Changes In Blood-brain Barrier Permeability Research Articles

Role of Imaging Modalities and N-Acetylcysteine Treatment in Sepsis-Associated Encephalopathy.

Sepsis-associated encephalopathy is a severe systemic infection complication. Although early stages involve pathophysiological changes, detection using conventional imaging is challenging. Glutamate chemical exchange saturation transfer and diffusion kurtosis imaging can noninvasively investigate cellular and molecular events in early disease stages using magnetic resonance imaging (MRI). N-Acetylcysteine, an antioxidant and precursor of glutathione, regulates neurotransmitter glutamate metabolism and participates in neuroinflammation. We investigated the protective role of n-acetylcysteine in sepsis-associated encephalopathy using a rat model and monitored changes in brain using magnetic resonance (MR) molecular imaging. Bacterial lipopolysaccharide was injected intraperitoneally to induce a sepsis-associated encephalopathy model. Behavioral performance was assessed using the open-field test. Tumor necrosis factor α and glutathione levels were detected biochemically. Imaging was performed using a 7.0-T MRI scanner. Protein expression, cellular damage, and changes in blood-brain barrier permeability were assessed using western blotting, pathological staining, and Evans blue staining, respectively. Lipopolysaccharide-induced rats showed reduced anxiety and depression after treatment with n-acetylcysteine. MR molecular imaging can identify pathological processes at different disease stages. Furthermore, rats treated with n-acetylcysteine showed increased glutathione levels and decreased tumor necrosis factor α, suggesting enhanced antioxidant capacity and inhibition of inflammatory processes, respectively. Western blot analysis showed reduced expression of nuclear factor kappa B (p50) protein after treatment, suggesting that n-acetylcysteine inhibits inflammation via this signaling pathway. Finally, n-acetylcysteine-treated rats showed reduced cellular damage by pathology and reduced extravasation of their blood-brain barrier by Evans Blue staining. Thus, n-acetylcysteine might be a therapeutic option for sepsis-associated encephalopathy and other neuroinflammatory diseases. Furthermore, noninvasive "dynamic visual monitoring" of physiological and pathological changes related to sepsis-associated encephalopathy was achieved using MR molecular imaging for the first time, providing a more sensitive imaging basis for early diagnosis, identification, and prognosis.

Monitoring Subtle Changes of Blood-Brain Barrier Permeability via Detection of MiRNA-155 in Brain Microvasculature.

The changes of blood-brain barrier (BBB) permeability need to be sensitively reported when purposefully regulating the BBB or during some brain diseases. Currently available techniques for assessment of BBB integrity all suffer from limited sensitivity and only report serious BBB damage. Here, a targeted activatable nanoprobe is created to monitor subtle changes of BBB permeability by detecting the expression levels of BBB permeability-related miRNA (miRNA-155) in brain microvessel endothelial cells (BMECs). The probe is fabricated by coating the BMEC membrane on calcium phosphate (CaP)-mineralized metal-organic framework (MOF) nanoparticles loaded with hybridization chain reaction (HCR) probes. The coating of the BMEC membrane endows the nanoprobe with homologous targeting ability to BBB, and HCR probes released and escaped from lysosomes can be specifically lightened by miRNA-155. The activatable nanoprobe is able to monitor BBB permeability in inflammatory and AD mice. This work provides a new idea for highly sensitive evaluation of the BBB permeability, which has guiding significance in regulating BBB and formulating targeted therapeutic strategies.

Research progress on perioperative blood-brain barrier damage and its potential mechanism.

The blood-brain barrier (BBB) is an important barrier separating the central nervous system from the periphery. The composition includes endothelial cells, pericytes, astrocytes, synapses and tight junction proteins. During the perioperative period, anesthesia and surgical operations are also a kind of stress to the body, which may be accompanied by blood-brain barrier damage and brain metabolism dysfunction. Perioperative blood-brain barrier destruction is closely associated with cognitive impairment and may increase the risk of postoperative mortality, which is not conducive to enhanced recovery after surgery. However, the potential pathophysiological process and specific mechanism of blood-brain barrier damage during the perioperative period have not been fully elucidated. Changes in blood-brain barrier permeability, inflammation and neuroinflammation, oxidative stress, ferroptosis, and intestinal dysbiosis may be involved in blood-brain barrier damage. We aim to review the research progress of perioperative blood-brain barrier damage and its potential adverse effects and potential molecular mechanisms, and provide ideas for the study of homeostasis maintenance of brain function and precision anesthesia.

