Blood-Brain Barrier Disruption for the Treatment of Primary Brain Tumors: Advances in the Past Half-Decade.

PURPOSE OF REVIEW: To review relevant advances in the past half-decade in the treatment of primary brain tumors via modification of blood-brain barrier (BBB) permeability. RECENT FINDINGS: BBB disruption is becoming increasingly common in the treatment of primary brain tumors. Use of mannitol in BBB disruption for targeted delivery of chemotherapeutics via superselective intra-arterial cerebral infusion (SIACI) is the most utilized strategy to modify the BBB. Mannitol is used in conjunction with chemotherapeutics, oligonucleotides, and other active agents. Convection-enhanced delivery has become an attractive option for therapeutic delivery while bypassing the BBB. Other technologic innovations include laser interstitial thermal therapy (LITT) and focused ultrasound (FUS) which have emerged as prime modalities to directly target tumors and cause significant local BBB disruption. In the past 5 years, interest has significantly increased in studying modalities to disrupt the BBB in primary brain tumors to enhance treatment responses and improve clinical outcomes.

The role of focused ultrasound for pediatric brain tumors: current insights and future implications on treatment strategies.

INTRODUCTION: Focused ultrasound (FUS) is an innovative and emerging technology for the treatment of adult and pediatric brain tumors and illustrates the intersection of various specialized fields, including neurosurgery, neuro-oncology, radiation oncology, and biomedical engineering. OBJECTIVE: The authors provide a comprehensive overview of the application and implications of FUS in treating pediatric brain tumors, with a special focus on pediatric low-grade gliomas (pLGGs) and the evolving landscape of this technology and its clinical utility. METHODS: The fundamental principles of FUS include its ability to induce thermal ablation or enhance drug delivery through transient blood-brain barrier (BBB) disruption, emphasizing the adaptability of high-intensity focused ultrasound (HIFU) and low-intensity focused ultrasound (LIFU) applications. RESULTS: Several ongoing clinical trials explore the potential of FUS in offering alternative therapeutic strategies for pathologies where conventional treatments fall short, specifically centrally-located benign CNS tumors and diffuse intrinsic pontine glioma (DIPG). A case illustration involving the use of HIFU for pilocytic astrocytoma is presented. CONCLUSION: Discussions regarding future applications of FUS for the treatment of gliomas include improved drug delivery, immunomodulation, radiosensitization, and other technological advancements.

Post-endovascular therapy contrast extravasation in the mesial temporal region on dual-energy CT is associated with outcome in acute ischemic stroke patients.

PURPOSE: Pre- and post-endovascular treatment (EVT) imaging may aid in predicting functional outcomes in acute middle cerebral artery (MCA) ischemic stroke. Low post-EVT contrast extravasation (CE)-ASPECTS is associated with poor functional outcomes. Besides the MCA regions included in the ASPECTS score, CE may be seen in the mesial temporal (MT) region. In this study, we investigated the frequency and prognostic implication of MT-CE in acute ischemic stroke patients. METHODS: Patients with an acute ischemic stroke due to anterior large vessel occlusion who received EVT and post-EVT DECT between 2010 and 2019 were included. Iodine overlay maps of DECT were assessed for the occurrence of CE, using the ASPECTS for occurrence in the MCA region and, calculating a CE-ASPECTS, for whether the MT region was involved. Multivariable linear and logistic regression were used to assess the relationship between involvement of MT-CE and 24-48h NIHSS, mRS, and mortality on a multiple imputed dataset. All models were adjusted significant variables in univariate analyses and for total CE-ASPECTS. RESULTS: 501/651 patients met the inclusion criteria. MT-CE occurred in 97 (19 %) patients, and was more often present in patients with internal carotid artery occlusions. MT-CE was associated with higher NIHSS scores at 24-hours (aß 2.2, 95 % CI 0.09-4.31), with increased risk of higher mRS scores (acOR 1.88, 95 % CI 1.16-3.06), and with increased risk of mortality (aOR 2.12, 95 % CI 1.16-3.86). CONCLUSION: MT-CE is a common finding on post-EVT DECT and is an independent predictor for worse functional outcomes.

