Normal spectrum of pulmonary parametric response map to differentiate lung collapsibility: distribution of densitometric classifications in healthy adult volunteers.

OBJECTIVES: Pulmonary parametric response map (PRM) was proposed for quantitative densitometric phenotypization of chronic obstructive pulmonary disease. However, little is known about this technique in healthy subjects. The purpose of this study was to describe the normal spectrum of densitometric classification of pulmonary PRM in a group of healthy adults. METHODS: 15 healthy volunteers underwent spirometrically monitored chest CT at total lung capacity (TLC) and functional residual capacity (FRC). The paired CT scans were analyzed by PRM for voxel-by-voxel characterization of lung parenchyma according to 4 densitometric classifications: normal lung (TLC ≥ -950 HU, FRC ≥ -856 HU); expiratory low attenuation area (LAA) (TLC ≥ -950 HU, FRC < -856 HU); dual LAA (TLC<-950 HU, FRC < -856 HU); uncharacterized (TLC < -950 HU, FRC ≥ -856 HU). RESULTS: PRM spectrum was 78 % ± 10 % normal lung, 20 % ± 8 % expiratory LAA, and 1 % ± 1 % dual LAA. PRM was similar between genders, there was moderate correlation between dual LAA and spirometrically assessed TLC (R = 0.531; p = 0.042), and between expiratory LAA and VolExp/Insp ratio (R = -0.572; p = 0.026). CONCLUSIONS: PRM reflects the predominance of normal lung parenchyma in a group of healthy volunteers. However, PRM also confirms the presence of physiological expiratory LAA seemingly related to air trapping and a minimal amount of dual LAA likely reflecting emphysema. KEY POINTS: • Co-registration of inspiratory and expiratory computed tomography allows dual-phase densitometry. • Dual-phase co-registered densitometry reflects heterogeneous regional changes in lung function. • Quantification of lung in healthy subjects is needed to set reference values. • Expiratory low attenuation areas <30 % could be considered within normal range.

The Impact of Sources of Variability on Parametric Response Mapping of Lung CT Scans.

Parametric response mapping (PRM) of inspiration and expiration computed tomography (CT) images improves the radiological phenotyping of chronic obstructive pulmonary disease (COPD). PRM classifies individual voxels of lung parenchyma as normal, emphysematous, or nonemphysematous air trapping. In this study, bias and noise characteristics of the PRM methodology to CT and clinical procedures were evaluated to determine best practices for this quantitative technique. Twenty patients of varying COPD status with paired volumetric inspiration and expiration CT scans of the lungs were identified from the baseline COPD-Gene cohort. The impact of CT scanner manufacturer and reconstruction kernels were evaluated as potential sources of variability in PRM measurements along with simulations to quantify the impact of inspiration/expiration lung volume levels, misregistration, and image spacing on PRM measurements. Negligible variation in PRM metrics was observed when CT scanner type and reconstruction were consistent and inspiration/expiration lung volume levels were near target volumes. CT scanner Hounsfield unit drift occurred but remained difficult to ameliorate. Increasing levels of image misregistration and CT slice spacing were found to have a minor effect on PRM measurements. PRM-derived values were found to be most sensitive to lung volume levels and mismatched reconstruction kernels. As with other quantitative imaging techniques, reliable PRM measurements are attainable when consistent clinical and CT protocols are implemented.

Parametric response mapping monitors temporal changes on lung CT scans in the subpopulations and intermediate outcome measures in COPD Study (SPIROMICS).

