Quantitative measurement of blood‐brain barrier permeability in human using dynamic contrast‐enhanced MRI with fast T1 mapping

Breakdown of the blood‐brain barrier (BBB), occurring in many neurological diseases, has been difficult to measure noninvasively in humans. Dynamic contrast‐enhanced magnetic resonance imaging measures BBB permeability. However, important technical challenges remain and normative data from healthy humans is lacking. We report the implementation of a method for measuring BBB permeability, originally developed in animals, to estimate BBB permeability in both healthy subjects and patients with white matter pathology. Fast T₁ mapping was used to measure the leakage of contrast agent Gadolinium diethylene triamine pentaacetic acid (Gd‐DTPA) from plasma into brain. A quarter of the standard Gd‐DTPA dose for dynamic contrast‐enhanced magnetic resonance imaging was found to give both sufficient contrast‐to‐noise and high T₁ sensitivity. The Patlak graphical approach was used to calculate the permeability from changes in 1/T₁. Permeability constants were compared with cerebrospinal fluid albumin index. The upper limit of the 95% confidence interval for white matter BBB permeability for normal subjects was 3 × 10^?4 L/g min. MRI measurements correlated strongly with levels of cerebrospinal fluid albumin in those subjects undergoing lumbar puncture. Dynamic contrast‐enhanced magnetic resonance imaging with low dose Gd‐DTPA and fast T₁ imaging is a sensitive method to measure subtle differences in BBB permeability in humans and may have advantages over techniques based purely on the measurement of pixel contrast changes. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

In vivo measurement of T2 distributions and water contents in normal human brain

Using a 32-echo imaging pulse sequence, T₂ relaxation decay curves were acquired from five white- and six gray-matter brain structures outlined in 12 normal volunteers. The water contents of white and gray matter were 0.71 (0.01) and 0.83 (0.03) g/ml, respectively. All white-matter structures had significantly higher myelin water percentages (signal percentage with T₂ between 10 and 50 ms) than all gray-matter structures. The range in geometric mean T₂ of the main peak for both white and gray matter was from 70 to 86 ms. T₂ distributions from the posterior internal capsules and splenium of the corpus callosum were significantly wider (width is related to water environment inhomogeneity) than those from any other white- or gray-matter structures. Thus, quantitative measurement and analysis of T₂ relaxation reveals differences in brain tissue water environments not discernible on conventional MR images. These differences may make short T₂ components reliable markers for normal myelin.     

Measurement of glycine in gray and white matter in the human brain in vivo by 1H MRS at 7.0 T

The concentration of glycine (Gly) was measured in gray matter (GM) and white matter (WM) in the human brain using single‐voxel localized ¹H MRS at 7 T. A point‐resolved spectroscopy sequence with echo time = 150 ms was used for measuring Gly levels in various regions of the frontal and occipital lobes in 11 healthy volunteers and one subject with a glioblastoma. The point‐resolved spectroscopy spectra were analyzed with LCModel using basis functions generated from density matrix simulations that included the effects of volume localized radio‐frequency and gradient pulses. The fraction of GM and white matter within the voxels was obtained from T₁‐weighted image segmentation. The metabolite concentrations within the voxels, estimated with respect to the GM + WM water concentrations, were fitted to a linear function of fractional GM content. The Gly concentrations in pure GM and white matter were estimated to be 1.1 and 0.1 mM, with 95% confidence intervals 1.0–1.2 and 0.0–0.2, respectively. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.     

