Measurement Of Blood-brain Barrier Permeability Research Articles

Associations between regional blood-brain barrier permeability, aging, and Alzheimer's disease biomarkers in cognitively normal older adults.

Increased blood-brain barrier permeability (BBBp) has been hypothesized as a feature of aging that may lead to the development of Alzheimer's disease (AD). We sought to identify the brain regions most vulnerable to greater BBBp during aging and examine their regional relationship with neuroimaging biomarkers of AD. We studied 31 cognitively normal older adults (OA) and 10 young adults (YA) from the Berkeley Aging Cohort Study (BACS). Both OA and YA received dynamic contrast-enhanced MRI (DCE-MRI) to quantify Ktrans values, as a measure of BBBp, in 37 brain regions across the cortex. The OA also received Pittsburgh compound B (PiB)-PET to create distribution volume ratios (DVR) images and flortaucipir (FTP)- PET to create partial volume corrected standardized uptake volume ratios (SUVR) images. Repeated measures ANOVA assessed the brain regions where OA showed greater BBBp than YA. In OA, Ktrans values were compared based on sex, Aβ positivity status, and APOE4 carrier status within a composite region across the areas susceptible to aging. We used linear models and sparse canonical correlation analysis (SCCA) to examine the relationship between Ktrans and AD biomarkers. OA showed greater BBBp than YA predominately in the temporal lobe, with some involvement of parietal, occipital and frontal lobes. Within an averaged ROI of affected regions, there was no difference in Ktrans values based on sex or Aβ positivity, but OA who were APOE4 carriers had significantly higher Ktrans values. There was no direct relationship between averaged Ktrans and global Aβ pathology, but there was a trend for an Ab status by tau interaction on Ktrans in this region. SCCA showed increased Ktrans was associated with increased PiB DVR, mainly in temporal and parietal brain regions. There was not a significant relationship between Ktrans and FTP SUVR. Our findings indicate that the BBB shows regional vulnerability during normal aging that overlaps considerably with the pattern of AD pathology. Greater BBBp in brain regions affected in aging is related to APOE genotype and may also be related to the pathological accumulation of Aβ.

Associations Between Cardiovascular Risk Factors and Arterial Spin Labelling Derived Perfusion Parameters

AbstractBackgroundDecreased cerebral blood flow (CBF) and deterioration of blood‐brain barrier (BBB) are suggested to be precursor conditions of cognitive impairment. Using a novel multi‐echo‐time arterial spin labelling (ASL) protocol, we examined the time of exchange (Tex) of water across the BBB as a measurement of BBB permeability. We further examined the association of cardiovascular risk factors with Tex in an ongoing cohort study.MethodData (n = 29, mean age: 55.9±6.1years, 69% women) were drawn from Neurological biomarkers of Blood, MRI and Cognition (NEURO‐BMC) study performed at National University of Singapore. NEURO‐BMC is an ongoing prospective cohort study (age: 45‐65 years) on brain changes in a subclinical phase of cognitive impairment. A multi‐echo, Hadamard‐encoded multi‐post‐labelling‐delay pseudo‐continuous ASL (PCASL) protocol was used on a 3T scanner. ExploreASL was used with a modified version of FSL FABBER(4) to quantify cerebral blood flow (CBF), arterial transit time (ATT), and Tex. ASL‐extracted parameters were compared with cardiovascular risk parameters such as blood pressure (BP), BMI and smoking status.ResultHigh systolic and diastolic BP were associated with significantly reduced Tex (Fig 1). Additionally, higher systolic and diastolic BP showed a trend of increased ATT and reduced CBF, though the associations were not statistically significant (Table 1). High BMI had a significant association with increased ATT and reduced CBF. However, no trend was observed between BMI and Tex. Participants who ever smoked were observed to have a reduced Tex and CBF and increased ATT, but statistical significance was only found for CBF (Fig 1).ConclusionIn this pilot study, we showed that BBB‐ASL‐derived parameters ‐ ATT, CBF, and Tex ‐ were associated with BP, BMI, and smoking status. While the sample size for this preliminary analysis was too small to make a definitive conclusion as not all associations were statistically significant, all studied cardiovascular risk factors showed their potential in increasing the risk of BBB deterioration. Further investigation with a larger sample size and other health risk factors to assess these observations is warranted.

