances in the pathogenesis of three distinct conditions: the archetypal white matter predominant neurocognitive dementia that is vascular dementia, a neuroinflammatory predominant disease (multiple sclerosis) and a neurodegenerative predominant disease (Alzheimer's). Finally, we then examine the shared landscape of vascular dysfunction in white matter dementia. By emphasizing the involvement of vascular dysfunction in the white matter, we put forward a hypothetical map of vascular dysfunction during disease-specific progression to guide future research aimed to improve diagnostics and facilitate the development of tailored therapies.

Zika Virus affects neurobehavioral development, and causes oxidative stress associated to blood–brain barrier disruption in a rat model of congenital infection

Zika virus (ZIKV) is a mosquito-borne flavivirus associated with several neurodevelopmental outcomes after in utero infection. Here, we studied a congenital ZIKV infection model with immunocompetent Wistar rats, able to predict disabilities and that could pave the way for proposing new effective therapies. We identified neurodevelopmental milestones disabilities in congenital ZIKV animals. Also, on 22nd postnatal day (PND), blood–brain barrier (BBB) proteins disturbances were detected in the hippocampus with immunocontent reduction of β_Catenin, Occludin and Conexin-43. Besides, oxidative stress imbalance on hippocampus and cortex were identified, without neuronal reduction in these structures. In conclusion, even without pups’ microcephaly-like phenotype, congenital ZIKV infection resulted in neurobehavioral dysfunction associated with BBB and oxidative stress disturbances in young rats. Therefore, our findings highlighted the multiple impact of the congenital ZIKV infection on the neurodevelopment, which reinforces the continuity of studies to understand the spectrum of this impairment and to provide support to future treatment development for patients affected by congenital ZIKV.

Neurospecific Proteins as Transdiagnostic Markers of Affective Disorders

Mental disorders have many differences in pathogenesis and clinical symptoms, however, they are characterized by general neurobiological processes that occur with a damage of nervous tissue, disturbance of blood-brain barrier, inclusion of autoimmune mechanisms, neurodegenerative processes and release of neurospecific proteins into the liquor and into the blood. We presented a review of current literature devoted to studies of the role of neurospecific proteins in the pathogenesis of affective disorders. Glial fibrillar acidic protein (GFAP), S-100 protein, myelin basic protein (MBP), and neuron specific enolase (NSE) reflect damage of neurons, astrocytes and oligodendrocytes in depressive disorders and they could be considered as transdiagnostic nonspecific markers of affective disorders.

Hepatic Encephalopathy and Treatment Modalities: A Review Article.

Hepatic encephalopathy (HE) is a condition that is commonly seen in individuals suffering from liver cirrhosis. After excluding brain illness, HE is described as a range of neuropsychiatric disorders in individuals with liver impairment. It is characterized by personality changes, intellectual impairment, and a depressed level of consciousness. Toxins that are typically eliminated from the body by the liver build up in the blood and eventually reach the brain, causing HE. Many signs and symptoms of HE may often be treated if caught early and treated properly. It is important to remember that not everyone who is affected may experience every symptom mentioned below. Affected individuals should speak with their doctor and medical staff about their specific disease, associated symptoms, and general prognosis. Many people only have minor symptoms, known as minimal HE. The exact pathophysiology of HE is still being debated, with the primary theories focusing on neurotoxins, reduced neurotransmission caused by alterations in brain energy metabolism, systemic inflammatory response, and blood-brain barrier (BBB) disturbances in liver failure, as well as metabolic irregularities.

Cerebrospinal fluid pressure dynamics reveal signs of effective spinal canal narrowing in ambiguous spine conditions.