The evolution of blood brain barrier permeability changes after stroke, and its implications on clinical outcome: a systematic review and meta-analysis.

Blood-brain barrier permeability (BBBp) is key process involved in ischemic stroke pathophysiology. However, there is a lack of consensus on how BBBp evolves after the ischaemic injury, and its clinical relevance at different time points post stroke. To assess BBBp evolution through stroke phases, and its implications on patient outcomes. We screened PubMed/MEDLINE, EMBASE, Web of Science, Scopus and Cochrane Central Register of Controlled Trials up to December 31, 2021. We included research quantitatively using neuroimaging to assess BBBp in stroke patients. BBBp in the different phases was evaluated by a random effect model based on the standardized mean difference (SMD) between the ipsilateral and contralateral sides of the brain. We performed subgroup analysis on clinical outcome, reperfusion treatment, haemorrhagic transformation and imaging method. We identified 3761 studies of which 22 (1592 patients, 1787 evaluations) were included in our study. Overall, 17 studies reported BBBp for the hyperacute phase, eight for the acute, five for the subacute and two for the chronic phase. All phases were associated with increased BBBp : 0.74 (0.48-0.99), 1.68 (0.94-2.42), 1.98 (0.96-3.00) and 1.00 (0.45-1.55) respectively. An increase in BBBp was associated with hemorrhagic transformation in the hyperacute phase, and with improved functional outcomes in the late subacute phase. BBBp is persistently increased after stroke, peaking in the acute and subacute phases. The degree of BBBp influences patient outcomes depending on stroke phase. Our findings support the clinical relevance of BBBp dynamics in stroke care.

Novel magnetic resonance KTRANS measurement of blood-brain barrier permeability correlated with covert HE.

Using dynamic contrast-enhanced (DCE) MR perfusion and MR spectroscopy this study aimed to characterize the blood-brain barrier permeability and metabolite changes in patients with cirrhosis and without covert HE. Covert HE was defined using psychometric HE score (PHES). The participants were stratified into 3 groups: cirrhosis with covert HE (CHE) (PHES<-4); cirrhosis without HE (NHE) (PHES≥-4); and healthy controls (HC). Dynamic contrast-enhanced MRI and MRS were performed to assess KTRANS, a metric derivative of blood-brain barrier disruption, and metabolite parameters. Statistical analysis was performed using IBM SPSS (v25). A total of 40 participants (mean age 63y; male 71%) were recruited as follows: CHE (n=17); NHE (n=13); and HC (n=10). The KTRANS measurement in the frontoparietal cortex demonstrated increased blood-brain barrier permeability, where KTRANS was 0.01±0.02 versus 0.005±0.005 versus 0.004±0.002 in CHE, NHE, and HC patients, respectively (p = 0.032 comparing all 3 groups). Relative to HC with a value of 0.28, the parietal glutamine/creatine (Gln/Cr) ratio was significantly higher in both CHE 1.12mmoL (p < 0.001); and NHE 0.49 (p = 0.04). Lower PHES scores correlated with higher glutamine/Cr (Gln/Cr) (r=-0.6; p < 0.001) and lower myo-inositol/Cr (mI/Cr) (r=0.6; p < 0.001) and lower choline/Cr (Cho/Cr) (r=0.47; p = 0.004). The dynamic contrast-enhanced MRI KTRANS measurement revealed increased blood-brain barrier permeability in the frontoparietal cortex. The MRS identified a specific metabolite signature with increased glutamine, reduced myo-inositol, and choline, which correlated with CHE in this region. The MRS changes were identifiable in the NHE cohort.

