Subtle Blood-brain Barrier Leakage Research Articles

Assessment of the clinical feasibility of detecting subtle blood-brain barrier leakage in cerebral small vessel disease using dynamic susceptibility contrast MRI

PurposeCerebral small vessel disease (cSVD) involves several pathologies affecting the small vessels, including blood-brain barrier (BBB) impairment. Dynamic susceptibility contrast (DSC) MRI is sensitive to both blood perfusion and BBB leakage, and correction methods may be crucial for obtaining reliable perfusion measures. These methods might also be applicable to detect BBB leakage itself. This study investigated to what extent DSC-MRI can measure subtle BBB leakage in a clinical feasibility setting. MethodsIn vivo DCE and DSC data were collected from fifteen cSVD patients (71 (±10) years, 6F/9M) and twelve elderly controls (71 (±10) years, 4F/8M). DSC-derived leakage fractions were obtained using the Boxerman-Schmainda-Weisskoff method (K2). K2 was compared with the DCE-derived leakage rate Ki, obtained from Patlak analysis. Subsequently, differences were assessed between white matter hyperintensities (WMH), cortical gray matter (CGM), and normal-appearing white matter (NAWM). Additionally, computer simulations were performed to assess the sensitivity of DSC-MRI to BBB leakage. ResultsK2 showed significant differences between tissue regions (P < 0.001 for CGM-NAWM and CGM-WMH, and P = 0.001 for NAWM-WMH). Conversely, according to the computer simulations the DSC sensitivity was insufficient to measure subtle BBB leakage, as the K2 values were below the derived limit of quantification (4∙10−3 min−1). As expected, Ki was elevated in the WMH compared to CGM and NAWM (P < 0.001). ConclusionsAlthough clinical DSC-MRI seems capable to detect subtle BBB leakage differences between WMH and normal-appearing brain tissue it is not recommended. K2 as a direct measure for subtle BBB leakage remains ambiguous as its signal effects are due to mixed T1- and T2∗-weighting. Further research is warranted to better disentangle perfusion from leakage effects.

Quantitative T1 mapping detects blood–brain barrier breakdown in apparently non-enhancing multiple sclerosis lesions

ObjectivesThe disruption of the blood–brain barrier (BBB) is a key and early feature in the pathogenesis of demyelinating multiple sclerosis (MS) lesions and has been neuropathologically demonstrated in both active and chronic plaques. The local overt BBB disruption in acute demyelinating lesions is captured as signal hyperintensity in post-contrast T1-weighted images because of the contrast-related shortening of the T1 relaxation time. On the contrary, the subtle BBB disruption in chronic lesions is not visible at conventional radiological evaluation but it might be of clinical relevance. Indeed, persistent, subtle BBB leakage might be linked to low-grade inflammation and plaque evolution. Here we hypothesised that 3D Quantitative Transient-state Imaging (QTI) was able to reveal and measure T1 shortening (ΔT1) reflecting small amounts of contrast media leakage in apparently non-enhancing lesions (ANELs). Materials and methodsThirty-four patients with relapsing remitting MS were included in the study. All patients underwent a 3 T MRI exam of the brain including conventional sequences and QTI acquisitions (1.1 mm isotropic voxel) performed both before and after contrast media administration. For each patient, a ΔT1 map was obtained via voxel-wise subtraction of pre- and post- contrast QTI-derived T1 maps. ΔT1 values measured in ANELs were compared with those recorded in enhancing lesions and in the normal appearing white matter. A reference distribution of ΔT1 in the white matter was obtained from datasets acquired in 10 non-MS patients with unrevealing MR imaging. ResultsMean ΔT1 in ANELs (57.45 ± 48.27 ms) was significantly lower than in enhancing lesions (297.71 ± 177.52 ms; p < 0. 0001) and higher than in the normal appearing white matter (36.57 ± 10.53 ms; p < 0.005). Fifty-two percent of ANELs exhibited ΔT1 higher than those observed in the white matter of non-MS patients. ConclusionsQTI-derived quantitative ΔT1 mapping enabled to measure contrast-related T1 shortening in ANELs. ANELs exhibiting ΔT1 values that deviate from the reference distribution in non-MS patients may indicate persistent, subtle, BBB disruption. Access to this information may be proved useful to better characterise pathology and objectively monitor disease activity and response to therapy.

