Gregory J. Metzger

The Alzheimer's Disease Neuroimaging Initiative (ADNI): MRI methods

The Alzheimers Disease Neuroimaging Initiative (ADNI) is a longitudinal multisite observational study of healthy elders, mild cognitive impairment (MCI), and Alzheimers disease. Magnetic resonance imaging (MRI), (18F)‐fluorodeoxyglucose positron emission tomography (FDG PET), urine serum, and cerebrospinal fluid (CSF) biomarkers, as well as clinical/psychometric assessments are acquiredat multiple time points. All data will be cross‐linked and made available to the general scientific community. The purpose of this report is to describe the MRI methods employed in ADNI. The ADNI MRI core established specifications thatguided protocol development. A major effort was devoted toevaluating 3D T1‐weighted sequences for morphometric analyses. Several options for this sequence were optimized for the relevant manufacturer platforms and then compared in a reduced‐scale clinical trial. The protocol selected for the ADNI study includes: back‐to‐back 3D magnetization prepared rapid gradient echo (MP‐RAGE) scans; B1‐calibration scans when applicable; and an axial proton density‐T2 dual contrast (i.e., echo) fast spin echo/turbo spin echo (FSE/TSE) for pathology detection. ADNI MRI methods seek to maximize scientific utility while minimizing the burden placed on participants. The approach taken in ADNI to standardization across sites and platforms of the MRI protocol, postacquisition corrections, and phantom‐based monitoring of all scanners could be used as a model for other multisite trials. J. Magn. Reson. Imaging 2008.

Myocardial triglycerides and systolic function in humans: in vivo evaluation by localized proton spectroscopy and cardiac imaging.

Recent experimental data suggest that adiposity directly damages the heart by promoting ectopic deposition of triglyceride, a process known as myocardial steatosis. The goal of this study was to develop and validate proton magnetic resonance spectroscopy (1H MRS) as an in vivo tool to measure myocardial lipid content. Complementary studies in rat tissue ex vivo and in 15 healthy humans in vivo provided evidence that 1H MRS constitutes a reproducible technique for the measurement of myocardial triglyceride. In myocardial tissue from Zucker rats, the 1H MRS measurement of triglyceride matched that obtained by biochemical measurement (P < 0.001). In human subjects triglyceride was evident in the hearts of even the very lean individuals and was elevated in overweight and obese subjects. Increased myocardial triglyceride content was accompanied by elevated LV mass and suppressed septal wall thickening as measured by cardiac imaging. Magn Reson Med 49:417–423, 2003.

Local B1+ shimming for prostate imaging with transceiver arrays at 7T based on subject-dependent transmit phase measurements

High‐quality prostate images were obtained with transceiver arrays at 7T after performing subject‐dependent local transmit B1 (B1+) shimming to minimize B1+ losses resulting from destructive interferences. B1+ shimming was performed by altering the input phase of individual RF channels based on relative B1+ phase maps rapidly obtained in vivo for each channel of an eight‐element stripline coil. The relative transmit phases needed to maximize B1+ coherence within a limited region around the prostate greatly differed from those dictated by coil geometry and were highly subject‐dependent. A set of transmit phases determined by B1+ shimming provided a gain in transmit efficiency of 4.2 ± 2.7 in the prostate when compared to the standard transmit phases determined by coil geometry. This increased efficiency resulted in large reductions in required RF power for a given flip angle in the prostate which, when accounted for in modeling studies, resulted in significant reductions of local specific absorption rates. Additionally, B1+ shimming decreased B1+ nonuniformity within the prostate from (24 ± 9%) to (5 ± 4%). This study demonstrates the tremendous impact of fast local B1+ phase shimming on ultrahigh magnetic field body imaging. Magn Reson Med 59:396–409, 2008.