Blood-brain barrier permeability by CT perfusion predicts parenchymal hematoma after recanalization with thrombectomy.

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. 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 (rKtrans ) 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. 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, rKtrans , 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 rKtrans in predicting parenchymal hematoma transformation after thrombectomy (P·S area under the curve [AUC] .844 vs. rKtrans AUC .753, z=2.064, p=.039; rE AUC .907 vs. rKtrans AUC .753, z=2.399, p=.017). 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.

Blood-brain barrier permeability and electroconvulsive therapy: a systematic review.

The cause of cognitive side effects after electroconvulsive therapy (ECT) is largely unknown. Alterations in the blood-brain barrier (BBB) have been considered in several recent ECT studies. We therefore found it worthwhile to perform a systematic review of the literature to examine if electrically induced seizures affect the permeability of the BBB. PubMed/MEDLINE and Embase were searched 16 November 2022. Studies with a direct measurement of BBB permeability in animals treated with modified electroconvulsive stimulation (ECS) and in humans treated with ECT were included. Synthesis of results was narrative due to the low number of studies and differences in study designs. Four animal and two human (31 participants) studies were included. In animals, two studies found increased BBB permeability to some smaller molecules after modified ECS, while the two other studies found marginally increased or unchanged permeability to albumin after treatment. In contrast, the human studies did not find increased BBB permeability to smaller molecules or albumin after ECT. Animal but not human studies support increased BBB permeability to some smaller molecules after electrically induced seizures. However, this conclusion is confined by the low number of studies and the lack of studies applying state-of-the-art methods. More studies using modern approaches to measuring of BBB permeability are warranted. The study was founded by Mental Health Services in the Capital Region of Denmark (grant number 61151-05) and was registered on PROSPERO before data extraction was initiated (CRD42022331385).

Improving measurement of blood-brain barrier permeability with reduced scan time using deep-learning-derived capillary input function

PurposeIn Dynamic contrast-enhanced MRI (DCE-MRI), Arterial Input Function (AIF) has been shown to be a significant contributor to uncertainty in the estimation of kinetic parameters. This study is to assess the feasibility of using a deep learning network to estimate local Capillary Input Function (CIF) to estimate blood-brain barrier (BBB) permeability, while reducing the required scan time. Materials and MethodA total of 13 healthy subjects (younger (<40 y/o): 8, older (> 67 y/o): 5) were recruited and underwent 25-min DCE-MRI scans. The 25 min data were retrospectively truncated to 10 min to simulate a reduced scan time of 10 min. A deep learning network was trained to predict the CIF using simulated tissue contrast dynamics with two vascular transport models. The BBB permeability (PS) was measured using 3 methods: (i) Ca-25min, using DCE-MRI data of 25 min with individually sampled AIF (Ca); (ii) Ca-10min, using truncated 10min data with AIF (Ca); and (iii) Cp-10min, using truncated 10 min data with CIF (Cp). The PS estimates from the Ca-25min method were used as reference standard values to assess the accuracy of the Ca-10min and Cp-10min methods in estimating the PS values. ResultsWhen compared to the reference method(Ca-25min), the Ca-10min and Cp-10min methods resulted in an overestimation of PS by 217 ± 241 % and 48.0 ± 30.2 %, respectively. The Bland Altman analysis showed that the mean difference from the reference was 8.85 ± 1.78 (x10−4 min−1) with the Ca-10min, while it was reduced to 1.63 ± 2.25 (x10−4 min−1) with the Cp-10min, resulting in an average reduction of 81%. The limits of agreement also reduced by up to 39.2% with the Cp-10min. We found a 75% increase of BBB permeability in the gray matter and a 35% increase in the white matter, when comparing the older group to the younger group. ConclusionsWe demonstrated the feasibility of estimating the capillary-level input functions using a deep learning network. We also showed that this method can be used to estimate subtle age-related changes in BBB permeability with reduced scan time, without compromising accuracy. Moreover, the trained deep learning network can automatically select CIF, reducing the potential uncertainty resulting from manual user-intervention.

