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Breakthroughs in medical imaging and ultrasound transducer design have led to feasible application of focused ultrasound (FUS) to intracranial pathologies. Currently, one of the most active fields in FUS has been the temporary disruption the blood-brain barrier. In addition to enhancing drug delivery to the brain, FUS blood-brain barrier disruption may allow liberation of biomarkers from the brain, thus facilitating ease of detection and adding the element of spatial specificity to an otherwise nonspecific test. This study reviews the current evidence to support FUS liquid biopsy and the challenges of advancing this field., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: P-glycoprotein (P-gp) is an efflux transporter which is abundantly expressed at the blood-brain barrier (BBB) and which has been implicated in the pathophysiology of various brain diseases. The radiolabelled antiemetic drug [ 11 C]metoclopramide is a P-gp substrate for positron emission tomography (PET) imaging of P-gp function at the BBB. To assess whether [ 11 C]metoclopramide can detect increased P-gp function in the human brain, we employed drug-resistant temporal lobe epilepsy (TLE) as a model disease with a well characterised, regional P-gp up-regulation at the BBB., Methods: Eight patients with drug-resistant (DRE) TLE, 5 seizure-free patients with drug-sensitive (DSE) focal epilepsy, and 15 healthy subjects underwent brain PET imaging with [ 11 C]metoclopramide on a fully-integrated PET/MRI system. Concurrent with PET, arterial blood sampling was performed to generate a metabolite-corrected arterial plasma input function for kinetic modelling. The choroid plexus was outmasked on the PET images to remove signal contamination from the neighbouring hippocampus. Using a brain atlas, 10 temporal lobe sub-regions were defined and analysed with a 1-tissue-2-rate constant compartmental model to estimate the rate constants for radiotracer transfer from plasma to brain (K 1 ) and from brain to plasma (k 2 ), and the total volume of distribution (V T = K 1 /k 2 )., Results: DRE patients but not DSE patients showed significantly higher k 2 values and a trend towards lower V T values in several temporal lobe sub-regions located ipsilateral to the epileptic focus as compared to healthy subjects (k 2 : hippocampus: +34%, anterior temporal lobe, medial part: +28%, superior temporal gyrus, posterior part: +21%)., Conclusions: [ 11 C]Metoclopramide PET can detect a seizure-induced P-gp up-regulation in the epileptic brain. The efflux rate constant k 2 seems to be the most sensitive parameter to measure increased P-gp function with [ 11 C]metoclopramide. Our study provides evidence that disease-induced alterations in P-gp expression at the BBB can lead to changes in the distribution of a central nervous system-active drug to the human brain, which could affect the efficacy and/or safety of drugs. [ 11 C]Metoclopramide PET may be used to assess or predict the contribution of increased P-gp function to drug resistance and disease pathophysiology in various brain diseases., Trial Registration: EudraCT 2019-003137-42. Registered 28 February 2020., (© 2024. The Author(s).)

Traumatic brain injury (TBI), a major cause of death and disability among young people, leads to significant public health and economic challenges. Despite its frequency, treatment options remain largely unsuitable. However, examination of the blood-brain barrier (BBB) can assist with understanding the mechanisms and dynamics of brain dysfunction, which affects TBI sufferers secondarily to the injury. Here, we present a rat model of TBI focused on two standard BBB assessment markers, high- and low-molecular-weight complexes, in order to understand BBB disruption. In addition, we tested a new technique to evaluate BBB disruption on a single brain set, comparing the new technique with neuroimaging. A total of 100 Sprague-Dawley rats were separated into the following five groups: naive rats ( n = 20 rats), control rats with administration ( n = 20 rats), and TBI rats ( n = 60 rats). Rats were assessed at different time points after the injury to measure BBB disruption using low- and high-molecular-weight complexes. Neurological severity score was evaluated at baseline and at 24 h following TBI. During the neurological exam after TBI, the rats were scanned with magnetic resonance imaging and euthanized for assessment of the BBB permeability. We found that the two markers displayed different examples of BBB disruption in the same set of brain tissues over the period of a week. Our innovative protocol for assessing BBB permeability using high- and low-molecular-weight complexes markers in a single brain set showed appropriate results. Additionally, we determined the lower limit of sensitivity, therefore demonstrating the accuracy of this method.

Background: The nigrostriatal system is especially vulnerable to neurodegeneration in Parkinson's disease (PD) and the blood-brain barrier (BBB) is a limiting factor for delivery of therapeutic agents to the brain. This pilot study aimed to demonstrate safety, feasibility and tissue penetration (by 18F-Choline-positron emission tomography (PET)) of MR-guided focused ultrasound (MRgFUS) simultaneous BBB opening (BBB-O) in the substantia nigra (SN) and putamen in PD., Methods: Three patients underwent MRgFUS for midbrain and putamen BBB-O. Patients were evaluated clinically and underwent brain MRI with gadolinium (baseline, 24 hours, 14 days and 3 months postprocedure). In two patients, BBB-O was repeated after 2-3 weeks, and 18F-Choline-PET was performed immediately after., Results: The right SN and putamen were simultaneously opened unilaterally in 3 patients once and the left SN in 1 patient in a different session. No severe clinical or neuroimaging adverse events developed in any patient. 18F-Choline-PET uptake was enhanced in the targeted SN and putamen regions., Conclusion: BBB-O of the nigrostriatal system is a feasible and well-tolerated approach in patients with PD. 18F-Choline-PET uptake indicates penetration into the parenchyma after BBB-O, which suggests that the opening is functionally effective. This minimally invasive technique could facilitate delivery of putative neurorestorative molecules to brain regions vulnerable to neurodegeneration., Competing Interests: Competing interests: CG-S has received lecture honoraria from Exeltis, Zambon, Palex, Fundación ACE, and Società Italiana Parkinson e Disordini del Movimento, and reimbursement of travel expenses to attend a scientific conference from Boston Scientific. EN-V was supported in 2021 by a fellowship from the Movement Disorders Group of the Spanish Neurology Society (Sociedad Española de Neurología) granted by Zambon and has received honoraria for lectures from Zambon and Palex. MM has received lecture honoraria from Teva, Zambon, Palex, the Spanish Neurological Society and the International Parkinson and Movement Disorders Society. MM has received research grants from the Michael J Fox Foundation and from the Nemesio Diez Foundation. RM-F has received speaker honoraria from Insightec, Palex, Bial and Zambon and reimbursement of travel expenses to attend scientific conferences from Insightec, Palex and Bial. He has a consulting agreement with Treefrog Therapeutics. IR and GT are employees of Insightec Ltd that has developed and commercialises the ultrasound transducer employed in this study. JAO has been a member of the Advisory Board of Insightec Ltd (2021-2022). The other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective. Cavitation dose monitoring plays a key role in ultrasound drug delivery to the brain. The use of capacitive micromachined ultrasonic transducer (CMUT) technology has a great potential for passive cavitation detection (PCD). Approach. Here, a circular (diameter 7 mm) CMUT centered at 5 MHz was designed to be inserted into a therapeutic transducer (1.5 MHz) used for ultrasound-induced blood-brain barrier (BBB) disruption on mice. CMUT-based real-time cavitation detection was performed during the ultrasound procedure (50 μ l intravenous injection of SonoVue microbubbles, frequency 1.5 MHz, PNP 480 kPa, duty Cycle 10%, PRF 10 Hz, duration 60 s). BBB disruption were confirmed by contrast-enhanced 7T-MRI. Main results. The CMUT device has a fractional bandwidth of 140%, almost twice a conventional piezocomposite PCD transducer. As expected, the CMUT device was able to detect the occurrence of harmonic, subharmonic and ultraharmonic frequencies as well as the increase of broadband signal indicating inertial cavitation in a wide frequency range (from 0.75 to 6 MHz). Signal-to-noise ratio was high enough (>40 dB) to perform ultrafast monitoring and follow the subtle intrapulse variations of frequency components at a rate of 10 kHz. Significance . This first in vivo proof of concept demonstrates the interest of CMUT for PCD and encourages us to develop devices for PCD in larger animals by integrating an amplifier directly to the CMUT front-end to considerably increase the signal-to-noise ratio., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Background: Vascular dysfunction is closely associated with the progression of Alzheimer's disease (AD). A critical research gap exists that no studies have explored the in vivo temporal changes of cerebrovascular alterations with AD progression in mouse models, encompassing both structure and flow dynamics at micron-scale resolution across the early, middle, and late stages of the disease., Methods: In this study, ultrasound localisation microscopy (ULM) was applied to image the cerebrovascular alterations of the transgenic female 5×FAD mouse model across different stages of disease progression: early (4 months), moderate (7 months), and late (12 months). Age-matched non-transgenic (non-Tg) littermates were used as controls. Immunohistology examinations were performed to evaluate the influence of disease progression on the β-amyloid (Aβ) load and microvascular alterations, including morphological changes and the blood-brain barrier (BBB) leakage., Findings: Our findings revealed a significant decline in both vascular density and flow velocity in the retrosplenial cortex of 5×FAD mice at an early stage, which subsequently became more pronounced in the visual cortex and hippocampus as the disease progressed. Additionally, we observed a reduction in vascular length preceding diminished flow velocities in cortical penetrating arterioles during the early stages. The quantification of vascular metrics derived from ULM imaging showed significant correlations with those obtained from vascular histological images. Immunofluorescence staining identified early vascular abnormalities in the retrosplenial cortex. As the disease advanced, there was an exacerbation of Aβ accumulation and BBB disruption in a regionally variable manner. The vascular changes observed through ULM imaging exhibited a negative correlation with amyloid load and were associated with the compromise of the BBB integrity., Interpretation: Through high-resolution, in vivo imaging of cerebrovasculature, this study reveals significant spatiotemporal dysfunction in cerebrovascular dynamics accompanying disease progression in a mouse model of AD, enhancing our understanding of its pathophysiology., Funding: This study is supported by grants from National Key Research and Development Program of China (2020YFA0908800), National Natural Science Foundation of China (12074269, 82272014, 82327804, 62071310), Shenzhen Basic Science Research (20220808185138001, JCYJ20220818095612027, JCYJ20210324093006017), STI 2030-Major Projects (2021ZD0200500) and Guangdong Natural Science Foundation (2024A1515012591, 2024A1515011342)., Competing Interests: Declaration of interests The authors declare that they have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Focused ultrasound (FUS) and microbubbles facilitate blood-brain barrier opening (BBBO) noninvasively, transiently, and safely for targeted drug delivery. Unlike state-of-the-art approaches, in this study, we demonstrate for the first time the simultaneous, bilateral BBBO in non-human primates (NHPs) using acoustic holograms at caudate and putamen structures. The simple and low-cost system with a single-element FUS transducer and 3-D printed acoustic hologram was guided by neuronavigation and a robotic arm. The advantages of holograms are transcranial aberration correction, simultaneous multifocus and high localization, and target-independent transducer positioning, defining a promising alternative for time- and cost-efficient FUS procedures. Holograms were designed with the k-space method by time-reversal techniques. T1-weighted MRI was used for treatment planning, while the computed tomography (CT) scan provided the head tissues acoustic properties. For the BBBO procedure, a robotic arm allowed transducer positioning errors below 0.1 mm and 0.1°. Following positioning, 0.5-0.6-MPa, 513-kHz microbubble-enhanced FUS was applied for 4 min. For BBBO assessment, Post-FUS T1-weighted MRI was acquired, and contrast enhancement indicated bilateral gadolinium extravasation at both caudate or putamen structures. The two BBBO locations were separated by 13.13 mm with a volume of 91.81 mm3 in the caudate, compared with 9.40 mm with a volume of 124.52 mm3 in simulation, while they were separated by 21.74 mm with a volume of 145.38 mm3 in the putamen and compared with 22.32 mm with a volume of 156.42 mm3 in simulation. No neurological damage was observed through T2-weighted and susceptibility-weighted imaging. This study demonstrates the feasibility and safety of hologram-assisted neuronavigation-guided-FUS for BBBO in NHP, providing thus an avenue for clinical translation.

