Improved measurement of labile proton concentration‐weighted chemical exchange rate (kws) with experimental factor‐compensated and T1‐normalized quantitative chemical exchange saturation transfer (CEST) MRI

Chemical exchange saturation transfer (CEST) MRI enables measurement of dilute CEST agents and microenvironment properties such as pH and temperature, holding great promise for in vivo applications. However, because of confounding concomitant radio frequency (RF) irradiation and relaxation effects, the CEST‐weighted MRI contrast may not fully characterize the underlying CEST phenomenon. We postulated that the accuracy of quantitative CEST MRI could be improved if the experimental factors (labeling efficiency and RF spillover effect) were estimated and taken into account. Specifically, the experimental factor was evaluated as a function of exchange rate and CEST agent concentration ratio, which remained relatively constant for intermediate RF irradiation power levels. Hence, the experimental factors can be calculated based on the reasonably estimated exchange rate and labile proton concentration ratio, which significantly improved quantification. The simulation was confirmed with creatine phantoms of serially varied concentration titrated to the same pH, whose reverse exchange rate (k_ws) was found to be linearly correlated with the concentration. In summary, the proposed solution provides simplified yet reasonably accurate quantification of the underlying CEST system, which may help guide the ongoing development of quantitative CEST MRI. Copyright © 2012 John Wiley & Sons, Ltd.     

3.0 T高场磁共振磁化传递成像对特发性癫痫的研究

目的 应用磁化传递成像(MTI)技术研究特发性癫痫患者脑微观结构的改变.材料与方法 对32例特发性癫痫患者和32例健康志愿者行MTI序列扫描.利用统计参数图软件(SPM2)对图像进行基于体素分析,采用两样本t检验比较病例组与对照组磁化传递率(MTR)的差异,并分析MTR值与病程的相关性.结果 与正常对照组比较,病例组在双侧额中回、小脑前叶,右侧内侧前额叶、中央旁小叶、额上回及左侧顶下小叶MTR值降低(P＜0.05).左侧小脑后叶及枕叶舌回、梭状回MTR值与病程呈负相关(P＜0.05).结论 MTI能够检测特发性癫痫潜在的神经病理变化,为癫痫病理生理机制研究提供理论依据.     

磁化传递成像和酰胺质子转移成像联合评价新生儿脑损伤的初步研究

目的应用酰胺质子转移成像(amide proton transfer,APT)联合磁化传递(magnetization transfer,MT)成像对新生儿从脑内环境角度评估新生儿脑损伤。材料与方法新生儿共38名,脑损伤13例,为病例组;常规MRI检查脑内无异常25例为对照组。常规MRI检查后补充APT-MT成像扫描。测量所有新生儿双侧额叶深部白质、基底节区、枕叶深部白质的APT值以及磁化传递率(magnetization transfer ratio,MTR)值(以下用APT/MTR表示),以及病例组病灶区及其对侧的APT/MTR值。采用SPSS 19.0软件进行统计分析。结果 (1)对照组中,额叶深部白质、基底节及枕叶深部白质APT/MTR值均有显著性差异(P0.05)。(2)对照组中,APT/MTR值随孕龄增长而逐渐升高。(3)病例组病灶内APT/MTR值低于对侧(P0.05)。结论围产期缺氧缺血是全脑代谢变化,APT-MT成像可从内环境及分子水平评估新生儿脑损伤。     

3DSPGR磁化传递成像在鉴别脑脓肿与坏死囊变性脑肿瘤的应用

目的探讨3DSPGR磁化传递成像(MTI)在鉴别脑脓肿与坏死囊变性胶质瘤和脑转移瘤的应用价值。方法7例经手术病理(3例)或临床随访(4例)证实的脑脓肿、9例经手术病理证实的坏死囊变性胶质瘤和8例经临床证实的坏死囊变性转移瘤在治疗前接受了常规MR和3DSPGR序列MTI检查,测量并计算病灶囊性区、实性区、同层面对侧正常脑白质区和脑脊液的平均磁化传递率(magnetization transfer ratio,MTR)。结果病灶囊性区、实性区、同层面对侧正常脑白质区和脑脊液的MTR分别依次为(0.0803±0.04)、(0.2259±0.03)、(0.3475±0.02)、(-0.1546±0.15);病灶囊性区与脑脊液的MTR之间存在显著性差异,t=8.911,P<0.001,病灶实性区与正常脑白质区的MTR之间存在显著性差异(t=-20.208,P<0.001);脑脓肿与坏死囊变性胶质瘤和脑转移瘤囊性区的MTR均存在显著性差异(F=37.390,P<0.001),其中脑脓肿与胶质瘤存以及脑脓肿与脑转移瘤有显著性差异(P<0.001),胶质瘤和脑转移瘤无明显差异(P=0.179);实性区域的MTR三者之间无差异。结论3DSPGR-MTI以及MTR的测量在鉴别脑脓肿与坏死囊变性胶质瘤和脑转移瘤有重要价值,可作为常规MRI序列的重要补充。     

