Gregory J. Metzger

Bio: Gregory J. Metzger is an academic researcher from University of Minnesota. The author has contributed to research in topics: Prostate cancer & Medicine. The author has an hindex of 27, co-authored 82 publications receiving 5515 citations. Previous affiliations of Gregory J. Metzger include University of Texas Southwestern Medical Center & Philips.

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

Abstract: Dementia, one of the most feared associates of increasing longevity, represents a pressing public health problem and major research priority. Alzheimer's disease (AD) is the most common form of dementia, affecting many millions around the world. There is currently no cure for AD, but large numbers of novel compounds are currently under development that have the potential to modify the course of the disease and slow its progression. There is a pressing need for imaging biomarkers to improve understanding of the disease and to assess the efficacy of these proposed treatments. Structural magnetic resonance imaging (MRI) has already been shown to be sensitive to presymptomatic disease (1-10) and has the potential to provide such a biomarker. For use in large-scale multicenter studies, however, standardized methods that produce stable results across scanners and over time are needed. The Alzheimer's Disease Neuroimaging Initiative (ADNI) study is a longitudinal multisite observational study of elderly individuals with normal cognition, mild cognitive impairment (MCI), or AD (11,12). It is jointly funded by the National Institutes of Health (NIH) and industry via the Foundation for the NIH. The study will assess how well information (alone or in combination) obtained from MRI, (18F)-fludeoyglucose positron emission tomography (FDG PET), urine, serum, and cerebrospinal fluid (CSF) biomarkers, as well as clinical and neuropsychometric assessments, can measure disease progression in the three groups of elderly subjects mentioned above. At the 55 participating sites in North America, imaging, clinical, and biologic samples will be collected at multiple time points in 200 elderly cognitively normal, 400 MCI, and 200 AD subjects. All subjects will be scanned with 1.5 T MRI at each time point, and half of these will also be scanned with FDG PET. Subjects not assigned to the PET arm of the study will be eligible for 3 T MRI scanning. The goal is to acquire both 1.5 T and 3 T MRI studies at multiple time points in 25% of the subjects who do not undergo PET scanning [R2C1]. CSF collection at both baseline and 12 months is targeted for 50% of the subjects. Sampling varies by clinical group. Healthy elderly controls will be sampled at 0, 6, 12, 24, and 36 months. Subjects with MCI will be sampled at 0, 6, 12, 18, 24, and 36 months. AD subjects will be sampled at 0, 6, 12, and 24 months. Major goals of the ADNI study are: to link all of these data at each time point and make this repository available to the general scientific community; to develop technical standards for imaging in longitudinal studies; to determine the optimum methods for acquiring and analyzing images; to validate imaging and biomarker data by correlating these with concurrent psychometric and clinical assessments; and to improve methods for clinical trials in MCI and AD. The ADNI study overall is divided into cores, with each core managing ADNI-related activities within its sphere of expertise: clinical, informatics, biostatistics, biomarkers, and imaging. The purpose of this report is to describe the MRI methods and decision-making process underlying the selection of the MRI protocol employed in the ADNI study.

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

Abstract: 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 ((1)H 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 (1)H MRS constitutes a reproducible technique for the measurement of myocardial triglyceride. In myocardial tissue from Zucker rats, the (1)H 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.

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

Abstract: Immunohistochemical (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. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1649068103671302