RATIONALE AND OBJECTIVES: The longitudinal relationship between regional air trapping and emphysema remains unexplored. We have sought to demonstrate the utility of parametric response mapping (PRM), a computed tomography (CT)-based biomarker, for monitoring regional disease progression in chronic obstructive pulmonary disease (COPD) patients, linking expiratory- and inspiratory-based CT metrics over time. MATERIALS AND METHODS: Inspiratory and expiratory lung CT scans were acquired from 89 COPD subjects with varying Global Initiative for Chronic Obstructive Lung Disease (GOLD) status at 30 days (n = 13) or 1 year (n = 76) from baseline as part of the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) clinical trial. PRMs of CT data were used to quantify the relative volumes of normal parenchyma (PRM(Normal)), emphysema (PRM(Emph)), and functional small airways disease (PRM(fSAD)). PRM measurement variability was assessed using the 30-day interval data. Changes in PRM metrics over a 1-year period were correlated to pulmonary function (forced expiratory volume at 1 second [FEV1]). A theoretical model that simulates PRM changes from COPD was compared to experimental findings. RESULTS: PRM metrics varied by ∼6.5% of total lung volume for PRM(Normal) and PRM(fSAD) and 1% for PRM(Emph) when testing 30-day repeatability. Over a 1-year interval, only PRM(Emph) in severe COPD subjects produced significant change (19%-21%). However, 11 of 76 subjects showed changes in PRM(fSAD) greater than variations observed from analysis of 30-day data. Mathematical model simulations agreed with experimental PRM results, suggesting fSAD is a transitional phase from normal parenchyma to emphysema. CONCLUSIONS: PRM of lung CT scans in COPD patients provides an opportunity to more precisely characterize underlying disease phenotypes, with the potential to monitor disease status and therapy response.

Image registration for quantitative parametric response mapping of cancer treatment response.

Imaging biomarkers capable of early quantification of tumor response to therapy would provide an opportunity to individualize patient care. Image registration of longitudinal scans provides a method of detecting treatment associated changes within heterogeneous tumors by monitoring alterations in the quantitative value of individual voxels over time, which is unattainable by traditional volumetric-based histogram methods. The concepts involved in the use of image registration for tracking and quantifying breast cancer treatment response using parametric response mapping (PRM), a voxel-based analysis of diffusion-weighted magnetic resonance imaging (DW-MRI) scans, are presented. Application of PRM to breast tumor response detection is described, wherein robust registration solutions for tracking small changes in water diffusivity in breast tumors during therapy are required. Methodologies that employ simulations are presented for measuring expected statistical accuracy of PRM for response assessment. Test-retest clinical scans are used to yield estimates of system noise to indicate significant changes in voxel-based changes in water diffusivity. Overall, registration-based PRM image analysis provides significant opportunities for voxel-based image analysis to provide the required accuracy for early assessment of response to treatment in breast cancer patients receiving neoadjuvant chemotherapy.

Quantifying iron-oxide nanoparticles at high concentration based on longitudinal relaxation using a three-dimensional SWIFT Look-Locker sequence.

PURPOSE: Iron-oxide nanoparticles (IONPs) have proven utility as contrast agents in many MRI applications. Previous quantitative IONP mapping has been performed using mainly T2 * mapping methods. However, in applications requiring high IONP concentrations, such as magnetic nanoparticles based thermal therapies, conventional pulse sequences are unable to map T2 * because the signal decays too rapidly. In this article, sweep imaging with Fourier transformation (SWIFT) sequence is combined with the Look-Locker method to map T1 of IONPs in high concentrations. METHODS: T1 values of agar containing IONPs in different concentrations were measured with the SWIFT Look-Locker method and with inversion recovery spectroscopy. Precisions of Look-Locker and variable flip angle (VFA) methods were compared in simulations. RESULTS: The measured R1 (=1/T1 ) has a linear relationship with IONP concentration up to 53.6 mM of Fe. This concentration exceeds concentrations measured in previous work by almost an order of magnitude. Simulations show SWIFT Look-Locker method is also much less sensitive to B1 inhomogeneity than the VFA method. CONCLUSION: SWIFT Look-Locker can accurately measure T1 of IONP concentrations ≤53.6 mM. By mapping T1 as a function of IONP concentration, IONP distribution maps might be used in the future to plan effective magnetic nanoparticle hyperthermia therapy.