Investigating the benefits of multi-echo EPI for fMRI at 7 T

Functional MRI studies on humans with BOLD contrast are increasingly performed at high static magnetic field in order to exploit the increased sensitivity. The downside of high-field fMRI using the gradient-echo echo-planar imaging (GE-EPI) method is that images are typically very strongly affected by image distortion and signal loss. It has been demonstrated at 1.5 T and 3 T that image artifacts can be reduced and functional sensitivity simultaneously increased by the use of parallel-accelerated multi-echo EPI. Using sensitivity measurements and an activation study with a cognitive Stroop task experiment (N = 7) we here investigate the potential of this method at 7 T. The main findings are: (a) image quality compared to a conventional acquisition scheme is drastically improved; (b) according to CNR estimations the average BOLD sensitivity increases by 6.1 ± 4.3% and 13.9 ± 5.5% for unweighted and CNR-weighted echo summation, respectively; (c) both functional signal changes and sensitivity in the multi-echo data do not exhibit a pronounced dependence on TE. The consequence is that (d) in practice the performance of simple echo summation at very high field is comparable to that based on a CNR filter. Finally, (e) temporal noise observed in the different echo time courses is not strongly correlated, thus explaining why echo summation is advantageous.The results at typical spatial resolution show that multi-echo EPI acquisition leads to considerable artifact reduction and sensitivity gains, making it superior to conventional GE-EPI for fMRI at 7 T.     

1.5 T磁共振不同NEX脑部肿瘤酰胺质子转移成像的应用初探

目的探讨1.5 T磁共振不同NEX脑部肿瘤酰胺质子转移(amide proton transfer,APT)成像对ATP成像图像采集及后处理的影响。材料与方法采用GE Signa HDe 1.5 T MRI仪进行对比分析组和随机分组分析组病例的不同NEX的化学交换饱和转移(chemical exchange saturation transfer,CEST)成像和常规MRI检查的数据采集。CEST成像分别采集opmt=1,磁化传递频率为-224 Hz和224 Hz,及opmt=0 3组图像,并通过该3组图像进行后处理得出APT图。所得数据采用MATLAB平台上自主编译的后处理软件进行CEST-APT成像,分别对原始图信号、APT信号进行评价分析。数据分析采用SPSS 16.0进行独立样本t检验和方差分析等统计学分析。结果对比分析组,NEX=2和8,原始图图像质量得分分别为(4.55±0.83)分、(4.60±0.68)分,差异无统计学意义(P0.05);APT图的图像质量得分分别为(2.7±1.03)分、(3.35±0.81)分,差异有统计学意义(P0.05)。原始图检出率均为100%,APT图的敏感度分别为70%和90%。随机分组分析组,NEX=2和8,原始图图像质量得分分别为(4.54±0.78)分、(4.69±0.63)分,差异无统计学意义(P0.05);APT图的图像质量得分分别为(2.89±0.96)分、(3.60±0.69)分,差异有统计学意义(P0.05)。原始图检出率均为100%,APT图检出率分别为77.1%和94.3%。无论是哪一组的结果 ,APT图整体比原始图评分降一档。图像质量上APT图略差,但均能显示并区分病灶。结论优化参数后的APT成像,可以明确区分脑部肿瘤的病灶分布,从分子影像学层面呈现脑肿瘤的代谢物等生物学信息,早期诊断和综合评估肿瘤的范围及其与周围解剖结构的关系,对肿瘤的预后及治疗具有重要意义。如果受检者无法耐受,可以采用NEX为2次的参数采集,也可以提供相对满意的APT成像效果。     

Direct quantitative comparison between cross-relaxation imaging and diffusion tensor imaging of the human brain at 3.0 T