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

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

Acute endurance exercise modulates growth differentiation factor 11 in cerebrospinal fluid of healthy young adults.

Strong evidence supports the benefits of exercise for healthy ageing, including reduced risk of neurodegenerative diseases. Recent studies suggested interorgan crosstalk as a key element of systemic adaptive response, however, the role of specific molecules in mediating exercise effects on the human brain are not fully understood. In the present study, we explored the exercise-related regulation of Growth Differentiation Factor 11 (GDF11) in cerebrospinal fluid (CSF) and blood. The samples of serum, plasma and CSF were obtained before and 60min after acute exercise (90min run) from twenty healthy young individuals. Additional serum and plasma samples were collected immediately after run. GDF11 protein content (immunoblotting), body composition (bioelectrical impedance), physical fitness (VO2max, cycle spiroergometry) and cognitive functions (standardized computerized tests, Cogstate) were evaluated. Running decreased GDF11 protein content in CSF (-20.6%. p=0.046), while GDF11 in plasma and serum were not regulated. Two GDF11-specific antibodies of different origin were used to corroborate this result. Individuals with higher physical fitness displayed greater exercise-induced decrease of GDF11 in CSF than those with lower physical fitness (p=0.025). VO2max correlated positively with GDF11 in serum (r=0.63, p=0.020) as well as with the exercise-induced change in GDF11 levels in CSF (r=0.59, p=0.042). Indirect measure of blood-brain barrier permeability (i.e. CSF/serum albumin ratio) tended to positively correlate with CSF/serum GDF11 ratio (p=0.060). CSF levels of GDF11 correlated positively with cognitive functions, including working memory, both before and after run (p<0.05). Running-induced down-regulation of the GDF11 protein in the cerebrospinal fluid of healthy young individuals indicates the potential role of GDF11 in the exercise-induced cross-talk between periphery and the brain.

Blood-brain barrier disruption measured by albumin index correlates with inflammatory fluid biomarkers

Blood-brain barrier (BBB) permeability can be measured by the ratio of albumin in cerebrospinal fluid (CSF) and blood and by dynamic contrast-enhanced MRI (DCEMRI). Albumin is a large molecule measured in CSF and blood to form the albumin index (Qalb), which is a global measure of BBB permeability, while the smaller Gadolinium molecule measures regional transfer (Ktrans); few studies have directly compared them in the same patients. We used both methods as part of a study of mechanisms of white matter injury in patients with different forms of dementia. In addition, we also measured biomarkers for inflammation, including proteases, angiogenic growth factors, and cytokines, and correlated them with the BBB results. We found that there was no correlation between Qalb and Ktrans. The Qalb was associated with the matrix metalloproteinases (MMP-2, MMP-3, and MMP-10), the angiogenic factors (VEGF-C and PlGF), and the cytokines (IL-6, IL-8 and TNF-α). On the other hand, Ktrans was associated with the diffusion measures, mean free water and PSMD, which indicate white matter injury. Our results show that the Qalb and Ktrans measure different aspects of BBB permeability, with albumin being a measure of inflammatory BBB opening and Ktrans indicating white matter injury.

Reproducibility and Optimal Arterial Input Function Selection in Dynamic Contrast-Enhanced Perfusion MRI in the Healthy Brain.