SPION-enhanced magnetic resonance imaging of Alzheimer's disease plaques in AßPP/PS-1 transgenic mouse brain.

In our program to develop non-invasive magnetic resonance imaging (MRI) methods for the diagnosis of Alzheimer's disease (AD), we have synthesized antibody-conjugated, superparamagnetic iron oxide nanoparticles (SPIONs) for use as an in vivo agent for MRI detection of amyloid-ß plaques in AD. Here we report studies in AßPP/PS1 transgenic mice, which demonstrate the ability of novel anti-AßPP conjugated SPIONs to penetrate the blood-brain barrier to act as a contrast agent for MR imaging of plaques. The conspicuity of the plaques increased from an average Z-score of 5.1 ± 0.5 to 8.3 ± 0.2 when the plaque contrast to noise ratio was compared in control AD mice with AD mice treated with SPIONs. The number of MRI-visible plaques per brain increased from 347 ± 45 in the control AD mice, to 668 ± 86 in the SPION treated mice. These results indicated that our SPION enhanced amyloid-ß detection method delivers an efficacious, non-invasive MRI detection method in transgenic mice.

Short echo-time 3D radial gradient-echo MRI using concurrent dephasing and excitation.

Ultrashort echo-time imaging and sweep imaging with Fourier transformation are powerful techniques developed for imaging ultrashort T(2) species. However, it can be challenging to implement them on standard clinical MRI systems due to demanding hardware requirements. In this article, the limits of what is possible in terms of the minimum echo-time and repetition time with 3D radial gradient-echo sequences, which can be readily implemented on a standard clinical scanner, are investigated. Additionally, a new 3D radial gradient-echo sequence is introduced, called COncurrent Dephasing and Excitation (CODE). The unique feature of CODE is that the initial dephasing of the readout gradient is performed during RF excitation, which allows CODE to effectively achieve echo-times on the order of ∼0.2 ms and larger in a clinical setting. The minimum echo-time achievable with CODE is analytically described and compared with a standard 3D radial gradient-echo sequence. CODE was implemented on a clinical 3 T scanner (Siemens 3 T MAGNETOM Trio), and both phantom and in vivo human knee images are shown for demonstration.

Elevated blood pressure causes larger hematoma in a rat model of intracerebral hemorrhage.

Hypertension has been recognized as an independent risk factor for intracerebral hemorrhage (ICH). The objective of this study was to assess the effect of chronically elevated blood pressure on amount of hematoma in a rat model of ICH. A total of 46 rats were divided into two groups-normotensive group (n = 18) and spontaneously hypertensive group (n = 28). To induce ICH, we delivered 2 µL of collagenase solution (0.1 U/1 µL normal saline) into the striatum. Each animal's brain was removed 24 h post-surgery for spectrophotometric hemoglobin assay. Equal or unequal variance t tests were performed to assess changes in variables between the hypertensive and normotensive groups. Tissue analysis revealed a statistically significant difference in optical density percent change at 540-nm wavelength for the hypertensive vs. the normotensive group (261.47 ± 103.68 and 133.33 ± 58.53, p < 0.0001, respectively). As compared to the normotensive rats, hypertensive rats exhibited a higher neurological deficit, loss of balance and coordination, and loss of motor function. Our results demonstrated that hypertensive rats had significantly higher amounts of hemorrhage in comparison to normotensive ones. These findings support the need for further adequately powered studies to investigate differences in amount of hematoma and corresponding functional impairments due to ICH among hypertensive vs. normotensive rats.

In Vivo Imaging and Quantification of Iron Oxide Nanoparticle Uptake and Biodistribution.

