Status Of Blood-brain Barrier Research Articles

Near-infrared-IIb fluorescent nanozymes for imaging-guided treatment of traumatic brain injury

Traumatic brain injury (TBI) often results in damage to the blood–brain barrier (BBB), leading to secondary effects such as neuroinflammation mediated by reactive oxygen species (ROS), which can increase the risk of long-term neurological dysfunction. Therefore, it is crucial to remove excessive ROS and monitor the status of BBB for timely clinical intervention. Here, we developed a fluorescent nanozyme by doping Mn atoms into PbS/CdS quantum dots (QDs) that emit in the near-infrared-II (NIR-IIb, 1500–1700 nm) region, enabling imaging-guided treatment of TBI. The QD-based nanozyme exhibited excellent antioxidant activity due to uniformly distributed Mn atoms on the surface, which effectively scavenged ROS and inhibited the release of pro-inflammatory factors, thus providing neuroprotective effects for TBI treatment. Additionally, the nanozyme demonstrated exceptional NIR-IIb fluorescence performance, allowing for dynamic monitoring of BBB status with high spatiotemporal resolution to guide precise TBI treatment.

SARS-CoV-2 envelope protein triggers depression-like behaviors and dysosmia via TLR2-mediated neuroinflammation in mice

BackgroundDepression and dysosmia have been regarded as primary neurological symptoms in COVID-19 patients, the mechanism of which remains unclear. Current studies have demonstrated that the SARS-CoV-2 envelope (E) protein is a pro-inflammatory factor sensed by Toll-like receptor 2 (TLR2), suggesting the pathological feature of E protein is independent of viral infection. In this study, we aim to ascertain the role of E protein in depression, dysosmia and associated neuroinflammation in the central nervous system (CNS).MethodsDepression-like behaviors and olfactory function were observed in both female and male mice receiving intracisternal injection of E protein. Immunohistochemistry was applied in conjunction with RT-PCR to evaluate glial activation, blood–brain barrier status and mediators synthesis in the cortex, hippocampus and olfactory bulb. TLR2 was pharmacologically blocked to determine its role in E protein-related depression-like behaviors and dysosmia in mice.ResultsIntracisternal injection of E protein evoked depression-like behaviors and dysosmia in both female and male mice. Immunohistochemistry suggested that the E protein upregulated IBA1 and GFAP in the cortex, hippocampus and olfactory bulb, while ZO-1 was downregulated. Moreover, IL-1β, TNF-α, IL-6, CCL2, MMP2 and CSF1 were upregulated in both cortex and hippocampus, whereas IL-1β, IL-6 and CCL2 were upregulated in the olfactory bulb. Furtherly, inhibiting microglia, rather than astrocytes, alleviated depression-like behaviors and dysosmia induced by E protein. Finally, RT-PCR and immunohistochemistry suggested that TLR2 was upregulated in the cortex, hippocampus and olfactory bulb, the blocking of which mitigated depression-like behaviors and dysosmia induced by E protein.ConclusionsOur study demonstrates that envelope protein could directly induce depression-like behaviors, dysosmia, and obvious neuroinflammation in CNS. TLR2 mediated depression-like behaviors and dysosmia induced by envelope protein, which could serve as a promising therapeutic target for neurological manifestation in COVID-19 patients.

Near-infrared-IIb emitting single-atom catalyst for imaging-guided therapy of blood-brain barrier breakdown after traumatic brain injury

The blood-brain barrier breakdown, as a prominent feature after traumatic brain injury, always triggers a cascade of biochemical events like inflammatory response and free radical-mediated oxidative damage, leading to neurological dysfunction. The dynamic monitoring the status of blood-brain barrier will provide potent guidance for adopting appropriate clinical intervention. Here, we engineer a near-infrared-IIb Ag2Te quantum dot-based Mn single-atom catalyst for imaging-guided therapy of blood-brain barrier breakdown of mice after traumatic brain injury. The dynamic change of blood-brain barrier, including the transient cerebral hypoperfusion and cerebrovascular damage, could be resolved with high spatiotemporal resolution (150 ms and ~ 9.6 µm). Notably, the isolated single Mn atoms on the surface of Ag2Te exhibited excellent catalytic activity for scavenging reactive oxygen species to alleviate neuroinflammation in brains. The timely injection of Mn single-atom catalyst guided by imaging significantly promoted the reconstruction of blood-brain barrier and recovery of neurological function after traumatic brain injury.