Dynamic contrast-enhanced MRI (DCE-MRI) has seen increasing use for quantification of low level of blood-brain barrier (BBB) leakage in various pathological disease states and correlations with clinical outcomes. However, currently there exists limited studies on reproducibility in healthy controls, which is important for the establishment of a normality threshold for future research. To investigate the reproducibility of DCE-MRI and to evaluate the effect of arterial input function (AIF) selection and manual region of interests (ROI) delineation vs. automated global segmentation. Prospective. A total of 16 healthy controls; 11 females; mean age 28.7 years (SD 10.1). A 3T; GE DCE; 3D TFE T1WI. 2D TSE T2. The influx constant Ki , a measure of BBB permeability, and Vp , the blood plasma volume, was calculated using the Patlak model. Cerebral blood flow (CBF) was calculated using Tikhonov model free deconvolution. Manual tissue ROIs, drawn by H.J.S. (30+ years of experience), were compared to automatic tissue segmentation. Intraclass correlation coefficient (ICC) and repeatability coefficient (RC) was used to assess reproducibility. Bland-Altman plots were used to evaluate agreement between measurements day 1 vs. day 2, and manual vs. segmentation method. Ki showed excellent reproducibility in both white and gray matter with an ICC between 0.79 and 0.82 and excellent agreement between manual ROI and automatic segmentation, with an ICC of 0.89 for Ki in WM. Furthermore, Ki values in gray and white matter conforms with histological tissue characteristics, where gray matter generally has a 2-fold higher vessel density. The highest reproducibility measures of Ki (ICC=0.83), CBF (ICC=0.77) and Vd (ICC=0.83) was obtained with the AIF sampled in the internal carotid artery (ICA). DCE-MRI shows excellent reproducibility of pharmacokinetic variables derived from healthy controls. 2 TECHNICAL EFFICACY: Stage 2.

Minimally Invasive Surgery for ICH Evacuation Combined With Deferoxamine Treatment Increased Perihematomal Claudin-5 and ZO-1 Expression Levels and Decreased BBB Permeability in Rabbits.

ObjectiveTo investigate the role of minimally invasive surgery (MIS) in intracerebral hemorrhage (ICH) evacuation combined with deferoxamine (DFX) treatment on perihematomal tight junction protein (claudin-5 and ZO-1) expression levels and blood-brain barrier (BBB) permeability in rabbits.MethodsWe randomly assigned 65 male rabbits (weight: 1.9–2.6 kg) to a normal control group (NC group, 13 rabbits), hemorrhage model group (HM group, 13), DFX treatment group (DFX group, 13 rabbits), MIS group (MIS group, 13 rabbits), or MIS combined with DFX treatment group (MIS + DFX group, 13 rabbits). ICH was established in all of the groups except the NC group. MIS was performed to evacuate the hematoma 6 h after the ICH model was created in the MIS and MIS + DFX groups. The DFX and MIS + DFX groups were treated with DFX (100 mg/kg, dissolved in 2 mL of 0.9% saline solution, administered intramuscularly) at 2 h, and then every 12 h for 7 d. The same dose of 0.9% saline solution was administered to the NC, HM, and MIS groups at the same time points. Sixty-five rabbits were divided into 5 groups, and 13 rabbits in each group. Neurological deficit (i.e., Purdy's score) was recorded in all rabbits before euthanasia (N total = 65). In each group, 2 rabbits were used for iron concentration measurement (N total = 10), 2 rabbits were used for brain water content measurement (N total = 10), 3 rabbits were used for BBB permeability measurement (N total = 15), 3 rabbits were used for claudin-5, ZO-1 expression detection by Western Blotting (N total = 15), and 3 rabbits were used for claudin-5, ZO-1 mRNA detection by real-time PCR (N total = 15). On day 7, the rabbits were sacrificed and the perihematomal brain tissue was harvested to test the iron concentration, brain water content (BWC), tight junction proteins (claudin-5 and ZO-1) expression, and BBB permeability.ResultsPurdy's score, iron concentration, and BWC were lower in the MIS and MIS + DFX groups compared to the HM and DFX groups. The MIS + DFX group showed a significant decrease in these indicators. The use of MIS to evacuate the hematoma led to increased expression levels of claudin-5 and ZO-1, as well as decreased BBB permeability. The MIS + DFX group exhibited a remarkable increase in claudin-5 and ZO-1 expression levels and a significant decrease in BBB permeability.ConclusionsMIS combined with DFX treatment could increase the expression levels of perihematomal tight junction proteins (claudin-5 and ZO-1) expression, reduce BBB permeability, and improve the neurological function. MIS combined with DFX treatment may also prevent secondary brain damage following ICH.

Robust Multi-TE ASL-Based Blood-Brain Barrier Integrity Measurements.