Mild Traumatic Brain Injury Induces Time- and Sex-Dependent Cerebrovascular Dysfunction and Stroke Vulnerability.

Mild traumatic brain injury (mTBI) produces subtle cerebrovascular impairments that persist over time and promote increased ischemic stroke vulnerability. We recently established a role for vascular impairments in exacerbating stroke outcomes 1 week after TBI, but there is a lack of research regarding long-term impacts of mTBI-induced vascular dysfunction, as well as a significant need to understand how mTBI promotes stroke vulnerability in both males and females. Here, we present data using a mild closed head TBI model and an experimental stroke occurring either 7 or 28 days later in both male and female mice. We report that mTBI induces larger stroke volumes 7 days after injury, however, this increased vulnerability to stroke persists out to 28 days in female but not male mice. Importantly, mTBI-induced changes in blood-brain barrier permeability, intravascular coagulation, angiogenic factors, total vascular area, and glial expression were differentially altered across time and by sex. Taken together, these data suggest that mTBI can result in persistent cerebrovascular dysfunction and increased susceptibility to worsened ischemic outcomes, although these dysfunctions occur differently in male and female mice.

Improving the estimation of subtle blood-brain barrier permeability changes in aging using a deep learning approach

Background: Increasing evidence suggests detecting the subtle changes in blood-brain barrier (BBB) permeability in normal aging and in Alzheimer’s disease by using dynamic contrast-enhanced MRI (DCE-MRI) (Figure 1).1,2 However, measuring these subtle changes poses a great challenge for accurate measurement, resulting in inconsistent results among previous studies.1,2 Two major challenges are long scan times, as suggested by other studies, and the selection of the arterial input function (AIF). In this study, we aim to estimate the capillary level input function (CIF) using a deep learning network to overcome these two challenges.&#x0D; Methods: Healthy volunteers (n=12, age 21-78) were recruited for DCE-MRI scan for 28 min. Golden-angle radial sampling parallel (GRASP) sequence was used to obtain the dynamic images at ~5s/frame. Individual AIF was sampled from the superior sagittal sinus of the brain. FSL3 was used to segment the gray and white matter. Each voxel was fitted using the graphical Patlak model4 to assess the vascular permeability-surface area product (PS) for both 28-min data and 10-min truncated data. We used a 3x3 kernel sliding through the images, and feed each voxel’s dynamic as the input to our vision-transformer.5 Training data were generated using individual AIFs with a mathematical model and used to simulate dynamic patches using the extended Patlak model.4&#x0D; Results: The conventional approach with AIF results in the majority of voxels exhibiting negative PS, regardless of scan time. This is not physiologically valid, as this indicates the contrast agent extravasates into the vessel. However, the proposed approach with the network-predicted CIF results in most voxels in positive PS, even with a scan-time of 10 min. The estimated PS levels are in good accordance with the previous studies.1 Due to the limited sample size, we could not find the difference in BBB permeability between young and old groups.&#x0D; Conclusions: Our approach showed promising quantification of subtle permeability. The results in this study suggest that our proposed CIF-based approach provides an appropriate input function for DCE analysis, allowing assessment of subtle permeability changes in the BBB even with a reduced scan time of 10 min. Future studies will include larger cohorts to investigate the BBB permeability changes in normal aging.

Blood brain barrier permeability and immune function of brain in rainbow trout responding to IHNV infection

Viral infection of the central nervous system (CNS) is often associated with blood-brain barrier (BBB) disruption. Mammals have developed complicated and efficient immune strategies to protect the BBB. However, the immune defense of brain and BBB permeability changes are not well-understood in teleost during virus invading. In this study, we constructed an infectious hematopoietic necrosis virus (IHNV) immersion infected rainbow trout model. After IHNV infection, pathological changes occurred in the brain, and MPO and ROS activities were significantly increased. In addition, the expression levels of BBB permeability-related genes were also changed. Transcriptome analysis showed that immune-related genes and signaling pathways in the brain were activated after IHNV infection. These results showed that the permeability of BBB increased significantly after IHNV infection, thus activating immune related factors and cells to enter the CNS through blood circulation to resist pathogenic infection.