Spinal canal narrowing with consecutive spinal cord compression is considered a key mechanism in degenerative cervical myelopathy (DCM). DCM is a common spine condition associated with progressive neurological disability, and timely decompressive surgery is recommended. However, the clinical and radiological diagnostic workup is often ambiguous, challenging confident proactive treatment recommendations. Cerebrospinal fluid pressure dynamics (CSFP) are altered by spinal canal narrowing. Therefore, we aim to explore the potential value of bedside CSFP assessments for qualitative and quantitative assessment of spinal canal narrowing in DCM. In this prospective case series, seven patients with DCM underwent bedside lumbar puncture with measurement of CSFP dynamics and routine CSF analysis (NCT02170155). The patients were enrolled when standard diagnostic algorithms did not permit a clear treatment decision. Measurements include baseline CSFP, cardiac-driven CSFP peak-to-trough amplitude (CSFPp), and the Queckenstedt's test (firm pressure on jugular veins) in neutral and reclined head position. From the Queckenstedt's test, proxies for craniospinal elastance (i.e., relative pulse pressure coefficient; RPPC-Q) were calculated analogously to infusion testing. CSFP metrics were deemed suspicious of canal narrowing when numbers were lower than the minimum value from a previously tested elderly spine-healthy cohort (N = 14). Mean age was 56 ± 13 years (range, 38–75; 2F); symptom severity was mostly mild to moderate (mean mJOA, 13.5 ± 2.6; range, 9–17). All the patients showed some extent of cervical stenosis in the MRI of unclear significance (5/7 following decompressive cervical spine surgery with an adjacent level or residual stenosis). Baseline CSFP was normal except for one patient (range, 4.7–17.4 mmHg). Normal values were found for CSFPp (0.4–1.3 mmHg) and the Queckenstedt's test in normal head positioning (9.-25.3 mmHg). During reclination, the Queckenstedt's test significantly decreased in one, and CSFPp in another case (>50% compared to normal position). RPPC-Q (0.07–0.19) aligned with lower values from spine-healthy (0.10–0.44). Routine CSF examinations showed mild total protein elevation (mean, 522 ± 108 mg/ml) without further evidence for the disturbed blood brain barrier. Intrathecal CSFP measurements allow discerning disturbed from normal CSFP dynamics in this population. Prospective longitudinal studies should further evaluate the diagnostic utility of CSFP assessments in DCM.

Association of High Ratio of CSF/Plasma HIV-1 RNA with Central Nervous System Co-Infection in HIV-1-Positive Treatment-Naive Patients.

Cerebrospinal fluid (CSF) human immunodeficiency virus-1 (HIV-1) ribonucleic acid (RNA) at higher levels than in plasma has been observed in HIV-1-positive patients and defined as CSF/plasma discordance or CSF escape. Discordance is particularly seen in untreated patients with antiretroviral agents. Quantitative data regarding its association with blood–brain barrier (BBB) damage and intracranial co-infection with other pathogens are limited. Therefore, we used the CSF to plasma HIV-1 RNA ratio (HRR) to determine its relation to central nervous system (CNS) co-infection in HIV-1-positive treatment-naïve individuals. We retrospectively recruited the subjects with HIV-1-positive and potential neurological deficits. A lumbar puncture was performed before the antiretroviral therapy. The paired CSF/plasma HIV-1 RNA samples were analyzed. Univariate and multivariate logistic regression models and multiple spine regression analyses were performed to assess the association between the HRR and CNS co-infection. A total of 195 patients with 78% males (median age: 49 years) were included in this study, of whom 98 (50.2%) had CNS co-infection with other pathogens. The receiver-operating characteristic curve analysis showed that the optimal cutoff value for the HRR to predict the CNS co-infection was 1.00. Higher HRR (≥1) was significantly associated with tuberculous meningitis (OR 6.50, 95% CI 2.08–20.25, p = 0.001), cryptococcus meningitis (OR 7.58, 95% CI 2.10–27.32, p = 0.001), and multiple co-infection (OR 4.04, 95% CI 1.02–16.04, p = 0.047). Higher HRR (≥1) (OR 3.01, 95% CI 1.09–8.73, p = 0.032) was independently associated with the CNS co-infection after adjusting for covariates. No significant nonlinear association was found between the HRR and CNS co-infection in the multivariate spline regression (p > 0.05) and a positive relationship was found between the HRR and CNS co-infection when the HRR was ≥0.78. Higher HRR was associated with an increased risk of CNS co-infection in HIV-1-positive patients. The relationship between the HRR and CNS co-infection may be related to the BBB disturbance and warrants further investigation with a large, longitudinal cohort.

Cerebral Iron Deposition in Neurodegeneration.

Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson’s disease, Friedreich’s disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood–brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.

Adolescent intermittent ethanol exposure produces Sex-Specific changes in BBB Permeability: A potential role for VEGFA