Evaluation of blood-brain barrier integrity by the analysis of dynamic contrast-enhanced MRI - a comparison of quantitative and semi-quantitative methods.

Disruption of the blood-brain barrier (BBB) is a key feature of various brain disorders. To assess its integrity a parametrization of dynamic magnetic resonance imaging (DCE MRI) with a contrast agent (CA) is broadly used. Parametrization can be done quantitatively or semi-quantitatively. Quantitative methods directly describe BBB permeability but exhibit several drawbacks such as high computation demands, reproducibility issues, or low robustness. Semi-quantitative methods are fast to compute, simply mathematically described, and robust, however, they do not describe the status of BBB directly but only as a variation of CA concentration in measured tissue. Our goal was to elucidate differences between five semi-quantitative parameters: maximal intensity (Imax), normalized permeability index (NPI), and difference in DCE values between three timepoints: baseline, 5 min, and 15 min (delta5-0, delta15-0, delta15-5) and two quantitative parameters: transfer constant (Ktrans) and an extravascular fraction (Ve). For the purpose of comparison, we analyzed DCE data of four patients 12-15 days after the stroke with visible CA enhancement. Calculated parameters showed abnormalities spatially corresponding with the ischemic lesion, however, findings in individual parameters morphometrically differed. Ktrans and Ve were highly correlated. Delta5-0 and delta15-0 were prominent in regions with rapid CA enhancement and highly correlated with Ktrans. Abnormalities in delta15-5 and NPI were more homogenous with less variable values, smoother borders, and less detail than Ktrans. Moreover, only delta15-5 and NPI were able to distinguish vessels from extravascular space. Our comparison provides important knowledge for understanding and interpreting parameters derived from DCE MRI by both quantitative and semi-quantitative methods.

In vivo targeting and multimodal imaging of cerebral amyloid-β aggregates using hybrid GdF3 nanoparticles.

Aim: To propose a new multimodal imaging agent targeting amyloid-β (Aβ) plaques in Alzheimer's disease. Materials & methods: A new generation of hybrid contrast agents, based on gadolinium fluoride nanoparticles grafted with a pentameric luminescent-conjugated polythiophene, was designed, extensively characterized and evaluated in animal models of Alzheimer's disease through MRI, two-photon microscopy and synchrotron x-ray phase-contrast imaging. Results & conclusion: Two different grafting densities of luminescent-conjugated polythiophene were achieved while preserving colloidal stability and fluorescent properties, and without affecting biodistribution. In vivo brain uptake was dependent on the blood-brain barrier status. Nevertheless, multimodal imaging showed successful Aβ targeting in both transgenic mice and Aβ fibril-injected rats.

Development of a strategy for assessing blood-brain barrier disruption using serum S100 calcium-binding protein B and neuron-specific enolase in early stage of neuroemergencies: A preliminary study.