Introduction: Although ischemia-reperfusion (I/R) injury varies between cortical and subcortical regions, its effects on specific regions remain unclear. In this study, we used various magnetic resonance imaging (MRI) techniques to examine the spatiotemporal dynamics of I/R injury within the salvaged ischemic penumbra (IP) and reperfused ischemic core (IC) of a rodent model, with the aim of enhancing therapeutic strategies by elucidating these dynamics., Materials and Methods: A total of 17 Sprague-Dawley rats were subjected to 1 h of transient middle cerebral artery occlusion with a suture model. MRI, including diffusion tensor imaging (DTI), T2-weighted imaging, perfusion-weighted imaging, and T1 mapping, was conducted at multiple time points for up to 5 days during the I/R phases. The spatiotemporal dynamics of blood-brain barrier (BBB) modifications were characterized through changes in T1 within the IP and IC regions and compared with mean diffusivity (MD), T2, and cerebral blood flow., Results: During the I/R phases, the MD of the IC initially decreased, normalized after recanalization, decreased again at 24 h, and peaked on day 5. By contrast, the IP remained relatively stable. Both the IP and IC exhibited hyperperfusion, with the IP reaching its peak at 24 h, followed by resolution, whereas hyperperfusion was maintained in the IC until day 5. Despite hyperperfusion, the IP maintained an intact BBB, whereas the IC experienced persistent BBB leakage. At 24 h, the IC exhibited an increase in the T2 signal, corresponding to regions exhibiting BBB disruption at 5 days., Conclusions: Hyperperfusion and BBB impairment have distinct patterns in the IP and IC. Quantitative T1 mapping may serve as a supplementary tool for the early detection of malignant hyperemia accompanied by BBB leakage, aiding in precise interventions after recanalization. These findings underscore the value of MRI markers in monitoring ischemia-specific regions and customizing therapeutic strategies to improve patient outcomes., 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 © 2024 Elsevier Inc. All rights reserved.)

Objective: Holographic methods can be used with phased array transducers to shape an ultrasound field. We tested a simple method to create holograms with a hemispherical 1024-element phased array transducer and explored how it could benefit ultrasound-mediated blood-brain barrier (BBB) disruption., Methods: With this method, individual acoustic simulations for each element of the transducer were simultaneously loaded into computer memory. Each element's phase was systematically modulated until the combined field matched a desired pattern. The method was evaluated with a 220 kHz transducer being tested clinically to enhance drug delivery via BBB disruption. The holograms were evaluated in a tissue-mimicking phantom and in vivo in experiments disrupting the BBB in rats and in a macaque. We also explored whether this approach could mitigate secondary reflections from the skull using simulations of transcranial focusing in clinical treatments of transcranial sonication for BBB disruption., Results: This approach can enlarge the focal volume in a patient-specific manner and could reduce the number of sonication targets needed to disrupt large volumes, improve the homogeneity of the disruption, and improve our ability to detect microbubble activity in tissues with low vascular density. Simulations suggest that the method could also mitigate secondary reflections during transcranial sonication.

Background: Blood-brain barrier (BBB) integrity is presumed to be impaired in hypertension, resulting from cerebral endothelial dysfunction. Hypertension precedes various cerebrovascular diseases, such as cerebral small vessel disease, and is a risk factor for developing neurodegenerative diseases for which BBB disruption is a preceding pathophysiological process. In this cross-sectional study, we investigated the relation between hypertension, current blood pressure, and BBB leakage in human subjects., Methods: BBB leakage was determined in 22 patients with hypertension and 19 age- and sex-matched normotensive controls (median age [range], 65 [45-80] years; 19 men) using a sparsely time-sampled contrast-enhanced 7T magnetic resonance imaging protocol. Structural cerebral small vessel disease markers were visually rated. Multivariable regression analyses, adjusted for age, sex, cardiovascular risk factors, and cerebral small vessel disease markers, were performed to determine the relation between hypertension status, systolic and diastolic blood pressure, mean arterial pressure, drug treatment, and BBB leakage., Results: Both hypertensive and normotensive participants showed mild scores of cerebral small vessel disease. BBB leakage did not differ between hypertensive and normotensive participants; however, it was significantly higher for systolic blood pressure, diastolic blood pressure, and mean arterial pressure in the cortex, and diastolic blood pressure and mean arterial pressure in the gray matter. Effectively treated patients showed less BBB leakage than those with current hypertension., Conclusions: BBB integrity in the total and cortical gray matter decreases with increasing blood pressure but is not related to hypertension status. These findings show that BBB disruption already occurs with increasing blood pressure, before the presence of overt cerebral tissue damage. Additionally, our results suggest that effective antihypertensive medication has a protective effect on the BBB., Registration: URL: https://trialsearch.who.int/; Unique identifier: NL7537., Competing Interests: None.

Growing evidence indicates an important role of neurovascular unit (NVU) dysfunction in the pathophysiology of cerebral small vessel disease (cSVD). Individually measurable functions of the NVU have been correlated with cognitive function, but a combined analysis is lacking. We aimed to perform a unified analysis of NVU function and its relation with cognitive performance. The relationship between NVU function in the white matter and cognitive performance (both latent variables composed of multiple measurable variables) was investigated in 73 patients with cSVD (mean age 70 ± 10 years, 41% women) using canonical correlation analysis. MRI-based NVU function measures included (1) the intravoxel incoherent motion derived perfusion volume fraction (f) and microvascular diffusivity (D*), reflecting cerebral microvascular flow; (2) the IVIM derived intermediate volume fraction (f int ), indicative of the perivascular clearance system; and (3) the dynamic contrast-enhanced MRI derived blood-brain barrier (BBB) leakage rate (K i ) and leakage volume fraction (V L ), reflecting BBB integrity. Cognitive performance was composed of 13 cognitive test scores. Canonical correlation analysis revealed a strong correlation between the latent variables NVU function and cognitive performance (r 0.73; p = 0.02). For the NVU, the dominating variables were D*, f int , and K i . Cognitive performance was driven by multiple cognitive tests comprising different cognitive domains. The functionality of the NVU is correlated with cognitive performance in cSVD. Instead of focusing on individual pathophysiological mechanisms, future studies should target NVU dysfunction as a whole to acquire a coherent understanding of the complex disease mechanisms that occur in the NVU in cSVD.Trial registration: NTR3786 (Dutch Trial Register)., (© 2024. The Author(s).)