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

Abstract: The use of high magnetic fields can improve our ability to investigate the etiology and development of prostate cancer. Gains may also be expected in diagnosis, treatment monitoring, and in the development of new therapies. Improved diagnosis of extracapsular extension through T2w anatomic imaging has been reported, while greater benefits were anticipated for spectroscopy and dynamic contrast-enhanced imaging when progressing from 1.5–3.0T (1). Using even higher magnetic fields can bring further benefits by exploiting the advantages of increased signal-to-noise ratio (SNR) (2), spectral resolution (3), and parallel imaging performance (4). However, imaging the human body at the ultrahigh magnetic field (UHF) of 7T is very challenging. As a result, virtually all MRI and MRS studies that have been reported so far in humans at UHF have focused on the brain; only recently, efforts from our laboratory have demonstrated that human torso imaging may also be feasible at UHF (5–7). Arguably, the most difficult challenges encountered at UHF are due to strong transmit B1 (B1+) field heterogeneities in large biological samples. As the RF wavelength used in MR approaches or becomes shorter than the dimensions of the object to be imaged, significant B1+ field distortions occur that are dependent on tissue electromagnetic properties and geometry (8,9). At 7T the RF wavelength in biological tissues at the Larmor frequency (≈300 MHz) is ≈12 cm on average; these rather short wavelengths result in complex transmit and receive B1 profiles in human tissues (10,11). However, the consequences are dramatically different, first, between receive and transmit B1 fields, and second, between surface and volume RF coils. On the receive side the use of multiple coils with independent receive channels for data sampling are now available on most clinical scanners. By correctly combining the data from these multiple receivers it is possible to avoid destructive interferences between receive B1 fields (B1−), resulting in optimized SNR in the reconstructed images. On the transmit side, single surface coils can still be utilized at UHF in ways similar to those at lower field, sharing with the latter a stronger B1+ field magnitude within the vicinity of the RF coil. However, the B1+ profiles of volume RF coils at UHF exhibit higher magnitude in the center than in the periphery (2), a feature often described as a “bright center.” This is the result of a complicated combination of destructive and constructive interferences, dielectric phenomenon, and damping wave patterns (10–14). It had been shown by Vaughan et al. (15) that a more homogeneous B1+ field can be obtained by adjusting individual current-carrying elements within a volume coil at high field, but the adjustments needed for this B1+ shimming (also referred to as RF shimming or field focusing) approach are not trivial and depend on both a given subject’s anatomy and the positioning of the coil. More recently, a strong interest has developed in utilizing multiple, independent transmit RF coils to cover a volume rather than a traditional one-channel transmit volume coil (16,17). Such coil designs allow for more flexible B1+ shimming approaches by potentially modulating the phase and/or magnitude of each transmit element in an array (9,18), a property that becomes far more critical at 7T and higher fields (19–21). When B1+ shimming is considered at UHF with a transmit coil array, it is essential to appreciate two different sources of transmit B1+ heterogeneity. One source is the intrinsically distorted B1+ pattern of each transmitting coil element observed at high field with lossy dielectric biological tissues. Such a distorted B1+ pattern obtained with a single coil element cannot be altered for a given coil and sample geometry, except if electromagnetic properties of the surrounding media are altered, as was demonstrated with dielectric padding (22). Another source, however, results from interactions between the individual complex B1+ patterns from each coil element. Indeed, the volume excitation pattern of a transmit coil array corresponds to the linear combination of each individual coil’s complex B1+ maps, the constructive or destructive nature of which being defined by the local relative phases of each transmit B1+ field: constructive when relative B1+ phases are coherent, destructive when they are incoherent. It has been demonstrated at 7T that the complex and distorted nature of relative B1+ phase patterns within an array of transmit coils is responsible for large and spatially nonuniform destructive B1+ interferences (12). The presence of these destructive interferences results in two major, direct consequences with implications for transmit array coils at very high fields in humans. First, the sum of any set of B1+ phases and magnitudes will produce in some spatial locations significant losses in combined B1+ magnitude compared with the direct sum of all B1+ magnitudes in the same location. Second, because B1+ profiles vary relatively slowly through space, it is possible to avoid most of B1+ cancellation within any chosen, relatively small, region of interest (ROI) by setting the average local B1+ phase of each transmit coil to an identical value (12,21). The principle of controlling transmit phases (18,19) or transmit phases and amplitudes (9) with multiple independent transmit channels in order to alter B1+ profiles in humans has been previously demonstrated. However, the experimental adjustments described in most of those studies were empirically obtained by iteratively trying different sets of phase and/or magnitude over multiple coils and estimating the results with image comparisons. In the present study we demonstrate a fast, local B1+ shimming approach based on subject-dependent calibration data to obtain B1+ phase coherence within a limited ROI (21) drawn around the prostate. This method is demonstrated to produce significant increases in local B1+ magnitude for a given RF power input, resulting in a decrease of the required RF power levels. Furthermore, B1+ becomes more homogeneous within the ROI, yielding greatly improved image quality with more uniform contrast. We report significant variations in relative transmit phases between coil elements from subject to subject, even when utilizing the same transmit RF coil array. These results emphasize the importance of measuring the relative B1+ phases at UHF (12), rather than iteratively trying different sets of phases (18) in order to perform local B1+ shimming. The methods presented should facilitate the development of clinical MR spectroscopy and imaging investigations at UHF, not only in the prostate (23) but also in a variety of organs (e.g., heart or brain) when a local B1+ adjustment is needed and sufficient (24). In contrast to B1+ shimming methods that include channel-dependent transmit amplitude optimization, the local phase-based approach has several advantages. First, local B1+ phase shimming does not require the absolute mapping of B1+ magnitude for each transmit channel. While rapid B1+ mapping strategies are under active development, acquiring these data for multiple transmit coil elements is still not trivial. Another important consideration concerns the simplicity of the hardware required for local B1+ phase shimming that can be performed with a single transmit channel through the means of commercially available high-power RF splitters and phase shifters, as demonstrated in the present study. This is standard hardware for most UHF sites and therefore makes the proposed methods practical, and in cases focusing on small ROIs, completely sufficient. On the contrary, methods employing amplitude adjustments require the use of multiple independent RF amplifiers and associated safety monitoring. While this is a rapidly expanding area of development, only a few centers currently have the required hardware to perform this type of optimization in vivo. In addition, where a single transmit channel setup can utilize the RF power monitoring interface existing on standard consoles, significant hardware and software modifications are required to ensure RF safety for in vivo applications on systems with multiple independent transmitters. Optimizing transmit RF amplitudes, additionally to transmit RF phases, typically becomes desirable when a primary goal is to improve transmit B1+ homogeneity over a certain ROI. However, it is demonstrated in this article that for the prostate, which is an organ of limited size and approximately centered in the body along the XY plane, optimizing the effective local B1+ magnitude based solely on a local B1+ phase results in high B1+ homogeneity within the prostate.