Metabolite proton T2 mapping in the healthy rhesus macaque brain at 3 T

The structure and metabolism of the rhesus macaque brain, an advanced model for neurologic diseases and their treatment response, is often studied noninvasively with MRI and ¹H‐MR spectroscopy. Due to the shorter transverse relaxation time (T₂) at the higher magnetic fields these studies favor, the echo times used in ¹H‐MR spectroscopy subject the metabolites to unknown T₂ weighting, decreasing the accuracy of quantification which is key for inter‐ and intra‐animal comparisons. To establish the “baseline” (healthy animal) T₂ values, we mapped them for the three main metabolites' T₂s at 3 T in four healthy rhesus macaques and tested the hypotheses that their mean values are similar (i) among animals; and (ii) to analogs regions in the human brain. This was done with three‐dimensional multivoxel ¹H‐MR spectroscopy at (0.6 × 0.6 × 0.5 cm)³ = 180 μL spatial resolution over a 4.2 × 3.0 × 2.0 = 25 cm³ (～30%) of the macaque brain in a two‐point protocol that optimizes T₂ precision per unit time. The estimated T₂s in several gray and white matter regions are all within 10% of those reported in the human brain (mean ± standard error of the mean): N‐acetylaspartate = 316 ± 7, creatine = 177 ± 3, and choline = 264 ± 9 ms, with no statistically significant gray versus white matter differences. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Evaluation of cerebral gray and white matter metabolite differences by spectroscopic imaging at 4.1T

Using a 4.1 T whole body system, we have acquired ¹H spectroscopic imaging (SI) data of N-acetyl (NA) compounds, creatine (CR), and choline (CH) with nominal voxel sizes of 0.5 cc (1.15 cc after filtering). We have used the SI data to estimate differences in cerebral metabolites of human gray and white matter. To evaluate the origin of an increased CWNA and CWNA ratios in gray matter relative to white matter, we measured the T₁ and T₂ of CR, NA, and CH in gray and white matter using moderate resolution SI imaging. In white matter the T₂s of NA, CR, and CH were 233 ± 27,141 ± 18, and 167 ± 20 ms, respectively, and 227 ± 27,140 ± 16, and 189 ± 25 ms in gray matter. The T, values for NA, CR, and CH were 1267 ±141, 1487 ± 146, and 1111 ± 136 ms in gray matter and 1260 ± 154, 1429 & 233, and 1074 ± 146 ms in white matter. After correcting for T₁ and T₂ losses, creatine content was significantly lower in white matter than gray (P < e 0.01, t-test), with a white/gray content ratio of 0.8, in agreement with biopsy and in vivo measurements at 1.5 and 2.0T.     

Regional metabolite T2 in the healthy rhesus macaque brain at 7T

Although the rhesus macaque brain is an excellent model system for the study of neurological diseases and their responses to treatment, its small size requires much higher spatial resolution, motivating use of ultra‐high‐field (B₀) imagers. Their weaker radio‐frequency fields, however, dictate longer pulses; hence longer TE localization sequences. Due to the shorter transverse relaxation time (T₂) at higher B₀s, these longer TEs subject metabolites to T₂‐weighting, that decrease their quantification accuracy. To address this we measured the T₂s of N‐acetylaspartate (NAA), choline (Cho), and creatine (Cr) in several gray matter (GM) and white matter (WM) regions of four healthy rhesus macaques at 7T using three‐dimensional (3D) proton MR spectroscopic imaging at (0.4 cm)³ = 64 μl spatial resolution. The results show that macaque T₂s are in good agreement with those reported in humans at 7T: 169 ± 2.3 ms for NAA (mean ± SEM), 114 ± 1.9 ms for Cr, and 128 ± 2.4 ms for Cho, with no significant differences between GM and WM. The T₂ histograms from 320 voxels in each animal for NAA, Cr, and Cho were similar in position and shape, indicating that they are potentially characteristic of “healthy” in this species. Magn Reson Med 59:1165–1169, 2008. © 2008 Wiley‐Liss, Inc.     

Simultaneous quantification of T2 and T′2 using a combined gradient echo‐spin echo sequence at ultrahigh field

Measuring T₂ at 7.0 T is not trivial due to RF inhomogeneity effects, however, gradient echo sampling of a spin echo is insensitive to RF pulse errors, does not suffer from significant distortions, and allows T′₂ and T₂ to be estimated simultaneously. Gradient echo sampling of a spin echo results are relatively sensitive to noise and therefore fitting methods and timing parameters were optimized: a weighted linear fit reduced the errors in T₂ compared to a nonlinear fit, the optimum spin echo time was approximately equal to the expected T₂ and decreasing the number of gradient echoes minimized the error of the estimated T₂. T₂, T′₂, and T*₂ decreased with field strength in frontal gray matter, occipital gray matter, and white matter, with T₂ having a linear dependence (frontal gray matter: 87, 76, 47 ms, occipital gray matter: 80, 68, 46 ms and white matter: 80, 71, 47 ms at 1.5, 3.0 and 7.0 T, respectively). Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Changes in the brain during long-term follow-up after liver transplantation

Purpose:

To examine changes in the brain before liver transplantation caused by the accumulation of paramagnetic ion deposits and to investigate recovery after liver transplantation over a long‐term horizon.