Recent advances in nanotechnology have allowed for the effective use of iron oxide nanoparticles (IONPs) for cancer imaging and therapy. When activated by an alternating magnetic field (AMF), intra-tumoral IONPs have been effective at controlling tumor growth in rodent models. To accurately plan and assess IONP-based therapies in clinical patients, noninvasive and quantitative imaging technique for the assessment of IONP uptake and biodistribution will be necessary. Proven techniques such as confocal, light and electron microscopy, histochemical iron staining, ICP-MS, fluorescent labeled mNPs and magnetic spectroscopy of Brownian motion (MSB), are being used to assess and quantify IONPs in vitro and in ex vivo tissues. However, a proven noninvasive in vivo IONP imaging technique has not yet been developed. In this study we have demonstrated the shortcomings of computed tomography (CT) and magnetic resonance imaging (MRI) for effectively observing and quantifying iron/IONP concentrations in the clinical setting. Despite the poor outcomes of CT and standard MR sequences in the therapeutic concentration range, ultra-short T2 MRI methods such as, Sweep Imaging With Fourier Transformation (SWIFT), provide a positive iron contrast enhancement and a reduced signal to noise ratio. Ongoing software development and phantom and in vivo studies, will further optimize this technique, providing accurate, clinically-relevant IONP biodistribution information.

Targeting vascular amyloid in arterioles of Alzheimer disease transgenic mice with amyloid ß protein antibody-coated nanoparticles.

The relevance of cerebral amyloid angiopathy (CAA) to the pathogenesis of Alzheimer disease (AD) and dementia in general emphasizes the importance of developing novel targeting approaches for detecting and treating cerebrovascular amyloid (CVA) deposits. We developed a nanoparticle-based technology that uses a monoclonal antibody against fibrillar human amyloid-ß42 that is surface coated onto a functionalized phospholipid monolayer. We demonstrate that this conjugated nanoparticle binds to CVA deposits in arterioles of AD transgenic mice (Tg2576) after infusion into the external carotid artery using 3 different approaches. The first 2 approaches use a blood vessel enrichment of homogenized brain and a leptomeningeal vessel preparation from thin tangential brain slices from the surface of the cerebral cortex. Targeting of CVA by the antibody-coated nanoparticle was visualized using fluorescent lissamine rhodamine-labeled phospholipids in the nanoparticles, which were compared with fluorescent staining of the endothelial cells and amyloid deposits using confocal laser scanning microscopy. The third approach used high-field strength magnetic resonance imaging of antibody-coated iron oxide nanoparticles after infusion into the external carotid artery. Dark foci of contrast enhancement in cortical arterioles were observed in T2*-weighted images of ex vivo AD mouse brains that correlated histologically with CVA deposits. The targeting ability of these nanoparticles to CVA provides opportunities for the prevention and treatment of CAA.

Magnetic resonance imaging of amyloid plaques in transgenic mouse models of Alzheimer's disease.

A major objective in the treatment of Alzheimer's disease is amyloid plaque reduction. Transgenic mouse models of Alzheimer's disease provide a controlled and consistent environment for studying amyloid plaque deposition in Alzheimer's disease. Magnetic resonance imaging is an attractive tool for longitudinal studies because it offers non-invasive monitoring of amyloid plaques. Recent studies have demonstrated the ability of magnetic resonance imaging to detect individual plaques in living mice. This review discusses the mouse models, MR pulse sequences, and parameters that have been used to image plaques and how they can be optimized for future studies.

Detecting Fleeting MRI Signals with Frequency-Modulated Pulses.