Binge drinking that typically begins during adolescence can have long-lasting neurobehavioral consequences, including alterations in the central and peripheral immune systems. Central and peripheral inflammation disrupts blood–brain barrier (BBB) integrity and exacerbates pathology in diseases commonly associated with disturbed BBB function. Thus, the goal of the present studies was to determine long-lasting effects of adolescent intermittent ethanol (AIE) on BBB integrity. For AIE, male and female Sprague Dawley rats were repeatedly exposed to ethanol (4 g/kg, intragastrically) or water during adolescence between postnatal day (P) 30 and P50. In adulthood (∼P75), rats were challenged with fluorescein isothiocyanate (FITC)-tagged Dextran of varying molecular weights (4, 20, & 70 kDa) for assessment of BBB permeability using gross tissue fluorometry (Experiment 1). Experiment 2 extended these effects using immunofluorescence, adding an adult ethanol-exposed group to test for a specific developmental vulnerability. Finally, as a first test of hypothesized mechanism, Experiment 3 examined the effect of AIE on Vascular Endothelial Growth Factor A (VEGFA) and its co-localization with pericytes (identified through expression of platelet derived growth factor receptor beta (PDGFRβ), a key regulatory cell embedded within the BBB. Male, but not female, rats with a history of AIE showed significantly increased dextran permeability in the nucleus accumbens (NAc), cingulate prefrontal cortex (cPFC), and amygdala (AMG). Similar increases in dextran were observed in the hippocampus (HPC) and ventral tegmental area (VTA) of male rats with a history of AIE or equivalent ethanol exposure during adulthood. No changes in BBB permeability were evident in females. When VEGFa expression was examined, male rats exposed to AIE were challenged with 3.5 g/kg ethanol (i.p.) or vehicle acutely in adulthood to assess long-lasting versus acute actions of ethanol. Adult rats with a history of AIE showed significantly fewer total cells expressing VEGFa in the AMG and dHPC following the acute ethanol challenge in adulthood. They also showed a significant reduction in the number of PDGFRβ positive cells that also expressed VEGFa signal. The anatomical distribution of these effects corresponded with increased BBB permeability after AIE (i.e., differential effects in the PVN, AMG, and dHPC). These studies demonstrated sex-specific effects of AIE, with males, but not females, demonstrating long-term increases in BBB permeability that correlated with changes in VEGFa and PDGFRβ protein, two factors known to influence BBB permeability.

Blood-Brain Barrier Overview: Structural and Functional Correlation.

The blood-brain barrier (BBB) is a semipermeable and extremely selective system in the central nervous system of most vertebrates, that separates blood from the brain's extracellular fluid. It plays a vital role in regulating the transport of necessary materials for brain function, furthermore, protecting it from foreign substances in the blood that could damage it. In this review, we searched in Google Scholar, Pubmed, Web of Science, and Saudi Digital Library for the various cells and components that support the development and function of this barrier, as well as the different pathways to transport the various molecules between blood and the brain. We also discussed the aspects that lead to BBB dysfunction and its neuropathological consequences, with the identification of some of the most important biomarkers that might be used as a biomarker to predict the BBB disturbances. This comprehensive overview of BBB will pave the way for future studies to focus on developing more specific targeting systems in material delivery as a future approach that assists in combinatorial therapy or nanotherapy to destroy or modify this barrier in pathological conditions such as brain tumors and brain stem cell carcinomas.

Mild Traumatic Brain Injury/Concussion Initiates an Atypical Astrocyte Response Caused by Blood-Brain Barrier Dysfunction.

Mild traumatic brain injury/concussion (mTBI) accounts for 70-90% of all reported TBI cases and causes long-lasting neurological consequences in 10-40% of patients. Recent clinical studies revealed increased blood-brain barrier (BBB) permeability in mTBI patients, which correlated with secondary damage after mTBI. However, the cascade of cellular events initiated by exposure to blood-borne factors resulting in sustained damage is not fully understood. We previously reported that astrocytes respond atypically to mTBI, rapidly losing many proteins essential to their homeostatic function, while classic scar formation does not occur. Here, we tested the hypothesis that mTBI-induced BBB damage causes atypical astrocytes through exposure to blood-borne factors. Using an mTBI mouse model, two-photon imaging, an endothelial cell-specific genetic ablation approach, and serum-free primary astrocyte cultures, we demonstrated that areas with atypical astrocytes coincide with BBB damage and that exposure of astrocytes to plasma proteins is sufficient to initiate loss of astrocyte homeostatic proteins. Although mTBI resulted in frequent impairment of both physical and metabolic BBB properties and leakage of small-sized blood-borne factors, deposition of the coagulation factor fibrinogen or vessel rupture were rare. Surprisingly, even months after mTBI, BBB repair did not occur in areas with atypical astrocytes. Together, these findings implicate that even relatively small BBB disturbances are sustained long term, and render nearby astrocytes dysfunctional, likely at the cost of neuronal health and function.