Materials and Methods:

Fifteen patients indicated for liver transplantation, 26 patients up to 2 years after, and 40 patients 8–15 years after liver transplantation were subjected to MR relaxometry. T₁ and T₂ relaxation times in the basal ganglia, thalamus, and white matter were evaluated.

Results:

Relaxometry revealed a shortening of the relaxation times due to the deposition of paramagnetic ions in the basal ganglia before liver transplantation (P < 0.05), complete normalization of the relaxation times shortly after transplantation in the globus pallidus and caudate nucleus, and partial recovery of T₂ in the putamen. Relaxation times remained stable even 15 years posttransplantation. Increased relaxation times posttransplantation were found in the white matter and thalamus.

Conclusion:

The shortening of the relaxation times observed in the basal ganglia before liver transplantation was caused by paramagnetic ion deposition. The recovery observable within 2 years after transplantation was permanent, and no recurrence of paramagnetic ion deposition was observed even 15 years posttransplantation. Changes in the white matter and thalamus after transplantation were attributed to damage caused by permanent exposure to immunosuppressants. J. Magn. Reson. Imaging 2012;35:1332–1337. © 2012 Wiley Periodicals, Inc.     

Fast bound pool fraction mapping using stimulated echoes

Magnetization transfer imaging advanced to an indispensible tool for investigating white matter changes. Quantitative magnetization transfer imaging methods allow the determination of the bound pool fraction (BPF), which is thought to be directly linked to myelin integrity. Long acquisition times and high specific absorption rates are still inhibiting broad in vivo utilization of currently available BPF mapping techniques. Herewith, a stimulated echoes amplitude modulation‐based, single‐shot echo planar imaging technique for BPF and T₁ quantification is presented at 3T. It allows whole brain mapping in 10–15 min and is low in specific absorption rates. The method was validated with different concentrations of bovine serum albumin (BSA) phantoms. Intra‐ and inter‐subject variability was assessed in vivo. Phantom measurements verified linearity between bovine serum albumin concentrations and measured BPF, which was independent of T₁ variations. T₁ values in the phantoms correlated well with values provided by standard T₁ mapping methods. Intrasubject variability was minimal and mean regional BPFs of 10 volunteers (e.g., left frontal white matter = 0.135 ± 0.003, right frontal white matter = 0.129 ± 0.006) were in line with previously published data. Assessment of interhemispheric BPF differences revealed significantly higher BPF for the left brain hemisphere. To sum up, these results suggest the proposed method useful for cross‐sectional and longitudinal studies of white matter changes in the human brain. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.     

Characterization of T2* heterogeneity in human brain white matter

Recent in vivo MRI studies at 7.0 T have demonstrated extensive heterogeneity of T₂* relaxation in white matter of the human brain. In order to study the origin of this heterogeneity, we performed T₂* measurements at 1.5, 3.0, and 7.0 T in normal volunteers. Formalin‐fixed brain tissue specimens were also studied using T₂*‐weighted MRI, histologic staining, chemical analysis, and electron microscopy. We found that T₂* relaxation rate (R₂* = 1/T₂*) in white matter in living human brain is linearly dependent on the main magnetic field strength, and the T₂* heterogeneity in white matter observed at 7.0 T can also be detected, albeit more weakly, at 1.5 and 3.0 T. The T₂* heterogeneity exists also in white matter of the formalin‐fixed brain tissue specimens, with prominent differences between the major fiber bundles such as the cingulum (CG) and the superior corona radiata. The white matter specimen with substantial difference in T₂* has no significant difference in the total iron content, as determined by chemical analysis. On the other hand, evidence from histologic staining and electron microscopy demonstrates these tissue specimens have apparent difference in myelin content and microstructure. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