Novel mitoNEET ligand NL-1 improves therapeutic outcomes in an aged rat model of cerebral ischemia/reperfusion injury

Cerebral ischemic stroke is a leading cause of mortality and disability worldwide. Currently, there are a lack of drugs capable of reducing neuronal cell loss due to ischemia/reperfusion-injury after stroke. Previously, we identified mitoNEET, a [2Fe-2S] redox mitochondrial protein, as a putative drug target for ischemic stroke. In this study, we tested NL-1, a novel mitoNEET ligand, in a preclinical model of ischemic stroke with reperfusion using aged female rats. Using a transient middle cerebral artery occlusion (tMCAO), we induced a 2 h ischemic injury and then evaluated the effects of NL-1 treatment on ischemic/reperfusion brain injury at 24 and 72 h. Test compounds were administered at time of reperfusion via intravenous dosing. Results of the study demonstrated that NL-1 (10 mg/kg) treatment markedly improved survival and reduced infarct volume and hemispheric swelling in the brain as compared aged rats treated with vehicle or a lower dose of NL-1 (0.25 mg/kg). Interestingly, the protective effect of NL-1 was significantly improved when encapsulated in PLGA nanoparticles, where a 40-fold lesser dose (0.25 mg/kg) of NL-1 produced an equivalent effect as the 10 mg/kg dose. Evaluation of changes in blood-brain barrier permeability and lipid peroxidation corroborated the protective actions of NL-1 (10 mg/kg) or NL-1 NP treatment demonstrated a reduced accumulation of parenchymal IgG, decreased levels of 4-hydroxynonenal (4-HNE) and a decreased TUNEL positive cells in the brains of aged female rats at 72 h after tMCAO with reperfusion. Our studies indicate that targeting mitoNEET following ischemia/reperfusion-injury is a novel drug target pathway that warrants further investigation.

A host–gut microbial amino acid co-metabolite, p-cresol glucuronide, promotes blood–brain barrier integrity in vivo

ABSTRACT The sequential activity of gut microbial and host processes can exert a powerful modulatory influence on dietary components, as exemplified by the metabolism of the amino acids tyrosine and phenylalanine to p-cresol by gut microbes, and then to p-cresol glucuronide (pCG) by host enzymes. Although such glucuronide conjugates are classically thought to be biologically inert, there is accumulating evidence that this may not always be the case. We investigated the activity of pCG, studying its interactions with the cerebral vasculature and the brain in vitro and in vivo. Male C57Bl/6 J mice were used to assess blood–brain barrier (BBB) permeability and whole-brain transcriptomic changes in response to pCG treatment. Effects were then further explored using the human cerebromicrovascular endothelial cell line hCMEC/D3, assessing paracellular permeability, transendothelial electrical resistance and barrier protein expression. Mice exposed to pCG showed reduced BBB permeability and significant changes in whole-brain transcriptome expression. Surprisingly, treatment of hCMEC/D3 cells with pCG had no notable effects until co-administered with bacterial lipopolysaccharide, at which point it was able to prevent the permeabilizing effects of endotoxin. Further analysis suggested that pCG acts as an antagonist at the principal lipopolysaccharide receptor TLR4. The amino acid phase II metabolic product pCG is biologically active at the BBB, antagonizing the effects of constitutively circulating lipopolysaccharide. These data add to the growing literature showing glucuronide conjugates to be more than merely metabolic waste products and highlight the complexity of gut microbe to host communication pathways underlying the gut–brain axis.

