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Background: 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., Methods: 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)., Results: A total of 40 participants (mean age 63 y; 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 1.12 mmoL (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)., Conclusion: 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., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: CSF-soluble platelet-derived growth factor receptor beta (sPDGFRβ) is closely associated with pericyte damage. However, the changes in CSF sPDGFRβ levels and their role in blood-brain barrier (BBB) leakage at different stages of Alzheimer's disease (AD), with or without cerebral small vessel disease (CSVD) burden, remain unclear., Methods: A total of 158 individuals from the China Aging and Neurodegenerative Disorder Initiative cohort were selected, including 27, 48, and 83 individuals with a clinical dementia rating (CDR) score of 0, 0.5, and 1-2, respectively. CSF total tau, phosphorylated tau181 (p-tau181), Aβ40, and Aβ42 were measured using the Simoa assay. Albumin and CSF sPDGFRβ were measured by commercial assay kits. CSVD burden was assessed by magnetic resonance imaging., Results: CSF sPDGFRβ was the highest level in the CDR 0.5 group. CSF sPDGFRβ was significantly correlated with the CSF/serum albumin ratio (Q-alb) in the CDR 0-0.5 group (β = 0.314, p = 0.008) but not in the CDR 1-2 group (β = - 0.117, p = 0.317). In the CDR 0-0.5 group, CSF sPDGFRβ exhibited a significant mediating effect between Aβ42/Aβ40 levels and Q-alb (p = 0.038). Q-alb, rather than CSF sPDGFRβ, showed a significant difference between individuals with or without CSVD burden. Furthermore, in the CDR 0.5 group, CSF sPDGFRβ was higher in subjects with progressive mild cognitive impairment than in those with stable mild cognitive impairment subjects (p < 0.001). Meanwhile, CSF sPDGFRβ was significantly associated with yearly changes in MMSE scores in the CDR 0.5 group (β = - 0.400, p = 0.020) and CDR 0.5 (A+) subgroup (β = - 0.542, p = 0.019)., Conclusions: We provide evidence that increased CSF sPDGFRβ is associated with BBB leakage in the early cognitive impairment stage of AD, which may contribute to cognitive impairment in AD progression., (© 2023. The Author(s).)

Low-intensity focused ultrasound (LIFU) uses ultrasonic pulsations at lower intensities than ultrasound and is being tested as a reversible and precise neuromodulatory technology. Although LIFU-mediated blood-brain barrier (BBB) opening has been explored in detail, no standardized technique for blood-spinal cord barrier (BSCB) opening has been established to date. Therefore, this protocol presents a method for successful BSCB disruption using LIFU sonication in a rat model, including descriptions of animal preparation, microbubble administration, target selection and localization, as well as BSCB disruption visualization and confirmation. The approach reported here is particularly useful for researchers who need a fast and cost-effective method to test and confirm target localization and precise BSCB disruption in a small animal model with a focused ultrasound transducer, evaluate the BSCB efficacy of sonication parameters, or explore applications for LIFU at the spinal cord, such as drug delivery, immunomodulation, and neuromodulation. Optimizing this protocol for individual use is recommended, especially for advancing future preclinical, clinical, and translational work.

The blood-brain barrier (BBB) is the interface between the central nervous system and systemic circulation. It tightly regulates what enters and is removed from the brain parenchyma and is fundamental in maintaining brain homeostasis. Increasingly, the BBB is recognised as having a significant role in numerous neurological disorders, ranging from acute disorders (traumatic brain injury, stroke, seizures) to chronic neurodegeneration (Alzheimer's disease, vascular dementia, small vessel disease). Numerous approaches have been developed to study the BBB in vitro, in vivo, and ex vivo. The complex multicellular structure and effects of disease are difficult to recreate accurately in vitro, and functional aspects of the BBB cannot be easily studied ex vivo. As such, the value of in vivo methods to study the intact BBB cannot be overstated. This review discusses the structure and function of the BBB and how these are affected in diseases. It then discusses in depth several established and novel methods for imaging the BBB in vivo, with a focus on MRI, nuclear imaging, and high-resolution intravital fluorescence microscopy., (© 2022. The Author(s).)

Optogenetics employs engineered viruses to genetically modify cells to express specific light-sensitive ion channels. The standard method for gene delivery in the brain involves invasive craniotomies that expose the brain and direct injections of viruses that invariably damage neural tissue along the syringe tract. A recently proposed alternative in which non-invasive optogenetics is performed with focused ultrasound (FUS)-mediated blood-brain barrier (BBB) openings has been found to non-invasively facilitate gene delivery for optogenetics in mice. Although gene delivery can be performed non-invasively, validating successful viral transduction and expression of encoded ion channels in target tissue typically involves similar invasive techniques, such as craniotomies in longitudinal studies and/or postmortem histology. Functional ultrasound imaging (fUSi) is an emerging neuroimaging technique that can be used to transcranially detect changes in cerebral blood volume following introduction of a stimulus. In this study, we implemented a fully non-invasive combined FUS-fUSi technique for performing optogenetics in mice. FUS successfully delivered viruses encoding the red-shifted channelrhodopsin variant ChrimsonR in all treated subjects. fUSi successfully identified stimulus-evoked cerebral blood volume changes preferentially in brain regions expressing the light-sensitive ion channels. Improvements in cell-specific targeting of viral vectors and transcranial ultrasound imaging will make the combined technique a useful tool for neuroscience research in small animals., Competing Interests: Conflict of interest disclosure The authors declare no conflicts of interest., (Copyright © 2022 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background: Blood-brain barrier (BBB) permeability can be assessed quantitatively using advanced imaging analysis., Hypothesis/objectives: Quantification and characterization of blood-brain barrier dysfunction (BBBD) patterns in dogs with brain tumors can provide useful information about tumor biology and assist in distinguishing between gliomas and meningiomas., Animals: Seventy-eight hospitalized dogs with brain tumors and 12 control dogs without brain tumors., Methods: In a 2-arm study, images from a prospective dynamic contrast-enhanced (DCE; n = 15) and a retrospective archived magnetic resonance imaging study (n = 63) were analyzed by DCE and subtraction enhancement analysis (SEA) to quantify BBB permeability in affected dogs relative to control dogs (n = 6 in each arm). For the SEA method, 2 ranges of postcontrast intensity differences, that is, high (HR) and low (LR), were evaluated as possible representations of 2 classes of BBB leakage. BBB score was calculated for each dog and was associated with clinical characteristics and tumor location and class. Permeability maps were generated, using the slope values (DCE) or intensity difference (SEA) of each voxel, and analyzed., Results: Distinctive patterns and distributions of BBBD were identified for intra- and extra-axial tumors. At a cutoff of 0.1, LR/HR BBB score ratio yielded a sensitivity of 80% and specificity of 100% in differentiating gliomas from meningiomas., Conclusions and Clinical Importance: Blood-brain barrier dysfunction quantification using advanced imaging analyses has the potential to be used for assessment of brain tumor characteristics and behavior and, particularly, to help differentiating gliomas from meningiomas., (© 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Blood-brain barrier (BBB) plays a critical role in protecting the brain from toxins and pathogens. However, in vivo tools to assess BBB permeability are scarce and often require the use of exogenous contrast agents. In this study, we aimed to develop a non-contrast arterial-spin-labeling (ASL) based MRI technique to estimate BBB permeability to water in mice. By determining the relative fraction of labeled water spins that were exchanged into the brain tissue as opposed to those that remained in the cerebral veins, we estimated indices of global BBB permeability to water including water extraction fraction (E) and permeability surface-area product (PS). First, using multiple post-labeling delay ASL experiments, we estimated the bolus arrival time (BAT) of the labeled spins to reach the great vein of Galen (VG) to be 691.2 ± 14.5 ms (N = 5). Next, we investigated the dependence of the VG ASL signal on labeling duration and identified an optimal imaging protocol with a labeling duration of 1200 ms and a PLD of 100 ms. Quantitative E and PS values in wild-type mice were found to be 59.9 ± 3.2% and 260.9 ± 18.9 ml/100 g/min, respectively. In contrast, mice with Huntington's disease (HD) revealed a significantly higher E (69.7 ± 2.4%, P = 0.026) and PS (318.1 ± 17.1 ml/100 g/min, P = 0.040), suggesting BBB breakdown in this mouse model. Reproducibility studies revealed a coefficient-of-variation (CoV) of 4.9 ± 1.7% and 6.1 ± 1.2% for E and PS, respectively. The proposed method may open new avenues for preclinical research on pathophysiological mechanisms of brain diseases and therapeutic trials in animal models., Competing Interests: Declaration of Competing Interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Extensive blood-brain barrier (BBB) leakage has been linked to cognitive impairment in SLE. This study aimed to examine the associations of brain functional connectivity (FC) with cognitive impairment and BBB dysfunction among patients with SLE., Methods: Cognitive function was assessed by neuropsychological testing (n = 77). Resting-state FC (rsFC) between brain regions, measured by functional MRI (n = 78), assessed coordinated neural activation in 131 regions across five canonical brain networks. BBB permeability was measured by dynamic contrast-enhanced MRI (n = 61). Differences in rsFC were compared between SLE patients with cognitive impairment (SLE-CI) and those with normal cognition (SLE-NC), between SLE patients with and without extensive BBB leakage, and with healthy controls., Results: A whole-brain rsFC comparison found significant differences in intra-network and inter-network FC in SLE-CI vs SLE-NC patients. The affected connections showed a reduced negative rsFC in SLE-CI compared with SLE-NC and healthy controls. Similarly, a reduced number of brain-wide connections was found in SLE-CI patients compared with SLE-NC (P = 0.030) and healthy controls (P = 0.006). Specific brain regions had a lower total number of brain-wide connections in association with extensive BBB leakage (P = 0.011). Causal mediation analysis revealed that 64% of the association between BBB leakage and cognitive impairment in SLE patients was mediated by alterations in FC., Conclusion: SLE patients with cognitive impairment had abnormalities in brain rsFC which accounted for most of the association between extensive BBB leakage and cognitive impairment., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The real-time monitoring of spectral characteristics of microbubble (MB) acoustic emissions permits the prediction of increases in blood-brain barrier (BBB) permeability and of tissue damage in MB-mediated focused ultrasound (FUS) brain therapy. Single-element passive cavitation detectors provide limited spatial information regarding MB activity, greatly affecting the performance of acoustic control. However, an array of receivers can be used to spatially map cavitation events and thus improve treatment control. The spectral content of the acoustic emissions provides additional information that can be correlated with the bio-effects, and wideband receivers can thus provide the most complete spectral information. Here, we develop a miniature polyvinylidene fluoride (PVDF thickness = 110 μm, active area = 1.2 mm 2 ) broadband receiver for the acoustic monitoring of MBs. The receiver has superior sensitivity (2.36-3.87 V/MPa) to those of a commercial fibre-optic hydrophone in the low megahertz frequency range (0.51-5.4 MHz). The receiver also has a wide -6 dB acceptance angle (54 degrees at 1.1 MHz and 13 degrees at 5.4 MHz) and the ability to detect subharmonic and higher harmonic MB emissions in phantoms. The overall acoustic performance of this low-cost receiver indicates its suitability for the eventual use within an array for MB monitoring and mapping in preclinical studies.