Multiple echo-time arterial spin labelling (multi-TE ASL) offers estimation of blood–tissue exchange dynamics by probing the T2 relaxation of the labelled spins. In this study, we provide a recipe for robust assessment of exchange time (Texch) as a proxy measure of blood–brain barrier (BBB) integrity based on a test-retest analysis. This includes a novel scan protocol and an extension of the two-compartment model with an “intra-voxel transit time” (ITT) to address tissue transit effects. With the extended model, we intend to separate the underlying two distinct mechanisms of tissue transit and exchange. The performance of the extended model in comparison with the two-compartment model was evaluated in simulations. Multi-TE ASL sequence with two different bolus durations was used to acquire in vivo data (n = 10). Cerebral blood flow (CBF), arterial transit time (ATT) and Texch were fitted with the two models, and mean grey matter values were compared. Additionally, the extended model also extracted ITT parameter. The test-retest reliability of Texch was assessed for intra-session, inter-session and inter-visit pairs of measurements. Intra-class correlation coefficient (ICC) and within-subject coefficient of variance (CoV) for grey matter were computed to assess the precision of the method. Mean grey matter Texch and ITT values were found to be 227.9 ± 37.9 ms and 310.3 ± 52.9 ms, respectively. Texch estimated by the extended model was 32.6 ± 5.9% lower than the two-compartment model. A significant ICC was observed for all three measures of Texch reliability (P < 0.05). Texch intra-session CoV, inter-session CoV and inter-visit CoV were found to be 6.6%, 7.9%, and 8.4%, respectively. With the described improvements addressing intra-voxel transit effects, multi-TE ASL shows good reproducibility as a non-invasive measure of BBB permeability. These findings offer an encouraging step forward to apply this potential BBB permeability biomarker in clinical research.

TMOD-11. A PREDICTIVE MICROFLUIDIC MODEL OF VASCULARIZED GLIOMA TUMORS TO ASSESS TRAFFICKING OF THERAPEUTICS ACROSS THE BLOOD-BRAIN BARRIER

Abstract Although important distinctions exist between subtypes of HGGs, all patients fare poorly with a 5-year survival of &amp;lt; 5%. The infiltrative growth of HGGs imposes significant challenges to treatment, with the presence of residual microscopic tumors post-surgery and hampered chemotherapeutic penetration due to the blood-brain barrier (BBB), a highly selective endothelium regulating transport between blood and brain. Moreover, current preclinical models are costly, low throughput, and often fail to predict drug performance in the clinic. There is thus an increasing need for in vitro models of HGG tumors, surrounded by a realistic BBB vasculature, to recapitulate therapeutic trafficking. To this end, we engineered a high-throughput microfluidic model composed entirely of human cells where HGG spheroids are embedded in a BBB microvascular network of endothelial cells, pericytes, and astrocytes. Tumors co-opt the vasculature as observed in patients and BBB permeability measurements with perfused dextran demonstrate unaltered paracellular transport near and far from the tumors. Lipoprotein receptor protein 1 (LRP1) expression, however, is increased near HGG spheroids. These results were leveraged to synthesize layer-by-layer nanoparticles with angiopep-2 ligands exhibiting high affinity to LRP1 for targeted delivery. Angiopep-2 nanoparticles displayed the largest permeability across the BBB near tumors compared to bare nanoparticles. Knock-down of LRP1 in the BBB-HGG model decreased angiopep-2 nanoparticle permeability confirming LRP1-mediated transport. We next assessed the therapeutic implications of our findings by encapsulating cisplatin in the particles. Administration of cisplatin-loaded angiopep-2 nanoparticles resulted in significant tumor shrinkage with targeted apoptosis in the tumor area compared to bare cisplatin nanoparticles or free cisplatin which damaged the surrounding healthy BBB vessels. Validations in orthotopic tumor-bearing mice are ongoing. In summary, we propose a novel preclinical model with a functional human BBB vasculature surrounding HGG tumors for high-throughput investigations and validate that this platform predicts the transport of targeted drug-loaded carriers.

LightBBB: computational prediction model of blood-brain-barrier penetration based on LightGBM.