Background: Blood-brain barrier (BBB) dysfunction has been viewed as a potential underlying mechanism of neurodegenerative disorders, possibly involved in the pathogenesis and progression of Alzheimer's disease (AD). However, a relation between BBB dysfunction and dementia with Lewy bodies (DLB) has yet to be systematically investigated. Given the overlapping clinical features and neuropathology of AD and DLB, we sought to evaluate BBB permeability in the context of DLB and determine its association with plasma amyloid-β (Aβ) using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)., Methods: For this prospective study, we examined healthy controls (n = 24, HC group) and patients diagnosed with AD (n = 29) or DLB (n = 20) between December 2020 and April 2022. Based on DCE-MRI studies, mean rates of contrast agent transfer from intra- to extravascular spaces (K trans ) were calculated within regions of interest. Spearman's correlation and multivariate linear regression were applied to analyze associations between K trans and specific clinical characteristics., Results: In members of the DLB (vs HC) group, K trans values of cerebral cortex (p = 0.024), parietal lobe (p = 0.007), and occipital lobe (p = 0.014) were significantly higher; and K trans values of cerebral cortex (p = 0.041) and occipital lobe (p = 0.018) in the DLB group were significantly increased, relative to those of the AD group. All participants also showed increased K trans values of parietal ( β  = 0.391; p = 0.001) and occipital ( β  = 0.357; p = 0.002) lobes that were significantly associated with higher scores of the Clinical Dementia Rating, once adjusted for age and sex. Similarly, increased K trans values of cerebral cortex ( β  = 0.285; p = 0.015), frontal lobe ( β  = 0.237; p = 0.043), and parietal lobe ( β = 0.265; p = 0.024) were significantly linked to higher plasma Aβ1-42/Aβ1-40 ratios, after above adjustments., Conclusion: BBB leakage is a common feature of DLB and possibly is even more severe than in the setting of AD for certain regions of the brain. BBB leakage appears to correlate with plasma Aβ1-42/Aβ1-40 ratio and dementia severity., (© 2024. The Author(s).)

The brain has a highly selective semipermeable blood barrier, termed the blood-brain barrier (BBB), which prevents the delivery of therapeutic macromolecular agents to the brain. The integration of MR-guided low-intensity pulsed focused ultrasound (FUS) with microbubble pre-injection is a promising technique for non-invasive and non-toxic BBB modulation. MRI can offer superior soft-tissue contrast and various quantitative assessments, such as vascular permeability, perfusion, and the spatial-temporal distribution of MRI contrast agents. Notably, contrast-enhanced MRI techniques with gadolinium-based MR contrast agents have been shown to be the gold standard for detecting BBB openings. This study outlines a comprehensive methodology involving MRI protocols and animal procedures for monitoring BBB opening in a rat model. The rat model provides the added benefit of jugular vein catheter utilization, which facilitates rapid medication administration. A stereotactic-guided preclinical FUS transducer facilitates the refinement and streamlining of animal procedures and MRI protocols. The resulting methods are characterized by reproducibility and simplicity, eliminating the need for specialized surgical expertise. This research endeavors to contribute to the optimization of preclinical procedures with rat models and encourage further investigation into the modulation of the BBB to enhance therapeutic interventions in neurological disorders.

The blood-brain barrier (BBB) is essential for protection and plays a crucial role in chronic neurological disorders like small-vessel disease and Alzheimer's disease. Its complexity poses significant challenges for effective diagnostics and treatments, highlighting the need for novel animal models and comprehensive BBB dysfunction studies. This study investigates chronic BBB dysfunction induction using osmotic disruption via mannitol in healthy adult male Sprague Dawley rats over 12 weeks. Group 1 received 1 bolus/week (2.0 g/kg), Group 2 received 3 boluses/week (1.5 g/kg), and Group 3 received 3 boluses/week (2.5 g/kg). BBB dysfunction was assessed using gadolinium (Gd) infusion and MRI to evaluate location, severity, evolution, and persistence. MR spectroscopy (MRS) examined the brain metabolism changes due to intravenous mannitol, with T2-weighted MRI assessing brain lesions. Biomarkers of neuroinflammation were analyzed in the highest mannitol dose group. Our data show chronic BBB dysfunction primarily in the cortex, hippocampus, and striatum, but not in the corpus callosum of rats under periodic mannitol dosing in groups 1 and 2. MRS identified a distinctive metabolite signature, including changes in alanine, choline, and N-acetyl aspartate in the striatum of Group 1. No significant differences were found in the serum levels of all pro- and anti-inflammatory cytokines analyzed in the high-dose Group 3. This study underscores the feasibility and implications of using osmotic disruption to model chronic BBB dysfunction, offering insights for future neuroprotection and therapeutic strategies research.

Objectives: Blood-brain barrier (BBB) disruption is an important pathological change after cerebral infarction that exacerbates brain injury. We aimed to investigate and compare the predictive utility of pre-treatment BBB permeability (BBBP) and BBBP within 1 h after endovascular treatment (EVT) for hemorrhagic transformation (HT) and 90-day prognosis., Methods: Patients underwent preoperative computed tomography perfusion (CTP) and non-contrast CT (NCCT) within 1 h after EVT. Preoperative BBBP was determined by the relative permeability surface area product (rPS) in the hypoperfusion area. Postoperative BBBP was determined by the post-EVT Alberta Stroke Program Early CT Score (Post-ASPECTS), which is based on brain parenchymal hyperdensity on the postoperative NCCT., Outcomes: We included 100 patients. Univariate logistic regression analysis revealed correlations of preoperative rPS with HT, poor outcomes, and death. However, these correlations were not observed in multivariate logistic regression. A Post-ASPECTS ≤7 and could independently predict poor outcomes, while Post-ASPECTS ≤6 could independently predict death and HT. The baseline National Institutes of Health Stroke Scale (NIHSS) score could independently predict poor outcomes and death but not HT. A combined model using the baseline NIHSS and Post-ASPECTS scores had better predictive performance for poor outcomes and death than baseline NIHSS score alone; however, it was not superior to the predictive performance of the Post-ASPECTS score., Conclusion: The preoperative rPS cannot independently predict clinical outcomes in EVT-treated patients; contrastingly, the Post-ASPECTS score could independently predict poor outcomes, death, and HT. This parameter could inform prompt postoperative treatment decisions., (© 2024. Fondazione Società Italiana di Neurologia.)

Cerebral small vessel disease (cSVD) is associated with increased blood-brain barrier (BBB) permeability. We sought to evaluate whether arterial stiffness might be associated with BBB permeability in patients with cSVD. We assessed BBB permeability using Dynamic Contrast-Enhanced MRI (DCE-MRI) in 29 patients that had suffered a recent small subcortical infarct (RSSI). BBB permeability in the whole brain (WB), gray matter (GM) and white matter (WM) was assessed with the parameter Ktrans. We used ambulatory blood pressure monitoring to measure 24-h systolic blood pressure (24-h SBP), diastolic blood pressure (24-h DBP), and pulse wave velocity (24-h PWV) both after stroke and following a 2-year follow-up. The differences between both measurements were calculated as Δ24-h SBP, Δ24-h DBP and Δ24-h PWV. DCE-MRI was acquired at a median (IQR) of 24 (19-27) months after stroke. Median age was 66.7 (9.7) years, and 24 (83%) patients were men. Median (IQR) Δ24-h PWV was 0.3 (-0.1, 0.5) m/s. WB-Ktrans, GM-Ktrans, and WM-Ktrans were associated with Δ24-h PWV (Spearman's, r [95% CI], WB 0.651 [0.363-0.839]; GM 0.657 [0.373-0.845], WM 0.530[0.197-0.777]) but not with Δ24-h SBP or Δ24-h DBP. These associations remained significant after adjustment with linear regression models, controlling for age, sex, body mass index, and Δ24-h SBP (b[95% CI], WB 0.725[0.384-1.127], GM 0.629 [0.316-1.369], WM 0.865 [0.455-0.892]) or Δ24-h DBP (b[95% CI], WM 0.707 [0.370-1.103], GM 0.643 [0.352-1.371], WM 0.772 [0.367-0.834]). Our results suggest that an increment on arterial stiffness in the months following a RSSI might increase BBB permeability., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Intravoxel incoherent motion (IVIM) MRI has emerged as a valuable technique for the assessment of tissue characteristics and perfusion. However, there is limited knowledge about the relationship between IVIM-derived measures and changes at the level of the vascular network. In this study, we investigated the potential use of IVIM MRI as a noninvasive tool for measuring changes in cerebral vascular density. Variations in quantitative immunohistochemical measurements of the vascular density across different regions in the rat brain (cortex, corpus callosum, hippocampus, thalamus, and hypothalamus) were related to the pseudo-diffusion coefficient D* and the flowing blood fraction f in healthy Wistar rats. We assessed whether region-wise differences in the vascular density are reflected by variations in the IVIM measurements and found a significant positive relationship with the pseudo-diffusion coefficient (p < 0.05, β = 0.24). The effect of cerebrovascular alterations, such as blood-brain barrier (BBB) disruption on the perfusion-related IVIM parameters, is not well understood. Therefore, we investigated the effect of BBB disruption on the IVIM measures in a rat model of metabolic and vascular comorbidities (ZSF1 obese rat) and assessed whether this affects the relationship between the cerebral vascular density and the noninvasive IVIM measurements. We observed increased vascular permeability without detecting any differences in diffusivity, suggesting that BBB leakage is present before changes in the tissue integrity. We observed no significant difference in the relationship between cerebral vascular density and the IVIM measurements in our model of comorbidities compared with healthy normotensive rats., (© 2024 John Wiley & Sons Ltd.)