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

Abstract: 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.

Cluster failure: Why fMRI inferences for spatial extent have inflated false-positive rates

Abstract: The most widely used task functional magnetic resonance imaging (fMRI) analyses use parametric statistical methods that depend on a variety of assumptions. In this work, we use real resting-state data and a total of 3 million random task group analyses to compute empirical familywise error rates for the fMRI software packages SPM, FSL, and AFNI, as well as a nonparametric permutation method. For a nominal familywise error rate of 5%, the parametric statistical methods are shown to be conservative for voxelwise inference and invalid for clusterwise inference. Our results suggest that the principal cause of the invalid cluster inferences is spatial autocorrelation functions that do not follow the assumed Gaussian shape. By comparison, the nonparametric permutation test is found to produce nominal results for voxelwise as well as clusterwise inference. These findings speak to the need of validating the statistical methods being used in the field of neuroimaging.

Mechanisms linking obesity with cardiovascular disease

Abstract: Obesity increases the risk of cardiovascular disease and premature death. Adipose tissue releases a large number of bioactive mediators that influence not only body weight homeostasis but also insulin resistance - the core feature of type 2 diabetes - as well as alterations in lipids, blood pressure, coagulation, fibrinolysis and inflammation, leading to endothelial dysfunction and atherosclerosis. We are now beginning to understand the underlying mechanisms as well as the ways in which smoking and dyslipidaemia increase, and physical activity attenuates, the adverse effects of obesity on cardiovascular health.

Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study.

