Endothelial Cell APOE3 Regulates Neurovascular, Neuronal, and Behavioral Function.

BACKGROUND: Specialized brain endothelial cells and human APOE3 are independently important for neurovascular function, yet whether APOE3 expression by endothelial cells contributes to brain function is currently unknown. In the present study, we determined whether the loss of endothelial cell APOE3 impacts brain vascular and neural function. METHODS: We developed APOE3fl/fl/Cdh5(PAC)-CreERT2+/- (APOE3Cre+/-) and APOE3fl/fl/Cdh5(PAC)-CreERT2-/- (APOE3Cre-/-, control) mice and induced endothelial cell APOE3 knockdown with tamoxifen at ≈4 to 5 weeks of age. Neurovascular and neuronal function were evaluated by biochemistry, immunohistochemistry, behavioral testing, and electrophysiology at 9 months of age. RESULTS: We found that the loss of endothelial APOE3 expression was sufficient to cause neurovascular dysfunction including higher permeability and lower vessel coverage in tandem with deficits in spatial memory and fear memory extinction and a disruption of cortical excitatory/inhibitory balance. CONCLUSIONS: Our data collectively support the novel concept that endothelial APOE3 plays a critical role in the regulation of the neurovasculature, neural circuit function, and behavior.

Applications of chemical exchange saturation transfer magnetic resonance imaging in identifying genetic markers in gliomas.

Chemical exchange saturation transfer (CEST) imaging is an important molecular magnetic resonance imaging technique that can image numerous low-concentration biomolecules with water-exchangeable protons (such as cellular proteins) and tissue pH. CEST, or more specially amide proton transfer-weighted imaging, has been widely used for the detection, diagnosis, and response assessment of brain tumors, and its feasibility in identifying molecular markers in gliomas has also been explored in recent years. In this paper, after briefing on the basic principles and quantification methods of CEST imaging, we review its early applications in identifying isocitrate dehydrogenase mutation status, MGMT methylation status, 1p/19q deletion status, and H3K27M mutation status in gliomas. Finally, we discuss the limitations or weaknesses in these studies.

Phase-independent thermometry by Z-spectrum MR imaging.

PURPOSE: Z-spectrum imaging, defined as the consecutive collection of images after saturating over a range of frequency offsets, has been recently proposed as a method to measure the fat-water fraction by the simultaneous detection of fat and water resonances. By incorporating a binomial pulse irradiated at each offset before the readout, the spectral selectivity of the sequence can be further amplified, making it possible to monitor the subtle proton resonance frequency shift that follows a change in temperature. METHODS: We tested the hypothesis in aqueous and cream phantoms and in healthy mice, all under thermal challenge. The binomial module consisted of 2 sinc-shaped pulses of opposite phase separated by a delay. Such a delay served to spread out off-resonance spins, with the resulting excitation profile being a periodic function of the delay and the chemical shift. RESULTS: During heating experiments, the water resonance shifted downfield, and by fitting the curve to a sine function it was possible to quantify the change in temperature. Results from Z-spectrum imaging correlated linearly with data from conventional MRI techniques like T1 mapping and phase differences from spoiled GRE. CONCLUSION: Because the measurement is performed solely on magnitude images, the technique is independent of phase artifacts and is therefore applicable in mixed tissues (e.g., fat). We showed that Z-spectrum imaging can deliver reliable temperature change measurement in both muscular and fatty tissues.

Review and consensus recommendations on clinical APT-weighted imaging approaches at 3T: Application to brain tumors.

Amide proton transfer-weighted (APTw) MR imaging shows promise as a biomarker of brain tumor status. Currently used APTw MRI pulse sequences and protocols vary substantially among different institutes, and there are no agreed-on standards in the imaging community. Therefore, the results acquired from different research centers are difficult to compare, which hampers uniform clinical application and interpretation. This paper reviews current clinical APTw imaging approaches and provides a rationale for optimized APTw brain tumor imaging at 3 T, including specific recommendations for pulse sequences, acquisition protocols, and data processing methods. We expect that these consensus recommendations will become the first broadly accepted guidelines for APTw imaging of brain tumors on 3 T MRI systems from different vendors. This will allow more medical centers to use the same or comparable APTw MRI techniques for the detection, characterization, and monitoring of brain tumors, enabling multi-center trials in larger patient cohorts and, ultimately, routine clinical use.