Effects of Diabetes Mellitus-Related Dysglycemia on the Functions of Blood-Brain Barrier and the Risk of Dementia.

Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of the blood-brain barrier (BBB), seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin-independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response, which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aß aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity.

Good outcome associated with blood-brain barrier disruption and lower blood pressure after endovascular therapy.

OBJECTIVES: To evaluate the association between post-endovascular thrombectomy (EVT) blood-brain barrier (BBB) disruption on MRI or CT and average systolic blood pressure (SBP) with favorable 90-day functional outcome. Observational studies have found elevated SBP associated with worse outcomes post-EVT, while recent randomized trials found no difference in targeted BP reduction. There may be a subgroup of patients who benefit from targeted BP reduction post-EVT. METHODS: This is a single-center study of 1) anterior large vessel occlusion stroke patients treated with EVT from 2015 to 2021, 2) achieved mTICI grade 2b or 3. Hyperintense acute reperfusion marker (HARM), hemorrhagic transformation (HT), and midline shift at 3 h post-EVT and 24 h imaging were assessed independently by multiple raters. Binary logistic regression models were used to determine the association of post-EVT SBP with outcomes. BBB disruption was defined as HT or HARM on 3h post-EVT imaging. RESULTS: Of 103 patients, those with SBP 100-129 versus SBP 130-160 found no significant difference in favorable 90-day outcome (64% vs. 46%, OR 2.11, 95% CI 0.78-5.76, p=0.143). However, among 71 patients with BBB disruption, a significant difference in favorable outcome of 64% in SBP 100-129 vs. 39% in SBP 130-160 group (OR 5.93, 95% CI 1.50-23.45, p=0.011) was found. There was no difference in symptomatic ICH, 90-day mortality, midline shift (≥5 mm), and hemicraniectomy, between BP or BBB groups. CONCLUSIONS: BBB disruption on 3h post-EVT imaging and lower SBP was associated with favorable outcome. This imaging finding may guide targeted BP therapy and suggests need for a randomized control trial.

Endogenous FGF21 attenuates blood-brain barrier disruption in penumbra after delayed recanalization in MCAO rats through FGFR1/PI3K/Akt pathway. / å† æºæ€§FGF21通过FGFR1/PI3K/Akt通路减轻MCAOå¤§é¼ å»¶è¿Ÿè¡€ç®¡å†é€šåŽåŠæš—å¸¦çš„è¡€è„‘å±éšœæŸä¼¤ï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Restoration of blood circulation within "time window" is the principal treating goal for treating acute ischemic stroke. Previous studies revealed that delayed recanalization might cause serious ischemia/reperfusion injury. However, plenty of evidences showed delayed recanalization improved neurological outcomes in acute ischemic stroke. This study aims to explore the role of delayed recanalization on blood-brain barrier (BBB) in the penumbra (surrounding ischemic core) and neurological outcomes after middle cerebral artery occlusion (MCAO). METHODS: Recanalization was performed on the 3rd day after MCAO. BBB disruption was tested by Western blotting, Evans blue dye, and immunofluorescence staining. Infarct volume and neurological outcomes were evaluated on the 7th day after MCAO. The expression of fibroblast growth factor 21 (FGF21), fibroblast growth factor receptor 1 (FGFR1), phosphatidylinositol-3-kinase (PI3K), and serine/threonine kinase (Akt) in the penumbra were observed by immunofluorescence staining and/or Western blotting. RESULTS: The extraversion of Evans blue, IgG, and albumin increased surrounding ischemic core after MCAO, but significantly decreased after recanalization. The expression of Claudin-5, Occludin, and zona occludens 1 (ZO-1) decreased surrounding ischemic core after MCAO, but significantly increased after recanalization. Infarct volume reduced and neurological outcomes improved following recanalization (on the 7th day after MCAO). The expressions of Claudin-5, Occludin, and ZO-1 decreased surrounding ischemic core following MCAO, which were up-regulated corresponding to the increases of FGF21, p-FGFR1, PI3K, and p-Akt after recanalization. Intra-cerebroventricular injection of FGFR1 inhibitor SU5402 down-regulated the expression of PI3K, p-Akt, Occludin, Claudin-5, and ZO-1 in the penumbra, which weakened the beneficial effects of recanalization on neurological outcomes after MCAO. CONCLUSIONS: Delayed recanalization on the 3rd day after MCAO increases endogenous FGF21 in the penumbra and activates FGFR1/PI3K/Akt pathway, which attenuates BBB disruption in the penumbra and improves neurobehavior in MCAO rats.