Rapid disease progression in neuroemergencies is associated with blood-brain barrier (BBB) disruption. We investigated a less invasive strategy for assessing BBB status by evaluating S100 calcium-binding protein B (S100B) and neuron-specific enolase (NSE) at early stages of the hypoxic-ischemic brain injury (HIBI) cascade. This retrospective study used prospectively collected data from patients with out-of-hospital cardiac arrest (August 2019-July 2021). Albumin specimens obtained from serum and cerebrospinal fluid via arterial catheter and lumbar puncture were used to measure the albumin quotient (Qa), which is widely accepted as the gold standard method for detecting BBB disruption. Serum S100B and NSE levels were measured simultaneously following the return of spontaneous circulation. We conducted linear regression to evaluate the relationship between S100B and Qa and the predictive performance of S100B for abnormal Qa. The primary study outcome was abnormal Qa (>0.007). Forty-one patients were enrolled; 30 showed an abnormal Qa suggestive of BBB disruption. S100B levels were significantly higher than in those with a normal Qa (0.244 μg/L [interquartile range [IQR], 0.146-0.823 vs 0.754 μg/L [IQR, 0.317-2.228], P = .03). We report a positive correlation between serum S100B and Qa (R2 = 0.110; P = .04). The area under the receiver operating characteristics curve (AUROC) evaluating the predictive performance of S100B with respect to abnormal Qa was 0.718 (95% confidence interval, 0.556-0.847). The cutoff value for S100B (with respect to BBB disruption) in the total cohort was 0.283 μg/L (sensitivity, 80.0%; specificity, 72.7%). Subgroup analyses in patients with serum neuron-specific enolase (NSE) levels of <40.8 ng/mL (excluding those with established neuronal cell injury) showed an improved correlation coefficient (R2 = 0.382; P < .01) and predictive performance (AUROC, 0.836 [95% confidence interval, 0.629-0.954]) compared with the total cohort. Serum S100B obtained at an early stage of the HIBI cascade is associated with abnormal Qa, suggesting BBB disruption. The predictive performance of S100B and the correlation between serum S100B and Qa can be improved using a complementary strategy (i.e., evaluations of S100B and NSE levels) that combines considerations of cell damage in astrocytes and neurons.

Реамберин у комплексі оптимізації та диференціації стратегії інтенсивної терапії вторинних гнійних менінгоенцефалітів

Стаття присвячена питанням покращання діагностики, застосування методик оцінки тяжкості стану хворих при надходженні у відділення інтенсивної терапії, у динаміці спостереження за ними, оптимізації інтенсивної терапії (ІТ) вторинного гнійного менінгоенцефаліту (ВГМЕ). Загальна схема відбору пацієнтів, їх рандомізації, включення в дослідження й аналіз можуть бути подані в такий спосіб. Пацієнти з підтвердженим ВГМЕ методом рандомізації з урахуванням тяжкості стану та варіанту ІТ були розподілені на 2 групи. У I групу увійшли 22 пацієнти, котрим проводилася базисна ІТ із позицій доказової медицини відповідно до міжнародних рекомендацій Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septiс shock 2012, що доповнювалася включенням дексаметазону. У II групу увійшов 21 пацієнт, у яких ІТ, що проводилась у I групі, доповнювалась в/в введенням розчину реамберин. На початку дослідження не виявлено вірогідних відмінностей між групами за статтю, віком, локалізацією септичного вогнища, частотою реєстрації 4 ознак синдрому системної запальної відповіді, позитивних результатів бактеріологічних посівів ліквору та матеріалів із первинного вогнища, тобто вибірки були порівняними за цими ознаками. У цей же час серед пацієнтів II групи було в 2,8 раза більше хворих із рівнем свідомості «сопор» або «кома I ступеня» (76,2 % проти 27,2 %; р &lt; 0,001). Несприятливий прогноз (центральний перфузійний тиск &lt; 50 мм рт.ст.) при надходженні до стаціонару мали 22,7 % хворих із I групи і 28,6 % — із II (р &gt; 0,60). Незважаючи на початково більш тяжкий стан хворих із ВГМЕ в II групі, додавання до базисної терапії в/в введення розчину реамберин сприяло тому, що санація ліквору в II групі проходила більш плавно, без вторинного сплеску цитозу, характерного для I групи на 5-ту добу дослідження. Установлено, що в I групі С-реактивний білок у лікворі зникав до 3-ї доби дослідження, з’являвся на 5-ту добу і був відсутнім до 7-ї доби дослідження. У II групі наявність С-реактивного білка було зафіксовано лише на початку і 1-шу добу дослідження, що свідчить про більш стійкий характер відновлення функціонального стану гематоенцефалічного бар’єра в II групі, без вторинного (повторного) його прориву. Оцінка ефективності ІТ на 28-му добу дослідження показала, що відмічалось зменшення когнітивних дисфункцій у I групі на 28,4 %, у II — на 37,7 %; органних дисфункцій у I групі — з 76,3 до 43,8 %; у II — з 88,7 до 36,9 %. Показники істинної летальності становили 27,27 і 23,81 % (р &gt; 0,90) відповідно. Зниження прогнозованої летальності в I групі становило 4,73 %, у II — 16,19 %.