7T dynamic contrast-enhanced MRI for the detection of subtle blood-brain barrier leakage.

Background and PurposeDynamic contrast‐enhanced MRI (DCE‐MRI) can be employed to assess the blood–brain barrier (BBB) integrity. Detection of BBB leakage at lower field strengths (≤3T) is cumbersome as the signal is noisy, while leakage can be subtle. Utilizing the increased signal‐to‐noise ratio at higher field strengths, we explored the application of 7T DCE‐MRI for assessing BBB leakage.MethodsA dual‐time resolution DCE‐MRI method was implemented at 7T and a slow injection rate (0.3 ml/s) and low dose (3 mmol) served to obtain signal changes linearly related to the gadolinium concentration, that is, minimized for T2 * degradation effects. With the Patlak graphical approach, the leakage rate (Ki ) and blood plasma volume fraction (vp ) were calculated. The method was evaluated in 10 controls, an ischemic stroke patient, and a patient with a transient ischemic attack.Results Ki and vp were significantly higher in gray matter compared to white matter of all participants. These Ki values were higher in both patients compared to the control subjects. Finally, for the lesion identified in the ischemic stroke patient, higher leakage values were observed compared to normal‐appearing tissue.ConclusionWe demonstrate how a dual‐time resolution DCE‐MRI protocol at 7T, with administration of half the clinically used contrast agent dose, can be used for assessing subtle BBB leakage. Although the feasibility of DCE‐MRI for assessing the BBB integrity at 3T is well known, we showed that a continuous sampling DCE‐MRI method tailored for 7T is also capable of assessing leakage with a high sensitivity over a range of Ki values.

Sources of systematic error in DCE-MRI estimation of low-level blood-brain barrier leakage.

Dynamic contrast-enhanced (DCE) -MRI with Patlak model analysis is increasingly used to quantify low-level blood-brain barrier (BBB) leakage in studies of pathophysiology. We aimed to investigate systematic errors due to physiological, experimental, and modeling factors influencing quantification of the permeability-surface area product PS and blood plasma volume vp , and to propose modifications to reduce the errors so that subtle differences in BBB permeability can be accurately measured. Simulations were performed to predict the effects of potential sources of systematic error on conventional PS and vp quantification: restricted BBB water exchange, reduced cerebral blood flow, arterial input function (AIF) delay and error. The impact of targeted modifications to the acquisition and processing were evaluated, including: assumption of fast versus no BBB water exchange, bolus versus slow injection of contrast agent, exclusion of early data from model fitting and correction. The optimal protocol was applied in a cohort of recent mild ischaemic stroke patients. Simulation results demonstrated substantial systematic errors due to the factors investigated (absolute PS error ≤ 4.48 × 10-4 min-1 ). However, these were reduced (≤0.56 × 10-4 min-1 ) by applying modifications to the acquisition and processing pipeline. Processing modifications also had substantial effects on in-vivo normal-appearing white matter PS estimation (absolute change ≤ 0.45 × 10-4 min-1 ). Measuring subtle BBB leakage with DCE-MRI presents unique challenges and is affected by several confounds that should be considered when acquiring or interpreting such data. The evaluated modifications should improve accuracy in studies of neurodegenerative diseases involving subtle BBB breakdown.

A four-dimensional computational model of dynamic contrast-enhanced magnetic resonance imaging measurement of subtle blood-brain barrier leakage

Dynamic contrast-enhanced MRI (DCE-MRI) is increasingly used to quantify and map the spatial distribution of blood-brain barrier (BBB) leakage in neurodegenerative disease, including cerebral small vessel disease and dementia. However, the subtle nature of leakage and resulting small signal changes make quantification challenging. While simplified one-dimensional simulations have probed the impact of noise, scanner drift, and model assumptions, the impact of spatio-temporal effects such as gross motion, k-space sampling and motion artefacts on parametric leakage maps has been overlooked. Moreover, evidence on which to base the design of imaging protocols is lacking due to practical difficulties and the lack of a reference method. To address these problems, we present an open-source computational model of the DCE-MRI acquisition process for generating four dimensional Digital Reference Objects (DROs), using a high-resolution brain atlas and incorporating realistic patient motion, extra-cerebral signals, noise and k-space sampling. Simulations using the DROs demonstrated a dominant influence of spatio-temporal effects on both the visual appearance of parameter maps and on measured tissue leakage rates. The computational model permits greater understanding of the sensitivity and limitations of subtle BBB leakage measurement and provides a non-invasive means of testing and optimising imaging protocols for future studies.