Technical Principles and Clinical Workflow of Transcranial MR-Guided Focused Ultrasound.

Transcranial MR-guided focused ultrasound (MRgFUS) is a rapidly developing technology in neuroscience for manipulating brain structure and function without open surgery. The effectiveness of transcranial MRgFUS for thermoablation is well established, and the technique is actively employed worldwide for movement disorders including essential tremor. A growing number of centers are also investigating the potential of microbubble-mediated focused ultrasound-induced opening of the blood-brain barrier (BBB) for targeted drug delivery to the brain. Here, we provide a technical overview of the principles, clinical workflow, and operator considerations of transcranial MRgFUS procedures for both thermoablation and BBB opening.

Neuropathophysiology of coronavirus disease 2019: neuroinflammation and blood brain barrier disruption are critical pathophysiological processes that contribute to the clinical symptoms of SARS-CoV-2 infection.

Coronavirus disease 2019 (COVID-19) is caused by the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) first discovered in Wuhan, Hubei province, China in December 2019. SARS-CoV-2 has infected several millions of people, resulting in a huge socioeconomic cost and over 2.5 million deaths worldwide. Though the pathogenesis of COVID-19 is not fully understood, data have consistently shown that SARS-CoV-2 mainly affects the respiratory and gastrointestinal tracts. Nevertheless, accumulating evidence has implicated the central nervous system in the pathogenesis of SARS-CoV-2 infection. Unfortunately, however, the mechanisms of SARS-CoV-2 induced impairment of the central nervous system are not completely known. Here, we review the literature on possible neuropathogenic mechanisms of SARS-CoV-2 induced cerebral damage. The results suggest that downregulation of angiotensin converting enzyme 2 (ACE2) with increased activity of the transmembrane protease serine 2 (TMPRSS2) and cathepsin L in SARS-CoV-2 neuroinvasion may result in upregulation of proinflammatory mediators and reactive species that trigger neuroinflammatory response and blood brain barrier disruption. Furthermore, dysregulation of hormone and neurotransmitter signalling may constitute a fundamental mechanism involved in the neuropathogenic sequelae of SARS-CoV-2 infection. The viral RNA or antigenic peptides also activate or interact with molecular signalling pathways mediated by pattern recognition receptors (e.g., toll-like receptors), nuclear factor kappa B, Janus kinase/signal transducer and activator of transcription, complement cascades, and cell suicide molecules. Potential molecular targets and therapeutics of SARS-CoV-2 induced neurologic damage are also discussed.

Cilostazol ameliorates ischemia/reperfusion-induced tight junction disruption in brain endothelial cells by inhibiting endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress is essential for brain ischemia/reperfusion (I/R) injury. However, whether it contributes to I/R-induced blood-brain barrier (BBB) injury remains unclear. cilostazol exerts protective effects toward I/R-induced BBB injury, with unclear mechanisms. This study explored the potential role of ER stress in I/R-induced endothelial cell damage and determined whether the therapeutic potential of cilostazol, with respect to I/R-induced endothelial cell damage, is related to inhibition of ER stress. We found that exposing brain endothelial cells (bEnd.3) to oxygen-glucose deprivation/reoxygenation (OGD/R) significantly activated ER stress and diminished the barrier function of cell monolayers; treatment with the ER stress inhibitor 4-phenylbutyric acid (4-PBA) or cilostazol prevented OGD/R-induced ER stress and preserved barrier function. Furthermore, OGD/R induced the expression and secretion of matrix metalloproteinase-9 and nuclear translocation of phosphorylated NF-κB. These changes were partially reversed by 4-PBA or cilostazol treatment. In vivo, 4-PBA or cilostazol significantly attenuated I/R-induced ER stress and ameliorated Evans blue leakage and tight junction loss. These results demonstrate that I/R-induced ER stress participates in BBB disruption. Targeting ER stress could be a useful strategy to protect the BBB from ischemic stroke, and cilostazol is a promising therapeutic agent for this process.-Nan, D., Jin, H., Deng, J., Yu, W., Liu, R., Sun, W., Huang, Y. Cilostazol ameliorates ischemia/reperfusion-induced tight junction disruption in brain endothelial cells by inhibiting endoplasmic reticulum stress.