We describe a fundamentally different approach to MRI referred to as SWIFT (sweep imaging with Fourier transformation). SWIFT exploits time-shared RF excitation and signal acquisition, allowing capture of signal from spins with extremely short transverse relaxation time, T(2)*. The MR signal is acquired in gaps inserted into a broadband frequency-swept excitation pulse, which results in acquisition delays of only 1 - 2 microseconds. In SWIFT, 3D k-space is sampled in a radial manner, whereby one projection of the object is acquired in the gaps of each frequency-swept pulse, allowing a repetition time (TR) on the order of the pulse length (typically 1 - 3 milliseconds). Since the orientation of consecutive projections varies in a smooth manner (i.e., only small increments in the values of the x, y, z gradients occur from view to view), SWIFT scanning is close to inaudible and is insensitive to gradient timing errors and eddy currents. SWIFT images can be acquired in scan times similar to and sometimes faster than conventional 3D gradient echo techniques. With its ability to capture signals from ultrashort T(2)* spins, SWIFT promises to expand the role of MRI in areas of research where MRI previously played no or negligible role. In this article, we show wood and tooth images obtained with SWIFT as examples of materials with ultrashort T(2)*. Early experience suggests SWIFT can play a role in materials science and porous media research.

Simultaneous fMRI and local field potential measurements during epileptic seizures in medetomidine-sedated rats using raser pulse sequence.

Simultaneous electrophysiological and functional magnetic resonance imaging measurements of animal models of epilepsy are methodologically challenging, but essential to better understand abnormal brain activity and hemodynamics during seizures. In this study, functional magnetic resonance imaging of medetomidine-sedated rats was performed using novel rapid acquisition by sequential excitation and refocusing (RASER) fast imaging pulse sequence and simultaneous local field potential measurements during kainic acid-induced seizures. The image distortion caused by the hippocampal-measuring electrode was clearly seen in echo planar imaging images, whereas no artifact was seen in RASER images. Robust blood oxygenation level-dependent responses were observed in the hippocampus during kainic acid-induced seizures. The recurrent epileptic seizures were detected in the local field potential signal after kainic acid injection. The presented combination of deep electrode local field potential measurements and functional magnetic resonance imaging under medetomidine anesthesia, which does not significantly suppress kainic acid-induced seizures, provides a unique tool for studying abnormal brain activity in rats.

Comparison of amyloid plaque contrast generated by T2-weighted, T2*-weighted, and susceptibility-weighted imaging methods in transgenic mouse models of Alzheimer's disease.

One of the hallmark pathologies of Alzheimer's disease (AD) is amyloid plaque deposition. Plaques appear hypointense on T(2)-weighted and T(2)*-weighted MR images probably due to the presence of endogenous iron, but no quantitative comparison of various imaging techniques has been reported. We estimated the T(1), T(2), T(2)*, and proton density values of cortical plaques and normal cortical tissue and analyzed the plaque contrast generated by a collection of T(2)-weighted, T(2)*-weighted, and susceptibility-weighted imaging (SWI) methods in ex vivo transgenic mouse specimens. The proton density and T(1) values were similar for both cortical plaques and normal cortical tissue. The T(2) and T(2)* values were similar in cortical plaques, which indicates that the iron content of cortical plaques may not be as large as previously thought. Ex vivo plaque contrast was increased compared to a previously reported spin-echo sequence by summing multiple echoes and by performing SWI; however, gradient echo and SWI were found to be impractical for in vivo imaging due to susceptibility interface-related signal loss in the cortex.

RASER: a new ultrafast magnetic resonance imaging method.

A new MRI method is described to acquire a T(2)-weighted image from a single slice in a single shot. The technique is based on rapid acquisition by sequential excitation and refocusing (RASER). RASER avoids relaxation-related blurring because the magnetization is sequentially refocused in a manner that effectively creates a series of spin echoes with a constant echo time. RASER uses the quadratic phase produced by a frequency-swept chirp pulse to time-encode one dimension of the image. In another implementation the pulse can be used to excite multiple slices with phase-encoding and frequency-encoding in the other two dimensions. The RASER imaging sequence is presented along with single-shot and multislice images, and is compared to conventional spin-echo and echo-planar imaging sequences. A theoretical and empirical analysis of the spatial resolution is presented, and factors in choosing the spatial resolution for different applications are discussed. RASER produces high-quality single-shot images that are expected to be advantageous for a wide range of applications.