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 Ag 2 Te 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 Ag 2 Te 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., (© 2023. The Author(s).)

Objectives: The disruption of the blood-brain barrier (BBB) is a key and early feature in the pathogenesis of demyelinating multiple sclerosis (MS) lesions and has been neuropathologically demonstrated in both active and chronic plaques. The local overt BBB disruption in acute demyelinating lesions is captured as signal hyperintensity in post-contrast T1-weighted images because of the contrast-related shortening of the T1 relaxation time. On the contrary, the subtle BBB disruption in chronic lesions is not visible at conventional radiological evaluation but it might be of clinical relevance. Indeed, persistent, subtle BBB leakage might be linked to low-grade inflammation and plaque evolution. Here we hypothesised that 3D Quantitative Transient-state Imaging (QTI) was able to reveal and measure T1 shortening (ΔT1) reflecting small amounts of contrast media leakage in apparently non-enhancing lesions (ANELs)., Materials and Methods: Thirty-four patients with relapsing remitting MS were included in the study. All patients underwent a 3 T MRI exam of the brain including conventional sequences and QTI acquisitions (1.1 mm isotropic voxel) performed both before and after contrast media administration. For each patient, a ΔT1 map was obtained via voxel-wise subtraction of pre- and post- contrast QTI-derived T1 maps. ΔT1 values measured in ANELs were compared with those recorded in enhancing lesions and in the normal appearing white matter. A reference distribution of ΔT1 in the white matter was obtained from datasets acquired in 10 non-MS patients with unrevealing MR imaging., Results: Mean ΔT1 in ANELs (57.45 ± 48.27 ms) was significantly lower than in enhancing lesions (297.71 ± 177.52 ms; p < 0. 0001) and higher than in the normal appearing white matter (36.57 ± 10.53 ms; p < 0.005). Fifty-two percent of ANELs exhibited ΔT1 higher than those observed in the white matter of non-MS patients., Conclusions: QTI-derived quantitative ΔT1 mapping enabled to measure contrast-related T1 shortening in ANELs. ANELs exhibiting ΔT1 values that deviate from the reference distribution in non-MS patients may indicate persistent, subtle, BBB disruption. Access to this information may be proved useful to better characterise pathology and objectively monitor disease activity and response to therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The pathogenesis of cerebral microbleeds (CMBs) is incompletely understood, but blood-brain barrier (BBB) leakage may play a key role. This study aimed to investigate the relationship between compromised BBB integrity and CMBs as well as cognitive function., Methods: Ninety-seven participants were enrolled in this cross-sectional study, involving 24 CMB patients. Dynamic contrast-enhanced-magnetic resonance imaging was used to measure BBB permeability, and cognitive function was assessed by Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA)., Results: Compared with participants without CMBs, CMB patients had higher volume transfer constant (Ktrans, all p &lt; 0.01) and area under the concentration curve (AUC, all p &lt; 0.05) in normal-appearing white matter (NAWM), white matter hyperintensities (WMH), cortical gray matter (CGM), and deep gray matter (DGM). Multivariable linear regression analyses revealed that CMB patients had significantly higher Ktrans in NAWM and AUC in NAWM, WMH, and CGM after adjustment for age, sex, vascular risk factors, and cognitive scores. MMSE and MoCA scores decreased with increasing Ktrans in WMH and DGM as well as AUC in WMH after adjustment for age, sex, CMB group, and education length., Conclusion: This study demonstrated that widespread BBB leakage was prevalent in CMB patients, suggesting that compromised BBB integrity may play a key role in the pathogenesis of CMBs and could lead to cognitive impairment., (© 2023 S. Karger AG, Basel.)

Objective: Dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) has previously shown alterations in cerebral perfusion in patients with systemic lupus erythematosus (SLE). However, the results have been inconsistent, in particular regarding neuropsychiatric (NP) SLE. Thus, we investigated perfusion-based measures in different brain regions in SLE patients with and without NP involvement, and additionally, in white matter hyperintensities (WMHs), the most common MRI pathology in SLE patients., Materials and Methods: We included 3 T MRI images (conventional and DSC) from 64 female SLE patients and 19 healthy controls (HC). Three different NPSLE attribution models were used: the Systemic Lupus International Collaborating Clinics (SLICC) A model (13 patients), the SLICC B model (19 patients), and the American College of Rheumatology (ACR) case definitions for NPSLE (38 patients). Normalized cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) were calculated in 26 manually drawn regions of interest and compared between SLE patients and HC, and between NPSLE and non-NPSLE patients. Additionally, normalized CBF, CBV and MTT, as well as absolute values of the blood-brain barrier leakage parameter (K 2 ) were investigated in WMHs compared to normal appearing white matter (NAWM) in the SLE patients., Results: After correction for multiple comparisons, the most prevalent finding was a bilateral significant decrease in MTT in SLE patients compared to HC in the hypothalamus, putamen, right posterior thalamus and right anterior insula. Significant decreases in SLE compared to HC were also found for CBF in the pons, and for CBV in the bilateral putamen and posterior thalamus. Significant increases were found for CBF in the posterior corpus callosum and for CBV in the anterior corpus callosum. Similar patterns were found for both NPSLE and non-NPSLE patients for all attributional models compared to HC. However, no significant perfusion differences were revealed between NPSLE and non-NPSLE patients regardless of attribution model. The WMHs in SLE patients showed a significant increase in all perfusion-based metrics (CBF, CBV, MTT and K 2 ) compared to NAWM., Conclusion: Our study revealed perfusion differences in several brain regions in SLE patients compared to HC, independently of NP involvement. Furthermore, increased K 2 in WMHs compared to NAWM may indicate blood-brain barrier dysfunction in SLE patients. We conclude that our results show a robust cerebral perfusion, independent from the different NP attribution models, and provide insight into potential BBB dysfunction and altered vascular properties of WMHs in female SLE patients. Despite SLE being most prevalent in females, a generalization of our conclusions should be avoided, and future studies including all sexes are needed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (Published by Elsevier Inc.)