Peripheral T-Cell Lymphoma Involvement of the Central Nervous System: Impact of Novel Therapeutics on Clinical Outcomes

Primary Central Nervous System (CNS) involvement of peripheral T-cell lymphoma (PTCL) is a rare phenomenon, with a reported incidence ranging from 2% to 16.7%. Similarly, secondary CNS lymphoma with PTCL phenotype is rare, with an approximately 2-6% incidence. Both clinical situations lead to dismal outcomes. Given the rarity of CNS involvement with PTCL, our understanding of this clinical manifestation is limited to retrospective studies, which have identified risk factors for CNS involvement such as extranodal involvement, stage III-IV disease, bone marrow involvement as well as ATLL subtype. Herein, we characterize CNS involvement of PTCL over a 26-year time period at a single institution, identify if there are any factors that have a positive impact on survival, and extrapolate risk factors for CNS involvement from this dataset.From the years 1996-2020, 222 patients were diagnosed with PTCL, of those, 25 patients developed CNS involvement. All patients had secondary CNS involvement. Baseline characteristics including first-line therapy are noted in Table 1. Four patients received intrathecal methotrexate for CNS prophylaxis, all of which were patients with an ATLL diagnosis. The median time from initial diagnosis to CNS involvement was 4.77 months (0-64 months). Upon CNS diagnosis, the median time to death was 1.13 months. With a median of 2 lines of treatment (range 1-5), 12 patients were exposed to novel therapeutic agents (HDAC inhibitors [HDACis], brentuximab vedotin, pralatrexate) and/or clinical trials investigating epigenetic combinations. Of these patients, 10 patients were exposed to novel therapeutics and/or epigenetic based clinical trials in the 2 nd line setting. There was a trend towards improved overall survival with exposure to novel therapeutics and/or treatment on epigenetic based clinical trials (p=0.1) (Figure 1). With the majority of patients surviving <6 months from CNS diagnosis, there were three excellent responders that survived >12 months, all of which were exposed to novel therapeutics. Two of the three excellent responders were diagnosed with CNS involvement upon initial diagnosis, while 1 patient relapsed in the fourth-line setting with CNS involvement. All three of the excellent responders were exposed to novel therapeutics, particularly pralatrexate as a commonality in the second line setting. Using logistic regression, an ATLL diagnosis, extranodal involvement, and a high ECOG score were associated with a higher risk of CNS involvement. Unlike other studies, a high IPI score was not associated with a predilection for CNS involvement.In conclusion, we describe one of the largest single-center collection of CNS PTCL involvement. CNS involvement of PTCL is rare, with a reported cumulative incidence in this cohort of 11.3% over a 26-year time period. Risk factors that were identified include an ATLL diagnosis, extranodal involvement, and poor performance status. Exposure to novel therapeutics leads to a trend towards improved outcomes possibly secondary to improved disease control, but overall, the majority of patients had dismal outcomes. Notably, of the novel therapeutics interrogated, romidepsin and pralatrexate have low penetrance into the CNS, while there is no current evidence to suggest brentuximab vedotin is able to cross the blood-brain barrier. The possibility of a disturbed blood-brain barrier to permit improved penetrance of these drugs is plausible, but further studies are warranted to support this. Although a small percentage of patients will suffer from CNS PTCL, there is a dire need to improve therapy for this patient population and to establish universal metrics to identify patients that are at risk of CNS involvement. Moreover, given the rarity of CNS PTCL involvement, a future endeavor would be to validate these findings in larger, multicenter initiative. [Display omitted] DisclosuresLue: AstraZeneca: Speakers Bureau; Kymera Therapeutics: Research Funding; TG Therapeutics: Consultancy; Epizyme: Consultancy; Kura Oncology: Consultancy. Marchi: Astex: Research Funding; Kyowa Kirin: Honoraria; Merck: Research Funding; BMS: Research Funding; Myeloid Therapeutics: Honoraria; Kymera Therapeutics: Other: Scientific Advisor. O'Connor: Myeloid Therapeutics: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Servier: Research Funding; Kymera: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; BMS: Research Funding; Merck: Research Funding; TG Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Nutritional Supplementation of Naturally Occurring Vitamin D to Improve Hemorrhagic Stroke Outcomes.