Early detection of increased marrow adiposity with age in rats using Z-spectral MRI at ultra-high field (7 T).

BACKGROUND: Nowadays, the drive towards high-field MRI is fueled by the pursuit of higher signal-to-noise ratio, spatial resolution, and imaging speed. However, high field strength is associated with field inhomogeneity, acceleration of T2 * decay, and increased chemical shift, which may pose challenges to conventional MRI for fat quantification in complex tissues such as bone marrow. With proton MRI spectroscopy (1 H-MRS), on the other hand, it is difficult to produce high resolution. As a novel alternative fat quantification method, high-resolution Z-spectral MRI (ZS-MRI) can achieve fat quantification by acquiring direct saturated images of both fat and water under the same TE , which may be less affected by T2 * decay and field inhomogeneity. PURPOSE: To demonstrate ZS-MRI for marrow adipose tissue (MAT) quantification in rat's lumbar spine and the early detection of MAT changes with age. METHODS: The accuracy of ZS-MRI for fat quantification at ultra-high-field MRI (7 T) was verified with MRS and conventional Dixon MRI in water-oil mixed phantoms with varying fat fraction (FF). Dixon MRI data were processed with iterative decomposition of water and fat with echo asymmetry and least-squares estimation. ZS-MRI was then used to longitudinally monitor the adiposity in the lumbar spine of young healthy rats at 13, 17, and 21 weeks to detect the early changes of FF with age in MAT. Hematoxylin-eosin staining of lumbar spines from separated rat groups was performed for verification. RESULTS: In ex vivo phantom experiments, both Dixon MRI and ZS-MRI were well correlated with 1 H-MRS for the quantification of FF at 7 T (R > 0.99). Compared with Dixon MRI, ZS-MRI showed reduced image artifacts due to field inhomogeneity and presented better agreement with 1 H-MRS for the early detection of increased MAT due to age at 7 T (ZS-MRI R = 0.78 versus Dixon MRI R = 0.34). The increased MAT FF due to age was confirmed by histology. CONCLUSION: ZS-MRI proves itself as an alternative fat quantification method for bone marrow in rats at 7 T.

Multi-parametric Z-spectral MRI may have a good performance for glioma stratification in clinical patients.

OBJECTIVES: To comprehensively and noninvasively risk-stratify glioma grade, isocitrate dehydrogenase (IDH) genotype, and 1p/19q codeletion status using multi-contrast Z-spectral magnetic resonance imaging (MRI). METHODS: One hundred and thirteen patients with glioma were retrospectively included. Multiple contrasts contributing to Z-spectra, including direct saturation of water (DSW), semi-solid magnetization transfer contrast (MTC), amide proton transfer (APT) effect, aliphatic nuclear Overhauser effect, and the 2-ppm chemical exchange saturation transfer peak (CEST@2ppm), were fitted with five individual Lorentzian functions. Z-spectral contrasts were compared according to the three most important risk stratifications: tumor grade, IDH genotype, and 1p/19q codeletion status. We further investigated the differentiation of 1p/19q codeletion status within IDH mutant gliomas. The stratification performance of individual Z-spectral contrasts and their combination was quantified using receiver operating characteristic (ROC) analyses. RESULTS: DSW was significantly different within grade, IDH genotypes, and 1p/19q codeletion status. APT was significantly different with grade and IDH mutation, but not with 1p/19q subtypes. CEST@2ppm was only significantly different with 1p/19q codeletion subtypes. DSW and CEST@2ppm were the two Z-spectral contrasts able to differentiate 1p/19q codeletion subtypes within IDH mutant gliomas. For differentiating glioma grades using ROC analyses, DSW achieved the largest AUC. For differentiating IDH genotypes, DSW and APT achieved comparable AUCs. DSW was the best metric for differentiating 1p/19q codeletion status within all patients and within the IDH mutant patients. Combining all Z-spectral contrasts improved sensitivity and specificity for all risk stratifications. CONCLUSIONS: Multi-parametric Z-spectral MRI serves as a useful, comprehensive, and noninvasive imaging technique for glioma stratification in clinical patients. KEY POINTS: • Multiple contrasts contributing to Z-spectra were separately fitted with Lorentzian functions. • Z-spectral contrasts were compared within the three most important and common tumor risk stratifications for gliomas: tumor grade, IDH genotype, and 1p/19q codeletion status. • The stratification performance of individual Z-spectral contrasts and their combination was quantified using receiver operating characteristic analyses, which found Z-spectral MRI to be a useful and comprehensive imaging biomarker for glioma stratification.