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.

Background: Focused ultrasound (FUS) combined with microbubbles (MBs) has emerged as a potential approach for opening the blood-brain barrier (BBB) for delivering drugs into the brain. However, MBs range in size of microns and thus can hardly extravasate into the brain parenchyma. Recently, growing attention has been paid to gas vesicles (GVs), which are genetically encoded gas-filled nanostructures with protein shells, due to their potential for extravascular targeting in ultrasound imaging and therapy. However, the use of GVs as agents for BBB opening has not yet been investigated., Methods: In this study, GVs were extracted and purified from Halobacterium NRC-1 . Ultrasound imaging performance of GVs was assessed in vitro and in vivo. Then, FUS/GVs-mediated BBB opening for small molecular Evans blue or large molecular liposome delivery across the BBB was examined., Results: The results showed a good contrast performance of GVs for brain perfusion ultrasound imaging in vivo. At the acoustic negative pressure of 1.5 MPa, FUS/GVs opened the BBB safely, and effectively enhanced Evans blue and 200-nm liposome delivery into the brain parenchyma., Conclusion: Our study suggests that biosynthetic GVs hold great potential to serve as local BBB-opening agents in the development of new targeted drug delivery strategies for central nervous system disorders., Competing Interests: The authors declare no conflicts of interest in this work., (© 2022 Zhang et al.)

Background: Despite the great potential of FUS-BBB disruption (FUS-BBBD), it is still controversial whether FUS-BBBD acts as an inducing factor of neuro-inflammation or not, and the biological responses after FUS-BBBD triggers the inflammatory process are poorly understood. The aim of this study is to investigate the safety window for FUS levels based on a comprehensive safety assessment., Methods: The mice were treated with two different ultrasound parameters (0.25 MPa and 0.42 MPa) in the thalamus region of brain. The efficacy of BBB opening was verified by dynamic contrast-enhanced MRI (DCE-MRI) and the cavitation monitoring. The transcriptome analysis was performed to investigate the molecular response for the two BBBD conditions after FUS-mediated BBB opening in time-dependent manners. Histological analysis was used for evaluation of the tissue damage, neuronal degeneration, and activation of glial cells induced by FUS-BBBD., Results: The BBBD, as quantified by the K trans , was approximately threefold higher in 0.42 MPa-treated group than 0.25 MPa-treated group. While the minimal tissue/cellular damage was found in 0.25 MPa-treated group, visible damages containing microhemorrhages and degenerating neurons were detected in 0.42 MPa-treated group in accordance with the extent of BBBD. In transcriptome analysis, 0.42 MPa-treated group exhibited highly dynamic changes in the expression levels of an inflammatory response or NF-κB pathway-relative genes in a time-dependent manner whereas, 0.25 MPa was not altered. Interestingly, although it is clear that 0.42 MPa induces neuroinflammation through glial activation, neuroprotective properties were evident by the expression of A2-type astrocytes., Conclusions: Our findings propose that a well-defined BBBD parameter of 0.25 MPa could ensure the safety without cellular/tissue damage or sterile inflammatory response in the brain. Furthermore, the fact that the excessive sonication parameters at 0.42 MPa could induce a sterile inflammation response via glial activation suggested the possibility that could lead to tissue repair toward the homeostasis of the brain microenvironment through A2-type reactive astrocytes., (© 2022. The Author(s).)

Focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening is crucial for enhancing glioblastoma (GBM) therapies. However, an in vivo imaging approach with a high spatial-temporal resolution to monitor the BBB opening process in situ and synchronously is still lacking. Herein, we report the use of indocyanine green (ICG)-dopped microbubbles (MBs-ICG) for visualizing the FUS-induced BBB opening and enhancing the photothermal therapy (PTT) against GBM. The MBs-ICG show bright fluorescence in the second near-infrared window (NIR-II), ultrasound contrast, and ultrasound-induced size transformation properties. By virtue of complementary contrast properties, MBs-ICG can be successfully applied for cerebral vascular imaging with NIR-II fluorescence resolution of ∼168.9 μm and ultrasound penetration depth of ∼7 mm. We further demonstrate that MBs-ICG can be combined with FUS for in situ and synchronous visualization of the BBB opening with a NIR-II fluorescence signal-to-background ratio of 6.2 ± 1.2. Finally, our data show that the MBs-ICG transform into lipid-ICG nanoparticles under FUS irradiation, which then rapidly penetrate the tumor tissues within 10 min and enhance PTT in orthotopic GBM-bearing mice. The multifunctional MBs-ICG approach provides a novel paradigm for monitoring BBB opening and enhancing GBM therapy., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2022 Science China Press. Published by Elsevier B.V. All rights reserved.)

Objective: MRI-guided low-intensity focused ultrasound (FUS) has been shown to reversibly open the blood-brain barrier (BBB), with the potential to deliver therapeutic agents noninvasively to target brain regions in patients with Alzheimer's disease (AD) and other neurodegenerative conditions. Previously, the authors reported the short-term safety and feasibility of FUS BBB opening of the hippocampus and entorhinal cortex (EC) in patients with AD. Given the need to treat larger brain regions beyond the hippocampus and EC, brain volumes and locations treated with FUS have now expanded. To evaluate any potential adverse consequences of BBB opening on disease progression, the authors report safety, imaging, and clinical outcomes among participants with mild AD at 6-12 months after FUS treatment targeted to the hippocampus, frontal lobe, and parietal lobe., Methods: In this open-label trial, participants with mild AD underwent MRI-guided FUS sonication to open the BBB in β-amyloid positive regions of the hippocampus, EC, frontal lobe, and parietal lobe. Participants underwent 3 separate FUS treatment sessions performed 2 weeks apart. Outcome assessments included safety, imaging, neurological, cognitive, and florbetaben β-amyloid PET., Results: Ten participants (range 55-76 years old) completed 30 separate FUS treatments at 2 participating institutions, with 6-12 months of follow-up. All participants had immediate BBB opening after FUS and BBB closure within 24-48 hours. All FUS treatments were well tolerated, with no serious adverse events related to the procedure. All 10 participants had a minimum of 6 months of follow-up, and 7 participants had a follow-up out to 1 year. Changes in the Alzheimer's Disease Assessment Scale-cognitive and Mini-Mental State Examination scores were comparable to those in controls from the Alzheimer's Disease Neuroimaging Initiative. PET scans demonstrated an average β-amyloid plaque of 14% in the Centiloid scale in the FUS-treated regions., Conclusions: This study is the largest cohort of participants with mild AD who received FUS treatment, and has the longest follow-up to date. Safety was demonstrated in conjunction with reversible and repeated BBB opening in multiple cortical and deep brain locations, with a concomitant reduction of β-amyloid. There was no apparent cognitive worsening beyond expectations up to 1 year after FUS treatment, suggesting that the BBB opening treatment in multiple brain regions did not adversely influence AD progression. Further studies are needed to determine the clinical significance of these findings. FUS offers a unique opportunity to decrease amyloid plaque burden as well as the potential to deliver targeted therapeutics to multiple brain regions in patients with neurodegenerative disorders.

Purpose: Caffeine is known to alter brain perfusion by acting as an adenosine antagonist, but its effect on blood-brain barrier (BBB) permeability is not fully elucidated. This study aimed to dynamically monitor BBB permeability to water after a single dose of caffeine tablet using a non-contrast MRI technique., Methods: Ten young healthy volunteers who were not regular coffee drinkers were studied. The experiment began with a pre-caffeine measurement, followed by four measurements at the post-caffeine stage. Water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST) MRI was used to assess the time dependence of BBB permeability to water following the ingestion of 200 mg caffeine. Other cerebral physiological parameters including cerebral blood flow (CBF), venous oxygenation (Y v ), and cerebral metabolic rate of oxygen (CMRO 2 ) were also examined. The relationships between cerebral physiological parameters and time were studied with mixed-effect models., Results: It was found that, after caffeine ingestion, CBF and Y v showed a time-dependent decrease (p < 0.001), while CMRO 2 did not change significantly. The fraction of arterial water crossing the BBB (E) showed a significant increase (p < 0.001). In contrast, the permeability-surface-area product (PS), i.e., BBB permeability to water, remained constant (p = 0.94). Additionally, it was observed that changes in physiological parameters were non-linear with regard to time and occurred at as early as 9 min after caffeine tablet ingestion., Conclusion: These results suggest an unchanged BBB permeability despite alterations in perfusion during a vasoconstrictive caffeine challenge., (© 2022 International Society for Magnetic Resonance in Medicine.)

