Noninvasive blood-brain barrier integrity mapping in patients with high-grade glioma and metastasis by multi-echo time-encoded arterial spin labeling

Abstract

Purpose: In brain tumors, disruption of the blood-brain barrier (BBB) indicates malignancy. Clinical assessment is qualitative; quantitative evaluation is feasible using the K₂ leakage parameter from dynamic susceptibility contrast MRI. However, contrast agent-based techniques are limited in patients with renal dysfunction and insensitive to subtle impairments. Assessing water transport times across the BBB (T_ex) by multi-echo arterial spin labeling promises to detect BBB impairments noninvasively and potentially more sensitively. We hypothesized that reduced T_ex indicates impaired BBB. Furthermore, we assumed higher sensitivity for T_ex than dynamic susceptibility contrast-based K₂, because arterial spin labeling uses water as a freely diffusible tracer.

Methods: We acquired 3T MRI data from 28 patients with intraparenchymal brain tumors (World Health Organization Grade 3 & 4 gliomas [n = 17] or metastases [n = 11]) and 17 age-matched healthy controls. The protocol included multi-echo and single-echo Hadamard-encoded arterial spin labeling, dynamic susceptibility contrast, and conventional clinical imaging. T_ex was calculated using a T₂-dependent multi-compartment model. Areas of contrast-enhancing tissue, edema, and normal-appearing tissue were automatically segmented, and parameter values were compared across volumes of interest and between patients and healthy controls.

Results: T_ex was significantly reduced (-20.3%) in contrast-enhancing tissue compared with normal-appearing gray matter and correlated well with |K₂| (r = -0.347). Compared with healthy controls, T_ex was significantly lower in tumor patients' normal-appearing gray matter (T_ex,tumor = 0.141 ± 0.032 s vs. T_ex,HC = 0.172 ± 0.036 s) and normal-appearing white matter (T_ex,tumor = 0.116 ± 0.015 vs. T_ex,HC = 0.127 ± 0.017 s), whereas |K₂| did not differ significantly. Receiver operating characteristic analysis showed a larger area under the curve for T_ex (0.784) than K₂ (0.604).

Conclusion: T_ex is sensitive to pathophysiologically impaired BBB. It agrees with contrast agent-based K₂ in contrast-enhancing tissue and indicates sensitivity to subtle leakage.

Keywords: arterial spin labeling (ASL); blood–brain barrier (BBB); brain tumor; dynamic susceptibility contrast (DSC); leakage; magnetic resonance imaging (MRI).

FIGURE 1

Overview of MRI protocol and image analysis. Arterial spin labeling (ASL)–based blood–brain barrier (BBB) mapping used two Hadamard‐encoded sequences. It was compared against contrast agent (CA)–based BBB mapping, which used dynamic susceptibility contrast (DSC) MRI. From concatenated single (Hadamard 8 [H8]) and multi‐echo (multi‐TE) Hadamard 4 data, arterial transit time (ATT), cerebral blood flow (CBF), and water exchange time (T _ex) were fitted. ASL‐based T _ex and DSC‐based K ₂ were compared as proxies of BBB integrity. From structural MRI, contrast‐enhancing tissue (CET), edema, normal‐appearing gray matter (NAGM), and normal‐appearing white matter (NAWM) were derived. Note that the scheme does not reflect the acquisition order. DSC and CA‐enhanced T₁‐weighted (T₁w) MRI were always acquired at the end of the MRI protocol. FLAIR, fluid‐attenuated inversion recovery.

FIGURE 2

Exemplary data of 2 patients. T₁‐weighted (T₁w) post–contrast agent (CA; A), fluid‐attenuated inversion recovery (FLAIR; B), tissue masks (C), T _ex (D), and K ₂ (E) maps are shown. The glioma patient's rim‐like CA uptake (arrows, A1) and pronounced edema (arrows, B1 ) are segmented into masks of contrast‐enhancing tissue (CET, bright red) and edema (dark red; C1). Additionally, volumes of interest of normal‐appearing gray matter (NAGM), normal‐appearing white matter (NAWM), and normal‐appearing cerebral spinal fluid (NACSF) are shown. T _ex is visibly reduced in the tumorous region (arrows, D1), resembling areas of increased K ₂ (arrows, E1), dominated by K ₂ > 0. The metastasis patient similarly shows a rim‐like CA uptake (arrow, A2) with edema (arrow, B2 ). Here, hypointense T _ex regions (arrow, D2) agree with areas where K ₂ < 0 (arrow, E2). ASL, arterial spin labeling; BBB, blood–brain barrier; DSC, dynamic susceptibility contrast.

FIGURE 3

Paired scatterplots of T _ex in brain tumor patients. T _ex in contrast‐enhancing tissue (CET; A,B) was significantly reduced compared with normal‐appearing gray matter (NAGM; A) but similar to normal‐appearing white matter (NAWM; B). Similarly, T _ex was reduced in edema (C,D) compared with NAGM (C) but similar to NAWM (D). Dots indicate volumes of interest (VOI) averages in single subjects and are connected between VOIs of the same patient with solid lines. Red dashed lines indicate group averages. Asterisks indicate statistically significant differences (p < 0.05). Note that CET was evaluated in 8 patients showing contrast agent leakage in VOIs larger than 2 cm³.

FIGURE 4

Correlation between T _ex and cerebral blood flow (CBF) in contrast‐enhancing tissue (CET). Pearson correlation analysis did not indicate any relation between T _ex and CBF in CET. Note that only 8 subjects showed CET volumes of interest larger than 2 mm³ and were therefore included in this analysis.

FIGURE 5

Correlation between T _ex in tumor versus normal‐appearing gray matter (NAGM) and normal‐appearing white matter (NAWM). T _ex in tumorous tissue (contrast‐enhancing tissue [CET] and edema) was significantly correlated with T _ex in NAGM (A; p < 0.001) as well as NAWM (B; p < 0.001). NA, normal appearing.

FIGURE 6

Group comparison of T _ex and |K ₂|. T _ex in tumor tissue as well as normal‐appearing gray matter (NAGM) and normal‐appearing white matter (NAWM) in patients (red) was significantly reduced compared with healthy controls (HCs; blue) (A). |K ₂| was significantly elevated in contrast‐enhancing tissue (CET) but not in edema or NAGM and NAWM compared with healthy subjects (B). Whisker plot boxes indicate 25th and 75th percentiles; median values are shown with a horizontal line; and outliers are visualized by crosses. Asterisks indicate statistically significant differences between patients and HCs (p < 0.05). Note that for HCs, |K ₂| consists of data of 8 subjects.

FIGURE 7

Pearson correlations between |K ₂| and T _ex in tumor patients. In contrast‐enhancing tissue (CET; A), larger |K ₂| values correlated well with decreased T _ex; no correlation was found in normal‐appearing gray matter (NAGM; B) or normal‐appearing white matter (NAWM; C). Note that CET evaluation could only be performed in 8 patients, which showed sufficiently large contrast agent leakage volumes of interest (> 2 cm³).

FIGURE 8

Receiver operating characteristic (ROC) analysis in normal‐appearing gray matter (NAGM). Performance of both leakage parameters to discriminate between healthy controls (HCs) and patients were tested by ROC analysis. True positive rates were drawn against false positive rates. T _ex (green) yielded a larger area under the curve (AUC, 0.78) compared with |K ₂| (purple, 0.60).