Vitamin D deficiency, if left untreated, is associated with bone disorders, cardiovascular damage, and an increased risk of ischemic stroke. While there are various nutritional options for the natural intake of vitamin D, we hope to elucidate the potential mechanisms dietary vitamin D may play in hemorrhagic stroke pathology. This scoping review outlines findings from studies relevant to the biochemical activity of vitamin D, the impact of vitamin D deficiency on hemorrhagic stroke outcomes, and the potential benefit of nutritional vitamin D on hemorrhagic stroke outcomes. Here, we analyze the relevant factors that can lead to vitamin D deficiency, and subsequently, a higher risk of hemorrhagic stroke incidence with worsened subsequent outcomes. The neuroprotective mechanisms through which vitamin D works to attenuate hemorrhagic stroke onset and post-stroke outcomes have not yet been thoroughly examined. However, researchers have proposed several potential protective mechanisms, including reduction of blood brain barrier disturbance by inhibiting the production of reactive oxygen species, mitigation of inflammation through a reduction of levels of proinflammatory cytokines, and prevention of cerebral vasospasm and delayed cerebral ischemia following subarachnoid hemorrhage and intracerebral hemorrhage. While more research is needed and there are limitations to vitamin D supplementation, vitamin D as a whole may play a significant role in the dynamics of hemorrhagic stroke. Further research should focus on expanding our understanding of the neuroprotective capacity and mechanisms of vitamin D, as well as how vitamin D supplementation could serve as an effective course of treatment of hemorrhagic strokes.

Viral mimetic triggers cerebral arteriopathy in juvenile brain via neutrophil elastase and NETosis

Stroke is among the top ten causes of death in children but has received disproportionally little attention. Cerebral arteriopathies account for up to 80% of childhood arterial ischemic stroke (CAIS) cases and are strongly predictive of CAIS recurrence and poorer outcomes. The underlying mechanisms of sensitization of neurovasculature by viral infection are undefined. In the first age-appropriate model for childhood arteriopathy—by administration of viral mimetic TLR3-agonist Polyinosinic:polycytidylic acid (Poly-IC) in juvenile mice—we identified a key role of the TLR3-neutrophil axis in disrupting the structural-functional integrity of the blood-brain barrier (BBB) and distorting the developing neurovascular architecture and vascular networks. First, using an array of in-vivo/post-vivo vascular imaging, genetic, enzymatic and pharmacological approaches, we report marked Poly-IC-mediated extravascular leakage of albumin (66kDa) and of a small molecule DiI (∼934Da) and disrupted tight junctions. Poly-IC also enhanced the neuroinflammatory milieu, promoted neutrophil recruitment, profoundly upregulated neutrophil elastase (NE), and induced neutrophil extracellular trap formation (NETosis). Finally, we show that functional BBB disturbances, NETosis and neuroinflammation are markedly attenuated by pharmacological inhibition of NE (Sivelestat). Altogether, these data reveal NE/NETosis as a novel therapeutic target for viral-induced cerebral arteriopathies in children.

Blood–Brain Barrier Disturbances and Potential Complications of Endovascular Management in Stroke—Technical Note with Limited Review

AbstractContrast enhancement (CE), contrast extravasation (CX), hemorrhagic transformation (HT), and cerebral hyperperfusion syndrome (CHS) in patients who have suffered ischemic stroke and have undergone revascularization. There are a handful of articles addressing these pathologies separately. But there is scant literature available combining them together, as the underlying pathophysiology involves disturbances of blood–brain barrier (BBB). We have reviewed literature and proposed a common mechanism for these events. We systematically searched PubMed, LibGen, Cochrane, and Sci-Hub databases for the studies published online regarding CE, CX, HT, and CHS after endovascular treatment for stroke. This review was conducted based on the PRISMA guidelines. The following medical search terms were used for the online search: contrast enhancement, contrast extravasation, hemorrhagic transformation, cerebral hyperperfusion syndrome, endovascular treatment, contrast staining, postprocedural attenuation, carotid stenting, intra-arterial thrombolysis, and stroke. We did a limited review of literature by analyzing the relevant articles and research papers published to date. We have randomly included prototype cases of CE, CX, HT, and CHS which we have encountered in our Interventional Department from our own database. In compliance with PRISMA guidelines, we screened 33 articles dealing with CE, 32 with CX, 26 articles that addressed CE and CX both, 53 articles dealing with HT, and 42 articles dealing with CHS. Overall, 88 articles were filtered on studying the abstract. Further, 15 more had to be excluded as reasoned in the flowchart, and finally 71 articles were included in our study, as again shown in the flowchart. We studied and discussed these articles and research papers in relation to pathophysiology, predisposing factors, preventive measures, and current treatment protocols. BBB disruption is the primary event in CE, CX, HT, and CHS with varying severity. Minimizing dose of contrast, optimum timing of revascularization and dose of thrombolytic, judicious selection of mechanical thrombectomy cases, and strict control of blood pressure in postrevascularization period are recommended preventive measures. High-index of clinical suspicion, early imaging to detect, and following-up the same on sequential imaging are key to avoid severe forms of HT and CHS.