Identification of blood-brain barrier (BBB) permeability of a compound is a major challenge in neurotherapeutic drug discovery. Conventional approaches for BBB permeability measurement are expensive, time-consuming and labor-intensive. BBB permeability is associated with diverse chemical properties of compounds. However, BBB permeability prediction models have been developed using small datasets and limited features, which are usually not practical due to their low coverage of chemical diversity of compounds. Aim of this study is to develop a BBB permeability prediction model using a large dataset for practical applications. This model can be used for facilitated compound screening in the early stage of brain drug discovery. A dataset of 7162 compounds with BBB permeability (5453 BBB+ and 1709 BBB-) was compiled from the literature, where BBB+ and BBB- denote BBB-permeable and non-permeable compounds, respectively. We trained a machine learning model based on Light Gradient Boosting Machine (LightGBM) algorithm and achieved an overall accuracy of 89%, an area under the curve (AUC) of 0.93, specificity of 0.77 and sensitivity of 0.93, when 10-fold cross-validation was performed. The model was further evaluated using 74 central nerve system compounds (39 BBB+ and 35 BBB-) obtained from the literature and showed an accuracy of 90%, sensitivity of 0.85 and specificity of 0.94. Our model outperforms over existing BBB permeability prediction models. The prediction server is available at http://ssbio.cau.ac.kr/software/bbb.

Blood–brain barrier permeability measurement by biexponentially modeling whole‐brain arterial spin labeling data with multiple T2‐weightings

Blood-brain barrier (BBB) permeability assessment remains of ongoing interest in clinical practice and research. Transitions between intravascular (IV) and extravascular (EV) gray matter (GM) compartments may provide information regarding the microstructural status of the BBB. Due to different transverse relaxation times (T2 ) of water protons in vessels and GM, it is possible to determine the compartment in which these protons are located. This work presents and investigates the feasibility of a simplified analytical approach for compartmentalizing the proportions of magnetically marked water protons into IV and EV GM components by biexponentially modeling T2 -weighted arterial spin labeling (ASL) data. Numerous model assumptions were used to stabilize the fit and achieve in vivo applicability. Particularly, transverse relaxation times of IV and EV water protons were determined from the analysis of two supporting T2 -weighted ASL measurements, utilizing a monoexponential signal model. This stabilized a two-parameter biexponential fit of ASL data with T2 preparation (PLD = 0.9/1.2/1.5/1.8 s, TET2Prep = 0/30/40/60/80/120/160 ms), which thereby robustly provided estimates of the IV and EV compartment fractions. Experiments were conducted with three healthy volunteers in a 3 T scanner. Averaged over all subjects, the labeled water protons inherit T2,IV = 200 ± 18 ms initially and adapt T2,EV = 91 ± 2 ms with a longer retention time in cerebral structures. Accordingly, the EVlocated ASL signal fraction rises with increasing PLD from 0.31 ± 0.11 at the shortest PLD of 0.9 s to 0.73 ± 0.02 at the longest PLD of 1.8s. These results indicate a transition of the water protons from IV to EV space. The findings support the potential of biexponential modeling for compartmentalizing ASL spin fractions between IV and EV space. The novel integration of monoexponential parameter estimates stabilizes the two-compartment model fit, suggesting that this technique is suitable for robustly estimating the BBB permeability in vivo.

Blood-Brain Barrier (BBB) Permeability and Transport Measurement In Vitro and In Vivo.

Quantification of the blood-brain barrier (BBB) permeability and transport in brain tissue is crucial in understanding brain disorders and developing systemic and non-systemic drug delivery strategies to the brain. This chapter summarizes BBB permeability measurement in vitro (Part I) and the in vivo non-invasive methods for quantifying the BBB permeability to solutes and brain tissue transport in rat brain by employing intravital multiphoton microscopy and a curving fitting method by using an unsteady mass transfer mathematical model (Part II).