In Vivo Proton Exchange Rate (kex ) MRI for the Characterization of Multiple Sclerosis Lesions in Patients.

BACKGROUND: Currently available radiological methods do not completely capture the diversity of multiple sclerosis (MS) lesion subtypes. This lack of information hampers the understanding of disease progression and potential treatment stratification. For example, inflammation persists in some lesions after gadolinium (Gd) enhancement resolves. Novel metabolic and molecular imaging methods may improve the current assessments of MS pathophysiology. PURPOSE: To compare the in vivo proton exchange rate (kex ) MRI with Gd-enhanced MRI for characterizing MS lesions. STUDY TYPE: Retrospective. SUBJECTS: Sixteen consecutively diagnosed relapsing-remitting multiple sclerosis (RRMS) patients. FIELD STRENGTH/SEQUENCE: 3.0T MRI with T2 -weighted imaging, postcontrast T1 -weighted imaging, and single-slice chemical exchange saturation transfer imaging. ASSESSMENT: MS lesions in white matter were assessed for Gd enhancement and kex elevation compared to normal-appearing white matter (NAWM). STATISTICAL TESTS: Student's t-test was used for analyzing the difference of kex values between lesions and NAWM, with statistical significance set at 0.05. RESULTS: Of all 153 MS lesions, 78 (51%) lesions were Gd-enhancing and 75 (49%) were Gd-negative. Without exception, all 78 Gd-enhancing lesions showed significantly elevated kex values compared to NAWM (924 ± 130 s-1 vs. 735 ± 61 s-1 , P < 0.05). Of 75 Gd-negative lesions, 18 lesions (24%) showed no kex elevation (762 ± 29 s-1 vs. 755 ± 28 s-1 , P = 0.47) and 57 (76%) showed significant kex elevation (950 ± 124 s-1 vs. 759 ± 48 s-1 , P < 0.05) compared to NAWM. MS lesions with kex elevation appeared nodular (118, 87.4%), ring-like (15, 11.1%), or irregular-shaped (2, 1.5%). DATA CONCLUSION: For Gd-enhancing lesions, kex MRI is highly consistent with Gd-enhanced images by showing 100% of elevated kex . For all Gd-negative lesions, the discrepancy on kex MRI may further differentiate active slowly expanding lesions or chronic inactive lesions, supporting kex as an imaging biomarker for tissue oxidative stress and inflammation. Level of Evidence 2 Technical Efficacy Stage 3 J. MAGN. RESON. IMAGING 2021;53:408-415.

Characterization of microenvironmental changes in the intervertebral discs of patients with chronic low back pain using multiparametric MRI contrasts extracted from Z-spectrum.

PURPOSE: Z-spectral MRI data were analyzed to produce multiparametric metabolic and microenvironmental contrasts for identifying intervertebral discs with/without pain symptom and sore pain. METHODS: Z-spectra data were collected from the lumbar discs of 26 patients with non-specific chronic low bck pain (CLBP) and 21 asymptomatic controls (AC) with a chemical exchange saturation transfer (CEST). Data were fitted to quantify the CEST effects from glycosaminoglycan, amide proton transfer (APT), nuclear Overhauser enhancement (NOE), semi-solid magnetization transfer contrast effects, and the direct saturation of water. Multiparametric maps were computed from the fitted peak amplitudes, and the average values were calculated from all five lumber discs. Those parameters were compared between the CLBP and AC groups and between the subgroups with and without (Nsore) sore pain. RESULTS: The discs in symptomatic patients have lower water content, collagen-bound water and collagen than the discs in AC (P < 0.05). Additionally, Z-sepctral MRI indicated that the discs in the sore subgroup had less water, collagen-bound water and collagen, and likely lower pH compared to the Nsore subgroup (P < 0.05). Lower pH as measured with reduced APT and NOE effects may be an important pathological factor causing sore pain of the back. CONCLUSION: Z-spectral MRI with its multiparametric metabolic and microenvironmental contrasts has been demonstrated to identify discs with and without pain symptom or sore pain, providing more important information of CLBP.

Evaluating the feasibility of creatine-weighted CEST MRI in human brain at 7 T using a Z-spectral fitting approach.