The choroid plexus (ChP) of the cerebral ventricles is a source of cerebrospinal fluid (CSF) production and also plays a key role in immune surveillance at the level of blood-to-CSF-barrier (BCSFB). In this study, we quantify ChP blood perfusion and BCSFB mediated water exchange from arterial blood into ventricular CSF using non-invasive continuous arterial spin labelling magnetic resonance imaging (CASL-MRI). Systemic administration of anti-diuretic hormone (vasopressin) was used to validate BCSFB water flow as a metric of choroidal CSF secretory function. To further investigate the coupling between ChP blood perfusion and BCSFB water flow, we characterized the effects of two anesthetic regimens known to have large-scale differential effects on cerebral blood flow. For quantification of ChP blood perfusion a multi-compartment perfusion model was employed, and we discovered that partial volume correction improved measurement accuracy. Vasopressin significantly reduced both ChP blood perfusion and BCSFB water flow. ChP blood perfusion was significantly higher with pure isoflurane anesthesia (2-2.5%) when compared to a balanced anesthesia with dexmedetomidine and low-dose isoflurane (1.0 %), and significant correlation between ChP blood perfusion and BCSFB water flow was observed, however there was no significant difference in BCSFB water flow. In summary, here we introduce a non-invasive, robust, and spatially resolved in vivo imaging platform to quantify ChP blood perfusion as well as BCSFB water flow which can be applied to study coupling of these two key parameters in future clinical translational studies., Competing Interests: Declaration of competing interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2022. Published by Elsevier Inc.)

Aim: To quantitatively evaluate blood-brain barrier (BBB) permeability in the perihaematomal region of spontaneous intracerebral haemorrhage (ICH) and investigate the association between the alterations in cerebral blood flow and BBB permeability around the haematoma., Materials and Methods: Spontaneous ICH patients underwent unenhanced computed tomography (CT) and CT perfusion (CTP) simultaneously. Haematoma volume was measured on CT. The values of cerebral haemodynamic parameters including cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP), and permeability-surface area product (PS) were measured in the perihaematomal region and the contralateral mirror region, and then relative values were calculated for statistical analysis. Linear regression was used to evaluate associations between BBB permeability and variables., Results: A total of 87 ICH patients were included in this study. The focally elevated BBB permeability was observed in the perihaematomal region in ICH patients. Linear regression showed that reduced rCBF (β = -0.379, p=0.001) and increased rCBV (β = 0.412, p=0.000) correlated independently with increased relative PS (rPS) value in deep ICH, while only increased rCBV (β = 0.423, p=0.071) correlated to increased rPS value in patients with lobar ICH., Conclusions: BBB permeability is focally elevated in the region around the haematoma. Cerebral haemodynamic alterations are associated with increased BBB permeability. Cerebral hypoperfusion may aggravate BBB compromise, and a compensatory increase in CBV may lead to reperfusion injury on BBB., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Pre-eclampsia is a hypertensive complication of pregnancy that is associated with an increased risk of long-term cardiovascular and cerebrovascular disorders. Although the underlying mechanism of persistent susceptibility to cerebral complications after pre-eclampsia remains largely unclear, impaired blood-brain barrier (BBB) integrity has been suggested to precede several cerebrovascular diseases. In this study, we aimed to investigate the integrity of the BBB years after pre-eclampsia., Methods: This was an observational study of premenopausal formerly pre-eclamptic women and controls with a history of normotensive pregnancy who underwent cerebral magnetic resonance imaging (MRI) at ultra-high field (7 Tesla) to assess the integrity of the BBB. Permeability of the BBB was determined by assessing leakage rate and fractional leakage volume of the contrast agent gadobutrol using dynamic contrast-enhanced MRI. BBB leakage measures were determined for the whole brain and lobar white and gray matter. Multivariable analyses were performed, and odds ratios were calculated to compare women with and those without a history of pre-eclampsia, adjusting for potential confounding effects of age, hypertension status at MRI and Fazekas score., Results: Twenty-two formerly pre-eclamptic women (mean age, 37.8 ± 5.4 years) and 13 control women with a history of normotensive pregnancy (mean age, 40.8 ± 5.5 years) were included in the study. The time since the index pregnancy was 6.6 ± 3.2 years in the pre-eclamptic group and 9.0 ± 3.7 years in controls. The leakage rate and fractional leakage volume were significantly higher in formerly pre-eclamptic women than in controls in the global white (P = 0.001) and gray (P = 0.02) matter. Regionally, the frontal (P = 0.04) and parietal (P = 0.009) cortical gray matter, and the frontal (P = 0.001), temporal (P &lt; 0.05) and occipital (P = 0.007) white matter showed higher leakage rates in formerly pre-eclamptic women. The odds of a high leakage rate after pre-eclampsia were generally higher in white-matter regions than in gray-matter regions., Conclusion: This observational study demonstrates global impairment of the BBB years after a pre-eclamptic pregnancy, which could be an early marker of long-term cerebrovascular disorders. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Low-intensity ultrasound combined with intravenously injected microbubbles (US +MB ) is a novel treatment modality for brain disorders, including Alzheimer's disease (AD), safely and transiently allowing therapeutic agents to overcome the blood-brain barrier (BBB) that constitutes a major barrier for therapeutic agents. Here, we first provide an update on immunotherapies in AD and how US +MB has been applied to AD mouse models and in clinical trials, considering the ultrasound and microbubble parameter space. In the second half of the review, we compare different in vitro BBB models and discuss strategies for combining US +MB with BBB modulators (targeting molecules such as claudin-5), and highlight the insight provided by super-resolution microscopy. Finally, we conclude with a short discussion on how in vitro findings can inform the design of animal studies, and how the insight gained may aid treatment optimization in the clinical ultrasound space., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Focused ultrasound (FUS) combined with microbubble-mediated blood-brain barrier (BBB) opening (FUS-BBBO) is not only a promising technique for clinical applications but also a powerful tool for preclinical research. However, existing FUS devices for preclinical research are expensive, bulky, and lack the precision needed for small animal research, which limits the broad adoption of this promising technique by the research community. Our objective was to design and fabricate an affordable, easy-to-use, high-precision FUS device for small animal research., Methods: We designed and fabricated in-house mini-FUS transducers (∼$80 each in material cost) with three frequencies (1.5, 3.0, and 6.0 MHz) and integrated them with a stereotactic frame for precise mouse brain targeting using established stereotactic procedures. The BBB opening volume by FUS at different acoustic pressures (0.20-0.57 MPa) was quantified using T1-weighted contrast-enhanced magnetic resonance imaging of gadolinium leakage and fluorescence imaging of Evans blue extravasation., Results: The targeting accuracy of the device as measured by the offset between the desired target location and the centroid of BBBO was 0.63 ± 0.19 mm. The spatial precision of the device in targeting individual brain structures was improved by the use of higher frequency FUS transducers. The BBB opening volume had high linear correlations with the cavitation index (defined by the ratio between acoustic pressure and frequency) and mechanical index (defined by the ratio between acoustic pressure and the square root of frequency). The correlation coefficient of the cavitation index was slightly higher than that of the mechanical index., Conclusion: This study demonstrated that spatially accurate and precise BBB opening was achievable using an affordable and easy-to-use FUS device. The BBB opening volume was tunable by modulating the cavitation index. This device is expected to decrease the barriers to the adoption of the FUS-BBBO technique by the broad research community.