Numerous studies suggest that blood-brain barrier (BBB) dysfunction may contribute to the progression of Alzheimer's disease (AD). Clinically available neuroimaging methods are needed for quantitative "scoring" of BBB permeability in AD patients. [ 18 F]2-fluoro-2-deoxy-sorbitol ([ 18 F]FDS), which can be easily obtained from simple chemical reduction of commercial [ 18 F]2-fluoro-2-deoxy-glucose ([ 18 F]FDG), was investigated as a small-molecule marker of BBB permeability, in a pre-clinical model of AD using in vivo PET imaging. Chemical reduction of [ 18 F]FDG to [ 18 F]FDS was obtained with a 100% conversion yield. Dynamic PET acquisitions were performed in the APP/PS1 rat model of AD (TgF344-AD, n=3) compared with age-matched littermates (WT, n=4). The brain uptake of [ 18 F]FDS was determined in selected brain regions, delineated from a coregistered rat brain template. The brain uptake of [ 18 F]FDS in the brain regions of AD rats versus WT rats was compared using a 2-way ANOVA. The uptake of [ 18 F]FDS was significantly higher in the whole brain of AD rats, as compared with WT rats (P<0.001), suggesting increased BBB permeability. Enhanced brain uptake of [ 18 F]FDS in AD rats was significantly different across brain regions (P<0.001). Minimum difference was observed in the amygdala (+89.0±7.6%, P<0.001) and maximum difference was observed in the midbrain (+177.8±29.2%, P<0.001). [ 18 F]FDS, initially proposed as radio-pharmaceutical to estimate renal filtration using PET imaging, can be repurposed for non-invasive and quantitative determination of BBB permeability in vivo. Making the best with the quantitative properties of PET imaging, it was possible to estimate the extent of enhanced BBB permeability in a rat model of AD., (Copyright © 2024. Published by Elsevier Masson SAS.)

Purpose of Review: Brain tumor treatment presents challenges for patients and clinicians, with prognosis for many of the most common brain tumors being poor. Focused ultrasound (FUS) can be deployed in several ways to circumvent these challenges, including the need to penetrate the blood-brain barrier and spare healthy brain tissue. This article reviews current FUS applications within neuro-oncology, emphasizing ongoing or recently completed clinical trials., Recent Findings: Most clinical interest in FUS for neuro-oncology remains focused on exploring BBB disruption to enhance the delivery of standard-of-care therapeutics. More recently, the application of FUS for radiosensitization, liquid biopsy, and sonodynamic therapy is garnering increased clinical attention to assist in tumor ablation, early detection, and phenotypic diagnosis. Preclinical studies show encouraging data for the immunomodulatory effects of FUS, but these findings have yet to be tested clinically., Summary: FUS is a burgeoning area of neuro-oncology research. Data from several forthcoming large clinical trials should help clarify its role in neuro-oncology care., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The potential of intranasal administered imaging agents to altogether bypass the blood-brain barrier offers a promising non-invasive approach for delivery directly to the brain. This review provides a comprehensive analysis of the advancements and challenges of delivering neuroimaging agents to the brain by way of the intranasal route, focusing on the various imaging modalities and their applications in central nervous system diagnostics and therapeutics. The various imaging modalities provide distinct insights into the pharmacokinetics, biodistribution, and specific interactions of imaging agents within the brain, facilitated by the use of tailored tracers and contrast agents. Methods: A comprehensive literature search spanned PubMed, Scopus, Embase, and Web of Science, covering publications from 1989 to 2024 inclusive. Starting with advancements in tracer development, we going to explore the rationale for integration of imaging techniques, and the critical role novel formulations such as nanoparticles, nano- and micro-emulsions in enhancing imaging agent delivery and visualisation. Results: The review highlights the use of innovative formulations in improving intranasal administration of neuroimaging agents, showcasing their ability to navigate the complex anatomical and physiological barriers of the nose-to-brain pathway. Various imaging techniques, MRI, PET, SPECT, CT, FUS and OI, were evaluated for their effectiveness in tracking these agents. The findings indicate significant improvements in brain targeting efficiency, rapid uptake, and sustained brain presence using innovative formulations. Conclusion: Future directions involve the development of optimised tracers tailored for intranasal administration, the potential of multimodal imaging approaches, and the implications of these advancements for diagnosing and treating neurological disorders., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objectives: This study aimed to monitor blood-brain barrier permeability within 24 h and during the delayed cerebral ischemia (DCI) time window (DCITW) spanning 4-14 days after aneurysmal subarachnoid hemorrhage (aSAH) and to investigate its correlation with both DCI occurrence and outcomes at three months., Methods: A total of 128 patients were stratified based on the DCI occurrence and three-month modified Rankin scale scores. Comparison of K trans at admission (admission K trans ) and during DCITW (DCITW K trans ) was conducted between DCI and non-DCI groups, as well as between groups with good and poor outcomes. Changes in K trans were also analyzed. Multivariate logistic regression analysis was performed to identify independent predictors of DCI and poor outcomes., Results: Admission K trans (0.58 ± 0.18 vs 0.47 ± 0.12, p = 0.002) and DCITW K trans (0.54 ± 0.19 vs 0.41 ± 0.14, p < 0.001) were significantly higher in the DCI group compared with the non-DCI group. Although both were higher in the poor outcome group than the good outcome group, the difference was not statistically significant at admission (0.53 ± 0.18 vs 0.49 ± 0.14, p = 0.198). K trans in the non-DCI group (0.47 ± 0.12 vs 0.41 ± 0.14, p = 0.004) and good outcome group (0.49 ± 0.14 vs 0.41 ± 0.14, p < 0.001) decreased significantly from the admission to DCITW. Multivariate analysis identified DCITW K trans and admission K trans as independent predictors of poor outcomes (OR = 1.73, 95%CI: 1.24-2.43, p = 0.001) and DCI (OR = 1.75, 95%CI: 1.25-2.44, p = 0.001), respectively., Conclusion: Elevated K trans at admission is associated with the occurrence of DCI. Continuous monitoring of K trans from admission to DCITW can accurately identify reversible and irreversible changes and can predict outcomes at 3 months., Clinical Relevance Statement: K trans measured with CT perfusion is a valuable tool for predicting both delayed cerebral ischemia and three-month outcomes following aneurysmal subarachnoid hemorrhage. Monitoring changes in K trans from admission to time window of delayed cerebral ischemia can guide treatment and management decisions for aneurysmal subarachnoid hemorrhage patients., Key Points: • K trans measured at admission and during the delayed cerebral ischemia time window (4-14 days) holds distinct clinical significance following aneurysmal subarachnoid hemorrhage. • Admission K trans serves as a predictor for delayed cerebral ischemia, while continuous assessment of K trans from admission to the delayed cerebral ischemia time window can predict three-month outcomes. • Monitoring K trans at different stages improves instrumental in enhancing decision-making and treatment planning for patients with aneurysmal subarachnoid hemorrhage., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

The etiology of brain fog associated with long COVID is not clear. Based on some preliminary work, disruption of the blood-brain barrier has been hypothesized, but has not been tested in patients with long COVID. In this case-control pilot study, we evaluated blood-brain barrier permeability in patients with long COVID and subjective memory loss or brain fog. We used 99 m Technetium diethylenetriaminepentaacetic acid single-photon emission computed tomography (SPECT) to measure blood-brain barrier permeability and a telephone assessment (T-cog) to measure cognitive function. The blood-brain barrier permeability was quantified via SPECT standard uptake value (SUV). We assessed the blood-brain barrier permeability in 14 long COVID patients and 10 control participants without subjective cognitive impairment or brain fog. Participants in the two groups were similar in age. The long COVID group had more comorbidities compared to the control group. There was no difference in the SUVs in the long COVID (0.22 ± 0.12) vs the control (0.17 ± 0.04) group. There was no difference in the T-cog results in the two groups either. We found no evidence of a difference in blood-brain permeability in patients with long COVID when compared to controls without a known history of COVID-19 infection. Larger studies are needed to confirm these findings., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background : Focused ultrasound (FUS) in combination with microbubbles has recently shown great promise in facilitating blood-brain barrier (BBB) opening for drug delivery and immunotherapy in Alzheimer's disease (AD). However, it is currently limited to systems integrated within the MRI suites or requiring post-surgical implants, thus restricting its widespread clinical adoption. In this pilot study, we investigate the clinical safety and feasibility of a portable, non-invasive neuronavigation-guided FUS (NgFUS) system with integrated real-time 2-D microbubble cavitation mapping. Methods : A phase 1 clinical study with mild to moderate AD patients (N = 6) underwent a single session of microbubble-mediated NgFUS to induce transient BBB opening (BBBO). Microbubble activity under FUS was monitored with real-time 2-D cavitation maps and dosing to ensure the efficacy and safety of the NgFUS treatment. Post-operative MRI was used for BBB opening and closure confirmation as well as safety assessment. Changes in AD biomarker levels in both blood serum and extracellular vesicles (EVs) were evaluated, while changes in amyloid-beta (Aβ) load in the brain were assessed through 18 F-florbetapir PET. Results : BBBO was achieved in 5 out of 6 subjects with an average volume of 983 ± 626 mm 3 following FUS at the right frontal lobe both in white and gray matter regions. The outpatient treatment was completed within 34.8 ± 10.7 min. Cavitation dose significantly correlated with the BBBO volume ( R 2 > 0.9, N = 4), demonstrating the portable NgFUS system's capability of predicting opening volumes. The cavitation maps co-localized closely with the BBBO location, representing the first report of real-time transcranial 2-D cavitation mapping in the human brain. Larger opening volumes correlated with increased levels of AD biomarkers, including Aβ42 ( R 2 = 0.74), Tau ( R 2 = 0.95), and P-Tau181 ( R 2 = 0.86), assayed in serum-derived EVs sampled 3 days after FUS ( N = 5). From PET scans, subjects showed a lower Aβ load increase in the treated frontal lobe region compared to the contralateral region. Reduction in asymmetry standardized uptake value ratios (SUVR) correlated with the cavitation dose ( R 2 > 0.9, N = 3). Clinical changes in the mini-mental state examination over 6 months were within the expected range of cognitive decline with no additional changes observed as a result of FUS. Conclusion : We showed the safety and feasibility of this cost-effective and time-efficient portable NgFUS treatment for BBBO in AD patients with the first demonstration of real-time 2-D cavitation mapping. The cavitation dose correlated with BBBO volume, a slowed increase in pathology, and serum detection of AD proteins. Our study highlights the potential for accessible FUS treatment in AD, with or without drug delivery., Competing Interests: Competing Interests: Some of the work presented herein is supported by patents optioned to Delsona Therapeutics, Inc. where EEK serves as co-founder and scientific adviser. SB, ANP, RJ, KL, SJG, OY, FNT, DK, AKS, AB, and LSH declare no conflict of interest., (© The author(s).)