Blood-brain barrier permeability changes in the first year after alemtuzumab treatment predict 2-year outcomes in relapsing-remitting multiple sclerosis

BackgroundIn relapsing-remitting multiple sclerosis (RRMS), early disease control reduces the risk of permanent disability. The blood–brain barrier (BBB) is compromised in MS, and its permeability is a potential biomarker. ObjectiveTo investigate BBB permeability measured by MRI as a marker of alemtuzumab efficacy. MethodsPatients with RRMS initiating alemtuzumab treatment were recruited prospectively. BBB permeability was assessed as the Patlak-derived influx constant (Ki) by dynamic contrast-enhanced MRI before and 6, 12, and 18 months after the first course of alemtuzumab. No Evidence of Disease Activity-3 (NEDA-3) status was ascertained two years after treatment initiation. ResultsPatients who maintained NEDA-3 status at two years (n = 7) had a larger decrease in Ki between baseline and six months (-0.029 ml/100 g/min [CI -0.005 − -0.053]) and between baseline and 12 months in normal appearing white matter (0.043 [CI 0.022 – -0.065]), than those who experienced disease activity (n = 8). ROC curve analysis of the Ki change between baseline and 12 months in NAWM predicted a loss of NEDA status at 2 years with 86% sensitivity and 86% specificity (AUC 0.98, p = 0.002). ConclusionBBB permeability predicted alemtuzumab efficacy at two years, indicating that BBB permeability is a biomarker of treatment response in RRMS.

Novel mitoNEET ligand NL‐1 improves therapeutic outcomes in an aged rat model of cerebral ischemia/reperfusion injury

Cerebral ischemic stroke is a leading cause of mortality and disability worldwide. Currently, there are a lack of drugs capable of reducing neuronal cell loss after ischemia/reperfusion‐injury after stroke. Previously, we identified mitoNEET, a [2Fe‐2S] redox mitochondrial protein, as a putative drug target for stroke. In this study, we tested the novel mitoNEET ligand, NL‐1, in a preclinical model of ischemic stroke with reperfusion using aged female rats. Using a transient middle cerebral artery occlusion (tMCAO), we induced a 2 h ischemic injury and then evaluated the effects of NL‐1 treatment on ischemic/reperfusion brain injury at 24 and 72 h. Test drugs were administered at time of reperfusion via IV dosing. Results demonstrated that NL‐1 (10 mg/kg) treatment markedly reduced infarct volume and hemispheric swelling in the brain as compared rats treated with vehicle or a lower concentration of NL‐1 (0.25 mg/kg). Surprisingly, the protective effect of NL‐1 was significantly improved when encapsulated in PLGA nanoparticles, where a 40‐fold lesser dose (0.25 mg/kg) of NL‐1 produced an equivalent effect as the 10 mg/kg dose. Evaluation of changes in blood‐brain barrier permeability and oxidative stress using immunohistochemical staining corroborated the protective actions of NL‐1, showing reduced extravasation of IgG and decreased levels of 4‐hydroxynonenal (4‐HNE) in the brains of aged female rats at 72 h after tMCAO with reperfusion. Our studies indicate that targeting mitoNEET following ischemia/reperfusion‐injury is a novel drug target pathway that warrants further investigation.

Inhibition of triple negative breast cancer-associated inflammation, tumor growth and brain colonization by targeting monoacylglycerol lipase

While the prevalence of breast cancer metastasis in the brain is significantly higher in triple negative breast cancers (TNBCs), there is a lack of novel and/or improved therapies for these patients. Monoacylglycerol lipase (MAGL) is a hydrolase involved in lipid metabolism that catalyzes the degradation of 2-arachidonoylglycerol (2-AG) linked to generation of pro- and anti-inflammatory molecules. Here, we targeted MAGL in TNBCs, using a potent carbamate-based inhibitor AM9928 (hMAGL IC50 = 9 nM) with prolonged pharmacodynamic effects (46 h of target residence time). AM9928 blocked TNBC cell adhesion and transmigration across human brain microvascular endothelial cells (HBMECs) in 3D co-cultures. In addition, AM9928 inhibited the secretion of IL-6, IL-8, and VEGF-A from TNBC cells. TNBC-derived exosomes activated HBMECs resulting in secretion of elevated levels of IL-8 and VEGF, which were inhibited by AM9928. Using in vivo studies of syngeneic GFP-4T1-BrM5 mammary tumor cells, AM9928 inhibited tumor growth in the mammary fat pads and attenuated blood brain barrier (BBB) permeability changes, resulting in reduced TNBC colonization in brain. Together, these results support the potential clinical application of MAGL inhibitors as novel treatments for TNBC.