Cross-relaxation imaging (CRI) describes the magnetization transfer within tissues between mobile water protons and macromolecular protons. Whole-brain parametric maps of the principle kinetic components of magnetization transfer, the fraction of macromolecular protons (f) and the rate constant (k), revealed detailed anatomy of white matter (WM) fiber tracts at 1.5 T. In this study, CRI was first adapted to 3.0 T, and constraints for transverse relaxation times of water and macromolecular protons were identified to enable unbiased f and k estimation. Subsequently, whole-brain CRI and diffusion tensor imaging (DTI) were performed in five healthy subjects. The parameters f and k were compared to DTI indices (fractional anisotropy (FA), apparent diffusion coefficient (ADC), radial diffusivity (RD), and axial diffusivity (AD)) across a range of anatomic regions. In WM, neither f nor k was significantly correlated to FA, RD, and AD. In contrast, both f (r = 0.90 and r = − 0.80) and k (r = 0.92 and r = − 0.89) in gray matter (GM) were strongly correlated to FA and RD, respectively. A moderate correlation between ADC and k (r = 0.48) was identified in WM, while an inverse correlation was identified in GM (r = − 0.72). The lack of association between CRI and FA in WM is consistent with differences in the underlying physical principles between techniques — fiber density vs. directionality, respectively. The association in GM may be attributable to variable axonal density unique to each structure. Our findings suggest that whole-brain CRI provides distinct quantitative information compared to DTI, and CRI parameters may prove constructive as biomarkers in neurological diseases.     

How transfer rates generate Gd‐BOPTA concentrations in rat liver compartments: implications for clinical liver imaging with hepatobiliary contrast agents

Following the injection of hepatobiliary contrast agents, MRI detects all molecules included in a region of interest but cannot estimate true concentrations in sinusoids, interstitium, hepatocytes or bile canaliculi. The aim of the study was to measure true concentrations in hepatocytes and to show how transfer rates across sinusoidal and canalicular membranes generate these concentrations. We perfused livers isolated from normal rats with 200 μM Gd‐DTPA and Gd‐BOPTA and measured clearances from sinusoids to liver and from hepatocytes to bile canaliculi or back to interstitium. We detected Gd‐BOPTA with a gamma probe and determined true concentrations in each liver compartment knowing their liver volumes. No pharmacokinetic modelling was applied. Gd‐BOPTA clearance from sinusoids to liver (2.5 ± 0.4 mL/min) was 50 times higher than that of Gd‐DTPA (0.05 ± 0.02 mL/min) when portal flow rate was 30 mL/min (p < 0.0001). Gd‐BOPTA clearance from sinusoids to liver was always superior to hepatocyte clearance, and hepatocyte Gd‐BOPTA concentrations measured by the probe increased over time. Gd‐BOPTA concentrations reached 439 ± 83 μM in hepatocytes and 15 × 700 ± 3100 μM in bile canaliculi, while concentrations in sinusoids were 200 μM. Gd‐BOPTA true concentrations in hepatocytes depend on the simultaneous clearances from sinusoids to hepatocytes and from hepatocytes to bile canaliculi and back to sinusoids. The study better defines how signal intensities are generated when hepatobiliary contrast agents are injected in clinical imaging. Copyright © 2016 John Wiley & Sons, Ltd.     

Resting-state networks in the macaque at 7 T

Assessment of brain connectivity has revealed that the structure and dynamics of large-scale network organization are altered in multiple disease states suggesting their use as diagnostic or prognostic indicators. Further investigation into the underlying mechanisms, organization, and alteration of large-scale brain networks requires a homologous animal model that would allow neurophysiological recordings and experimental manipulations. The current study presents a comprehensive assessment of macaque resting-state networks based on evaluation of intrinsic low-frequency fluctuations of the blood oxygen-level-dependent signal using group independent component analysis. Networks were found underlying multiple levels of sensory, motor, and cognitive processing. The results demonstrate that macaques share remarkable homologous network organization with humans, thereby providing strong support for their use as an animal model in the study of normal and abnormal brain connectivity as well as aiding the interpretation of electrophysiological recordings within the context of large-scale brain networks.     

The pH sensitivity of –NH exchange in LnDOTA–tetraamide complexes varies with amide substituent

The amide proton exchange rates in various lanthanide(III) DOTA–tetraamide complexes were investigated by CEST as a function of variable chemical structures and charges on the amide substituents. Comparisons were made between YbDOTA–(gly)₄^? (Yb‐1), YbDOTA–(NHCH₂PO₃)₄^5? (Yb‐2) and YbDOTA–(NHCH₂PO₃Et₂)₄³⁺ (Yb‐3). The general shapes of the CEST vs pH profiles were similar for the three complexes but they showed maximum CEST intensities at different pH values, pH 8.3, 8.8 and 6.9 for Yb‐1, Yb‐2 and Yb‐3, respectively. This indicates that a more negatively charged substituent on the amide helps stabilize the partial positive charge on the amide nitrogen and consequently more base is required to catalyze proton exchange. The chemical shifts of the –NH protons in Yb‐1 and Yb‐2 were similar (?17 ppm) while the –NH proton in Yb‐3 was at ?13 ppm. This shows that the crystal field produced by the amide oxygen donor atoms in Yb‐3 is substantially weaker than that in the other two complexes. In an effort to expand the useful range of pH values that might be measured using these complexes as CEST agents, the shapes of the CEST vs pH curves were also determined for two thulium(III) complexes with much larger hyperfine shifted –NH proton resonances. The ratio of CEST from –NH exchange in Tm‐1 compared with CEST from –NH exchange in Tm‐3 was found to be linear over an extended pH range, from 6.3 to 7.4. This demonstrates a potential advantage of using mixtures of lanthanide(III) DOTA–tetraamides for mapping tissue pH by use of ratiometric CEST imaging. Copyright © 2011 John Wiley & Sons, Ltd.     