Non-invasive imaging of GSK-3 expression in the brain will help to understand the role of GSK-3 in disease pathology and progression. Herein, we report the radiosynthesis and evaluation of two novel isonicotinamide based 18 F labeled PET probes, [ 18 F]2 and [ 18 F]6 for noninvasive imaging of GSK3. Among the developed PET probes, the in vitro blood-brain permeability coefficient of 2 (38 ± 20 × 10 -6  cm/s, n = 3) was found to be better than 6 (8.75 ± 3.90 × 10 -6  cm/s, n = 5). The reference compounds 2 and 6 showed nanomolar affinity towards GSK-3α and GSK-3β. PET probe [ 18 F]2 showed higher stability (100%) in mouse and human serums compared to [ 18 F]6 (67.01 ± 4.93%, n = 3) in mouse serum and 66.20 ± 6.38%, n = 3) in human serum at 120 min post incubation. The in vivo imaging and blocking studies were performed in wild-type mice only with [ 18 F]2 due to its observed stability. [ 18 F]2 showed a SUV of 0.92 ± 0.28 (n = 6) in mice brain as early as 5 min post-injection followed by gradual clearance over time., (© 2024. The Author(s).)

Following a stroke, an inflammatory response occurs, characterized by an increased blood-brain barrier permeability, expression of endothelial trafficking molecules, and infiltration of immune cells. Adhesion molecules expressed on activated brain endothelial cells are potential biomarkers of intraparenchymal inflammation. However, in current clinical practice, it is not possible to measure endothelial activation using clinically available imaging. Using targeted micro-sized particles of iron oxide (MPIO), immuno-MRI enables the detection of endothelial adhesion molecules at high resolution and, consequently, facilitates the detection of stroke-induced brain inflammation. In this review, we highlight the most recent studies that used immuno-MRI in models of neurovascular disorders, including transient ischemic attack, ischemic stroke, intracranial hemorrhage, and subarachnoid hemorrhage. We also discuss the potential of immuno-MRI in clinical practice and the necessary next steps for its implementation in patients., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Blood-brain barrier (BBB) disruption may contribute to cognitive decline, but questions remain whether this association is more pronounced for certain brain regions, such as the hippocampus, or represents a whole-brain mechanism. Further, whether human BBB leakage is triggered by excessive vascular pulsatility, as suggested by animal studies, remains unknown. In a prospective cohort (N = 50; 68-84 years), we used contrast-enhanced MRI to estimate the permeability-surface area product (PS) and fractional plasma volume ( v p ), and 4D flow MRI to assess cerebral arterial pulsatility. Cognition was assessed by the Montreal Cognitive Assessment (MoCA) score. We hypothesized that high PS would be associated with high arterial pulsatility, and that links to cognition would be specific to hippocampal PS. For 15 brain regions, PS ranged from 0.38 to 0.85 (·10 -3  min -1 ) and v p from 0.79 to 1.78%. Cognition was related to PS (·10 -3  min -1 ) in hippocampus (β = - 2.9; p = 0.006), basal ganglia (β = - 2.3; p = 0.04), white matter (β = - 2.6; p = 0.04), whole-brain (β = - 2.7; p = 0.04) and borderline-related for cortex (β = - 2.7; p = 0.076). Pulsatility was unrelated to PS for all regions (p > 0.19). Our findings suggest PS-cognition links mainly reflect a whole-brain phenomenon with only slightly more pronounced links for the hippocampus, and provide no evidence of excessive pulsatility as a trigger of BBB disruption., (© 2024. The Author(s).)

Metastatic tumours in the brain now represent one of the leading causes of death from cancer. Current treatments are largely ineffective owing to the combination of late diagnosis and poor delivery of therapies across the blood-brain barrier (BBB). Conjugating magnetic resonance imaging (MRI) contrast agents with a monoclonal antibody for VCAM-1 (anti-VCAM1) has been shown to enable detection of micrometastases, two to three orders of magnitude smaller in volume than those currently detectable clinically. The aim of this study was to exploit this targeting approach to enable localised and temporary BBB opening at the site of early-stage metastases using functionalised microbubbles and ultrasound. Methods: Microbubbles functionalised with anti-VCAM1 were synthesised and shown to bind to VCAM-1-expressing cells in vitro . Experiments were then conducted in vivo in a unilateral breast cancer brain metastasis mouse model using Gadolinium-DTPA (Gd-DTPA) enhanced MRI to detect BBB opening. Following injection of Gd-DTPA and targeted microbubbles, the whole brain volume was simultaneously exposed to ultrasound (0.5 MHz, 10% duty cycle, 0.7 MPa peak negative pressure, 2 min treatment time). T1-weighted MRI was then performed to identify BBB opening, followed by histological confirmation via immunoglobulin G (IgG) immunohistochemistry. Results: In mice treated with targeted microbubbles and ultrasound, statistically significantly greater extravasation of Gd-DTPA and IgG was observed in the left tumour-bearing hemisphere compared to the right hemisphere 5 min after treatment. No acute adverse effects were observed. There was no investigation of longer term bioeffects owing to the nature of the study. Conclusion: The results demonstrate the feasibility of using targeted microbubbles in combination with low intensity ultrasound to localise opening of the BBB to metastatic sites in the brain. This approach has potential application in the treatment of metastatic tumours whose location cannot be established a priori with conventional imaging methods., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The quantitative relationship between the disruption of the blood-brain barrier (BBB) and the recruitment of glial cells was explored in a mouse model of endotoxemia. [ 18 F]2-Fluoro-2-deoxy-sorbitol ([ 18 F]FDS) PET imaging was used as a paracellular marker for quantitative monitoring of BBB permeability after i.v injection of increasing doses of lipopolysaccharide (LPS) or vehicle (saline, n = 5). The brain distribution of [ 18 F]FDS ( V T , mL.cm -3 ) was estimated using kinetic modeling. LPS dose-dependently increased the brain V T of [ 18 F]FDS after injection of LPS 4 mg/kg (5.2 ± 2.4-fold, n = 4, p < 0.01) or 5 mg/kg (9.0 ± 9.1-fold, n = 4, p < 0.01) but not 3 mg/kg (p > 0.05, n = 7). In 12 individuals belonging to the different groups, changes in BBB permeability were compared with expression of markers of astrocyte (GFAP) and microglial cell (CD11b) using ex vivo immunohistochemistry. Increased expression of CD11b and GFAP expression was observed in mice injected with 3 mg/kg of LPS, which did not increase with higher LPS doses. Quantitative [ 18 F]FDS PET imaging can capture different levels of BBB permeability in vivo. A biphasic effect was observed with the lowest dose of LPS that triggered neuroinflammation without disruptive changes in BBB permeability, and higher LPS doses that increased BBB permeability without additional recruitment of glial cells., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

To date, earlier diagnosis of Alzheimer's disease (AD) is still challenging. Recent studies revealed the elevated expression of connective tissue growth factor (CTGF) in AD brain is an upstream regulator of amyloid-beta (Aβ) plaque, thus CTGF could be an earlier diagnostic biomarker of AD than Aβ plaque. Herein, we develop a peptide-coated gold nanocluster that specifically targets CTGF with high affinity (KD ~ 21.9 nM). The probe can well penetrate the blood-brain-barrier (BBB) of APP/PS1 transgenic mice at early-stage (earlier than 3-month-old) in vivo, allowing non-invasive NIR-II imaging of CTGF when there is no appearance of Aβ plaque deposition. Notably, this probe can also be applied to measuring CTGF on postmortem brain sections by multimodal analysis, including fluorescence imaging, peroxidase-like chromogenic imaging, and ICP-MS quantitation, which enables distinguishment between the brains of AD patients and healthy people. This probe possesses great potential for precise diagnosis of earlier AD before Aβ plaque formation., (© 2024. The Author(s).)