The use of a priori knowledge to quantify short echo in vivo 1h mr spectra

In vivo ¹H MR spectra of the prefrontal cortex acquired with the stimulated echo acquisition mode (STEAM) TE = 20 ms sequence were quantified to determine relative levels of cerebral metabolites. A priori knowledge of spectra from individual metabolites in aqueous solution was incorporated into a frequency domain quantification technique. The accuracy and precision of modeling these metabolites were investigated with simulated spectra of varying signal-to-noise ratios (SNRs) and relative metabolite levels. The efficacy of modeling in vivo data was tested by quantifying 10 repeated measures of two consecutively acquired in vivo spectra (an 8?cm³ volume of interest (VOI) and a 4?cm³ VOI positioned within the 8?cm³ VOI) on the same normal subject. The differences in levels of glutamate (Glu), phosphocreatine plus creatine (PCr+Cr) and choline-containing compounds (Cho₁ between spectra from the 8? and 4?cm³ VOIs corresponded with the expected differences observed in the proportions of gray matter within the VOIs (estimated from ¹H images). Correcting for the T₁ and T₂ relaxation, the estimated concentrations of N-acetylaspartate, PCr+Cr, Cho₁, Glu, and glutamine were consistent with previous in vivo and in vitro reports.     

1H chemical shift imaging reveals loss of brain tumor choline signal after administration of Gd-contrast

¹H MR spectra obtained by chemical shift imaging (CSI) of contrast-enhancing brain tumors before and after the administration of Gd-contrast agent were quantitated and compared with the results in normal brain tissue included in the volume of interest. Twenty-seven combined magnetic resonance imaging and spectroscopy (MRI, MRS) examinations of brain tumor lesions included T₁-weighted MRI and CSI (TR/TE 1500/135 ms double-spin echo) repeated 5–10 min after the administration of Gd-contrast agent (0.1–0.2 mM). In ¹H MR spectra of contrast-enhancing tumor Gd-contrast induced a mean loss of 15% of the peak area of choline-containing compounds (Cho, P < 0.001) that was correlated with precontrast Cho linewidth (r = ?0.72, P < 0.00001). This phenomenon limits the diagnostic use of brain tumor MRS examinations performed immediately after contrast-enhanced MRI.     

Direct saturation MRI: Theory and application to imaging brain iron

When applying RF saturation to tissue, MRI signal reductions occur due to magnetization transfer (MT) and direct saturation (DS) effects on water protons. It is shown that the direct effects, often considered a nuisance, can be used to distinguish gray matter (GM) regions with different iron content. DS effects were selected by reducing the magnitude and duration of RF irradiation to minimize confounding MT effects. Contrary to MT saturation spectra, direct water saturation spectra are characterized by a symmetric Lorentzian‐shaped frequency dependence that can be described by an exact analytical solution of the Bloch equations. The effect of increased transverse relaxation, e.g., due to the presence of iron, will broaden this saturation spectrum. As a first application, DS ratio (DSR) images were acquired to visualize GM structures in the human brain. Similar to T₂^*‐weighted images, the quality of DSR images was affected by local field inhomogeneity, but this could be easily corrected for by centering the saturation spectrum on a voxel‐by‐voxel basis. The results show that, contrary to commonly used T₂^*‐weighted and absolute R₂ images, the DSR images visualize all GM structures, including cortex. A direct correlation between DSR and iron content was confirmed for these structures. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Feature space analysis of MRI