Mapping magnetic susceptibility anisotropies of white matter in vivo in the human brain at 7 T

High-resolution magnetic resonance phase- or frequency-shift images acquired at high field show contrast related to magnetic susceptibility differences between tissues. Such contrast varies with the orientation of the organ in the field, but the development of quantitative susceptibility mapping (QSM) has made it possible to reproducibly image the intrinsic tissue susceptibility contrast. However, recent studies indicate that magnetic susceptibility is anisotropic in brain white matter and, as such, needs to be described by a symmetric second-rank tensor( ?χ). To fully determine the elements of this tensor, it would be necessary to acquire frequency data at six or more orientations. Assuming cylindrical symmetry of the susceptibility tensor in myelinated white matter fibers, we propose a simplified method to reconstruct the susceptibility tensor in terms of a mean magnetic susceptibility, MMS=(χ(//)+2 χ(⊥))/3 and a magnetic susceptibility anisotropy, MSA=χ(//)-χ(⊥), where χ(//) and χ(⊥) are susceptibility parallel and perpendicular to the white matter fiber direction, respectively. Computer simulations show that with a practical head rotation angle of around 20°-30°, four head orientations suffice to reproducibly reconstruct the tensor with good accuracy. We tested this approach on whole brain 1 × 1 × 1 mm(3) frequency data acquired from five healthy subjects at 7 T. The frequency information from phase images collected at four head orientations was combined with the fiber direction information extracted from diffusion tensor imaging (DTI) to map the white matter susceptibility tensor. The MMS and MSA were quantified for regions in several large white matter fiber structures, including the corona radiata, posterior thalamic radiation and corpus callosum. MMS ranged from -0.037 to -0.053 ppm (referenced to CSF being about zero). MSA values could be quantified without the need for a reference and ranged between 0.004 and 0.029 ppm, in line with the expectation that the susceptibility perpendicular to the fiber is more diamagnetic than the one parallel to it.     

Susceptibility induced gray-white matter MRI contrast in the human brain

MR phase images have shown significantly improved contrast between cortical gray and white matter regions compared to magnitude images obtained with gradient echo sequences. A variety of underlying biophysical mechanisms (including iron, blood, myelin content, macromolecular chemical exchange, and fiber orientation) have been suggested to account for this observation but assessing the individual contribution of these factors is limited in vivo.For a closer investigation of iron and myelin induced susceptibility changes, postmortem MRI of six human corpses (age range at death: 56-80 years) was acquired in situ. Following autopsy, the iron concentrations in the frontal and occipital cortex as well as in white matter regions were chemically determined. The magnetization transfer ratio (MTR) was used as an indirect measure for myelin content. Susceptibility effects were assessed separately by determining R2* relaxation rates and quantitative phase shifts. Contributions of myelin and iron to local variations of the susceptibility were assessed by univariate and multivariate linear regression analysis.Mean iron concentration was lower in the frontal cortex than in frontal white matter (26 ± 6 vs. 45 ± 6 mg/kg wet tissue) while an inverse relation was found in the occipital lobe (cortical gray matter: 41 ± 10 vs. white matter: 34 ± 10 mg/kg wet tissue). Multiple regression analysis revealed iron and MTR as independent predictors of the effective transverse relaxation rate R2* but solely MTR was identified as source of MR phase contrast. R2* was correlated with iron concentrations in cortical gray matter only (r = 0.42, p < 0.05).In conclusion, MR phase contrast between cortical gray and white matter can be mainly attributed to variations in myelin content, but not to iron concentration. Both, myelin and iron impact the effective transverse relaxation rate R2* significantly. Magnitude contrast is limited because it only reflects the extent but not the direction of the susceptibility shift.     