Different Stratification of Physiological Factors Affecting Cerebral Perfusion Pressure in Hypoxic-Ischemic Brain Injury after Cardiac Arrest According to Visible or Non-Visible Primary Brain Injury: A Retrospective Observational Study

We aimed to explore the stratification of physiological factors affecting cerebral perfusion pressure, including arterial oxygen tension, arterial carbon dioxide tension, mean arterial pressure, intracranial pressure (ICP), and blood-brain barrier (BBB) status, with respect to primary or secondary brain injury (PBI or SBI) after out-of-hospital cardiac arrest (OHCA). Among the retrospectively enrolled 97 comatose OHCA survivors undergoing post-cardiac arrest (PCA) care, 46 (47.4%) with already established PBI (high signal intensity (HSI) on diffusion-weighted imaging (DWI) had higher ICP (p = 0.02) and poorer BBB status (p < 0.01) than the non-HSI group. On subgroup analysis within the non-HSI group to exclude the confounding effect of already established PBI, 40 (78.4%) patients with good neurological outcomes had lower ICP at 24 h (11.0 vs. 16.0 mmHg, p < 0.01) and more stable BBB status (p = 0.17 in pairwise comparison) compared to those with poor neurological outcomes, despite the non-significant differences in other physiological factors. OHCA survivors with HSI on DWI showed significantly higher ICP and poorer BBB status at baseline before PCA care than those without HSI. Despite the negative DWI findings before PCA care, OHCA survivors have a cerebral penumbra at risk for potentially leading the poor neurological outcome from unsuppressed SBI, which may be associated with increased ICP and BBB permeability.

Systemic Effects by Intrathecal Administration of Triamcinolone Acetonide in Patients With Multiple Sclerosis.

In patients suffering from multiple sclerosis (MS), intrathecal injection of triamcinolone acetonide (TCA) has been shown to improve symptoms of spasticity. Although repeated intrathecal injection of TCA has been used in a number of studies in late-stage MS patients with spinal cord involvement, no clinical-chemical data are available on the distribution of TCA in cerebrospinal fluid (CSF) or serum. Moreover, the effects of intrathecal TCA administration on the concentrations of endogenous steroids remain poorly understood. Therefore, we have quantified TCA and selected endogenous steroids in CSF and serum of TCA-treated MS patients suffering from spasticity. Concentrations of steroids were quantified by LC-MS, ELISA, or ECLIA and compared with the blood-brain barrier status, diagnosed with the Reibergram. The concentration of TCA in CSF significantly increased during each treatment cycle up to >5 μg/ml both in male and female patients (p < 0.001). Repeated TCA administration also evoked serum concentrations of TCA up to >30 ng/ml (p < 0.001) and severely depressed serum levels of cortisol and corticosterone (p < 0.001). In addition, concentrations of circulating estrogen were significantly suppressed (p < 0.001). Due to the potent suppressive effects of TCA on steroid hormone concentrations both in the brain and in the periphery, we recommend careful surveillance of adrenal function following repeated intrathecal TCA injections in MS patients.

Dolutegravir Cerebrospinal Fluid Diffusion in HIV-1–Infected Patients with Central Nervous System Impairment

This study aimed to determine dolutegravir cerebrospinal fluid (CSF) diffusion in 13 patients with HIV-related cerebral impairment enrolled in a real-life observational study. Dolutegravir median (range) CSF concentration [9.6 (3.6–22.8) ng/mL] reached CSF therapeutic concentrations whatever the blood-brain barrier status and diffused in correlation with the albumin quotient (P = .0186).

Multimodal MRI-Based Triage for Acute Stroke Therapy: Challenges and Progress.