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.

Visualization of blood-brain barrier disruption with dual-wavelength high-resolution photoacoustic microscopy.

The blood-brain barrier (BBB) strictly regulates the substance exchange between the vascular network and the central nervous system, and plays a critical role in maintaining normal brain homeostasis. Impaired BBB is often accompanied with the emergence of cerebral diseases and probably further leads to severe neuroinflammation or even neurological degeneration. Hence, there is an urgent need to precisely monitor the impaired BBB to understand its pathogenesis and better guide the enactment of therapeutic strategies. However, there is a lack of high-resolution imaging techniques to visualize and evaluate the large-scale BBB disruption in pre-clinical and clinical aspects. In this study, we propose a dual-wavelength photoacoustic imaging (PAI) methodology that simultaneously reveals the abnormal microvasculature and impaired BBB within the cerebral cortex. In in vivo studies, BBB disruption in both mice and rats were induced by local hot-water stimulation and unilateral carotid arterial perfusion of hyperosmolar mannitol, respectively. Subsequently, the exogenous contrast agent (CA) was injected into the microcirculation via the tail vein, and photoacoustic (PA) images of the microvasculature and leaked CA within the cerebral cortex were obtained by dual-wavelength photoacoustic microscopy to evaluate the BBB disruption. Besides, analysis of distribution and concentration of leaked CA in lesion region was further conducted to quantitatively reveal the dynamic changes of BBB permeability. Furthermore, we exploited this approach to investigate the reversibility of BBB disruption within the two distinct models. Based on the experimental results, this new proposed approach presents excellent performance in visualizing microvasculature and leaked CA, and enabling it possesses great potential in evaluating the abnormal microvasculature and impaired BBB result from cerebrovascular diseases.

Chronic cerebral hypoperfusion and blood-brain barrier disruption in uninjured brain areas of rhesus monkeys subjected to transient ischemic stroke

Blood-brain barrier (BBB) disruption is a pivotal pathophysiological process in ischemic stroke. Although temporal changes in BBB permeability during the acute phase have been widely studied, little is known about the chronic phase of cerebrovascular changes that may have a large impact on the long-term outcome. Therefore, this study was aimed to measure cerebral vascular abnormalities using CT perfusion in nine rhesus monkeys subjected to transient middle cerebral artery occlusion (tMCAO) for ≥1 year (MCAO-1Y+). The level of cerebral perfusion demonstrated by mean transit time was significantly higher in the ipsilateral caudate nucleus, white matter, thalamus, hippocampus, and contralateral thalamus in MCAO-1Y+ compared with the other nine age-matched control monkeys. The increase in BBB permeability measured through the permeability surface was found in the same ten regions of interest ipsilaterally and contralaterally. We also found decreased levels of Aβ 42/40 ratio in the cerebrospinal fluid (CSF), suggesting a potential link between post-MCAO cognitive decline and Aβ metabolism. Overall, we demonstrated significant cerebral hypoperfusion, BBB disruption, and CSF Aβ decrease during the rehabilitation stage of ischemic stroke in a non-human primate model. Future studies are needed to elucidate the cause-effect relationship between cerebrovascular disruptions and long-term neurological deficits.