The blood-brain barrier (BBB) prevents harmful toxins from entering brain but can also inhibit therapeutic molecules designed to treat neurodegenerative diseases. Focused ultrasound (FUS) combined with microbubbles can enhance permeability of BBB and is often performed under MRI guidance. We present an all-ultrasound system capable of targeting desired regions to open BBB with millimeter-scale accuracy in two dimensions based on Doppler images. We registered imaging coordinates to FUS coordinates with target registration error of 0.6 ± 0.3 mm and used the system to target microbubbles flowing in cellulose tube in two in vitro scenarios (agarose-embedded and through a rat skull), while receiving echoes on imaging transducer. We created passive acoustic maps from received echoes and found error between intended location in imaging plane and location of pixel with maximum intensity after passive acoustic maps reconstruction to be within 2 mm in 5/6 cases. We validated ultrasound-guided procedure in three in vivo rat brains by delivering MRI contrast agent to cortical regions of rat brains after BBB opening. Landmark-based registration of vascular maps created with MRI and Doppler ultrasound revealed BBB opening inside the intended focus with targeting accuracy within 1.5 mm. Combined use of power Doppler imaging with passive acoustic mapping demonstrates an ultrasound-based solution to guide focused ultrasound with high precision in rodents., (© 2022. The Author(s).)

Efficient transport of solutes in the cerebrospinal fluid (CSF) plays a critical role in their clearance from the brain. Convective bulk flow of solutes in the CSF in the perivascular space (PVS) is considered one of the important mechanisms behind solute movement in the brain, before their ultimate drainage to the systemic lymphatic system. Acoustic pressure waves can impose radiation force on a medium in its path, inducing localized and directional fluidic flow, known as acoustic streaming. We transcranially applied low-intensity focused ultrasound (FUS) to rats that received an intracisternal injection of fluorescent CSF tracers (dextran and ovalbumin, having two different molecular weights-M w ). The sonication pulsing parameter was determined on the set that propelled the aqueous solution of toluidine blue O dye into a porous media (melamine foam) at the highest level of infiltration. Fluorescence imaging of the brain showed that application of FUS increased the uptake of ovalbumin at the sonicated plane, particularly around the ventricles, whereas the uptake of high-M w dextran was unaffected. Numerical simulation showed that the effects of sonication were non-thermal. Sonication did not alter the animals' behavior or disrupt the blood-brain barrier (BBB) while yielding normal brain histology. The results suggest that FUS may serve as a new non-invasive means to promote interstitial CSF solute transport in a region-specific manner without disrupting the BBB, providing potential for enhanced clearance of waste products from the brain., (© 2022. The Author(s).)

Background and Objectives: Petechial cerebral hemorrhages can be caused by various factors, such as traumas, cerebral infarctions, and aging, and is related to the disruption of the blood-brain barrier or the cellular damage of blood vessels. However, there is no animal model that recapitulates cerebral petechial hemorrhages. Materials and Methods: Here, we implemented a petechial hemorrhage using a novel technology, i.e., microbubble-assisted focused ultrasound (MB + FUS). Results: This method increases the permeability of the blood-brain barrier by directly applying mechanical force to the vascular endothelial cells through cavitation of the microbubbles. Microbubble-enhanced cavitation has the advantage of controlling the degree and location of petechial hemorrhages. Conclusions: We thus generated a preclinical rat model using noninvasive focal MB + FUS. This method is histologically similar to actual petechial hemorrhages of the brain and allows the achievement of a physiologically resembling petechial hemorrhage. In the future, this method shall be considered as a useful animal model for studying the pathophysiology and treatment of petechial cerebral hemorrhages.

Objective: Non-invasive methods to enhance drug delivery and efficacy in the brain have been pursued for decades. Focused ultrasound hyperthermia (HT) combined with thermosensitive therapeutics have been demonstrated promising in enhancing local drug delivery to solid tumors. We hypothesized that the presence of microbubbles (MBs) combined with transcranial MR-guided focused ultrasound (MRgFUS) could be used to reduce the ultrasound power required for HT while simultaneously increasing drug delivery by locally opening the blood-brain barrier (BBB)., Methods: Transcranial HT (42 °C, 10 min) was performed in wild-type mice using a small animal MRgFUS system incorporated into a 9.4T Bruker MR scanner, with infusions of saline or Definity MBs with doses of 20 or 100 µl/kg/min (denoted as MB-20 and MB-100). MR thermometry data was continuously acquired as feedback for the ultrasound controller during the procedure., Results: Spatiotemporally precise transcranial HT was achieved in both saline and MB groups. A significant ultrasound power reduction (-45.7%, p = 0.006) was observed in the MB-20 group compared to saline. Localized BBB opening was achieved in MB groups confirmed by CE-T1w MR images. There were no structural abnormalities, edema, hemorrhage, or acutemicroglial activation in all groups, confirmed by T2w MR imaging and histology., Conclusion: Our investigations showed that it is feasible and safe to achieve spatiotemporally precise brain HT at significantly reduced power and simultaneous localized BBB opening via transcranial MRgFUS and MBs., Significance: This study provides a new synergistic brain drug delivery method with clinical translation potential.

Ozone is a widespread air toxicant. Although its primary target organ is the lungs, emerging evidence suggests that ozone also has harmful effects on the brain. The vascular blood-brain barrier (BBB), an endothelial interface that regulates passage of substances between the brain and peripheral tissues, is a likely mediator of ozone's adverse effects on the brain. Ozone can cause BBB disruption, a pathological state in which the BBB becomes leaky, resulting in the unregulated entry of circulating substances into the brain. BBB disruption can be detected using many methods, which each have their strengths and limitations. Recent data suggest that BBB disruption can occur in mice following ozone exposures, albeit at a low level. Therefore, robust and highly sensitive assays for BBB disruption are needed. Assays commonly used to detect BBB disruption, however, can be time consuming, lack sensitivity, and can be vulnerable to artifacts that are typically not addressed in the experimental design. Radiochemical assays are among the most sensitive and specific for detecting subtle disruptions of the BBB and require minimal sample processing for detection. Radiochemical assays can also be multiplexed to include radiotracer conjugates of large and small molecular weights, and the uptake of each of them can provide information about the severity and mechanism of BBB disruption. Here, we describe a protocol to use two of these radiotracer conjugates, 14 C-sucrose and 99m Tc- albumin, to measure BBB disruption following an acute exposure to ozone in mice. We provide the steps to expose mice acutely to ozone, to label albumin with 99m Tc-pertechnetate, and to measure BBB disruption by evaluating permeability to 99m Tc-albumin and 14 C-sucrose after ozone exposure. These methods can be adapted to different ozone exposure paradigms and to different rodent species/strains, allowing for the sensitive and rapid assessment of BBB disruption that is detectable in whole brains or in brain regions. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Ozone exposures in mice Basic Protocol 2: Measurement of blood-brain barrier disruption by evaluating permeability to 14 C-sucrose and 99m Tc-albumin Support Protocol: Labeling of bovine serum albumin with 99m Tc., (© 2022 Wiley Periodicals LLC.)

Recent studies using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with gadolinium-based contrast agents (GBCA) have demonstrated subtle blood-brain barrier (BBB) leaks in the human brain during normal aging, in individuals with age-related cognitive dysfunction, genetic risk for Alzheimer's disease (AD), mild cognitive impairment, early AD, cerebral small vessel disease (SVD), and other neurodegenerative disorders. In these neurological conditions, the BBB leaks, quantified by the unidirectional BBB GBCA tracer's constant K trans maps, are typically orders of magnitude lower than in brain tumors, after stroke and/or during relapsing episodes of multiple sclerosis. This puts extra challenges for the DCE-MRI technique by pushing calculations towards its lower limits of detectability. In addition, presently, there are no standardized multivendor protocols or evidence of repeatability and reproducibility. Nevertheless, subtle BBB leaks may critically contribute to the pathophysiology of cognitive impairment and dementia associated with AD or SVD, and therefore, efforts to improve sensitivity of detection, reliability, and reproducibility are warranted. A larger number of participants scanned by different MR scanners at different clinical sites are sometimes required to detect differences in BBB integrity between control and at-risk groups, which impose additional challenges. Here, we focus on these new challenges and propose some approaches to normalize and harmonize DCE data between different scanners. In brief, we recommend specific regions to be used for the tracer's vascular input function and DCE data processing and how to find and correct negative K trans values that are physiologically impossible. We hope this information will prove helpful to new investigators wishing to study subtle BBB damage in neurovascular and neurodegenerative conditions and in the aging human brain., (© 2022. The Author(s), under exclusive licence to American Aging Association.)