Revascularization therapies have been established as the treatment mainstay for acute ischemic stroke. However, a substantial number of patients are either ineligible for revascularization therapy, or the treatment fails or is futile. At present, non-contrast computed tomography is the first-line neuroimaging modality for patients with acute stroke. The use of magnetic resonance imaging (MRI) to predict the response to early revascularization therapy and to identify patients for delayed treatment is desirable. MRI could provide information on stroke pathophysiologies, including the ischemic core, perfusion, collaterals, clot, and blood–brain barrier status. During the past 20 years, there have been significant advances in neuroimaging as well as in revascularization strategies for treating patients with acute ischemic stroke. In this review, we discuss the role of MRI and post-processing, including machine-learning techniques, and recent advances in MRI-based triage for revascularization therapies in acute ischemic stroke.

Real-time monitoring of focused ultrasound blood-brain barrier opening via subharmonic acoustic emission detection: implementation of confocal dual-frequency piezoelectric transducers

Burst-tone focused ultrasound exposure in the presence of microbubbles has been demonstrated to be effective at inducing temporal and local opening of the blood-brain barrier (BBB), which promises significant clinical potential to deliver therapeutic molecules into the central nervous system (CNS). Traditional contrast-enhanced imaging confirmation after focused ultrasound (FUS) exposure serves as a post-operative indicator of the effectiveness of FUS-BBB opening, however, an indicator that can concurrently report the BBB status and BBB-opening effectiveness is required to provide effective feedback to implement this treatment clinically. In this study, we demonstrate the use of subharmonic acoustic emission detection with implementation on a confocal dual-frequency piezoelectric ceramic structure to perform real-time monitoring of FUS-BBB opening.A confocal dual-frequency (0.55 MHz/1.1 MHz) focused ultrasound transducer was designed. The 1.1 MHz spherically-curved ceramic was employed to deliver FUS exposure to induce BBB-opening, whereas the outer-ring 0.55 MHz ceramic was employed to detect the subharmonic acoustic emissions originating from the target position. In stage-1 experiments, we employed spectral analysis and performed an energy spectrum density (ESD) calculation. An optimized 0.55 MHz ESD level change was shown to effectively discriminate the occurrence of BBB-opening. Wideband acoustic emissions received from 0.55 MHz ceramics were also analyzed to evaluate its correlations with erythrocyte extravasations. In stage-2 real-time monitoring experiments, we applied the predetermined ESD change as a detection threshold in PC-controlled algorithm to predict the FUS exposure intra-operatively.In stage-1 experiment, we showed that subharmonic ESD presents distinguishable dynamics between intact BBB and opened BBB, and therefore a threshold ESD change level (5.5 dB) can be identified for BBB-opening prediction. Using this ESD change threshold detection as a surrogate to on/off control the FUS exposure in stage-2 experiments, we demonstrated both excellent sensitivity (92%) and specificity (92.3%) in discriminating BBB-opening occurrence can be obtained in animal treatments, while concurrently achieving a high positive predicted value (95.8%). Wideband ESD was also highly correlated with the occurrence and level of erythrocyte extravasations (r 2 = 0.81).The proposed system configuration and corresponding analysis based on subharmonic acoustic emissions has the potential to be implemented as a real-time feedback control structure for reliable indication of intact FUS-BBB opening for CNS brain drug delivery.

Mechanical Injury Induces Brain Endothelial-Derived Microvesicle Release: Implications for Cerebral Vascular Injury during Traumatic Brain Injury.