Time-efficient measurement of subtle blood-brain barrier leakage using a T1 mapping MRI protocol at 7 T.

PurposeBlood–brain barrier (BBB) disruption is commonly measured with DCE‐MRI using continuous dynamic scanning. For precise measurement of subtle BBB leakage, a long acquisition time (>20 minutes) is required. As extravasation of the contrast agent is slow, discrete sampling at strategic time points might be beneficial, and gains scan time for additional sequences. Here, we aimed to explore the feasibility of a sparsely sampled MRI protocol at 7 T.MethodsThe scan protocol consisted of a precontrast quantitative T1 measurement, using an MP2RAGE sequence, and after contrast agent injection, a fast‐sampling dynamic gradient‐echo perfusion scan and two postcontrast quantitative T1 measurements were applied. Simulations were conducted to determine the optimal postcontrast sampling time points for measuring subtle BBB leakage. The graphical Patlak approach was used to quantify the leakage rate (Ki) and blood plasma volume (vp) of normal‐appearing white and gray matter.ResultsThe simulations showed that two postcontrast T1 maps are sufficient to detect subtle leakage, and most sensitive when the last T1 map is acquired late, approximately 30 minutes, after contrast agent administration. The in vivo measurements found Ki and vp values in agreement with other studies, and significantly higher values in gray matter compared with white matter (both p = .04).ConclusionThe sparsely sampled protocol was demonstrated to be sensitive to quantify subtle BBB leakage, despite using only three T1 maps. Due to the time‐efficiency of this method, it will become more feasible to incorporate BBB leakage measurements in clinical research MRI protocols.

Optimal Detection of Subtle Gadolinium Leakage in CSF with Heavily T2-Weighted Fluid-Attenuated Inversion Recovery Imaging.

Pericortical enhancement on postcontrast FLAIR images is a marker for subtle leptomeningeal blood-brain barrier leakage. We explored the optimal FLAIR sequence parameters for the detection of low gadolinium concentrations within the CSF. On the basis of phantom experiments and human in vivo data, we showed that detection of subtle pericortical enhancement can be facilitated by using a relatively long TE. Future studies should choose their FLAIR sequence parameters carefully when assessing pericortical enhancement due to subtle blood-brain barrier leakage.

Subtle blood-brain barrier leakage rate and spatial extent: Considerations for dynamic contrast-enhanced MRI.

Dynamic contrast-enhanced (DCE) MRI can be used to measure blood-brain barrier (BBB) leakage. In neurodegenerative disorders such as small vessel disease and dementia, the leakage can be very subtle and the corresponding signal can be rather noisy. For these reasons, an optimized DCE-MRI measurement and study design is required. To this end, a new measure indicative of the spatial extent of leakage is introduced and the effects of scan time and sample size are explored. Dual-time resolution DCE-MRI was performed in 16 patients with early Alzheimer's disease (AD) and 17 healthy controls. The leakage rate (Ki ) and volume fraction of detectable leaking tissue (vL ) to quantify the spatial extent of BBB leakage were calculated in cortical gray matter and white matter using noise-corrected histogram analysis of leakage maps. Computer simulations utilizing realistic Ki histograms, mimicking the strong effect of noise and variation in Ki values, were performed to understand the influence of scan time on the estimated leakage. The mean Ki was very low (order of 10-4 min-1 ) and highly influenced by noise, causing the Ki to be increasingly overestimated at shorter scan times. In the white matter, the Ki was not different between patients with early AD and controls, but was higher in the cortex for patients, reaching significance after 14.5 min of scan time. To detect group differences, vL proved more suitable, showing significantly higher values for patients compared with controls in the cortex after 8 minutes of scan time, and in white matter after 15.5 min. Several ways to improve the sensitivity of a DCE-MRI experiment to subtle BBB leakage were presented. We have provided vL as an attractive and potentially more time-efficient alternative to detect group differences in subtle and widespread blood-brain barrier leakage compared with leakage rate Ki . Recommendations on group size and scan time are made based on statistical power calculations to aid future research.