The current study aims to evaluate the feasibility of creatine (Cr) chemical exchange saturation transfer (CEST)-weighted MRI at 7 T in the human brain by optimizing the saturation pulse parameters and computing contrast using a Z-spectral fitting approach. The Cr-weighted (Cr-w) CEST contrast was computed from phantoms data. Simulations were carried out to obtain the optimum saturation parameters for Cr-w CEST with lower contribution from other brain metabolites. CEST-w images were acquired from the brains of four human subjects at different saturation parameters. The Cr-w CEST contrast was computed using both asymmetry analysis and Z-spectra fitting approaches (models 1 and 2, respectively) based on Lorentzian functions. For broad magnetization transfer (MT) effect, Gaussian and Super-Lorentzian line shapes were also evaluated. In the phantom study, the Cr-w CEST contrast showed a linear dependence on concentration in physiological range and a nonlinear dependence on saturation parameters. The in vivo Cr-w CEST map generated using asymmetry analysis from the brain represents mixed contrast with contribution from other metabolites as well and relayed nuclear Overhauser effect (rNOE). Simulations provided an estimate for the optimum range of saturation parameters to be used for acquiring brain CEST data. The optimum saturation parameters for Cr-w CEST to be used for brain data were around B1rms  = 1.45 µT and duration = 2 seconds. The Z-spectral fitting approach enabled computation of individual components. This also resulted in mitigating the contribution from MT and rNOE to Cr-w CEST contrast, which is a major source of underestimation in asymmetry analysis. The proposed modified z-spectra fitting approach (model 2) is more stable to noise compared with model 1. Cr-w CEST contrast obtained using fitting was 6.98 ± 0.31% in gray matter and 5.45 ± 0.16% in white matter. Optimal saturation parameters reduced the contribution from other CEST effects to Cr-w CEST contrast, and the proposed Z-spectral fitting approach enabled computation of individual components in Z-spectra of the brain. Therefore, it is feasible to compute Cr-w CEST contrast with a lower contribution from other CEST and rNOE.

Improving the detection specificity of endogenous MRI for reactive oxygen species (ROS).

BACKGROUND: The detection of tissue reactive oxygen species (ROS) using endogenous MRI methods has great potential applications in research and the clinic. We recently demonstrated that ROS produce a significant T1 -shortening effect. However, T1 or T1 -weighted contrast is not specific, as there are many other factors that alter tissue T1 . PURPOSE: To investigate whether the presence of ROS alters tissue environmental conditions such as the proton exchange rate (K ex ) to improve the detection specificity of endogenous ROS MRI. STUDY TYPE: Prospective. SUBJECTS/PHANTOM: The ROS-producing phantoms consisted of fresh egg white treated with H2 O2 and healthy mice injected with pro-oxidative rotenone. FIELD STRENGTH/SEQUENCE: T1 mapping was performed based on fast spin-echo sequence and K ex was evaluated using chemical exchange saturation transfer (CEST) MRI with varied saturation power (QUESP) on a 9.4 T animal scanner. ASSESSMENT: Phantom experiments were conducted to evaluate the overall K ex of CEST-expressing metabolites in fresh egg white treated with H2 O2 of various concentrations (0, 0.025, 0.05, 0.1, and 0.25 v/v%). The egg white phantom continuously produced ROS for more than 3 hours. Various experiments were performed to rule out potential contributing factors to the observed K ex changes. In addition, in vivo MRI study was conducted with a well-established rotenone-exposed mouse model. STATISTICAL TESTS: Student's t-test. RESULTS: Egg white phantoms treated with H2 O2 of various concentrations showed a 26-85% increase in K ex compared with controls. In addition, the K ex of egg white is negligibly affected by other potential confounding factors, including paramagnetic contrast agents (<11%), oxygen (2.3%), and iron oxidation (<10%). Changes in temperature (<1°C) and pH (ΔpH <0.1) in H2 O2 -treated egg white were also negligible. Results from the in vivo rotenone study were consistent with the phantom studies by showing reduced T1 relaxation time (6%) and increased K ex (9%) in rotenone-treated mice. DATA CONCLUSION: We demonstrate that the specificity of endogenous ROS MRI can be improved with the aid of proton exchange rate mapping. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:583-591.

Amid proton transfer (APT) and magnetization transfer (MT) MRI contrasts provide complimentary assessment of brain tumors similarly to proton magnetic resonance spectroscopy imaging (MRSI).