It is well established that the endothelium responds to mechanical forces induced by changes in shear stress and strain. However, our understanding of vascular remodeling following traumatic brain injury (TBI) remains incomplete. Recently published studies have revealed that lung and umbilical endothelial cells produce extracellular microvesicles (eMVs), such as microparticles, in response to changes in mechanical forces (blood flow and mechanical injury). Yet, to date, no studies have shown whether brain endothelial cells produce eMVs following TBI. The brain endothelium is highly specialized and forms the blood-brain barrier (BBB), which regulates diffusion and transport of solutes into the brain. This specialization is largely due to the presence of tight junction proteins (TJPs) between neighboring endothelial cells. Following TBI, a breakdown in tight junction complexes at the BBB leads to increased permeability, which greatly contributes to the secondary phase of injury. We have therefore tested the hypothesis that brain endothelium responds to mechanical injury, by producing eMVs that contain brain endothelial proteins, specifically TJPs. In our study, primary human adult brain microvascular endothelial cells (BMVEC) were subjected to rapid mechanical injury to simulate the abrupt endothelial disruption that can occur in the primary injury phase of TBI. eMVs were isolated from the media following injury at 2, 6, 24, and 48 h. Western blot analysis of eMVs demonstrated a time-dependent increase in TJP occludin, PECAM-1 and ICAM-1 following mechanical injury. In addition, activation of ARF6, a small GTPase linked to extracellular vesicle production, was increased after injury. To confirm these results in vivo, mice were subjected to sham surgery or TBI and blood plasma was collected 24 h post-injury. Isolation and analysis of eMVs from blood plasma using cryo-EM and flow cytometry revealed elevated levels of vesicles containing occludin following brain trauma. These results indicate that following TBI, the cerebral endothelium undergoes vascular remodeling through shedding of eMVs containing TJPs and endothelial markers. The detection of this shedding potentially allows for a novel methodology for real-time monitoring of cerebral vascular health (remodeling), BBB status and neuroinflammation following a TBI event.

MB-19 * MEDULLOBLASTOMA SUBTYPES SPECIFY INTER-TUMORAL VASCULAR BLOOD BRAIN BARRIER HETEROGENEITY

Medulloblastoma is the most common malignant childhood brain tumor, consisting of four molecularly and clinically distinct subtypes. Recent work has advanced our understanding about the basic pathological processes, identifying unique mutations and anatomical locations that contribute to medulloblastoma subtype heterogeneity. Recognizing how subtype-specific genetic alterations dictate treatment response is critical to advancing treatments for all patients. The central nervous system (CNS) contains a unique vascular system that tightly regulates exchange between the blood and brain, termed the blood brain barrier (BBB). How brain tumors specify BBB properties in newly formed blood vessels, and if this dictates tumor behavior remains unanswered. Here we show that WNT-subtype medulloblastomas create a microenvironment that inhibits BBB formation, producing tumors with a highly permeable aberrant vascular network. We found human and mouse WNT-subtype tumors display increased vascularization and hemorrhaging, along with decreased expression of endothelial BBB associated genes. Fenestrated blood vessels, normally associated with peripheral organs, are highly enriched in WNT-subtype tumors, allowing unrestricted exchange of substances between blood and tumor. Canonical Wnt signaling is essential for normal CNS BBB formation and maintenance. WNT-subtype tumors express high levels of secreted Wnt antagonists, creating a microenvironment that is inhibitory to canonical Wnt signaling and BBB formation in neighboring endothelial cells. Differences in BBB status between WNT and SHH-subtype tumors result in differential in vivo treatment response and drug penetration, suggesting the abnormal vasculature might contribute to the excellent clinical prognosis associated with WNT-subtype patients. Our data offer insight into brain tumor-vascular BBB specification, and should benefit ongoing efforts to improve response, survival, and quality of life for all medulloblastoma patients.

The contribution of CXCL12-expressing radial glia cells to neuro-vascular patterning during human cerebral cortex development.

This study was conducted on human developing brain by laser confocal and transmission electron microscopy (TEM) to make a detailed analysis of important features of blood-brain barrier (BBB) microvessels and possible control mechanisms of vessel growth and differentiation during cerebral cortex vascularization. The BBB status of cortex microvessels was examined at a defined stage of cortex development, at the end of neuroblast waves of migration, and before cortex lamination, with BBB-endothelial cell markers, namely tight junction (TJ) proteins (occludin and claudin-5) and influx and efflux transporters (Glut-1 and P-glycoprotein), the latter supporting evidence for functional effectiveness of the fetal BBB. According to the well-known roles of astroglia cells on microvessel growth and differentiation, the early composition of astroglia/endothelial cell relationships was analyzed by detecting the appropriate astroglia, endothelial, and pericyte markers. GFAP, chemokine CXCL12, and connexin 43 (Cx43) were utilized as markers of radial glia cells, CD105 (endoglin) as a marker of angiogenically activated endothelial cells (ECs), and proteoglycan NG2 as a marker of immature pericytes. Immunolabeling for CXCL12 showed the highest level of the ligand in radial glial (RG) fibers in contact with the growing cortex microvessels. These specialized contacts, recognizable on both perforating radial vessels and growing collaterals, appeared as CXCL12-reactive en passant, symmetrical and asymmetrical, vessel-specific RG fiber swellings. At the highest confocal resolution, these RG varicosities showed a CXCL12-reactive dot-like content whose microvesicular nature was confirmed by ultrastructural observations. A further analysis of RG varicosities reveals colocalization of CXCL12 with Cx43, which is possibly implicated in vessel-specific chemokine signaling.