Measuring subtle leakage of the blood-brain barrier in cerebrovascular disease with DCE-MRI: Test-retest reproducibility and its influencing factors

Increased blood-brain barrier (BBB) permeability has been shown to play a significant role in the pathophysiology of cerebrovascular disease and it may provide an early functional marker of progression or treatment effects. The aim of the study was to investigate the test-retest reproducibility and influencing factors of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in measuring subtle leakage in patients with cerebrovascular disease. DCE-MRI (3T) was performed on two separate days in 16 patients (age 66 ± 9 years) with cerebrovascular disease, prospectively. The leakage rate was quantified for white matter (WM) and gray matter (GM) using the Patlak graphical approach with individual vascular input functions (VIFs). Furthermore, the influence of session-averaged VIFs, the average of the VIFs obtained on two days, and shorter scan times (range 5-25 minutes) on the reproducibility were evaluated in WM and GM. Coefficients of variation (CV) ≤14.4% (WM and GM), intraclass correlation coefficients (ICCs) of 0.77 (WM) and 0.49 (GM), were observed for the leakage rate. Session-averaged VIFs hardly affected these results (CV ≤13.4%). The repeatability coefficients (RCs) of the leakage rate decreased from 2.7·10-3 to 0.4·10-3 min-1 in WM (P < 0.01) and 4.4·10-3 to 0.9·10-3 min-1 in GM (P < 0.01) with increasing scan time (range 5-25 minutes). Based on the moderate CVs and moderate-to-excellent ICCs, we demonstrate that measuring subtle BBB leakage using DCE-MRI is moderate-to-excellent reproducible. Longer scan times improve the reproducibility. The provided RCs at various scan times may assist future clinical studies investigating BBB leakage using DCE-MRI. 2 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:159-166.

Blood-brain barrier leakage is more widespread in patients with cerebral small vessel disease.

As blood-brain barrier (BBB) dysfunction may occur in normal aging but may also play a pivotal role in the pathophysiology of cerebral small vessel disease (cSVD), we used dynamic contrast-enhanced (DCE)-MRI to quantify the rate and the spatial extent of BBB leakage in patients with cSVD and age- and sex-matched controls to discern cSVD-related BBB leakage from aging-related leakage. We performed structural brain MRI and DCE-MRI in 80 patients with clinically overt cSVD and 40 age- and sex-matched controls. Using the Patlak pharmacokinetic model, we calculated the leakage rate. The mean leakage rate and relative leakage volume were calculated using noise-corrected histogram analysis. Leakage rate and leakage volume were compared between patients with cSVD and controls for the normal-appearing white matter (NAWM), white matter hyperintensities (WMH), cortical gray matter (CGM), and deep gray matter. Multivariable linear regression analyses adjusting for age, sex, and cardiovascular risk factors showed that the leakage volume of the NAWM, WMH, and CGM was significantly larger in patients with cSVD compared with controls. No significant difference was found for leakage rate in any of the tissue regions. We demonstrated a larger tissue volume with subtle BBB leakage in patients with cSVD than in controls. This was shown in the NAWM, WMH, and CGM, supporting the generalized nature of cSVD.

Rapid endothelial cytoskeletal reorganization enables early blood-brain barrier disruption and long-term ischaemic reperfusion brain injury.

The mechanism and long-term consequences of early blood–brain barrier (BBB) disruption after cerebral ischaemic/reperfusion (I/R) injury are poorly understood. Here we discover that I/R induces subtle BBB leakage within 30–60 min, likely independent of gelatinase B/MMP-9 activities. The early BBB disruption is caused by the activation of ROCK/MLC signalling, persistent actin polymerization and the disassembly of junctional proteins within microvascular endothelial cells (ECs). Furthermore, the EC alterations facilitate subsequent infiltration of peripheral immune cells, including MMP-9-producing neutrophils/macrophages, resulting in late-onset, irreversible BBB damage. Inactivation of actin depolymerizing factor (ADF) causes sustained actin polymerization in ECs, whereas EC-targeted overexpression of constitutively active mutant ADF reduces actin polymerization and junctional protein disassembly, attenuates both early- and late-onset BBB impairment, and improves long-term histological and neurological outcomes. Thus, we identify a previously unexplored role for early BBB disruption in stroke outcomes, whereby BBB rupture may be a cause rather than a consequence of parenchymal cell injury.