Purpose: The determination of blood-brain barrier (BBB) integrity and partial pressure of oxygen (pO 2 ) in the brain is of substantial interest in several neurological applications. This study aimed to assess the feasibility of using trityl OX071-based pulse electron paramagnetic resonance imaging (pEPRI) to provide a quantitative estimate of BBB integrity and pO 2 maps in mouse brains as a function of neuroinflammatory disease progression., Methods: Five Connexin-32 (Cx32)-knockout (KO) mice were injected with lipopolysaccharide to induce neuroinflammation for imaging. Three wild-type mice were also used to optimize the imaging procedure and as control animals. An additional seven Cx32-KO mice were used to establish the BBB leakage of trityl using the colorimetric assay. All pEPRI experiments were performed using a preclinical instrument, JIVA-25 (25 mT/720 MHz), at times t = 0, 4, and 6 h following lipopolysaccharide injection. Two pEPRI imaging techniques were used: (a) single-point imaging for obtaining spatial maps to outline the brain and calculate BBB leakage using the signal amplitude, and (b) inversion-recovery electron spin echo for obtaining pO 2 maps., Results: A statistically significant change in BBB leakage was found using pEPRI with the progression of inflammation in Cx32 KO animals. However, the change in pO 2 values with the progression of inflammation for these animals was not statistically significant., Conclusions: For the first time, we show the ability of pEPRI to provide pO 2 maps in mouse brains noninvasively, along with a quantitative assessment of BBB leakage. We expect this study to open new queries from the field to explore the pathology of many neurological diseases and provide a path to new treatments., (© 2024 International Society for Magnetic Resonance in Medicine.)

Increased blood-brain barrier permeability (BBBP) after ischemic stroke predisposes patients to hemorrhagic conversion. While altered BBBP can impact patient recovery, it is not routinely assessed during the workup of acute ischemic stroke (AIS). We study the effectiveness of the non-contrast MRI sequences diffusion-prepared pseudocontinuous arterial spin labeling (DP-pCASL) and Neurite Orientation Dispersion and Density Imaging (NODDI) in assessing BBBP and correlating to tissue microstructure after ischemic insult. Twelve patients with AIS were prospectively enrolled to undergo our multimodal MR imaging, which generated the DP-pCASL-derived cerebral blood flow (CBF), arterial transit time (ATT), and water exchange rate (k w ) and the NODDI-derived b0, mean diffusivity (MD), orientation dispersion index (ODI), intracellular volume fraction (ICVF), and isotropic volume fraction (ISO) parametric maps. The mean age of the patients was 70.2 ± 14.8 with an average NIHSS of 13.0 (7.3-19.8). MR imaging was performed on average at 53.7 (27.8-93.3) hours from stroke symptom onset. The water exchange rate (k w) of the infarcted area and its contralateral territory were 89.7 min -1 (66.7-121.9) and 89.9 min -1 (65.9-106.0) respectively (p = 0.887). Multivariable linear regression analysis showed that b0, ODI, ISO and mechanical thrombectomy were significant predictors of k w . DP-pCASL and NODDI are promising non-contrast sequences for the routine assessment of BBBP., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The development of bispecific antibodies that can traverse the blood-brain barrier has paved the way for brain-directed immunotherapy and when radiolabelled, immunoPET imaging. The objective of this study was to investigate how indium-111 ( 111 In) radiolabelling with compatible chelators affects the brain delivery and peripheral biodistribution of the bispecific antibody RmAb158-scFv8D3, which binds to amyloid-beta (Aβ) and the transferrin receptor (TfR), in Aβ pathology-expressing tg-ArcSwe mice and aged-matched wild-type control mice., Methods: Bispecific RmAb158-scFv8D3 (biAb) was radiolabelled with 111 In using CHX-A"-DTPA, DOTA, or DOTA-tetrazine (DOTA-Tz). Affinity toward TfR and Aβ, as well as stability, was investigated in vitro . Mice were then intravenously administered with the three different radiolabelled biAb variants, and blood samples were collected for monitoring pharmacokinetics. Brain concentration was quantified after 2 and 72 h, and organ-specific retention was measured at 72 h by gamma counting. A subset of mice also underwent whole-body Single-photon emission computed tomography (SPECT) scanning at 72 h after injection. Following post-mortem isolation, the brains of tg-ArcSwe and WT mice were sectioned, and the spatial distribution of biAb was further investigated with autoradiography., Results: All three [ 111 In]biAb variants displayed similar blood pharmacokinetics and brain uptake at 2 h after administration. Radiolabelling did not compromise affinity, and all variants showed good stability, especially the DOTA-Tz variant. Whole-body SPECT scanning indicated high liver, spleen, and bone accumulation of all [ 111 In]biAb variants. Subsequent ex vivo measurement of organ retention confirmed SPECT data, with retention in the spleen, liver, and bone - with very high bone marrow retention. Ex vivo gamma measurement of brain tissue, isolated at 72 h post-injection, and ex vivo autoradiography showed that WT mice, despite the absence of Aβ, exhibited comparable brain concentrations of [ 111 In]biAb as those found in the tg-ArcSwe brain., Conclusions: The successful 111 In-labelling of biAb with retained binding to TfR and Aβ, and retained ability to enter the brain, demonstrated that 111 In can be used to generate radioligands for brain imaging. A high degree of [ 111 In]biAb in bone marrow and intracellular accumulation in brain tissue indicated some off-target interactions or potential interaction with intrabrain TfR resulting in a relatively high non-specific background signal., Competing Interests: The authors report no conflict of interest., (© 2024 The Author(s).)

Introduction: Hyperbaric oxygen has been used as a medical treatment tool in hyperbaric chambers and is an integral part of professional and combat divers' activity. In extreme cases, exposure to hyperbaric oxygen can develop central nervous system oxygen toxicity (CNS-OT), which leads to seizures and eventually death. CNS-OT is caused by neuronal hyperactivity due to high oxygen levels, potentially damaging brain cells including the blood-brain barrier (BBB). However, the effect of hyperbaric oxygen levels on the healthy BBB has not been characterized directly yet., Methods: Six or three different groups of ~ eight rats or mice, respectively, were exposed to increasing levels of partial pressure of oxygen (0.21 to 5 ATA) in a hyperbaric chamber, followed by MRI scanning with gadolinium. Statistical significance (adjusted p-value ≤ 0.05) was assessed using linear regression and ordinary one-way (rats) or two-way (mice) ANOVA with correction of multiple comparison tests. In rats, the effect of 100% oxygen at 5 ATA was independently validated using FITC-Dextran (5 kDa). Statistical significance (p-value ≤ 0.05) was assessed using Welch's t-test and effect size was calculated by Cohen's D., Results: In rats, analyzed MRI scans showed a significant trend of increase in the % gadolinium in brain tissues as a result of hyperbaric oxygen pressures (p-value = 0.0079). The most significant increase was measured at 4 ATA compared to air (adjusted p-value = 0.0461). Significant increased FITC-Dextran levels were measured in the rats' brains under 100% oxygen at 5 ATA versus air (p-value = 0.0327; Effect size = 2.0). In mice, a significant increase in gadolinium penetration into the hippocampus and frontal cortex was measured over time (adjusted p-value < 0.05) under 100% oxygen at 3 and 5 ATA versus air, and between the treatments (adjusted p-value < 0.0001)., Conclusions: The BBB is increasingly disrupted due to higher levels of hyperbaric oxygen in rodents, indicating a direct relation between hyperbaric oxygen and BBB dysregulation for the first time. We suggest considering this risk in different diving activities, and protocols using a hyperbaric chamber. On the other hand, this study highlights the potential therapeutic usage of hyperbaric oxygen for controlled drug delivery through the BBB into brain tissues in different brain-related diseases., (© 2024. The Author(s).)