The impact of chronic blood–brain barrier breach on intracortical electrode function

Brain-computer interfaces (BCIs) have allowed control of prosthetic limbs in paralyzed patients. Unfortunately, the electrodes of the BCI that interface with the brain only function for a short period of time before the signal quality on these electrodes becomes substantially diminished. To truly realize the potential of BCIs, it is imperative to have electrodes that function chronically. In order to elucidate the physiological determinants of a chronically functional neural interface, we studied the role of the blood–brain barrier (BBB) in electrode function, because it is a key mediator of neuronal hemostasis. We monitored the status of the BBB and the consequences of BBB breach on electrode function using non-invasive imaging, electrophysiology, genomic, and histological analyses. Rats implanted with commercially available intracortical electrodes demonstrated an inverse correlation between electrode performance and BBB breach over a period of 16 weeks. Genomic analysis showed that chronically functional electrodes elicit an enhanced wound healing response. Conversely, in poorly functioning electrodes, chronic BBB breach led to local accumulation of neurotoxic factors and an influx of pro-inflammatory myeloid cells, which negatively affect neuronal health. These findings were further verified in a subset of electrodes with graded electrophysiological performance. In this study, we determine the mechanistic link between intracortical electrode function and failure. Our results indicate that BBB status is a critical physiological determinant of intracortical electrode function and can inform future electrode design and biochemical intervention strategies to enhance the functional longevity of BCIs.

The prospective application of a hypoxic radiosensitizer, doranidazole to rat intracranial glioblastoma with blood brain barrier disruption

BackgroundGlioblastoma is one of the intractable cancers and is highly resistant to ionizing radiation. This radioresistance is partly due to the presence of a hypoxic region which is widely found in advanced malignant gliomas. In the present study, we evaluated the effectiveness of the hypoxic cell sensitizer doranidazole (PR-350) using the C6 rat glioblastoma model, focusing on the status of blood brain barrier (BBB).MethodsReproductive cell death in the rat C6 glioma cell line was determined by means of clonogenic assay. An intracranial C6 glioma model was established for the in vivo experiments. To investigate the status of the BBB in C6 glioma bearing brain, we performed the Evans blue extravasation test. Autoradiography with [14C]-doranidazole was performed to examine the distribution of doranidazole in the glioma tumor. T2-weighted MRI was employed to examine the effects of X-irradiation and/or doranidazole on tumor growth.ResultsDoranidazole significantly enhanced radiation-induced reproductive cell death in vitro under hypoxia, but not under normoxia. The BBB in C6-bearing brain was completely disrupted and [14C]-doranidazole specifically penetrated the tumor regions. Combined treatment with X-irradiation and doranidazole significantly inhibited the growth of C6 gliomas.ConclusionsOur results revealed that BBB disruption in glioma enables BBB-impermeable radiosensitizers to penetrate and distribute in the target region. This study is the first to propose that in malignant glioma the administration of hydrophilic hypoxic radiosensitizers could be a potent strategy for improving the clinical outcome of radiotherapy without side effects.

Changes in the blood–brain barrier status closely correlate with the rate of disease progression in patients with multiple system atrophy: A longitudinal study

BackgroundThe pathomechanisms responsible for disease progression in multiple system atrophy are unknown. The blood–brain barrier status may act as a modifier of disease progression in neurodegenerative diseases. MethodsWe evaluated the 12-month longitudinal change of the blood–brain barrier in 16 multiple system atrophy patients and analyzed its correlation with changes in clinical severity. ResultsThe baseline blood–brain barrier index did not correlate significantly with change in disease severity. However, changes in the blood–brain barrier indices over 12 months had significant positive correlations with changes in total unified multiple system atrophy rating scale (r = 0.56, p = 0.024) and part II scores (r = 0.56, p = 0.025). These correlation coefficients were higher after adjusting for baseline neurological deficits. ConclusionsThese data suggest that changes in the blood–brain barrier status are closely coupled with the rate of disease progression in multiple system atrophy, potentially acting as a contributor to disease progression.