Hindered diffusion of MRI contrast agents in rat brain extracellular micro‐environment assessed by acquisition of dynamic T1 and T2 maps

The knowledge of brain tissues characteristics (such as extracellular space and tortuosity) represents valuable information for the design of optimal MR probes for specific biomarkers targeting. This work proposes a methodology based on dynamic acquisition of relaxation time maps to quantify in vivo MRI contrast agent concentration after intra‐cerebral injection in rat brain. It was applied to estimate the hindered diffusion in brain tissues of five contrast agents with different hydrodynamic diameters (Dotarem® ≈ 1 nm, P846 ≈ 4 nm, P792 ≈ 7 nm, P904 ≈ 22 nm and Gd‐based emulsion ≈ 170 nm). In vivo apparent diffusion coefficients were compared with those estimated in an obstacle‐free medium to determine brain extracellular space and tortuosity. At a 2 h imaging timescale, all contrast agents except the Gd‐based emulsion exhibited significant diffusion through brain tissues, with characteristic times compatible with MR molecular imaging (<70 min to diffuse between two capillaries). In conclusion, our experiments indicate that MRI contrast agents with sizes up to 22 nm can be used to perform molecular imaging on intra‐cerebral biomarkers. Our quantification methodology allows a precise estimation of apparent diffusion coefficients, which is helpful to calibrate optimal timing between contrast agent injection and MRI observation for molecular imaging studies. Copyright © 2012 John Wiley & Sons, Ltd.     

In vitro Gd‐DTPA relaxometry studies in oxygenated venous human blood and aqueous solution at 3 and 7 T

In vitro T₁ and T₂^* relaxivities (r₁ and r₂^*) of Gd‐DTPA (GaD) in oxygenated human venous blood (OVB) and aqueous solution (AS) at 3 and 7 T were calculated. GaD concentrations ([GaD]) in OVB and AS were prepared in the range 0‐5 mM. All measurements were acquired at 37 ± 2 °C. At both 3 and 7 T, a linear relationship was observed between [GaD] and R₁ in both AS and OVB. At 7 T, r₁ in AS decreased by 7.5% (p = 0.045) while there was a negligible change in OVB. With respect to R₂^*, a linear relationship with [GaD] was only observed in AS, while a more complex relationship was observed in OVB; quadratic below and linear above 2 mM at both field strengths. There was a significant increase of over 4‐fold in r₂^* with GaD in OVB at 7 T (for [GaD] above 2 mM, p <<0.01) as compared with 3 T. Furthermore, in comparison to r₁, r₂^* in AS was less than 2‐fold higher at both field strengths while in OVB it was ~20‐fold and ~90‐fold higher at 3 and 7 T, respectively. This observation emphasizes the importance of r₂^* knowledge at high magnetic fields, ≥3 T. The comparison between r₁ and r₂^* presented in this work is crucial in the design and optimization of high‐field MRI studies making use of paramagnetic contrast agents. This is especially true in multiple compartment systems such as blood, where r₂^* dramatically increases while r₁ remains relatively constant with increasing magnetic field strength. Copyright © 2014 John Wiley & Sons, Ltd.     

In vitro and in vivo characterization of several functionalized ultrasmall particles of iron oxide,vectorized against amyloid plaques and potentially able to cross the blood–brain barrier: toward earlier diagnosis of Alzheimer's disease by molecular imaging

Alzheimer's disease (AD) is a neurodegenerative disorder most often diagnosed 10 years after its onset and development. It is characterized by the accumulation of amyloid‐β peptide (ABP) into amyloid plaques between nerve cells, which produces a massive local neurodegeneration. Molecular magnetic resonance imaging allows diagnosis of AD by showing ABP accumulation in the brain. The ultrasmall particles of iron oxide (USPIO) derivatives proposed in the present work were functionalized with peptides that present an affinity for ABP, independently of its state of aggregation. Their nanomolar K_d* confirms the high affinity of our vectorized contrast agents (VCA) for ABP and therefore their high labeling potential, specificity and sensitivity. Their lack of toxicity has been demonstrated, both by in vitro studies using the MTT method on several cell types, and by in vivo investigations with assessment of renal and hepatic biomarkers and by histopathology evaluation. The results of biodistribution studies corroborated by MRI demonstrate that USPIO‐PHO (USPIO coupled to peptide C‐IPLPFYN‐C) are able to cross the blood–brain barrier without any facilitating strategy, and accumulates in the brain 90 min after its injection in NMRI mice. None of the USPIO derivatives were found in any organs one week after administration. To conclude, USPIO‐PHO seems to have a genuine potential for labeling amyloid plaques in the brain; it has a nanomolar binding affinity, no toxic effects, and its elimination half‐life is about 3 h. Further tests will be made on transgenic mice, aimed at confirming the potential of early AD diagnosis using our VCA. Copyright © 2014 John Wiley & Sons, Ltd.