Stress and the gut-brain axis: Cognitive performance, mood state, and biomarkers of blood-brain barrier and intestinal permeability following severe physical and psychological stress

BackgroundPhysical and psychological stress alter gut-brain axis activity, potentially causing intestinal barrier dysfunction that may, in turn, induce cognitive and mood impairments through exacerbated inflammation and blood brain barrier (BBB) permeability. These interactions are commonly studied in animals or artificial laboratory environments. However, military survival training provides an alternative and unique human model for studying the impacts of severe physical and psychological stress on the gut-brain axis in a realistic environment. PurposeTo determine changes in intestinal barrier and BBB permeability during stressful military survival training and identify relationships between those changes and markers of stress, inflammation, cognitive performance, and mood state. Materials and methodsSeventy-one male U.S. Marines (25.2 ± 2.6 years) were studied during Survival, Evasion, Resistance, and Escape (SERE) training. Measurements were conducted on day 2 of the 10-day classroom phase of training (PRE), following completion of the 7.5-day field-based simulation phase of the training (POST), and following a 27-day recovery period (REC). Fat-free mass (FFM) was measured to assess the overall physiologic impact of the training. Biomarkers of intestinal permeability (liposaccharide-binding protein [LBP]) and BBB permeability (S100 calcium-binding protein B [S100B]), stress (cortisol, dehydroepiandrosterone sulfate [DHEA-S] epinephrine, norepinephrine) and inflammation (interleukin-6 [IL-6], high-sensitivity C-reactive protein [hsCRP]) were measured in blood. Cognitive performance was assessed by psychomotor vigilance (PVT) and grammatical reasoning (GR) tests, and mood state by the Profile of Mood States (total mood disturbance; TMD), General Anxiety Disorder-7 (GAD-7), and Patient Health (PHQ-9) questionnaires. ResultsFFM, psychomotor vigilance, and LBP decreased from PRE to POST, while TMD, anxiety, and depression scores, and S100B, DHEA-S, IL-6, norepinephrine, and epinephrine concentrations all increased (all p ≤ 0.01). Increases in DHEA-S were associated with decreases in body mass (p = 0.015). Decreases in FFM were associated with decreases in LBP concentrations (p = 0.015), and both decreases in FFM and LBP were associated with increases in TMD and depression scores (all p < 0.05) but not with changes in cognitive performance. Conversely, increases in S100B concentrations were associated with decreases in psychomotor vigilance (p < 0.05) but not with changes in mood state or LBP concentrations. ConclusionsEvidence of increased intestinal permeability was not observed in this military survival training-based model of severe physical and psychological stress. However, increased BBB permeability was associated with stress and cognitive decline, while FFM loss was associated with mood disturbance, suggesting that distinct mechanisms may contribute to decrements in cognitive performance and mood state during the severe physical and psychological stress experienced during military survival training.

Whole-Brain Permeability Analysis on Admission Improves Prediction of Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage

PurposeTo evaluate the changes of blood-brain barrier permeability (BBBP) after aneurysmal subarachnoid hemorrhage (aSAH) and find out whether BBBP within 24 h after onset can further improve prediction of delayed cerebral ischemia (DCI). MethodsCT perfusion (CTP) was performed within 24 h after onset and in the DCI time window (DCITW). Whole brain average values of flow extraction product (mKtrans), qualitative and quantitative CTP parameters, and clinical data were compared between DCI and non-DCI groups. The changes of mKtrans were analysed using a Paired t test. Multivariate logistic regression analysis and ROC analyses were performed to identify predictors of DCI and evaluate the predictive performance. ResultsOne hundred and forty of 179 consecutive patients were included, 45 of whom (32%) developed DCI. mKtrans was higher in the DCI group both on admission and in the DCITW (P<0.001). mKtrans decreased significantly in the non-DCI group (P=0.003), but not in DCI group (P=0.285). Multivariate logistic regression analysis showed that mKtrans (OR=1.07, 95%CI: 1.03-1.11, P<0.001), World Federation of Neurosurgery Scale (OR=6.73, 95%CI: 1.09-41.41, P=0.040), Hunt-Hess grade (OR=0.16, 95%CI: 0.02-1.19, P=0.073), modified Fisher Score (OR=3.74, 95%CI: 1.30-10.75, P=0.014), and qualitative CTP (OR=4.31, 95%CI: 1.49-12.47, P=0.007) were independent predictors of DCI. The model with Ktrans produced a larger AUC of 0.88 (95%CI: 0.81-0.95), with corresponding sensitivity and specificity of 84% and 86%, respectively. ConclusionBBBP measurement within 24 h after onset can improve the prediction of DCI. Early moderate BBB disruption may be reversible, whereas severe BBBP disruption indicates the risk of DCI.