In vitro investigation of poor cerebrospinal fluid suppression on fluid‐attenuated inversion recovery images in the presence of a gadolinium‐based contrast agent

Cerebrospinal fluid (CSF) enhancement on fluid-attenuated inversion recovery (FLAIR) images obtained post-gadolinium (Gd)-based agent injection is described in stroke and multiple sclerosis. Blood brain barrier (BBB) disruption with contrast agent extravasation into CSF shortens T(1) relaxation times, reducing fluid suppression. Reduced fluid suppression on FLAIR images was investigated in vitro in the presence of escalating gadopentetate dimeglumine (Gd-DTPA) concentrations mixed with artificial CSF. Low Gd-DTPA concentrations impair fluid suppression of FLAIR imaging in association with progressively reduced T(1) values. At higher concentrations, the prevalent T(2) shortening effect can explain signal intensity (SI) reduction. Post-Gd FLAIR may be useful in detecting subtle BBB leakage.

A study of subtle blood brain barrier disruption in a placebo-controlled trial of natalizumab in relapsing remitting multiple sclerosis

Natalizumab, an anti-alpha4 integrin antibody, significantly reduces the number of visibly enhancing multiple sclerosis (MS) lesions. In this substudy of a 2-year trial of natalizumab monotherapy versus placebo, contrast-enhanced imaging investigated for subtle blood brain barrier (BBB) leakage in relapsing remitting (RRMS) patients, and whether such leakage is modified by natalizumab. After 24 weeks on treatment, 40 patients from 3 centres (27 on natalizumab and 13 on placebo) were studied. T1 weighted images were obtained before and at set timepoints up to 46 minutes after gadolinium (Gd)-DTPA (0.3 mmol/kg to 18 patients, 0.15 mmol/kg to 22). Paired regions of interest were placed around non-enhancing lesions and contralateral normal appearing white matter (NAWM). BBB leakage was inferred through post-Gd T1 weighted signal intensity (SI) change. SI change was greater in T2 non-enhancing lesions than paired NAWM at all timepoints (P<0.005), indicating BBB leakage in lesions. No significant difference in inferred BBB leakage was observed between treatment arms as measured by SI change of lesions (P>0.05 for all timepoints, joint test P=0.24), or in SI change of NAWM (joint test P=0.37). T1 hypointense and isointense lesions exhibited similar SI changes (joint test P=0.12). There is evidence of a subtle BBB leakage within visibly non-enhancing lesions in RRMS that was not modified by alpha4 integrin blockade in this substudy cohort.

Vascular volume and blood‐brain barrier permeability measured by dynamic contrast enhanced MRI in hippocampus and cerebellum of patients with MCI and normal controls

To measure the cerebrovascular volume and blood-brain barrier (BBB) permeability indices in hippocampus and cerebellum of patients with mild cognitive impairment (MCI) using dynamic contrast-enhanced MRI (DCE-MRI), and compare to that of normal controls. A total of 11 MCI subjects and 11 healthy elderly controls participated in this prospective study. DCE-MRI was performed to measure the contrast enhancement kinetics. The early enhancement percentage (at 50 seconds after injection) was defined as the vascular volume index, and the ratio between the four to five-minute enhancement relative to the 50-second enhancement was defined as the BBB permeability index. The enhancement kinetics measured from hippocampus of MCI individuals demonstrated a lower magnitude and slower decay than healthy controls, suggesting that they had a smaller vascular volume (significant in the right side; P <0.001) and a higher BBB permeability (not reaching significance level). The vascular volume index was significantly correlated with naming ability (P 0.05). These results suggest that changes in cerebrovasculature may occur in hippocampus of MCI. DCE-MRI may provide a noninvasive means to measure the subtle BBB leakage associated with the cerebrovascular pathology commonly found in Alzheimer's disease.