OBJECTIVES: Using MRSI as comparison, we aimed to explore the difference between amide proton transfer (APT) MRI and conventional semi-solid magnetization transfer ratio (MTR) MRI, and to investigate if molecular APT and structural MTR can provide complimentary information in assessing brain tumors. METHODS: Seventeen brain tumor patients and 17 age- and gender-matched volunteers were included and scanned with anatomical MRI, APT and MT-weighted MRI, and MRSI. Multi-voxel choline (Cho) and N-acetylaspartic acid (NAA) signals were quantified from MRSI and compared with MTR and MTRasym(3.5ppm) contrasts averaged from corresponding voxels. Correlations between contrasts were explored voxel-by-voxel by pooling values from all voxels into Pearson's correlation analysis. Differences in correlation coefficients were tested with the Z-test (set at p<0.05). RESULTS: APT and MT provide good contrast and quantitative parameters in tumor imaging, as do the metabolite (Cho and NAA) maps. MTRasym(3.5ppm) significantly correlated with MTR (R=-0.61, p<0.0001), Cho (R=0.568, p<0.0001) and NAA (R=-0.619, p<0.0001) in tumors, and MTR also significantly correlated with Cho (R=-0.346, p<0.0001) and NAA (R=0.624, p<0.0001). In healthy volunteers, MTRasym(3.5ppm) was non-significantly correlated with MTR (R=-0.049, p=0.239), Cho (R=0.030, p=0.478) and NAA (R=-0.083, p=0.046). Significant correlations were found among MTR with Cho (R=0.199, p<0.0001) and NAA (R=0.263, p<0.0001) in the group of healthy volunteers with lower correlation R values than those in tumor patients. CONCLUSIONS: APT and MT could provide independent and supplementary information for the comprehensive assessment of molecular and structural changes due to brain tumor cancerogenesis. KEY POINTS: • MTR asym(3.5ppm) positively correlated with Cho while negatively with NAA in tumors. • MTR positively correlated with NAA while negatively with Cho in tumors. • Combining APT/MT provides molecular and structural information similarly to MRSI.

Characterization of the microstructure of the intervertebral disc in patients with chronic low back pain by diffusion kurtosis imaging.

PURPOSE: Multivariate analysis of T2-weighted signal, diffusion ADC, and DKI parameters and tractography were used to differentiate chronic non-specific low back pain (CLBP) patients and asymptomatic controls (AC). METHODS: A total of 30 patients with CLBP and 23 AC underwent diffusion kurtosis imaging (DKI) of lumbar spine with a 3T MRI scanner to get the ADC values and seven parameters of DKI in the nucleus pulposus (NP) of the intervertebral disc. The tractography and the tract-related parameters as other parameters were also generated to indicate the intactness of annulus fibrosus (AF). T2-grades of the discs were also quantified based on an eight-grade degeneration grading system. ADC and T2-grades were compared with DKI parameters for the differentiation of CLBP and AC groups. RESULTS: There was no difference in the T2 grades, ADC value, and multiple parameters in DKI of NP between CLBP and AC groups (P > 0.05). The average FA values in NP in AC group were found significantly higher than in the CLBP group (P < 0.05). The scores for the intactness of AF of the intervertebral discs were significantly different in CLBP and AC groups, with 90% of sensitivity and 70% specificity (P < 0.05). Additionally, there were significantly differences in the length and volume values of the AF in CLBP and AC groups (P < 0.05). CONCLUSION: DKI is a good noninvasive method, and it might help to differentiate CLBP from AC. Particularly, the continuation of DKI tractography reflects the presence of annulus fibrosus fissures, an important character in the generation of the low back pain. These slides can be retrieved under Electronic Supplementary Material.

Diffusion kurtosis imaging provides quantitative assessment of the microstructure changes of disc degeneration: an in vivo experimental study.