DOTATATE is a somatostatin peptide analog used in the clinic to detect somatostatin receptors which are highly expressed on neuroendocrine tumors. Somatostatin receptors are found naturally in the intestines, pancreas, lungs, and brain (mainly cortex). In vivo measurement of the somatostatin receptors in the cortex has been challenging because available tracers cannot cross the blood-brain barrier (BBB) due to their intrinsic polarity. A peptide called melittin, a main component of honeybee venom, has been shown to disrupt plasma membranes and increase the permeability of biological membranes. In this study, we assessed the feasibility of using melittin to facilitate the passage of [ 64 Cu]Cu-DOTATATE through the BBB and its binding to somatostatin receptors in the cortex. Evaluation included in vitro autoradiography on Long Evans rat brains to estimate the binding affinity of [ 64 Cu]Cu-DOTATATE to the somatostatin receptors in the cortex and an in vivo evaluation of [ 64 Cu]Cu-DOTATATE binding in NMRI mice after injection of melittin. This study found an in vitro B max  = 89 ± 4 nM and K D  = 4.5 ± 0.6 nM in the cortex, resulting in a theoretical binding potential (BP) calculated as B max /K D  ≈ 20, which is believed suitable for in vivo brain PET imaging. However, the in vivo results showed no significant difference between the control and melittin injected mice, indicating that the honeybee venom failed to open the BBB. Additional experiments, potentially involving faster injection rates are required to verify that melittin can increase brain uptake of non-BBB permeable PET tracers. Furthermore, an evaluation of whether a venom with a narrow therapeutic range can be used for clinical purposes needs to be considered., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Transcranial histotripsy has shown promise as a non-invasive neurosurgical tool, as it has the ability to treat a wide range of locations in the brain without overheating the skull. One important effect of histotripsy in the brain is the blood-brain barrier (BBB) opening (BBBO) at the ablation site, but there is a knowledge gap concerning the extent of histotripsy-induced BBBO. Here we describe induction of BBBO by transcranial histotripsy and use of magnetic resonance imaging (MRI) and histology to quantify changes in BBBO at the periphery of the histotripsy ablation zone over time in the healthy mouse brain., Methods: An eight-element, 1 MHz histotripsy transducer with a focal distance of 32.5 mm was used to treat the brains of 23 healthy female BL6 mice. T1-gadolinium (T1-Gd) MR images were acquired immediately following histotripsy treatment and during each of the subsequent 4 wk to quantify the size and intensity of BBB leakage., Results: The T1-Gd MRI results revealed that the hyperintense BBBO volume increased over the first week and subsided gradually over the following 3 wk. Histology revealed complete loss of tight junction proteins and blood vessels in the center of the ablation region immediately after histotripsy, partial recovery in the periphery of the ablation zone 1 wk following histotripsy and near-complete recovery of tight junction complex after 4 wk., Conclusion: These results provide the first evidence of transcranial histotripsy-induced BBBO and repair at the periphery of the ablation zone., Competing Interests: Conflict of interest Z.X. and the University of Michigan have a financial interest in HistoSonics, Inc. All other authors have no financial disclosures or conflicts of interest to disclose., (Copyright © 2023 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Hyperglycemia has been linked to worsening outcomes after subarachnoid hemorrhage (SAH). Nevertheless, the mechanisms involved in the pathogenesis of SAH have been scarcely evaluated so far. The role of hyperglycemia was assessed in an experimental model of SAH by T 2 weighted, dynamic contrast-enhanced magnetic resonance imaging (T 2 W and DCE-MRI), [ 18 F]BR-351 PET imaging and immunohistochemistry. Measures included the volume of bleeding, the extent of cerebral infarction and brain edema, blood brain barrier disruption (BBBd), neutrophil infiltration and matrix metalloprotease (MMP) activation. The neurofunctional outcome, neurodegeneration and myelinization were also investigated. The induction of hyperglycemia increased mortality, the size of the ischemic lesion, brain edema, neurodegeneration and worsened neurological outcome during the first 3 days after SAH in rats. In addition, these results show for the first time the exacerbating effect of hyperglycemia on in vivo MMP activation, Intercellular Adhesion Molecule 1 (ICAM-1) expression and neutrophil infiltration together with increased BBBd, bleeding volume and fibrinogen accumulation at days 1 and 3 after SAH. Notably, these data provide valuable insight into the detrimental effect of hyperglycemia on early BBB damage mediated by neutrophil infiltration and MMP activation that could explain the worse prognosis in SAH., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Purpose: The purpose of this study is to evaluate the feasibility of using 3-dimensional (3D) ultra-short echo time (UTE) radial imaging method for measurement of the permeability of the blood-brain barrier (BBB) to gadolinium-based contrast agent. In this study, we propose to use the golden-angle radial sparse parallel (GRASP) method with 3D center-out trajectories for UTE, hence named as 3D UTE-GRASP. We first examined the feasibility of using 3D UTE-GRASP dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) for differentiating subtle BBB disruptions induced by focused ultrasound (FUS). Then, we examined the BBB permeability changes in Alzheimer's disease (AD) pathology using Alzheimer's disease transgenic mice (5xFAD) at different ages., Methods: For FUS experiments, we used four Sprague Dawley rats at similar ages where we compared BBB permeability of each rat receiving the FUS sonication with different acoustic power (0.4-1.0 MPa). For AD transgenic mice experiments, we included three 5xFAD mice (6, 12, and 16 months old) and three wild-type mice (4, 8, and 12 months old)., Results: The result from FUS experiments showed a progressive increase in BBB permeability with increase of acoustic power (p < .05), demonstrating the sensitivity of DCE-MRI method for detecting subtle changes in BBB disruption. Our AD transgenic mice experiments suggest an early BBB disruption in 5xFAD mice, which is further impaired with aging., Conclusion: The results in this study substantiate the feasibility of using the proposed 3D UTE-GRASP method for detecting subtle BBB permeability changes expected in neurodegenerative diseases, such as AD., (© 2024 American Society of Neuroimaging.)

Objective: Interictal blood-brain barrier dysfunction in chronic epilepsy has been demonstrated in animal models and pathological specimens. Ictal blood-brain barrier dysfunction has been shown in humans in vivo using an experimental quantitative magnetic resonance imaging (MRI) protocol. Here, we hypothesized that interictal blood-brain barrier dysfunction is also present in people with drug-resistant epilepsy., Methods: Thirty-nine people (21 females, mean age at MRI ± SD = 30 ± 8 years) with drug-resistant epilepsy were prospectively recruited and underwent interictal T1-relaxometry before and after administration of a paramagnetic contrast agent. Likewise, quantitative T1 was acquired in 29 people without epilepsy (12 females, age at MRI = 48 ± 18 years). Quantitative T1 difference maps were calculated and served as a surrogate imaging marker for blood-brain barrier dysfunction. Values of quantitative T1 difference maps inside hemispheres ipsilateral to the presumed seizure onset zone were then compared, on a voxelwise level and within presumed seizure onset zones, to the contralateral side of people with epilepsy and to people without epilepsy., Results: Compared to the contralateral side, ipsilateral T1 difference values were significantly higher in white matter (corrected p < .05), gray matter (uncorrected p < .05), and presumed seizure onset zones (p = .04) in people with epilepsy. Compared to people without epilepsy, significantly higher T1 difference values were found in the anatomical vicinity of presumed seizure onset zones (p = .004). A subgroup of people with hippocampal sclerosis demonstrated significantly higher T1 difference values in the ipsilateral hippocampus and in regions strongly interconnected with the hippocampus compared to people without epilepsy (corrected p < .01). Finally, z-scores reflecting the deviation of T1 difference values within the presumed seizure onset zone were associated with verbal memory performance (p = .02) in people with temporal lobe epilepsy., Significance: Our results indicate a blood-brain barrier dysfunction in drug-resistant epilepsy that is detectable interictally in vivo, anatomically related to the presumed seizure onset zone, and associated with cognitive deficits., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Concussion, caused by a rotational acceleration/deceleration injury mild enough to avoid structural brain damage, is insufficiently captured in recent preclinical models, hampering the relation of pathophysiological findings on the cellular level to functional and behavioral deficits. We here describe a novel model of unrestrained, single vs. repetitive concussive brain injury (CBI) in male C56Bl/6j mice. Longitudinal behavioral assessments were conducted for up to seven days afterward, alongside the evaluation of structural cerebral integrity by in vivo magnetic resonance imaging (MRI, 9.4 T), and validated ex vivo by histology. Blood-brain barrier (BBB) integrity was analyzed by means of fluorescent dextran- as well as immunoglobulin G (IgG) extravasation, and neuroinflammatory processes were characterized both in vivo by positron emission tomography (PET) using [ 18 F]DPA-714 and ex vivo using immunohistochemistry. While a single CBI resulted in a defined, subacute neuropsychiatric phenotype, longitudinal cognitive testing revealed a marked decrease in spatial cognition, most pronounced in mice subjected to CBI at high frequency (every 48 h). Functional deficits were correlated to a parallel disruption of the BBB, (R 2 = 0.29, p < 0.01), even detectable by a significant increase in hippocampal uptake of [ 18 F]DPA-714, which was not due to activation of microglia, as confirmed immunohistochemically. Featuring a mild but widespread disruption of the BBB without evidence of macroscopic damage, this model induces a characteristic neuro-psychiatric phenotype that correlates to the degree of BBB disruption. Based on these findings, the BBB may function as both a biomarker of CBI severity and as a potential treatment target to improve recovery from concussion.