Elevated Serum Ubiquitin Carboxy-Terminal Hydrolase L1 Is Associated with Abnormal Blood–Brain Barrier Function after Traumatic Brain Injury

Serum S100B elevations accurately reflect blood-brain barrier (BBB) damage. Because S100B is also present in peripheral tissues, release of this protein may not be specific to central nervous system (CNS) injury. Ubiquitin C-terminal hydrolase 1 (UCHL1), and phosphorylated neurofilament heavy chain (pNF-H) are found exclusively in neurons, but their relationship to BBB dysfunction has not been determined. The objective of this study was to determine the accuracy of serum UCHL1 and pNF-H as measures of BBB integrity after traumatic brain injury (TBI), to and compare them to S100B. We performed a prospective study of 16 patients with moderate to severe TBI (Glasgow Coma Scale [GCS] score ≤12) and 6 patients with non-traumatic headache who had cerebrospinal fluid (CSF) collected by ventriculostomy or lumbar puncture (LP). Serum and CSF were collected at the time of LP for headache patients and at 12, 24, and 48 h after injury for TBI patients. BBB function was determined by calculating albumin quotients (Q(A)), where Q(A)=[albumin(CSF)]/[albumin(serum)]. S100B, UCHL1, and pNF-H were measured by enzyme-linked immunosorbent assay (ELISA). Pearson's correlation coefficient and area under the receiver operator characteristic (ROC) curve were used to determine relationships between serum markers and Q(A). At 12 hours after TBI, a significant relationship was found between Q(A) and serum UCHL1 concentrations (AUC=0.76; 95% CI 0.55,1.00), and between Q(A) and serum S100B concentrations (AUC=0.794; 95% CI 0.57,1.02). There was no significant relationship found between these markers and Q(A) at other time points, or between pNF-H and Q(A) at any time point. We conclude that serum concentrations of UCHL1 are associated with abnormal BBB status 12 h after moderate to severe TBI. This relationship is similar to that observed between serum S100B and Q(A,) despite the fact that S100B may be released from peripheral tissues after multi-trauma. We conclude that peripheral release of S100B after multi-trauma is probably negligible and that UCHL1 may have some utility to monitor BBB disruption following TBI.

Tissue concentration of systemically administered antineoplastic agents in human brain tumors

The blood-brain-barrier (BBB) limits the penetration of many systemic antineoplastic therapies. Consequently, many agents may be used in clinical studies and clinical practice though they may not achieve therapeutic levels within the tumor. We sought to compile the currently available human data on antineoplastic drug concentrations in brain and tumor tissue according to BBB status. A review of the literature was conducted for human studies providing concentrations of antineoplastic agents in blood and metastatic brain tumors or high-grade gliomas. Studies were considered optimal if they reported simultaneous tissue and blood concentration, multiple sampling times and locations, MRI localization, BBB status at sampling site, tumor histology, and individual subject data. Twenty-Four studies of 19 compounds were included. These examined 18 agents in contrast-enhancing regions of high-grade gliomas, with optimal data for 2. For metastatic brain tumors, adequate data was found for 9 agents. Considerable heterogeneity was found in the measurement value, tumor type, measurement timing, and sampling location within and among studies, limiting the applicability of the results. Tissue to blood ratios ranged from 0.054 for carboplatin to 34 for mitoxantrone in high-grade gliomas, and were lowest for temozolomide (0.118) and etoposide (0.116), and highest for mitoxantrone (32.02) in metastatic tumors. The available data examining the concentration of antineoplastic agents in brain and tumor tissue is sparse and limited by considerable heterogeneity. More studies with careful quantification of antineoplastic agents in brain and tumor tissue is required for the rational development of therapeutic regimens.