Sonobiopsy for minimally invasive, spatiotemporally-controlled, and sensitive detection of glioblastoma-derived circulating tumor DNA.

Though surgical biopsies provide direct access to tissue for genomic characterization of brain cancer, they are invasive and pose significant clinical risks. Brain cancer management via blood-based liquid biopsies is a minimally invasive alternative; however, the blood-brain barrier (BBB) restricts the release of brain tumor-derived molecular biomarkers necessary for sensitive diagnosis.Methods: A mouse glioblastoma multiforme (GBM) model was used to demonstrate the capability of focused ultrasound (FUS)-enabled liquid biopsy (sonobiopsy) to improve the diagnostic sensitivity of brain tumor-specific genetic mutations compared with conventional blood-based liquid biopsy. Furthermore, a pig GBM model was developed to characterize the translational implications of sonobiopsy in humans. Magnetic resonance imaging (MRI)-guided FUS sonication was performed in mice and pigs to locally enhance the BBB permeability of the GBM tumor. Contrast-enhanced T1-weighted MR images were acquired to evaluate the BBB permeability change. Blood was collected immediately after FUS sonication. Droplet digital PCR was used to quantify the levels of brain tumor-specific genetic mutations in the circulating tumor DNA (ctDNA). Histological staining was performed to evaluate the potential for off-target tissue damage by sonobiopsy.Results: Sonobiopsy improved the detection sensitivity of EGFRvIII from 7.14% to 64.71% and TERT C228T from 14.29% to 45.83% in the mouse GBM model. It also improved the diagnostic sensitivity of EGFRvIII from 28.57% to 100% and TERT C228T from 42.86% to 71.43% in the porcine GBM model.Conclusion: Sonobiopsy disrupts the BBB at the spatially-targeted brain location, releases tumor-derived DNA into the blood circulation, and enables timely collection of ctDNA. Converging evidence from both mouse and pig GBM models strongly supports the clinical translation of sonobiopsy for the minimally invasive, spatiotemporally-controlled, and sensitive molecular characterization of brain cancer.

LncRNA SNHG8 sponges miR-449c-5p and regulates the SIRT1/FoxO1 pathway to affect microglia activation and blood-brain barrier permeability in ischemic stroke.

Ischemic stroke (IS) can cause disability and death, and microglia as the immune component of the CNS can release inflammatory factors and participate in blood-brain barrier (BBB) dysfunction. This study aimed to investigate the effects of long noncoding RNA (lncRNA) SNHG8 on microglia activation and BBB permeability in IS. A rat model of permanent middle cerebral artery occlusion (p-MCAO) and a cell model of oxygen and glucose deprivation (OGD) in microglia were established, followed by evaluation of neurobehavioral function, BBB permeability, brain edema, and pathologic changes of microglia in brain tissue. The activation status of microglia and expressions of inflammatory factors were detected. Cell viability and integrity of microglia membrane were assessed. The downstream microRNA (miR), gene, and pathway of SNHG8 were analyzed. LncRNA SNHG8 was down-regulated in MCAO rats. Overexpression of SNHG8 improved the neural function defect, reduced brain water content, BBB permeability, brain tissue damage and inflammation, and inhibited microglia activation. In OGD-induced microglia, overexpression of SNHG8 or miR-449c-5p down-regulation increased cell viability and decreased lactate dehydrogenase activity. Moreover, SNHG8 sponged miR-449c-5p to regulate SIRT1. Overexpression of SNHG8 increased the expression of SIRT1 and FoxO1. MiR-449c-5p mimic could annul the effect of SNHG8 overexpression on ischemic microglia. Collectively, SNHG8 inhibits microglia activation and BBB permeability via the miR-449c-5p/SIRT1/FoxO1 pathway, thus eliciting protective effects on ischemic brain injury.