Mechanisms of Blood-Brain Barrier Dysfunction in Traumatic Brain Injury.

Traumatic brain injuries (TBIs) account for the majority of injury-related deaths in the United States with roughly two million TBIs occurring annually. Due to the spectrum of severity and heterogeneity in TBIs, investigation into the secondary injury is necessary in order to formulate an effective treatment. A mechanical consequence of trauma involves dysregulation of the blood-brain barrier (BBB) which contributes to secondary injury and exposure of peripheral components to the brain parenchyma. Recent studies have shed light on the mechanisms of BBB breakdown in TBI including novel intracellular signaling and cell-cell interactions within the BBB niche. The current review provides an overview of the BBB, novel detection methods for disruption, and the cellular and molecular mechanisms implicated in regulating its stability following TBI.

Superselective intraarterial cerebral infusion of cetuximab with blood brain barrier disruption combined with Stupp Protocol for newly diagnosed glioblastoma.

OBJECTIVE: We describe the first case of a novel treatment for a newly diagnosed glioblastoma (GBM) using superselective intraarterial cerebral infusion (SIACI) of cetuximab after osmotic disruption of the blood-brain barrier (BBB) with mannitol. A 51year-old female underwent craniotomy for removal of a right frontal GBM. Pathology confirmed EGFR amplification, and she underwent three treatments of SIACI of cetuximab to the tumor site. The first treatment was given within a week of starting standard of care chemoradiation (Stupp protocol), which is a combination of radiation treatment (2 Gy per/ day x 30 days, total of 60 Gy) and oral temozolomide (75 mg/m2). The second and third SIACI of cetuximab were administered 3 and 6 months later, while the patient continued on maintenance temozolomide. Post-radiation changes on MRI were stable, and there were no signs of recurrence at 4 and 6 months post-resection. Herein, we detail the technical aspects of this novel treatment paradigm and suggest that SIACI of cetuximab after BBB disruption using mannitol, combined with the standard of care chemoradiation therapy, may be an effective treatment method for newly diagnosed EGFR amplified glioblastoma.

Intracerebral synthesis of glutamine from hyperpolarized glutamate.

PURPOSE: Changes in glutamate (Glu) levels occur in a number of neurodegenerative diseases. We proposed the use of 13 C spectroscopy and the highly amplified signal generated by hyperpolarization to achieve spatial and temporal resolutions adequate for in vivo studies of Glu metabolism in the healthy rat brain. Thus, we investigated uptake of hyperpolarized [1-13C ]Glu after a temporary blood-brain barrier (BBB) disruption protocol and its conversion to glutamine (Gln) in the brain. METHODS: [1-13 C]Glu was hyperpolarized using the dynamic nuclear polarization process. A temporary BBB disruption using mannitol allowed hyperpolarized [1-13 C]Glu to reach the brain. Then, hyperpolarized [1-13 C]Glu brain metabolism was observed in vivo by MR spectroscopy experiments at 3T. Products synthesized from [1-13 C]Glu were assigned via liquid chromatography-mass spectrometry. RESULTS: Hyperpolarized [1-13 C]Glu reached 20% ± 2.3% polarization after 90 min. After validation of the BBB disruption protocol, hyperpolarized [1-13 C]Glu (175.4 ppm) was detected inside the rat brain, and the formation of [1-13 C]Gln at 174.9 ppm was also observed. CONCLUSION: The Gln synthesis from hyperpolarized [1-13 C]Glu can be monitored in vivo in the healthy rat brain after opening the BBB. Magn Reson Med 78:1296-1305, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Long-term benefit of intra-arterial bevacizumab for recurrent glioblastoma.