This paper presents an MRI feature-space image-analysis method and its application to brain tumor studies. The proposed method generates a transformed feature space in which the normal tissues (white matter, gray matter, and CSF) become orthonormal. As such, the method is expected to have site-to-site and patient-to-patient consistency, and is useful for identification of tissue types, segmentation of tissues, and quantitative measurements on tissues. The steps of the work accomplished are as follows: (1) Four T₂-weighted and two T₁-weighted images (before and after injection of gadolinium) were acquired for 10 tumor patients. (2) Images were analyzed by an image analyst according to the proposed algorithm. (3) Biopsy samples were extracted from each patient and were subsequently analyzed by the pathology laboratory. (4) Image-analysis results were compared with the biopsy results. Pre- and postsurgery feature spaces were also compared. The proposed method made it possible to visualize the MRI feature space and to segment the image. In all cases, the operators were able to find clusters for normal and abnorma tissues. Also, clusters for different zones of the tumor were found. The method successfully segmented the image into normal tissues (white matter, gray matter, and CSF) and different zones of the lesion (tumor, cyst, edema, radiation necrosis, necrotic core, and infiltrated tumor). The results agreed with those obtained from the biopsy samples. Comparison of pre- with postsurgery and radiation feature spaces illustrated that the original solid tumor was not present in the second study, but a new tissue component appeared in a different location of the feature space. This tissue could be radiation necrosis generated as a result of radiation.     

High resolution quantitative relaxation and diffusion mri of three different experimental brain tumors in rat

The potential of quantitative parameter images of the relaxation times T₁ and T₂, the proton density p and the apparent diffusion coefficient (ADC) to characterize three different experimental rat brain tumors (F98 glioma, RN6 Schwannoma, and E376 neuroblastoma) was studied. All parameter values, as determined in histologically confirmed regions of interest (ROI), were higher in edema than in tumor, which in turn were elevated with respect to normal brain. ROI values of ADC and T₂ delivered statistically significant (P < 0.01) differentiation between tumor and edema. Multidimensional parameter combinations improved differentiation between different tissues. However, the three tumor types could not be differentiated. All parameter maps allowed the identification of the whole tumoredema area. On T₂ images, edema could be identified best, whereas the tumor itself was hardly visualized. In many cases, tumor presentation using T₁ maps corresponded best with histology, nevertheless suffering from a poor tumoredema differentiation.     

Proton T1 relaxation times of metabolites in human occipital white and gray matter at 7 T

Proton T₁ relaxation times of metabolites in the human brain have not previously been published at 7 T. In this study, T₁ values of CH₃ and CH₂ group of N‐acetylaspartate and total creatine as well as nine other brain metabolites were measured in occipital white matter and gray matter at 7 T using an inversion‐recovery technique combined with a newly implemented semi‐adiabatic spin‐echo full‐intensity acquired localized spectroscopy sequence (echo time = 12 ms). The mean T₁ values of metabolites in occipital white matter and gray matter ranged from 0.9 to 2.2 s. Among them, the T₁ of glutathione, scyllo‐inositol, taurine, phosphorylethanolamine, and N‐acetylaspartylglutamate were determined for the first time in the human brain. Significant differences in T₁ between white matter and gray matter were found for water (?28%), total choline (?14%), N‐acetylaspartylglutamate (?29%), N‐acetylaspartate (+4%), and glutamate (+8%). An increasing trend in T₁ was observed when compared with previously reported values of N‐acetylaspartate (CH₃), total creatine (CH₃), and total choline at 3 T. However, for N‐acetylaspartate (CH₃), total creatine, and total choline, no substantial differences compared to previously reported values at 9.4 T were discernible. The T₁ values reported here will be useful for the quantification of metabolites and signal‐to‐noise optimization in human brain at 7 T. Magn Reson Med 69:931–936, 2013. © 2012 Wiley Periodicals, Inc.     

Measurement of brain perfusion,blood volume,and blood‐brain barrier permeability,using dynamic contrast‐enhanced T1‐weighted MRI at 3 tesla

Assessment of vascular properties is essential to diagnosis and follow‐up and basic understanding of pathogenesis in brain tumors. In this study, a procedure is presented that allows concurrent estimation of cerebral perfusion, blood volume, and blood‐brain permeability from dynamic T₁‐weighted imaging of a bolus of a paramagnetic contrast agent passing through the brain. The methods are applied in patients with brain tumors and in healthy subjects. Perfusion was estimated by model‐free deconvolution using Tikhonov's method (gray matter/white matter/tumor: 72 ± 16/30 ± 8/56 ± 45 mL/100 g/min); blood volume (6 ± 2/4 ± 1/7 ± 6 mL/100 g) and permeability (0.9 ± 0.4/0.8 ± 0.3/3 ± 5 mL/100 g/min) were estimated by using Patlak's method and a two‐compartment model. A corroboration of these results was achieved by using model simulation. In addition, it was possible to generate maps on a pixel‐by‐pixel basis of cerebral perfusion, cerebral blood volume, and blood‐brain barrier permeability. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