Alzheimer Dementia and Microvascular Pathology: Blood-Brain Barrier Permeability Imaging

최근의 연구들은 알츠하이머병의 병리가 단순히 아밀로이드와 타우단백질의 축적만이 아닌, 혈액뇌장벽(blood brain barrier; 이하 BBB) 이상과 같은 미세혈관병리와 밀접한 관련이 있음을 밝히고 있다. BBB 투과도 변화는 아밀로이드 및 타우 단백질 축적뿐 아니라 신경염증과 신경 퇴행성변화를 일으킴으로써 결국 임상 치매를 야기한다. 최근에는 알츠하이머 및 관련 질환의 BBB 이상을 보기 위한 MR 영상의 이용이 증가하고 있다. 이 종설에서는 알츠하이머병에서 BBB와 관련된 병리를 소개하고, BBB 투과도 변화에 대한 MR 영상 연구들을 소개할 것이다. 또한 BBB 투과도 측정을 위한 MR 방법론 개요와 문제점들을 제시할 것이다.

Blood-brain barrier permeability measured using dynamic contrast-enhanced magnetic resonance imaging: a validation study.

Key points The blood–brain barrier (BBB) is an important and dynamic structure which contributes to homeostasis in the central nervous system.BBB permeability changes occur in health and disease but measurement of BBB permeability in humans is not straightforward.Dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) can be used to model the movement of gadolinium contrast into the brain, expressed as the influx constant K i.Here evidence is provided that K i as measured by DCE‐MRI behaves as expected for a marker of overall BBB leakage.These results support the use of DCE‐MRI for in vivo studies of human BBB permeability in health and disease. Blood–brain barrier (BBB) leakage can be measured using dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) as the influx constant K i. To validate this method we compared measured K i with biological expectations, namely (1) higher K i in healthy individual grey matter (GM) versus white matter (WM), (2) GM/WM cerebral blood volume (CBV) ratio close to the histologically established GM/WM vascular density ratio, (3) higher K i in visibly enhancing multiple sclerosis (MS) lesions versus MS normal appearing white matter (NAWM), and (4) higher K i in MS NAWM versus healthy individual NAWM. We recruited 13 healthy individuals and 12 patients with MS and performed whole‐brain 3D DCE‐MRI at 3 T. K i and CBV were calculated using Patlak modelling for manual regions of interest (ROI) and segmented tissue masks. K i was higher in control GM versus WM (P = 0.001). CBV was higher in GM versus WM (P = 0.005, mean ratio 1.9). K i was higher in visibly enhancing MS lesions versus MS NAWM (P = 0.002), and in MS NAWM versus controls (P = 0.014). Bland–Altman analysis showed no significant difference between ROI and segmentation methods (P = 0.638) and an intra‐class correlation coefficient showed moderate single measure consistency (0.610). K i behaves as expected for a compound marker of permeability and surface area. The GM/WM CBV ratio measured by this technique is in agreement with the literature. This adds evidence to the validity of K i measured by DCE‐MRI as a marker of overall BBB leakage.

Blood-brain barrier permeability assessed by perfusion computed tomography predicts hemorrhagic transformation in acute reperfusion therapy.

Hemorrhagic transformation (HT) is one of the most feared complications of acute recanalization therapies. The aim of this study was to evaluate whether blood-brain barrier permeability (BBBP) imaging can predict HT in the setting of acute recanalization therapy and to determine the sensitivity and specificity of BBBP for the prediction of HT according to the type of reperfusion therapy. We assessed a total of 46 patients who received recanalization therapy (intravenous (IV) recombinant tissue plasminogen activator (tPA), mechanical thrombectomy with a stent retriever or both) for acute ischemic stroke within the internal carotid artery or middle cerebral artery. BBBP above the threshold was significantly associated with HT after adjustment for confounding factors in all patients (OR 45.4, 95% CI 2.9~711.2, p = 0.007), patients who received IV tPA (OR 20.1, 95% CI 1.2-336.7, p = 0.037), and patients who received endovascular therapy (OR 47.2, 95% CI 1.9-1252.5, p = 0.022). The sensitivity and specificity of the initial BBBP measurement as a predictor of HT in the overall 46 patients were 80 and 71%, respectively. These values were 75 and 64% in only IV tPA group, 100 and 80% in only endovascular group, 77 and 67% in IV tPA with or without endovascular therapy group, and 86 and 76% in endovascular therapy with or without bridging IV tPA therapy group. Increased pretreatment BBBP values were significantly associated with HT after acute recanalization therapy. This correlation with HT was stronger in patients receiving endovascular mechanical thrombectomy than in patients receiving IV rtPA.