OBJECTIVE: Standard treatment for recurrent GBM is not yet established. We present a case demonstrating the benefit of intra-arterial (IA) bevacizumab with blood brain barrier disruption (BBBD) for the treatment of recurrent GBM. A 31 year-old man diagnosed with GBM, following primary resection, received temozolomide. After a second resection, he received one dose of IA bevacizumab with BBBD using mannitol, preventing regrowth for 2.5 years. Following tumor regrowth, the patient received another dose of IA bevacizumab with BBBD, which has prevented regrowth for another year.

Prediction of infarction development after endovascular stroke therapy with dual-energy computed tomography.

OBJECTIVES: After intraarterial recanalisation (IAR), the haemorrhage and the blood-brain barrier (BBB) disruption can be distinguished using dual-energy computed tomography (DECT). The aim of the present study was to investigate whether future infarction development can be predicted from DECT. METHODS: DECT scans of 20 patients showing 45 BBB disrupted areas after IAR were assessed and compared with follow-up examinations. Receiver operator characteristic (ROC) analyses using densities from the iodine map (IM) and virtual non-contrast (VNC) were performed. RESULTS: Future infarction areas are denser than future non-infarction areas on IM series (23.44 ± 24.86 vs. 5.77 ± 2.77; p < 0.0001) and more hypodense on VNC series (29.71 ± 3.33 vs. 35.33 ± 3.50; p < 0.0001). ROC analyses for the IM series showed an area under the curve (AUC) of 0.99 (cut-off: <9.97 HU; p < 0.05; sensitivity 91.18 %; specificity 100.00 %; accuracy 0.93) for the prediction of future infarctions. The AUC for the prediction of haemorrhagic infarctions was 0.78 (cut-off >17.13 HU; p < 0.05; sensitivity 90.00 %; specificity 62.86 %; accuracy 0.69). The VNC series allowed prediction of infarction volume. CONCLUSIONS: Future infarction development after IAR can be reliably predicted with the IM series. The prediction of haemorrhages and of infarction size is less reliable. KEY POINTS: • The IM series (DECT) can predict future infarction development after IAR. • Later haemorrhages can be predicted using the IM and the BW series. • The volume of definable hypodense areas in VNC correlates with infarction volume.

Finding a Balance between Protection and Pathology: The Dual Role of Perforin in Human Disease.

Perforin is critical for controlling viral infection and tumor surveillance. Clinically, mutations in perforin are viewed as unfavorable, as lack of this pore-forming protein results in lethal, childhood disease, familial hemophagocytic lymphohistiocytosis type 2 (FHL 2). However, many mutations in the coding region of PRF1 are not yet associated with disease. Animal models of viral-associated blood-brain barrier (BBB) disruption and experimental cerebral malaria (ECM) have identified perforin as critical for inducing pathologic central nervous system CNS vascular permeability. This review focuses on the role of perforin in both protecting and promoting human disease. It concludes with a novel hypothesis that diversity observed in the PRF1 gene may be an example of selective advantage that protects an individual from perforin-mediated pathology, such as BBB disruption.

Acute Alcohol Intoxication Aggravates Brain Injury Caused by Intracerebral Hemorrhage in Rats.

OBJECTIVE: Alcohol intoxication is associated with worse intracerebral hemorrhage (ICH) outcome, indicating the important role of alcohol in ICH pathogenesis. We intended to investigate the effects of ethanol pretreatment on the severity of ICH-induced brain injury in rats. METHODS: At 1 hour after intraperitoneal injection of ethanol (3 g/kg), 0.2 U bacterial collagenase was infused into the striatum of male Sprague-Dawley rats to induce ICH. Accumulative mortality rate, body weight changes, and motorsensory and neurological abnormalities were evaluated. The hemorrhagic volume, hematoma expansion, and water content were measured by Drabkin's method, morphometric assay, and dry/wet method, respectively. Blood-brain barrier disruption was assessed using Evans blue assay. Oxidative stress was evaluated by the enzymatic activity of glutathione peroxidase, oxidation of hydroethidine, and the production of malondialdehyde. Cerebral blood flow perfusion volume and hypo-/hyperperfusion neuroimaging were examined by magnetic resonance imaging. RESULTS: Ethanol pretreatment aggravates the hematoma hemolysis, hemorrhagic volume, hematoma expansion, brain edema, blood-brain barrier disruption, microglial activation, elevated oxidative stress, and neuroinflammation in the hemorrhagic striatum. The summation effect of these consequences is the major cause of marked neurological impairment and higher mortality rate (64%) in ethanol-pretreated rats with ICH. CONCLUSION: This is a novel model to evaluate the effects of high-dose alcohol administration on experimental ICH rats. IMPLICATIONS: The present study may provide clues for making novel strategies in the management of patients with ICH who overconsume alcoholic drinks before the attack.