Background: Blood-brain barrier (BBB) disruption may lead to endothelium dysfunction and inflammation in sickle cell disease (SCD). However, abnormalities of BBB in SCD, especially in pediatric patients for whom contrast agent administration less than optimal, have not been fully characterized., Purpose: To examine BBB permeability to water in a group of pediatric SCD participants using a non-invasive magnetic resonance imaging technique. We hypothesized that SCD participants will have increased BBB permeability., Study Type: Prospective cross-sectional., Population: Twenty-six pediatric participants (10 ± 1 years, 15F/11M) were enrolled, including 21 SCD participants and 5 sickle cell trait (SCT) participants, who were siblings of SCD patients., Field Strength/sequence: 3 T. Water extraction with phase-contrast arterial spin tagging with echo-planer imaging, phase-contrast and T 1 -weighted magnetization-prepared rapid acquisition of gradient echo., Assessment: Water extraction fraction (E), BBB permeability-surface area product (PS), cerebral blood flow, hematological measures (hemoglobin, hematocrit, hemoglobin S), neuropsychological scores (including domains of intellectual ability, attention and executive function, academic achievement and adaptive function, and a composite score). Regions of interest were drawn by Z.L. (6 years of experience)., Statistical Tests: Wilcoxon rank sum test and chi-square test for group comparison of demographics. Multiple linear regression analysis of PS with diagnostic category (SCD or SCT), hematological measures, and neuropsychological scores. A two-tailed P value of 0.05 or less was considered statistically significant., Results: Compared with SCT participants, SCD participants had a significantly higher BBB permeability to water (SCD: 207.0 ± 33.3 mL/100 g/minute, SCT: 171.2 ± 27.2 mL/100 g/minute). SCD participants with typically more severe phenotypes also had a significantly leakier BBB than those with typically milder phenotypes (severe: 217.3 ± 31.7 mL/100 g/minute, mild: 193.3 ± 31.8 mL/100 g/minute). Furthermore, more severe BBB disruption was associated with worse hematological symptoms, including lower hemoglobin concentrations (β = -8.84, 95% confidence interval [CI] [-14.69, -3.00]), lower hematocrits (β = -2.96, 95% CI [-4.84, -1.08]), and higher hemoglobin S fraction (β = 0.77, 95% CI [0.014, 1.53])., Data Conclusion: These findings support a potential role for BBB dysfunction in SCD pathogenesis of ischemic injury., Level of Evidence: 2 TECHNICAL EFFICACY: Stage 2., (© 2021 International Society for Magnetic Resonance in Medicine.)

Background: Factors contributing to cerebral edema in the post-hyperacute period of ischemic stroke (first 24-72 hours) are poorly understood. Blood-brain barrier (BBB) disruption and postischemic hyperperfusion reflect microvascular dysfunction and are associated with hemorrhagic transformation. We investigated the relationships between BBB integrity, cerebral blood flow, and space-occupying cerebral edema in patients who received acute reperfusion therapy., Methods: We performed a pooled analysis of patients treated for anterior circulation large vessel occlusion in the EXTEND-IA TNK and EXTEND-IA TNK part 2 trials who had MRI with dynamic susceptibility contrast-enhanced perfusion-weighted imaging 24 hours after treatment. We investigated the associations between BBB disruption and cerebral blood flow within the infarct with cerebral edema assessed using 2 metrics: first midline shift (MLS) trichotomized as an ordinal scale of negligible (<1 mm), mild (≥1 to <5 mm), or severe (≥5 mm), and second relative hemispheric volume (rHV), defined as the ratio of the 3-dimensional volume of the ischemic hemisphere relative to the contralateral hemisphere., Results: Of 238 patients analyzed, 133 (55.9%) had negligible, 93 (39.1%) mild, and 12 (5.0%) severe MLS at 24 hours. The associated median rHV was 1.01 (IQR, 1.00-1.028), 1.03 (IQR, 1.01-1.077), and 1.15 (IQR, 1.08-1.22), respectively. MLS and rHV were associated with poor functional outcome at 90 days ( P<0 .002). Increased BBB permeability was independently associated with more edema after adjusting for age, occlusion location, reperfusion, parenchymal hematoma, and thrombolytic agent used (MLS cOR, 1.12 [95% CI, 1.03-1.20], P =0.005; rHV β, 0.39 [95% CI, 0.24-0.55], P <0.0001), as was reduced cerebral blood flow (MLS cOR, 0.25 [95% CI, 0.10-0.58], P =0.001; rHV β, -2.95 [95% CI, -4.61 to -11.29], P =0.0006). In subgroup analysis of patients with successful reperfusion (extended Treatment in Cerebral Ischemia 2b-3, n=200), reduced cerebral blood flow remained significantly associated with edema (MLS cOR, 0.37 [95% CI, 0.14-0.98], P =0.045; rHV β, -2.59 [95% CI, -4.32 to -0.86], P =0.004)., Conclusions: BBB disruption and persistent hypoperfusion in the infarct after reperfusion treatment is associated with space-occupying cerebral edema. Further studies evaluating microvascular dysfunction during the post-hyperacute period as biomarkers of poststroke edema and potential therapeutic targets are warranted.

Focused ultrasound (FUS) for blood-brain barrier (BBB) opening is a safe, reversible and non-invasive strategy for targeted drug delivery to the brain, however extensive pre-planning strategies are necessary for successful FUS-mediated BBB opening through the structurally complex primate skull., Objective: This study aims to demonstrate a pre-planning pipeline consisting of transcranial simulations and in vitro experimentation used to inform synchronous BBB opening and power cavitation imaging (PCI) with a single theranostic ultrasound (TUS) phased array., Methods: Acoustic wave propagation simulation findings of pressure attenuation and focal shift through clinical-CT and micro-CT-based primate skull models were compared, while the latter were used to determine the impact of beam steering angle on focal shift and pressure attenuation. In vitro experimentation with a channel phantom enabled characterization of skull-induced receive focal shift (RFS), while in vivo BBB opening and PCI using in silico and in vitro pre-planning information was conducted using a custom Verasonics/MATLAB script., Results: Simulations confirmed steering angle dependent transcranial focal shift and pressure attenuation, while in vitro experiments revealed minimal (0.30-1.50 mm) skull-induced RFS. In vivo rodent experiments with overlaid primate skull fragments demonstrated successful TUS-mediated BBB opening and spatially correlated power cavitation images (PCI) with regions of BBB opening on T 1 -weighted magnetic resonance images (MRI)., Conclusion: We demonstrated the feasibility for TUS-mediated BBB opening in vivo using in silico and in vitro pre-planning information., Significance: TUS as an ultrasound-guided modality for BBB opening could serve as a promising alternative to current FUS-mediated BBB opening configurations in the clinic.

Transcranial focused ultrasound (FUS) in conjunction with circulating microbubbles injection is the sole non-invasive technique that temporally and locally opens the blood-brain barrier (BBB), allowing targeted drug delivery into the central nervous system (CNS). However, single-element FUS technologies do not allow the simultaneous targeting of several brain structures with high-resolution, and multi-element devices are required to compensate the aberrations introduced by the skull. In this work, we present the first preclinical application of acoustic holograms to perform a bilateral BBB opening in two mirrored regions in mice. The system consisted of a single-element focused transducer working at 1.68 MHz, coupled to a 3D-printed acoustic hologram designed to produce two symmetric foci in anesthetized mice in vivo and, simultaneously, compensate the aberrations of the wavefront caused by the skull bones. T1-weighed MR images showed gadolinium extravasation at two symmetric quasi-spherical focal spots. By encoding time-reversed fields, holograms are capable of focusing acoustic energy with a resolution near the diffraction limit at multiple spots inside the skull of small preclinical animals. This work demonstrates the feasibility of hologram-assisted BBB opening for low-cost and highly-localized targeted drug delivery in the CNS in symmetric regions of separate hemispheres.