Chronic neuroinflammation is characterized by increased blood-brain barrier (BBB) permeability, leading to molecular changes in the central nervous system that can be explored with biomarkers of active neuroinflammatory processes. Magnetic resonance imaging (MRI) has contributed to detecting lesions and permeability of the BBB. Ultra-small superparamagnetic particles of iron oxide (USPIO) are used as contrast agents to improve MRI observations. Therefore, we validate the interaction of peptide-88 with laminin, vectorized on USPIO, to explore BBB molecular alterations occurring during neuroinflammation as a potential tool for use in MRI. The specific labeling of NPS-P88 was verified in endothelial cells (hCMEC/D3) and astrocytes (T98G) under inflammation induced by interleukin 1β (IL-1β) for 3 and 24 hours. IL-1β for 3 hours in hCMEC/D3 cells increased their co-localization with NPS-P88, compared with controls. At 24 hours, no significant differences were observed between groups. In T98G cells, NPS-P88 showed similar nonspecific labeling among treatments. These results indicate that NPS-P88 has a higher affinity towards brain endothelial cells than astrocytes under inflammation. This affinity decreases over time with reduced laminin expression. In vivo results suggest that following a 30-minute post-injection, there is an increased presence of NPS-P88 in the blood and brain, diminishing over time. Lastly, EAE animals displayed a significant accumulation of NPS-P88 in MRI, primarily in the cortex, attributed to inflammation and disruption of the BBB. Altogether, these results revealed NPS-P88 as a biomarker to evaluate changes in the BBB due to neuroinflammation by MRI in biological models targeting laminin., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zapata-Acevedo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The blood-brain barrier (BBB) plays a vital role in maintaining brain homeostasis, but the integrity of this barrier deteriorates slowly with aging. Noninvasive water exchange magnetic resonance imaging (MRI) methods may identify changes in the BBB occurring with healthy aging., Purpose: To investigate age-related changes in the BBB permeability to water using multiple-echo-time (multi-TE) arterial spin labeling (ASL) MRI., Study Type: Prospective, cohort., Population: Two groups of healthy humans-older group (≥50 years, mean age = 56 ± 4 years, N = 13, females = 5) and younger group (≤20 years, mean age = 18 ± 1, N = 13, females = 7)., Field Strength/sequence: A 3T, multi-TE Hadamard pCASL with 3D Gradient and Spin Echo (GRASE) readout., Assessment: Two different approaches of variable complexity were applied. A physiologically informed biophysical model with a higher complexity estimating time ( T ex ) taken by the labeled water to move across the BBB and a simpler model of triexponential decay measuring tissue transition rate ( k lin ) ., Statistics: Two-tailed unpaired Student t-test, Pearson's correlation coefficient and effect size. P < 0.05 was considered significant., Results: Older volunteers showed significant differences of 36% lower T ex , 29% lower cerebral perfusion, 17% pronged arterial transit time and 22% shorter intra-voxel transit time compared to the younger volunteers. Tissue fraction ( f EV ) at the earliest TI = 1600 msec was significantly higher in the older group, which contributed to a significantly lower k lin compared to the younger group. f EV at TI = 1600 msec showed significant negative correlation with T ex (r = -0.80), and k lin and T ex showed significant positive correlation (r = 0.73)., Data Conclusions: Both approaches of Multi-TE ASL imaging showed sensitivity to detect age-related changes in the BBB permeability. High tissue fractions at the earliest TI and short T ex in the older volunteers indicate that the BBB permeability increased with age., Evidence Level: 2 TECHNICAL EFFICACY: Stage 1., (© 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Blood-brain barrier disruption (BBBD) using focused ultrasound (FUS) and microbubbles (MBs) is an effective tool for therapeutic delivery to the brain. Here, we present an optimized protocol for quantifying fluorescent molecules extravasation in mice. We describe steps for ultrasound treatment, injection of MBs and fluorescent dyes, brain harvesting, microscopy imaging, and image postprocessing algorithm. Our protocol has proven to successfully conduct a diameter-dependent analysis that measures vascular leakage following FUS-mediated BBBD at a single blood vessel resolution. For complete details on the use and execution of this protocol, please refer to Katz et al. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Loss of blood-brain barrier (BBB) integrity is hypothesised to be one of the earliest microvascular signs of Alzheimer's disease (AD). Existing BBB integrity imaging methods involve contrast agents or ionising radiation, and pose limitations in terms of cost and logistics. Arterial spin labelling (ASL) perfusion MRI has been recently adapted to map the BBB permeability non-invasively. The DEveloping BBB-ASL as a non-Invasive Early biomarker (DEBBIE) consortium aims to develop this modified ASL-MRI technique for patient-specific and robust BBB permeability assessments. This article outlines the study design of the DEBBIE cohorts focused on investigating the potential of BBB-ASL as an early biomarker for AD (DEBBIE-AD)., Methods and Analysis: DEBBIE-AD consists of a multicohort study enrolling participants with subjective cognitive decline, mild cognitive impairment and AD, as well as age-matched healthy controls, from 13 cohorts. The precision and accuracy of BBB-ASL will be evaluated in healthy participants. The clinical value of BBB-ASL will be evaluated by comparing results with both established and novel AD biomarkers. The DEBBIE-AD study aims to provide evidence of the ability of BBB-ASL to measure BBB permeability and demonstrate its utility in AD and AD-related pathologies., Ethics and Dissemination: Ethics approval was obtained for 10 cohorts, and is pending for 3 cohorts. The results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal., Competing Interests: Competing interests: FB is a consultant for Roche, Celltrion, Rewind Therapeutics, Merck, IXICO, Jansen, Combinostics, and has research agreements with Merck, Biogen, GE Healthcare, Roche. All other authors report no disclosures., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

New focused ultrasound spinal cord applications have emerged, particularly those improving therapeutic agent delivery to the spinal cord via blood-spinal cord barrier opening and the neuromodulation of spinal cord tracts. One hurdle in the development of these applications is safety. It may be possible to use safety trends from seminal and subsequent works in focused ultrasound to guide the development of safety guidelines for spinal cord applications. We collated data from decades of pre-clinical studies and illustrate a clear relationship between damage, time-averaged spatial peak intensity and exposure duration. This relationship suggests a thermal mechanism underlies ultrasound-induced spinal cord damage. We developed minimum and mean thresholds for damage from these pre-clinical studies. When these thresholds were plotted against the parameters used in recent pre-clinical ultrasonic spinal cord neuromodulation studies, the majority of the neuromodulation studies were near or above the minimum threshold. This suggests that a thermal neuromodulatory effect may exist for ultrasonic spinal cord neuromodulation, and that the thermal dose must be carefully controlled to avoid damage to the spinal cord. By contrast, the intensity-exposure duration threshold had no predictive value when applied to blood-spinal cord barrier opening studies that employed injected contrast agents. Most blood-spinal cord barrier opening studies observed slight to severe damage, except for small animal studies that employed an active feedback control method to limit pressures based on measured bubble oscillation behavior. The development of new focused ultrasound spinal cord applications perhaps reflects the recent success in the development of focused ultrasound brain applications, and recent work has begun on the translation of these technologies from brain to spinal cord. However, a great deal of work remains to be done, particularly with respect to developing and accepting safety standards for these applications., Competing Interests: Conflict of interest The authors declare no competing interests., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Parenchymal hematoma is a dreaded complication of mechanical thrombectomy after acute ischemic stroke. This study evaluated whether blood-brain barrier permeability measurements based on CT perfusion could be used as predictors of parenchymal hematoma after successful recanalization and compared the predictive value of various permeability parameters in patients with acute ischemic stroke., Methods: We enrolled 53 patients with acute ischemic stroke who underwent mechanical thrombectomy and achieved successful recanalization. Each patient underwent CT, CT angiography, and CT perfusion imaging before treatment. We used relative volume transfer constant (rK trans ) values, relative permeability-surface area product (rP·S), and relative extraction fraction (rE) to evaluate preoperative blood-brain barrier permeability in the delayed perfusion area., Results: Overall, 22 patients (37.7%) developed hemorrhagic transformation after surgery, including 10 patients (16.9%) with hemorrhagic infarction and 11 patients (20.8%) with parenchymal hematoma. The rP·S, rK trans , and rE of the hypoperfusion area in the parenchymal hematoma group were significantly higher than those in the hemorrhagic infarction and no-hemorrhage transformation groups (p < .01). We found that rE and rP·S were superior to rK trans in predicting parenchymal hematoma transformation after thrombectomy (P·S area under the curve [AUC] .844 vs. rK trans AUC .753, z = 2.064, p = .039; rE AUC .907 vs. rK trans AUC .753, z = 2.399, p = .017)., Conclusions: Patients with parenchymal hematoma after mechanical thrombectomy had higher blood-brain barrier permeability in hypoperfusion areas. Among blood-brain barrier permeability measurement parameters, rP·S and rE showed better accuracy for parenchymal hematoma prediction., (© 2023 American Society of Neuroimaging.)

The goal of this study was to investigate the origin of brain lactate (Lac) signal in the healthy anesthetized rat after injection of hyperpolarized (HP) [1- 13 C]pyruvate (Pyr). Dynamic two-dimensional spiral chemical shift imaging with flow-sensitizing gradients revealed reduction in both vascular and brain Pyr, while no significant dependence on the level of flow suppression was detected for Lac. These results support the hypothesis that the HP metabolites predominantly reside in different compartments in the brain (i.e., Pyr in the blood and Lac in the parenchyma). Data from high-resolution metabolic imaging of [1- 13 C]Pyr further demonstrated that Lac detected in the brain was not from contributions of vascular signal attributable to partial volume effects. Additionally, metabolite distributions and kinetics measured with dynamic imaging after injection of HP [1- 13 C]Lac were similar to Pyr data when Pyr was used as the substrate. These data do not support the hypothesis that Lac observed in the brain after Pyr injection was generated in other organs and then transported across the blood-brain barrier (BBB). Together, the presented results provide further evidence that even in healthy anesthetized rats, the transport of HP Pyr across the BBB is sufficiently fast to permit detection of its metabolic conversion to Lac within the brain., (© 2023 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Little has been reported about the association between cerebral hyperperfusion syndrome (CHS) and blood-brain barrier (BBB) disruption in human. We aimed to investigate the changes in permeability after bypass surgery in cerebrovascular steno-occlusive diseases using dynamic contrast-enhanced MRI (DCE-MRI) and to demonstrate the association between CHS and BBB disruption. This retrospective study included 36 patients (21 hemispheres in 18 CHS patients and 20 hemispheres in 18 controls) who underwent combined bypass surgery for moyamoya and atherosclerotic steno-occlusive diseases. DCE-MRI and arterial spin labeling perfusion-weighted imaging (ASL-PWI) were obtained at the baseline, postoperative state, and discharge. Perfusion and permeability parameters were calculated at the MCA territory (CBF (territorial) , K trans (territorial) , V p(territorial) ) and focal perianastomotic area (CBF (focal) , K trans (focal) , V p(focal) ) of operated hemispheres. As compared with the baseline, both CBF (territorial) and CBF (focal) increased in the postoperative period and decreased at discharge, corresponding well to symptoms in the CHS group. V p(focal) was lower in the postoperative period and at discharge, as compared with the baseline. In the control group, no parameters significantly differed among the three points. In conclusion, V p at the focal perianastomotic area significantly decreased in patients with CHS during the postoperative period. BBB disruption may be implicated in the development of CHS after bypass surgery., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.