Recombinant ADAMTS 13 Attenuates Brain Injury After Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Inflammatory responses and blood-brain barrier (BBB) dysfunction play important roles in brain injury after intracerebral hemorrhage (ICH). The metalloprotease ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type I motif, member 13) was shown to limit inflammatory responses through its proteolytic effects on von Willebrand factor. In the present study, we addressed the role of ADAMTS 13 after experimental ICH. METHODS: ICH was induced in mice by intracerebral infusion of autologous blood. The peri-hematomal inflammatory responses, levels of matrix metalloproteinase-9 and intercellular adhesion molecule-1, pericyte coverage on brain capillaries, and BBB permeability were quantified at 24 hours. Functional outcomes, cerebral edema, and hemorrhagic lesion volume were quantified at day 3. RESULTS: Treatment with recombinant ADAMTS 13 (rADAMTS 13) reduced the levels of chemokines and cytokines, myeloperoxidase activity, and microglia activation and neutrophil recruitment after ICH. rADAMTS 13 also decreased interleukin-6 expression in brain endothelial cells stimulated by lipopolysaccharide, whereas recombinant von Willebrand factor reversed this effect. The anti-inflammatory effect of rADAMTS 13 was accompanied by reduced expression of intercellular adhesion molecule-1 and less activation of matrix metalloproteinase, enhanced pericyte coverage of brain microvessels, and attenuated BBB disruption. Furthermore, neutrophil depletion protected against BBB damage, and rADAMTS 13 treatment had no further beneficial effect. Finally, treatment of mice with rADAMTS 13 reduced cerebral edema and hemorrhagic lesion volume and improved neurological functions. CONCLUSIONS: Our findings reveal the importance of rADAMTS 13 in regulating pathological inflammation and BBB function and suggest that rADAMTS 13 may provide a new therapeutic strategy for ICH.

Quantitative assessment of cerebral glucose metabolic rates after blood-brain barrier disruption induced by focused ultrasound using FDG-MicroPET.

The goal of this study was to evaluate the pharmacokinetics of (18)F-2-fluoro-2-deoxy-d-glucose ((18)F-FDG) and the expression of glucose transporter 1 (GLUT1) protein after blood-brain barrier (BBB) disruption of normal rat brains by focused ultrasound (FUS). After delivery of an intravenous bolus of ~37 MBq (1 mCi) (18)F-FDG, dynamic positron emission tomography scans were performed on rats with normal brains and those whose BBBs had been disrupted by FUS. Arterial blood sampling was collected throughout the scanning procedure. A 2-tissue compartmental model was used to estimate (18)F-FDG kinetic parameters in brain tissues. The rate constants Ki, K1, and k3 were assumed to characterize the uptake, transport, and hexokinase activity, respectively, of (18)F-FDG. The uptake of (18)F-FDG in brains significantly decreased immediately after the blood-brain barrier was disrupted. At the same time, the derived values of Ki, K1, and k3 for the sonicated brains were significantly lower than those for the control brains. In agreement with the reduction in glucose, Western blot analyses confirmed that focused ultrasound exposure significantly reduced the expression of GLUT1 protein in the brains. Furthermore, the effect of focused ultrasound on glucose uptake was transient and reversible 24h after sonication. Our results indicate that focused ultrasound may inhibit GLUT1 expression to decrease the glucose uptake in brain tissue during the period of BBB disruption.

Application of Delayed Contrast Extravasation Magnetic Resonance Imaging for Depicting Subtle Blood-Brain Barrier Disruption in a Traumatic Brain Injury Model.