Quantitative comparison of immunohistochemical staining measured by digital image analysis versus pathologist visual scoring

AbstractImmunohistochemical (IHC) assays performed on formalin-fixed paraffin-embedded (FFPE) tissue sections traditionally have been semi-quantified by pathologist visual scoring of staining. IHC is useful for validating biomarkers discovered through genomics methods as large clinical repositories of FFPE specimens support the construction of tissue microarrays (TMAs) for high throughput studies. Due to the ubiquitous availability of IHC techniques in clinical laboratories, validated IHC biomarkers may be translated readily into clinical use. However, the method of pathologist semi-quantification is costly, inherently subjective, and produces ordinal rather than continuous variable data. Computer-aided analysis of digitized whole slide images may overcome these limitations. Using TMAs representing 215 ovarian serous carcinoma specimens stained for S100A1, we assessed the degree to which data obtained using computer-aided methods correlated with data obtained by pathologist visual scoring. To evaluate computer-aided image classification, IHC staining within pathologist annotated and software-classified areas of carcinoma were compared for each case. Two metrics for IHC staining were used: the percentage of carcinoma with S100A1 staining (%Pos), and the product of the staining intensity (optical density [OD] of staining) multiplied by the percentage of carcinoma with S100A1 staining (OD*%Pos). A comparison of the IHC staining data obtained from manual annotations and software-derived annotations showed strong agreement, indicating that software efficiently classifies carcinomatous areas within IHC slide images. Comparisons of IHC intensity data derived using pixel analysis software versus pathologist visual scoring demonstrated high Spearman correlations of 0.88 for %Pos (p < 0.0001) and 0.90 for OD*%Pos (p < 0.0001). This study demonstrated that computer-aided methods to classify image areas of interest (e.g., carcinomatous areas of tissue specimens) and quantify IHC staining intensity within those areas can produce highly similar data to visual evaluation by a pathologist.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1649068103671302

MRI vs. histologic measurement of breast cancer following chemotherapy: Comparison with x-ray mammography and palpation

Twenty consecutive patients with breast cancer were evaluated following chemotherapy using MRI to assess the size of cancer residua and compare these data with subsequent histologic measurements of the viable tumor. This retrospective study also involved assessment of the preoperative size of the malignancy as determined by physical exam and x‐ray mammogram. These values were later compared with the histology. The tumor size correlation coefficient between MRI and pathologic analysis was the highest, at 0.93. Physical exam and x‐ray mammography (available for 17 patients) produced correlation coefficients of 0.72 and 0.63, respectively, compared to histologic measurement. The accuracy of MRI did not vary with the size of cancer residua. MRI is an accurate method for preoperative assessment of breast cancer residua following chemotherapy. J. Magn. Reson. Imaging 2001;13:868–875.

Performance of external and internal coil configurations for prostate investigations at 7 T

Three different coil configurations were evaluated through simulation and experimentally to determine safe operating limits and evaluate subject size‐dependent performance for prostate imaging at 7 T. The coils included a transceiver endorectal coil (trERC), a 16‐channel transceiver external surface array (trESA) and a trESA combined with a receive‐only ERC (trESA+roERC). Although the transmit B1 (B  1+ ) homogeneity was far superior for the trESA, the maximum achievable B  1+ is subject size dependent and limited by transmit chain losses and amplifier performance. For the trERC, limitations in transmit homogeneity greatly compromised image quality and limited coverage of the prostate. Despite these challenges, the high peak B  1+ close to the trERC and subject size‐independent performance provides potential advantages especially for spectroscopic localization where high‐bandwidth radiofrequency pulses are required. On the receive side, the combined trESA+roERC provided the highest signal‐to‐noise ratio and improved homogeneity over the trERC resulting in better visualization of the prostate and surrounding anatomy. In addition, the parallel imaging performance of the trESA+roERC holds strong promise for diffusion‐weighted imaging and dynamic contrast‐enhanced MRI. Magn Reson Med, 2010.

Nanoparticle delivered vascular disrupting agents (VDAs): use of TNF-alpha conjugated gold nanoparticles for multimodal cancer therapy.