Background: Temporary disruption of the blood-brain barrier (BBB) using pulsed ultrasound leads to the clearance of both amyloid and tau from the brain, increased neurogenesis, and mitigation of cognitive decline in pre-clinical models of Alzheimer's disease (AD) while also increasing BBB penetration of therapeutic antibodies. The goal of this pilot clinical trial was to investigate the safety and efficacy of this approach in patients with mild AD using an implantable ultrasound device., Methods: An implantable, 1-MHz ultrasound device (SonoCloud-1) was implanted under local anesthesia in the skull (extradural) of 10 mild AD patients to target the left supra-marginal gyrus. Over 3.5 months, seven ultrasound sessions in combination with intravenous infusion of microbubbles were performed twice per month to temporarily disrupt the BBB. 18 F-florbetapir and 18 F-fluorodeoxyglucose positron emission tomography (PET) imaging were performed on a combined PET/MRI scanner at inclusion and at 4 and 8 months after the initiation of sonications to monitor the brain metabolism and amyloid levels along with cognitive evaluations. The evolution of cognitive and neuroimaging features was compared to that of a matched sample of control participants taken from the Alzheimer's Disease Neuroimaging Initiative (ADNI)., Results: A total of 63 BBB opening procedures were performed in nine subjects. The procedure was well-tolerated. A non-significant decrease in amyloid accumulation at 4 months of - 6.6% (SD = 7.2%) on 18 F-florbetapir PET imaging in the sonicated gray matter targeted by the ultrasound transducer was observed compared to baseline in six subjects that completed treatments and who had evaluable imaging scans. No differences in the longitudinal change in the glucose metabolism were observed compared to the neighboring or contralateral regions or to the change observed in the same region in ADNI participants. No significant effect on cognition evolution was observed in comparison with the ADNI participants as expected due to the small sample size and duration of the trial., Conclusions: These results demonstrate the safety of ultrasound-based BBB disruption and the potential of this technology to be used as a therapy for AD patients. Research of this technique in a larger clinical trial with a device designed to sonicate larger volumes of tissue and in combination with disease-modifying drugs may further enhance the effects observed., Trial Registration: ClinicalTrials.gov, NCT03119961., (© 2022. The Author(s).)

Brain swelling occurs in cerebral malaria (CM) and may either reverse or result in fatal outcome. It is currently unknown how brain swelling in CM reverses, as brain swelling at the acute stage is difficult to study in humans and animal models with reliable induction of reversible edema are not known. In this study, we show that reversible brain swelling in experimental murine CM can be induced reliably after single vaccination with radiation-attenuated sporozoites as proven by in vivo high-field magnetic resonance imaging. Our results provide evidence that brain swelling results from transcellular blood-brain barrier disruption (BBBD), as revealed by electron microscopy. This mechanism enables reversal of brain swelling but does not prevent persistent focal brain damage, evidenced by microhemorrhages, in areas of most severe BBBD. In adult CM patients magnetic resonance imaging demonstrate microhemorrhages in more than one third of patients with reversible edema, emphasizing similarities of the experimental model and human disease. Our data suggest that targeting transcellular BBBD may represent a promising adjunct therapeutic approach to reduce edema and may improve neurological outcome., (© 2022 Jin et al.)

The blood-brain barrier (BBB) is the most important obstacle to delivery of therapeutics to the central nervous system. Low-intensity pulsed focused ultrasound (FUS) in combination with microbubbles applied under magnetic resonance imaging (MRI) control provides a non-invasive and safe technique for BBB opening (BBBo). In rodent models, however, settings and application protocols differ significantly. Depending on the strain and size, important variables include ultrasound attenuation and sound field distortion caused by the skull. We examined the ultrasound attenuation of the skull of Wistar rats using a targeted FUS system. By modifying the transducer elements and by varying and simulating the acoustic field of the FUS system, we measured a skull attenuation of about 60%. To evaluate potential application of the targeted FUS system in genetically modified animals with increased sensitivity to brain hemorrhage caused by vascular dysfunction, we assessed safety in healthy animals. Histological and MRI analyses of the central nervous system revealed an increase in the number and severity of hyperacute bleeds with focal pressure. At a pressure of 0.4 MPa, no bleeds were induced, albeit at the cost of a weaker hyperintense MRI signal post BBBo. These results indicate a relationship between pressure and the dimension of permeabilization., Competing Interests: Conflict of interest disclosure The authors declare no conflicts of interest., (Copyright © 2021. Published by Elsevier Inc.)

Background: The blood-brain barrier (BBB), which separates the intravascular and neuropil compartments, characterizes the vascular bed of the brain and is essential for its proper function. Recent advances in imaging techniques have driven the development of methods for quantitative assessment of BBB permeability., Hypothesis/objectives: Permeability of the BBB can be assessed quantitatively in dogs with meningoencephalitis of unknown origin (MUO) and its status is associated with the occurrence of seizures., Animals: Forty dogs with MUO and 12 dogs without MUO., Methods: Retrospective, prospective cohort study. Both dynamic contrast enhancement (DCE) and subtraction enhancement analysis (SEA) methods were used to evaluate of BBB permeability in affected (DCE, n = 8; SEA, n = 32) and control dogs (DCE, n = 6; SEA, n = 6). Association between BBB dysfunction (BBBD) score and clinical characteristics was examined. In brain regions where BBBD was identified by DCE or SEA magnetic resonance imaging (MRI) analysis, immunofluorescent staining for albumin, glial fibrillary acidic protein, ionized calcium binding adaptor molecule, and phosphorylated mothers against decapentaplegic homolog 2 were performed to detect albumin extravasation, reactive astrocytes, activated microglia, and transforming growth factor beta signaling, respectively., Results: Dogs with BBBD had significantly higher seizure prevalence (72% vs 19%; P = .01) when compared to MUO dogs with no BBBD. The addition of SEA to routine MRI evaluation increased the identification rate of brain pathology in dogs with MUO from 50% to 72%., Conclusions and Clinical Importance: Imaging-based assessment of BBB integrity has the potential to predict risk of seizures in dogs with MUO., (© 2022 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

The blood-brain barrier (BBB) is a key challenge for the successful delivery of drugs to the brain. Ultrasound exposure in the presence of microbubbles has emerged as an effective method to transiently and locally increase the permeability of the BBB, facilitating para- and transcellular transport of drugs across the BBB. Imaging the vasculature during ultrasound-microbubble treatment will provide valuable and novel insights on the mechanisms and dynamics of ultrasound-microbubble treatments in the brain. Here, we present an experimental procedure for intravital multiphoton microscopy using a cranial window aligned with a ring transducer and a 20x objective lens. This set-up enables high spatial and temporal resolution imaging of the brain during ultrasound-microbubble treatments. Optical access to the brain is obtained via an open-skull cranial window. Briefly, a 3-4 mm diameter piece of the skull is removed, and the exposed area of the brain is sealed with a glass coverslip. A 0.82 MHz ring transducer, which is attached to a second glass coverslip, is mounted on top. Agarose (1% w/v) is used between the coverslip of the transducer and the coverslip covering the cranial window to prevent air bubbles, which impede ultrasound propagation. When sterile surgery procedures and anti-inflammatory measures are taken, ultrasound-microbubble treatments and imaging sessions can be performed repeatedly over several weeks. Fluorescent dextran conjugates are injected intravenously to visualize the vasculature and quantify ultrasound-microbubble induced effects (e.g., leakage kinetics, vascular changes). This paper describes the cranial window placement, ring transducer placement, imaging procedure, common troubleshooting steps, as well as advantages and limitations of the method.

Objective: To evaluate the feasibility of intravoxel incoherent motion (IVIM) in assessing blood-brain barrier (BBB) integrity and microvasculature in tumoral tissue of glioma patients., Methods: Images from 8 high-grade and 4 low-grade glioma patients were acquired on a 3 T MRI scanner. Acquisition protocol included pre- and post-contrast T1- and T2-weighted imaging, FLAIR, dynamic susceptibility contrast (DSC), and susceptibility-weighted imaging (SWI). In addition, IVIM was acquired with 15 b-values and fitted under the non-negative least square (NNLS) model to output the diffusion (D) and pseudo-diffusion (D*) coefficients, perfusion fraction (f), and f times D* (fD*) maps., Results: IVIM perfusion-related maps were sensitive to (1) blood flow and perfusion alterations within the microvasculature of brain tumors, in agreement with intra-tumoral susceptibility signal (ITSS); (2) enhancing areas of BBB breakdown in agreement with DSC maps as well as areas of BBB abnormality that was not detected on DSC maps; (3) enhancing perfusion changes within edemas; (4) detecting early foci of increased perfusion within low-grade gliomas., Conclusion: The results suggest IVIM may be a promising approach to delineate tumor extension and progression in size, and to predict histological grade, which are clinically relevant information that characterize tumors and guide therapeutic decisions in patients with glioma., (© 2021. The Author(s), under exclusive licence to European Society for Magnetic Resonance in Medicine and Biology (ESMRMB).)