Permeability of the blood-brain barrier predicts no evidence of disease activity at 2 years after natalizumab or fingolimod treatment in relapsing-remitting multiple sclerosis.

ObjectiveTo investigate whether blood–brain barrier (BBB) permeability, as measured by dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI), can provide early detection of suboptimal treatment response in relapsing–remitting multiple sclerosis (RRMS).MethodsThirty‐five RRMS patients starting on fingolimod or natalizumab, drugs with a common effect of decreasing lymphocyte influx into the central nervous system, were scanned with DCE‐MRI at 3T prior to treatment and at 3 and 6 months posttreatment. We calculated the influx constant Ki, a measure of BBB permeability, using the Patlak model. Suboptimal treatment response was defined as loss of no evidence of disease activity (NEDA) status after 2 years of treatment.ResultsSubjects with loss of NEDA status at 2 years had a 51% higher mean Ki in normal‐appearing white matter (NAWM) measured after 6 months of treatment, compared to subjects with maintained NEDA status (mean difference = 0.06ml/100g/min, 95% confidence interval [CI] = 0.02–0.09, p = 0.002). Ki in NAWM at 6 months was a good predictor of loss of NEDA status at 2 years (area under the curve = 0.84, 95% CI = 0.70–0.99, p = 0.003), and a value above 0.136ml/100/g/min yielded an odds ratio of 12.4 for suboptimal treatment response at 2 years, with a sensitivity of 73% and a specificity of 82%.InterpretationOur results suggest that BBB permeability as measured by DCE‐MRI reliably predicts suboptimal treatment response and is a surrogate marker of the state of health of the BBB. We find a predictive threshold for disease activity, which is remarkably identical in clinically isolated syndrome as previously reported and established RRMS as investigated here. Ann Neurol 2018;83:902–914

Simultaneous UPLC–MS/MS analysis of two stable isotope labeled versions of sucrose in mouse plasma and brain samples as markers of blood-brain barrier permeability and brain vascular space

Blood Brain Barrier (BBB) permeability is frequently compromised in the course of diseases affecting the central nervous system (CNS). Sucrose is a low molecular weight, hydrophilic marker with slow permeability at the naive BBB and therefore one of the widely used indicators of barrier integrity. Our laboratory recently developed a highly sensitive UPLC–MS/MS method for stable isotope labeled [13C12]sucrose in biological matrices. Correction of total brain concentration for contribution of intravascular space is required in such experiments in order to accurately measure BBB permeability, and it is often accomplished by vascular perfusion with buffer solutions prior to brain sampling. The purpose of the present study was to develop a UPLC–MS/MS method, which allows simultaneous analysis of two different stable isotope labeled sucrose variants, one of which can be utilized as a vascular marker. The first analyte, [13C12]sucrose, serves to quantify brain uptake clearance as a measure of BBB permeability, while the second analyte, [13C6]sucrose, is administered just before termination of the animal experiment and is considered as the vascular marker. [2H2]sucrose is used as the internal standard for both 13C labeled compounds. Because the majority of recent studies on CNS diseases employ mice, another objective was to validate the new technique in this species. The UPLC–MS/MS method was linear (r2 ≥ 0.99) in the tested concentration ranges, from 10 to 1000 ng/mL for both analytes in plasma, from 2 to 400 ng/g [13C12]sucrose in brain and from 10 to 400 ng/g [13C6]sucrose in brain. It was also validated in terms of acceptable intra and inter run accuracy and precision values (n = 5). The dual analyte technique was applied in a study in mice. One group received intravenous bolus injections of 10 mg/kg [13C12]sucrose at time 0, and 10 mg/kg [13C6]sucrose at 14.5 min, and subsequent terminal blood and brain sampling was performed at 15 min. For comparison, another group received an intravenous bolus dose of 10 mg/kg [13C12]sucrose and was submitted to transcardiac perfusion with buffer after 15 min. We demonstrate that the two alternative techniques to correct for intravascular content deliver equivalent values for brain concentration and brain uptake clearance.