OBJECTIVE: Our aim was to assess the microstructural changes of intervertebral disc degeneration induced by annulus needle puncture in rats by diffusion kurtosis imaging (DKI). METHODS: Eighteen rats (36 discs) were punctured percutaneously at the intervertebral disc between C6/7, C7/8 (C-coccygeal vertebrae) with a 21-gauge needle. The rats were divided into six groups according to the time after the puncture: 3 h, 48 h, 3 days, 7 days, 10 days and 14 days. There were six discs in three rats in the control group. The rats' tail was imaged at 3T MRI with T2-weighted and diffusion-weighted and diffusion kurtosis imaging (DWI)/DKI sequences. The discs were categorized using a five-grade degeneration system based on the T2 images. The height of the discs and the parameters in DWI/DKI were measured and compared between the different time points. The histological images were also obtained from the discs. RESULTS: The histological study revealed that the discs in the rat of the punctured groups were degenerated. The T2 grades of different groups presented an increasing trend from 7 to 10 days after puncture (R2 = 0.9424, P < 0.001), while the DWI/DKI parameters changes were consistent with the histological changes at the different time points and showed significant differences between the different groups (P < 0.05). CONCLUSIONS: DKI provides quantitative assessment of the microstructure changes of disc degeneration, and it is a non-invasive method. The DKI multi-parameter analysis is sensitive to discs changes caused by puncture. These slides can be retrieved under Electronic Supplementary Material.

Imaging short-lived reactive oxygen species (ROS) with endogenous contrast MRI.

PURPOSE: To characterize the relaxation properties of reactive oxygen species (ROS) for the development of endogenous ROS contrast magnetic resonance imaging (MRI). MATERIALS AND METHODS: ROS-producing phantoms and animal models were imaged at 9.4T MRI to obtain T1 and T2 maps. Egg white samples treated with varied concentrations of hydrogen peroxide (H2 O2 ) were used to evaluate the effect of produced ROS in T1 and T2 for up to 4 hours. pH and temperature changes due to H2 O2 treatment in egg white were also monitored. The influences from H2 O2 itself and oxygen were evaluated in bovine serum albumin (BSA) solution producing no ROS. In addition, dynamic temporal changes of T1 in H2 O2 -treated egg white samples were used to estimate ROS concentration over time and hence the detection sensitivity of relaxation-based endogenous ROS MRI. The relaxivity of ROS was compared with that of Gd-DTPA as a reference. Finally, the feasibility of in vivo ROS MRI with T1 mapping acquired using an inversion recovery sequence was demonstrated with a well-established rotenone-treated mouse model (n = 6). RESULTS: pH and temperature changes in treated egg white samples were insignificant (<0.1 unit and <1°C, respectively). T1 relaxation time in the H2 O2 -treated egg white was reduced significantly (P < 0.05), while there was only small reduction in T2 (<10%). In the H2 O2 -treated BSA solution that produce no ROS, there was a small change in T1 due to H2 O2 itself (±1%), although a significant T2 -shortening effect was observed (>10%, P < 0.05). Also, there was a small reduction in T1 (13 ± 1%) and T2 (1 ± 2%) from molecular oxygen. The detection sensitivity of ROS MRI was estimated around 10 pM. The T1 relaxivity of ROS was found to be much higher than that of Gd-DTPA (3.4 × 107 vs. 0.9 s-1 ·mM-1 ). Finally, significantly reduced T1 was observed in rotenone-treated mouse brain (5.1 ± 2.5%, P < 0.05). CONCLUSION: We demonstrated in the study that endogenous ROS MRI based on the paramagnetic effect has sensitivity for in vitro and in vivo applications. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2018;47:222-229.

Mapping brown adipose tissue based on fat water fraction provided by Z-spectral imaging.

BACKGROUND: Brown adipose tissue (BAT) has a great relevance in metabolic diseases and has been shown to be reduced in obesity and insulin resistance patients. Currently, Dixon MRI is used to calculate fat-water fraction (FWF) and differentiate BAT from white adipose tissue (WAT). However, it may fail in areas of phase wrapping and introduce fat-water swapping artifacts. PURPOSE: To investigate the capacity of the Z-spectrum imaging (ZSI) for the identification of BAT in vivo. STUDY TYPE: Retrospective study. SPECIMENS: WAT, BAT, and lean tissue from healthy mice. ANIMALS: Four C57BL/6 healthy mice. POPULATION: Five healthy volunteers. FIELD STRENGTH: 9.4T, 3T for volunteers. SEQUENCE: Z-Spectra data were fitted to a model with three Lorentzian peaks reflecting the direct saturation of tissue water (W) and methylene fat (F), and the magnetization transfer from the semi-solid tissues. The peak amplitudes of water and fat were used to map the FWF. The novel FWF metric was calibrated with an oil and water mixture phantom and validated in specimens, mice and human subjects. ASSESSMEMT: FWF distribution was compared with published works and values compared with Dixon's MRI results. STATISTICAL TESTS: Comparisons were performed by t-tests. RESULTS: ZSI clearly differentiated WAT, BAT, and lean tissues by having FWF = 1, 0.5, and 0, respectively. Calibration with oil mixture phantoms revealed a linear relationship between FWF and the actual fat fraction (R2 = 0.98). In vivo experiments in mice confirmed in vitro results by showing FWF = 0.6 in BAT. FWF maps of human subjects showed the same FWF distribution as Dixon's MRI (P > 0.05). ZSI is independent from B0 field inhomogeneity and fat-water swapping because both lipid and water frequency offsets are determined simultaneously during Z-spectral fitting. DATA CONCLUSION: ZSI can derive artifact-free FWF maps, which can be used to identify BAT distribution in vivo noninvasively. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1527-1533.