The relation between brain iron and NMR relaxation times: An in vitro study

T₁ and T₂ relaxation times and iron concentrations were measured in 24 specimens of gray matter from fresh human and monkey brains at magnetic fields from 0.05 to 1.5 Tesla. Three different effects were found that correlate with iron content: a T₁-shortening that falls off somewhat at high fields, a T₂-shortening that is field-independent and thus important at low fields, and a contribution to 1/T₂ that increases linearly with field strength. This linear field dependence has been seen only in ferritin and other ferric oxyhydroxide particles. Our results are in agreement with in vivo MRI studies and are generally consistent with values for ferritin solution, except for differences such as clustering of ferritin in tissue. A cerebral cavernous hemangioma specimen showed similar T₂-shortening, but with a 2.7 times larger magnitude, attributed to larger clusters of hemosiderin in macrophages. The dependence on interecho time 2_T was measured in three brains; 1/T₂ increased significantly for T up to 32 ms, as expected from the size of the ferritin clusters. These findings support the theory that ferritin iron is the primary determinant of MRI contrast in normal gray matter.     

Brain metabolites B1‐corrected proton T1 mapping in the rhesus macaque at 3 T

The accuracy of metabolic quantification in MR spectroscopy is limited by the unknown radiofrequency field and T₁. To address both issues in proton (¹H) MR spectroscopy, we obtained radiofrequency field–corrected T₁ maps of N‐acetylaspartate, choline, and creatine in five healthy rhesus macaques at 3 T. For efficient use of the 4 hour experiment, we used a new three‐point protocol that optimizes the precision of T₁ in three‐dimensional ¹H‐MR spectroscopy localization for extensive, ～30%, brain coverage at 0.6 × 0.6 × 0.5 cm³ = 180‐μL spatial resolution. The resulting mean T₁s in 700 voxels were N‐acetylaspartate = 1232 ± 44, creatine = 1238 ± 23 and choline = 1107 ± 56 ms (mean ± standard error of the mean). Their histograms from all 140 voxels in each animal were similar in position and shape, characterized by standard errors of the mean of the full width at half maximum divided by their means of better than 8%. Regional gray matter N‐acetylaspartate, choline, and creatine T₁s (1333 ± 43, 1265 ± 52, and 1131 ± 28 ms) were 5–10% longer than white matter: 1188 ± 34, 1201 ± 24, and 1082 ± 50 ms (statistically significant for the N‐acetylaspartate only), all within 10% of the corresponding published values in the human brain. Magn Reson Med 63:865–871, 2010. © 2010 Wiley‐Liss, Inc.     

Effects of echo time on diffusion quantification of brain white matter at 1.5T and 3.0T

The aim was to investigate the effects of echo time (TE) on diffusion quantification of brain white matter. Seven rhesus monkeys (all males; age, 4–6 years; weight, 5–7 kg) underwent diffusion tensor imaging (DTI) with a series of TEs in 1.5T and 3.0T MR scanners. The mean diffusivity (MD), fractional anisotropy (FA), primary (λ₁), and transverse eigenvalues (λ₂₃) were measured in a region of interest at the bilateral internal capsule. Pearson correlation showed that the FA and λ₁ increased and λ₂₃ decreased with TE both at 1.5T and 3.0T except for the MD. Repeated measurement analysis of variance (ANOVA) also showed significantly higher FA and lower MD and λ₂₃ at 3.0T than those at 1.5T (P < 0.01), but no statistical differences were found in λ₁ between these two field strengths (P = 0.709). These findings implied that TE and field strength might influence diffusion quantification in brain white matter. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.