The blood-brain barrier (BBB) is composed of brain microvasculature that provides selective transport of solutes from the systemic circulation into the central nervous system to protect the brain and spinal microenvironment. Damage to the BBB in the acute phase after traumatic brain injury (TBI) is recognized as a major underlying mechanism leading to secondary long-term damage. Because of the lack of technological ability to detect subtle BBB disruption (BBBd) in the chronic phase, however, the presence of chronic BBBd is disputable. Thus, the dynamics and course of long-term BBBd post-TBI remains elusive. Thirty C57BL/6 male mice subjected to TBI using our weight drop closed head injury model and 19 naïve controls were scanned by magnetic resonance imaging (MRI) up to 540 days after injury. The BBB maps were calculated from delayed contrast extravasation MRI (DCM) with high spatial resolution and high sensitivity to subtle BBBd, enabling depiction and quantification of BBB permeability. At each time point, 2-6 animals were sacrificed and their brains were extracted, sectioned, and stained for BBB biomarkers including: blood microvessel coverage by astrocyte using GFAP, AQP4, ZO-1 gaps, and IgG leakage. We found that DCM provided depiction of subtle yet significant BBBd up to 1.5 years after TBI, with significantly higher sensitivity than standard contrast-enhanced T1-weighted and T2-weighted MRI (BBBd volumes main effect DCM/T1/T2 p < 0.0001 F(2,70) = 107.3, time point p < 0.0001 F(2,133, 18.66) = 23.53). In 33% of the cases, both in the acute and chronic stages, there was no detectable enhancement on standard T1-MRI, nor detectable hyperintensities on T2-MRI, whereas DCM showed significant BBBd volumes. The BBBd values of TBI mice at the chronic stage were found significantly higher compared with age matched naïve animals at 30, 60, and 540 days. The calculated BBB maps were histologically validated by determining significant correlation between the calculated levels of disruption and a diverse set of histopathological parameters obtained from different brain regions, presenting different components of the BBB. Cumulative evidence from recent years points to BBBd as a central component of the pathophysiology of TBI. Therefore, it is expected that routine use of highly sensitive non-invasive techniques to measure BBBd, such as DCM with advanced analysis methods, may enhance our understanding of the changes in BBB function after TBI. Application of the DCM technology to other CNS disorders, as well as to normal aging, may shed light on the involvement of chronic subtle BBBd in these conditions.

Focused ultrasound blood-brain barrier disruption in high-grade gliomas: Scoping review of clinical studies.

BACKGROUND: This scoping review aims to comprehensively review the available literature on the safety and efficacy of focused ultrasound (FUS) for blood-brain barrier disruption (BBBD) in patients with high-grade gliomas, including glioblastoma (GBM). High-grade gliomas pose significant challenges in neuro-oncology due to their aggressiveness and intricate location, often limiting the efficacy of traditional treatments. FUS offers a promising approach by transiently disrupting the blood-brain barrier, thereby facilitating enhanced drug delivery to tumor cells while minimizing systemic side effects. METHODS: A scoping review adhering to PRISMA guidelines was conducted to explore the literature on FUS-induced BBBD in glioma patients. PubMed and Embase databases were searched from inception to April 2024 using defined keywords. Original clinical studies focusing on FUS for BBBD in gliomas were included. Two reviewers independently screened records, with conflicts resolved by a third reviewer. Data extraction and quality assessment were performed accordingly. RESULTS: A total of 1,310 studies were initially identified, resulting in nine eligible studies after screening and selection. These studies, published between 2016 and 2024, included 106 patients (39.6 % female) with ages ranging from 29 to 80 years. Recurrent GBM was the most common diagnosis (100 patients), with other diagnoses including anaplastic astrocytoma, diffuse infiltrating glioma, and oligodendroglioma. Various FUS devices and microbubble contrast agents were employed across the studies. Safety and efficacy were assessed in both experimental and clinical settings, with no significant adverse events reported during BBBD procedures. Notably, BBBD facilitated enhanced drug delivery to tumor tissue, demonstrating potential therapeutic benefits. CONCLUSION: Studies investigating BBBD using FUS demonstrate promising outcomes in experimental and clinical settings. BBBD procedures in patients with malignant gliomas and recurrent GBM show safety and successful enhancement of drug delivery potential. Overall, FUS-mediated BBBD emerges as a safe and feasible approach for improving therapeutic outcomes in brain tumor patients, warranting further clinical exploration and optimization.