Discrimination of Malignant versus Benign Mediastinal Lymph Nodes Using Diffusion MRI with an IVIM Model.

OBJECTIVES: To investigate the value of an intravoxel incoherent motion (IVIM) diffusion model for discriminating malignant versus benign mediastinal lymph nodes (MLN). METHODS: Thirty-five subjects with enlarged MLN were scanned at 1.5 Tesla. Diffusion-weighted imaging was performed with eight b-values. IVIM parameters D, D*, and f, as well as apparent diffusion coefficient (ADC) from a mono-exponential model were obtained. 91 nodes (49 malignant and 42 benign) were analysed with pathologic (n=90) or radiologic (n=1) confirmations. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performance. RESULTS: The mean values of D, ADC, and f for the malignant group were significantly lower than those for the benign group (p<0.001), while D* showed no significant difference (p=0.281). In the ROC analysis, the combination of D and f produced the largest area under the curve (0.953) compared to ADC or other individual IVIM parameters, leading to the best specificity (92.9%) and diagnostic accuracy (90.1%). CONCLUSION: This study demonstrates that the combination of IVIM parameters can improve differentiation between malignant and benign MLN as compared to using ADC alone. KEY POINTS: • Diffusion MRI is useful for non-invasively discriminating malignant versus benign lymph nodes. • A mono-exponential model is not adequate to characterise diffusion process in lymph nodes. • IVIM model is advantageous over mono-exponential model for assessing lymph node malignancy. • Combination of IVIM parameters improves differentiation of malignant versus benign lymph nodes.

Brain white matter changes in CPAP-treated obstructive sleep apnea patients with residual sleepiness.

PURPOSE: To investigate white matter (WM) structural alterations using diffusion tensor imaging (DTI) in obstructive sleep apnea (OSA) patients, with or without residual sleepiness, following adherent continuous positive airway pressure (CPAP) treatment. Possible quantitative relationships were explored between the DTI metrics and two clinical assessments of somnolence. MATERIALS AND METHODS: Twenty-nine male patients (30-55 years old) with a confirmed diagnosis of OSA were recruited. The patients were treated with CPAP therapy only. The Psychomotor Vigilance Task (PVT) and Epworth Sleepiness Scale (ESS) were performed after CPAP treatment and additionally administered at the time of the magnetic resonance imaging (MRI) scan. Based on the PVT results, the patients were divided into a nonsleepy group (lapses ≤5) and a sleepy group (lapses >5). DTI was performed at 3T, followed by an analysis using tract-based spatial statistics (TBSS) to investigate the differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ1 ), and radial diffusivity (λ23 ) between the two groups. RESULTS: A higher MD (P < 0.05) was observed in the sleepy group than the nonsleepy group in the whole-brain TBSS analysis in the WM. The increased MD (17.8% of the fiber tracts; P < 0.05) was caused primarily by an elevated λ23 . Axial diffusivity (λ1 ) exhibited no significant difference (P > 0.17). The alterations in FA or MD of individual fiber tracts occurred mainly in the internal/external capsule, corona radiata, corpus callosum, and sagittal stratum regions. The FA and MD values correlated with the PVT and ESS assessments from all patients (R ≥ 0.517, P < 0.05). CONCLUSION: Global and regional WM alterations, as revealed by DTI, can be a possible mechanism to explain why OSA patients with high levels of CPAP use can have differing responses to treatment. Compromised myelin sheath, indicated by increased radial diffusivity, can be involved in the underlying WM changes. Evidence level: 1 J. MAGN. RESON. IMAGING 2017;45:1371-1378.