Abstract: Summary Background Similar to most chronic diseases, Alzheimer's disease (AD) develops slowly from a preclinical phase into a fully expressed clinical syndrome. We aimed to use longitudinal data to calculate the rates of amyloid β (Aβ) deposition, cerebral atrophy, and cognitive decline. Methods In this prospective cohort study, healthy controls, patients with mild cognitive impairment (MCI), and patients with AD were assessed at enrolment and every 18 months. At every visit, participants underwent neuropsychological examination, MRI, and a carbon-11-labelled Pittsburgh compound B ( 11 C-PiB) PET scan. We included participants with three or more 11 C-PiB PET follow-up assessments. Aβ burden was expressed as 11 C-PiB standardised uptake value ratio (SUVR) with the cerebellar cortex as reference region. An SUVR of 1·5 was used to discriminate high from low Aβ burdens. The slope of the regression plots over 3–5 years was used to estimate rates of change for Aβ deposition, MRI volumetrics, and cognition. We included those participants with a positive rate of Aβ deposition to calculate the trajectory of each variable over time. Findings 200 participants (145 healthy controls, 36 participants with MCI, and 19 participants with AD) were assessed at enrolment and every 18 months for a mean follow-up of 3·8 (95% CI CI 3·6–3·9) years. At baseline, significantly higher Aβ burdens were noted in patients with AD (2·27, SD 0·43) and those with MCI (1·94, 0·64) than in healthy controls (1·38, 0·39). At follow-up, 163 (82%) of the 200 participants showed positive rates of Aβ accumulation. Aβ deposition was estimated to take 19·2 (95% CI 16·8–22·5) years in an almost linear fashion—with a mean increase of 0·043 (95% CI 0·037–0·049) SUVR per year—to go from the threshold of 11 C-PiB positivity (1·5 SUVR) to the levels observed in AD. It was estimated to take 12·0 (95% CI 10·1–14·9) years from the levels observed in healthy controls with low Aβ deposition (1·2 [SD 0·1] SUVR) to the threshold of 11 C-PiB positivity. As AD progressed, the rate of Aβ deposition slowed towards a plateau. Our projections suggest a prolonged preclinical phase of AD in which Aβ deposition reaches our threshold of positivity at 17·0 (95% CI 14·9–19·9) years, hippocampal atrophy at 4·2 (3·6–5·1) years, and memory impairment at 3·3 (2·5–4·5) years before the onset of dementia (clinical dementia rating score 1). Interpretation Aβ deposition is slow and protracted, likely to extend for more than two decades. Such predictions of the rate of preclinical changes and the onset of the clinical phase of AD will facilitate the design and timing of therapeutic interventions aimed at modifying the course of this illness. Funding Science and Industry Endowment Fund (Australia), The Commonwealth Scientific and Industrial Research Organisation (Australia), The National Health and Medical Research Council of Australia Program and Project Grants, the Austin Hospital Medical Research Foundation, Victorian State Government, The Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association.

Myocardial Fatty Acid Metabolism in Health and Disease

Abstract: There is a constant high demand for energy to sustain the continuous contractile activity of the heart, which is met primarily by the β-oxidation of long-chain fatty acids. The control of fatty acid β-oxidation is complex and is aimed at ensuring that the supply and oxidation of the fatty acids is sufficient to meet the energy demands of the heart. The metabolism of fatty acids via β-oxidation is not regulated in isolation; rather, it occurs in response to alterations in contractile work, the presence of competing substrates (i.e., glucose, lactate, ketones, amino acids), changes in hormonal milieu, and limitations in oxygen supply. Alterations in fatty acid metabolism can contribute to cardiac pathology. For instance, the excessive uptake and β-oxidation of fatty acids in obesity and diabetes can compromise cardiac function. Furthermore, alterations in fatty acid β-oxidation both during and after ischemia and in the failing heart can also contribute to cardiac pathology. This paper reviews the regulation of myocardial fatty acid β-oxidation and how alterations in fatty acid β-oxidation can contribute to heart disease. The implications of inhibiting fatty acid β-oxidation as a potential novel therapeutic approach for the treatment of various forms of heart disease are also discussed.