Alzheimer's disease (AD) is a common, progressive neurodegenerative disease characterized by abnormal deposition of β-amyloid (Aβ) and hyperphosphorylated tau protein. Despite the fact that biomarkers and methods of treating AD are currently being actively studied, there is still no therapy that can significantly reduce the progression of this disease. Therefore, the search for therapeutic disease-modifying strategies is becoming increasingly popular. One such strategy is the use of focused ultrasound (FUS) under MRI guidance using a contrast agent (microbubbles). Under the influence of low-intensity FUS, the blood-brain barrier (BBB) is temporarily opened, which is the main obstacle to the effective delivery of therapeutic compounds to the brain, imposing dimensional and biochemical restrictions on the passage of molecules. One of the processes associated with AD is BBB dysfunction, and therefore the study of the effects of FUS in patients with AD is of interest. The literature data show the effectiveness of FUS in animal models of AD. The researchers attribute the effectiveness of the method to the fact that exposure to FUS induces the opening of BBB and reduces the number of amyloid plaques. It has also been demonstrated that FUS can facilitate the delivery of therapeutic drugs to the brain. This allows considering FUS as a new non-invasive method of treatment. Further research is needed to assess the effectiveness of this method in patients with AD.

Objective: To evaluate the relationship between blood pressure (BP) profile and blood-brain barrier (BBB) permeability in age-related cerebral microangiopathy (CMA) in patients with- and without controlled arterial hypertension (AH)., Material and Methods: 24-hour ambulatory BP monitoring (ABPM), brain MRI, including T1-weighted dynamic contrast images, were performed in 53 patients with CMA (age 60.1±6.8, women 69.8%, controlled hypertension/normal BP 84.8%/15.2%) and 17 healthy volunteers., Results: ABPM showed good control of AH with most of the assessed parameters associated with the severity of white matter hyperintensity (WMH). The permeability of the BBB in normal-appearing white matter (NAWM) and gray matter in patients with CMA was significantly higher than in the control group and was associated with ABPM parameters. The permeability of the BBB in WMH decreased with an increase in its severity., Conclusion: BBB permeability is a universal mechanism of NAWM and gray matter damage that supports the progression of WMH in CMA patients with controlled AH and without AH. The relationship of increased BBB permeability with slight deviations of ABPM can be explained by common mechanisms of their development due to endothelial dysfunction due to CMA and also points to the utility of more aggressive AH treatment. It is advisable to study the effect of antihypertensive and vascular drugs on BBB permeability with a view to their potential use in CMA.

Only partial deficiency/inhibition of P-glycoprotein (P-gp, ABCB1) function at the blood-brain barrier (BBB) is likely to occur in pathophysiological situations or drug-drug interactions. This raises questions regarding the sensitivity of available PET imaging probes to detect moderate changes in P-gp function at the living BBB. In vitro , the half-maximum inhibitory concentration (IC 50 ) of the potent P-gp inhibitor tariquidar in P-gp-overexpressing cells was significantly different using either [ 11 C]verapamil (44 nM), [ 11 C] N -desmethyl-loperamide (19 nM) or [ 11 C]metoclopramide (4 nM) as substrate probes. In vivo PET imaging in rats showed that the half-maximum inhibition of P-gp-mediated efflux of [ 11 C]metoclopramide, achieved using 1 mg/kg tariquidar ( in vivo IC 50  = 82 nM in plasma), increased brain exposure by 2.1-fold for [ 11 C]metoclopramide (p < 0.05, n = 4) and 2.4-fold for [ 11 C]verapamil (p < 0.05, n = 4), whereby cerebral uptake of the "avid" substrate [ 11 C] N -desmethyl-loperamide was unaffected (p > 0.05, n = 4). This comparative study points to differences in the "vulnerability" to P-gp inhibition among radiolabeled substrates, which were apparently unrelated to their "avidity" (maximal response to P-gp inhibition). Herein, we advocate that partial inhibition of transporter function, in addition to complete inhibition, should be a primary criterion of evaluation regarding the sensitivity of radiolabeled substrates to detect moderate but physiologically-relevant changes in transporter function in vivo .

Background: Single-element focused transducers applied in blood-brain barrier (BBB) disruption experiments to optimize intravascular therapies in CNS diseases have the advantage of low cost and portability. Most of the in vivo studies on non-human primates report the use of single-element transducers with an annular spherical shape and a central frequency of 500 kHz. High-frequency ultrasound has smaller focal area and less standing-wave effect but lower transcranial penetration efficiency. Our study reports the feasibility and safety concerns of BBB opening by single-element spherical transducers with central frequencies of 300, 650 and 800 kHz on two rhesus macaques., Methods: Pulsed ultrasound exposure (3-minute duration, 0.5-1% duty cycle) combined with microbubble injection (SonoVue, 0.2uL/g) was used to disrupt the BBB of the monkeys under the magnetic resonance imaging (MRI) guidance. Gadolinium contrast-enhanced MRI was used to confirm and evaluate the BBB opening after sonication. T2-weighted fast spin echo and T2 * -weighted gradient echo sequences were used to check the post-sonication complications, such as edema and micro-bleeding., Results: Contrast enhancement was found on the post-sonication T1 weighted images for all experiments, showing that the BBB was successfully opened under all the three frequencies on both monkeys. The enhanced area was largest at the lowest frequency. No obvious hypo-intensity or hyper-intensity was observed on either the T2 * weighted gradient echo images or T2-weighted fast-spin echo images, implying the safety of the opening procedure. However, signal enhancement was also observed in the subarachnoid space of the sulci for all frequencies, indicating that the BBB was also disrupted in the propagation path outside the focal area., Conclusions: The feasibility of BBB opening with single-element transducer under frequencies ranging from 300 kHz to 800 kHz was confirmed by experiments in two non-human primates in vivo. Further investigation into the off-target effects and transducer configurations is needed for safety optimization., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Recent studies have shown that choroid plexuses (CP) may be involved in the neuro-immune axes, playing a role in the interaction between the central and peripheral inflammation. Here we aimed to investigate CP volume alterations in depression and their associations with inflammation., Methods: 51 depressed participants (HDRS score > 13) and 25 age- and sex-matched healthy controls (HCs) from the Wellcome Trust NIMA consortium were re-analysed for the study. All the participants underwent full peripheral cytokine profiling and simultaneous [11C]PK11195 PET/structural MRI imaging for measuring neuroinflammation and CP volume respectively., Results: We found a significantly greater CP volume in depressed subjects compared to HCs (t (76) = +2.17) that was positively correlated with [ 11 C]PK11195 PET binding in the anterior cingulate cortex (r = 0.28, p = 0.02), prefrontal cortex (r = 0.24, p = 0.04), and insular cortex (r = 0.24, p = 0.04), but not with the peripheral inflammatory markers: CRP levels (r = 0.07, p = 0.53), IL-6 (r = -0.08, p = 0.61), and TNF-α (r = -0.06, p = 0.70). The CP volume correlated with the [ 11 C]PK11195 PET binding in CP (r = 0.34, p = 0.005). Integration of transcriptomic data from the Allen Human Brain Atlas with the brain map depicting the correlations between CP volume and PET imaging found significant gene enrichment for several pathways involved in neuroinflammatory response., Conclusion: This result supports the hypothesis that changes in brain barriers may cause reduction in solute exchanges between blood and CSF, disturbing the brain homeostasis and ultimately contributing to inflammation in depression. Given that CP anomalies have been recently detected in other brain disorders, these results may not be specific to depression and might extend to other conditions with a peripheral inflammatory component., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The blood-brain barrier (BBB) is the main obstacle to the effective delivery of therapeutic agents to the brain, compromising treatment efficacy for a variety of neurological disorders. Intra-arterial (IA) injection of hyperosmotic mannitol has been used to permeabilize the BBB and improve parenchymal entry of therapeutic agents following IA delivery in preclinical and clinical studies. However, the reproducibility of IA BBB manipulation is low and therapeutic outcomes are variable. We demonstrated that this variability could be highly reduced or eliminated when the procedure of osmotic BBB opening is performed under the guidance of interventional MRI. Studies have reported the utility and applicability of this technique in several species. Here we describe a protocol to open the BBB by IA injection of hyperosmotic mannitol under the guidance of MRI in mice. The procedures (from preoperative preparation to postoperative care) can be completed within ~1.5 h, and the skill level required is on par with the induction of middle cerebral artery occlusion in small animals. This MRI-guided BBB opening technique in mice can be utilized to study the biology of the BBB and improve the delivery of various therapeutic agents to the brain., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)