Surgery, radiation and chemotherapy remain the mainstay of current cancer therapy. However, treatment failure persists due to the inability to achieve complete local control of the tumor and curtail metastatic spread. Vascular disrupting agents (VDAs) are a class of promising systemic agents that are known to synergistically enhance radiation, chemotherapy or thermal treatments of solid tumors. Unfortunately, there is still an unmet need for VDAs with more favorable safety profiles and fewer side effects. Recent work has demonstrated that conjugating VDAs to other molecules (polyethylene glycol, CNGRCG peptide) or nanoparticles (liposomes, gold) can reduce toxicity of one prominent VDA (tumor necrosis factor alpha, TNF-α). In this report, we show the potential of a gold conjugated TNF-α nanoparticle (NP-TNF) to improve multimodal cancer therapies with VDAs. In a dorsal skin fold and hindlimb murine xenograft model of prostate cancer, we found that NP-TNF disrupts endothelial barrier function and induces a significant increase in vascular permeability within the first 1-2 h followed by a dramatic 80% drop in perfusion 2-6 h after systemic administration. We also demonstrate that the tumor response to the nanoparticle can be verified using dynamic contrast-enhanced magnetic resonance imaging (MRI), a technique in clinical use. Additionally, multimodal treatment with thermal therapies at the perfusion nadir in the sub- and supraphysiological temperature regimes increases tumor volumetric destruction by over 60% and leads to significant tumor growth delays compared to thermal therapy alone. Lastly, NP-TNF was found to enhance thermal therapy in the absence of neutrophil recruitment, suggesting that immune/inflammatory regulation is not central to its power as part of a multimodal approach. Our data demonstrate the potential of nanoparticle-conjugated VDAs to significantly improve cancer therapy by preconditioning tumor vasculature to a secondary insult in a targeted manner. We anticipate our work to direct investigations into more potent tumor vasculature specific combinations of VDAs and nanoparticles with the goal of transitioning optimal regimens into clinical trials.

7 Tesla (T) human cardiovascular magnetic resonance imaging using FLASH and SSFP to assess cardiac function: validation against 1.5 T and 3 T

We report the first comparison of cardiovascular magnetic resonance imaging (CMR) at 1.5 T, 3 T and 7 T field strengths using steady state free precession (SSFP) and fast low angle shot (FLASH) cine sequences. Cardiac volumes and mass measurements were assessed for feasibility, reproducibility and validity at each given field strength using FLASH and SSFP sequences. Ten healthy volunteers underwent retrospectively electrocardiogram (ECG) gated CMR at 1.5 T, 3 T and 7 T using FLASH and SSFP sequences. B1 and B0 shimming and frequency scouts were used to optimise image quality. Cardiac volume and mass measurements were not significantly affected by field strength when using the same imaging sequence (P > 0.05 for all parameters at 1.5 T, 3 T and 7 T). SSFP imaging returned larger end diastolic and end systolic volumes and smaller left ventricular masses than FLASH imaging at 7 T, and at the lower field strengths (P < 0.05 for each parameter). However, univariate general linear model analysis with fixed effects for sequence and field strengths found an interaction between imaging sequence and field strength (P = 0.03), with a smaller difference in volumes and mass measurements between SSFP and FLASH imaging at 7 T than 1.5 T and 3 T. SSFP and FLASH cine imaging at 7 T is technically feasible and provides valid assessment of cardiac volumes and mass compared with CMR imaging at 1.5 T and 3 T field strengths. Copyright

Dynamically applied B1+ shimming solutions for non-contrast enhanced renal angiography at 7.0 Tesla.

The purpose of this study was to detail a strategy for performing non‐contrast enhanced renal magnetic resonance angiography studies at 7.0 T. It is demonstrated that with proper B  1+ management, these studies can be successfully performed at ultrahigh field within local specific absorption rate constraints. An inversion prepared gradient echo acquisition, standard for non‐contrast renal magnetic resonance angiography studies, required radiofrequency pulse specific B  1+ shimming solutions to be dynamically applied to address the field dependent increases in both B0 and B  1+ inhomogeneity as well as to accommodate limitation in available power. By using more efficient B  1+ shimming solutions for the inversion preparation and more homogeneous solutions for the excitation, high quality images of the renal arteries were obtained without venous and background signal artifacts while working within hardware and safety constraints. Finite difference time domain simulations confirmed in vivo measurements with respect to B  1+ distributions and homogeneity for the range of shimming strategies used and allowed the calculation of peak local specific absorption rate values normalized by input power and B  1+ . Increasing B  1+ homogeneity was accompanied by decreasing local specific absorption rate per Watt and increasing maximum local specific absorption rate per [B  1+ ]2, which must be considered, along with body size and respiratory rate, when finalizing acquisition parameters for a given individual. Magn Reson Med, 2013.

A 16-channel combined loop-dipole transceiver array for 7 Tesla body MRI

To develop a 16‐channel transceive body imaging array at 7.0 T with improved transmit, receive, and specific absorption rate (SAR) performance by combining both loop and dipole elements and using their respective and complementary near and far field characteristics.