Influence of Free Radicals on the Intrinsic MRI Relaxation Properties.

Free radicals are critical contributors in various conditions including normal aging, Alzheimer's disease, cancer, and diabetes. Currently there is no non-invasive approach to image tissue free radicals based on endogenous contrast due to their extremely short lifetimes and low in vivo concentrations. In this study we aim at characterizing the influence of free radicals on the MRI relaxation properties. Phantoms containing free radicals were created by treating egg white with various H 2 O 2 concentrations and scanned on a 9.4 T MRI scanner at room temperature. T1 and T2 relaxation maps were generated from data acquired with an inversion recovery sequence with varied inversion times and a multi-echo spin echo sequence with varied echo times (TEs), respectively. Results demonstrated that free radicals express a strong shortening effect on T1, which was proportional to the H 2 O 2 concentration, and a relatively small reduction in T2 (<10%). Furthermore, the sensitivity of this approach in the detection of free radicals was estimated to be in the pM range that is within the physiological range of in vivo free radical expression. In conclusion, the free radicals show a strong paramagnetic effect that may be utilized as an endogenous MRI contrast for its non-invasive in vivo imaging.

Magnetization Transfer MRI Contrast May Correlate with Tissue Redox State in Prostate Cancer.

Developing imaging biomarkers for non-invasive measurement of the tissue redox state is a key research area. Recently, we presented the first non-invasive MR imaging method that demonstrated the correlation between the endogenous chemical exchange saturation transfer (CEST) contrast and the tissue redox state. It is well known that the broadband magnetization transfer (MT) can occur via chemical exchange (CEST) and/or dipole-dipole interactions. The present study investigated if the broadband MT also correlated with the tissue redox state. The preliminary result for the prostate tumor xenografts indeed showed a significant correlation between the broadband MT contrast and the NADH redox ratio quantified with the optical redox scanning. In vivo MT contrast, once calibrated, may potentially serve as an imaging biomarker for tissue redox state.

T1ρ MRI of healthy and fibrotic human livers at 1.5 T.

BACKGROUND: Liver fibrosis is a public health problem worldwide. There is a need of noninvasive imaging based methods for better diagnosis of this disease. In the current study, we aim to evaluate the potential of T1ρ MRI technique in detecting and characterizing different grades of liver fibrosis in vivo in humans. METHODS: Healthy subjects and patients with liver fibrosis were prospectively recruited for T1ρ MRI of liver on a 1.5 T MR scanner. Single slice T1ρ weighted images were acquired at different spin lock duration (0, 10, 20 and 30 ms) with spin lock amplitude of 500 Hz in a single breath-hold. Additionally, liver's T1ρ images were acquired from five healthy subjects on the same day (n = 2) and different day (n = 2) sessions for test-retest study. Liver biopsy samples from patients were obtained and used to calculate the METAVIR score to define the stage of fibrosis and inflammation grade. T1ρ maps were generated followed by computation of mean and standard deviation (SD) values. Coefficient of variation (COV) of T1ρ values between two MRI scans was computed to determine reproducibility in liver. T test was used to compare T1ρ values between healthy and fibrotic liver. Pearson correlation was performed between stages of liver fibrosis and T1ρ values. RESULTS: The mean (SD) T1ρ value among subject with healthy liver was 51.04 (3.06) ms. The COV of T1ρ values between two repetitions in the same day session was 0.83 ± 0.8% and in different day session was 5.4 ± 2.7%. T1ρ values in fibrotic liver were significantly higher compared to those of healthy liver (p < 0.05). A statically significant correlation between stages of fibrosis and T1ρ values was observed (r = 0.99, p < 0.05). Inflammation score for one patient was 2 and for remaining patients it was 1. CONCLUSIONS: Proposed T1ρ pulse sequence design and protocol enabled acquisition of a single slice T1ρ weighted images in a single breath-hold and hence mitigated breathing motion related artifacts. Preliminary results have shown the sensitivity of T1ρ values to changes induced by liver fibrosis, and may potentially be used as a clinical biomarker to delineate the stages of liver fibrosis. Further, studies on a large number of subjects are required to validate the observations of the current study. Nevertheless, T1ρ imaging can be easily setup on a clinical scanner to monitor the progression of liver fibrosis and to the evaluate efficacy of anti-fibrotic drugs.