Classes Of Imaging Markers

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Aside from their statistical classification as nominal, ordinal, or continuous data, imaging markers can be categorized as morphological, compositional, or process related. Morphological markers relate most closely to the traditional concept of anatomical imaging and include a variety of dimensional and geometrical measures. Examples include radiographic vertebral morphometry in osteoporosis; radiographic OARSI (Osteoarthritis Research Society, International) scoring [1] or whole organ MRI scoring (WORMS) [2,3] in osteoarthritis, radiographic Sharp scoring of bone erosions and joint-space narrowing in rheumatoid arthritis [4,5]; sonographic measurement of carotid intima-media thickness; MRI measurements of entorhinal cortex and hippocampal volume in Alzheimer's disease [6]; and dimensional measurements of tumor size in cancer. The technical challenge in all of these morphological assessments is edge detection and image segmentation. These depend on spatial resolution and image contrast between the structure of interest and background tissue, and both of these image parameters in turn depend on the details of the acquisition technique used. Therefore, success in morphological image analysis requires sophistication and experience in designing imaging protocols as well as a clear understanding of how different protocol decisions will affect the measurement algorithm to be used (Figs. 4 and 5).

A subcategory of morphological markers are measures that relate to the microstructural integrity of tissues. An emerging MRI technique, known as diffusion-weighted imaging, falls into this category. Diffusion-weighted imaging derives from the physical, random (Brownian) motion of water molecules. Importantly, the microenvironment of water molecules critically influences the freedom, or "mean free path," of diffusion. Intra- and extracellular apparent diffusion coefficients differ markedly. The "effective" diffusion coefficient, measured across an image pixel, typically represents an average of the contained diffusion environments, allowing delineation of regions of cellular swelling (e.g., in ischemia) or necrosis. The close correlation of diffusion-weighted images and derived apparent diffusion coefficient maps of tumors to postmortem histological sectioning and staining suggests a role for diffusion weighted imaging as a tool for virtual biopsy in vivo (Fig. 6). Diffusion-weighted imaging is also useful in stroke, as early acute changes in stroke associated with cytotoxic edema affect the microenvironment of local water molecules. Measuring the volume of regions of hyperintense signal in diffusion-weighted MR images captures this change and thereby helps estimate ischemic lesion size. A refinement of diffusion-weighted imaging is diffusion-tensor imaging. This technique maps the direction of water diffusion within anisotropic tissues, such as the brain (Fig. 7). Decreased anisotropy in the brain indicates disruption of white matter fiber tracts in neurodegenerative disorders, such as multiple sclerosis and Alzheimer's disease. Micro-CT and micro-MRI measurements of trabecular density, trabecular connectivity, and fractal dimension in bone are examples of microstructural markers applicable to osteoporosis [7,8]. In arthritis imaging, increased T2 relaxation of articular cartilage on MRI reflects disruption of the micro-organization of matrix collagen fibrils [9,10] (Fig. 8). Novel optical imaging techniques, such as optical coherence tomography (Fig. 9), not only provide very high spatial resolution (10 mm) but can also be combined with absorption or polarization spectroscopy to probe the microstructural integrity of thin tissues, such as articular cartilage or vascular walls.

Figure 4 Image acquisition dictates the scope of image analysis possible. Delineating the margins of a lesion for dimensional measurements depends on image contrast and spatial resolution. (A) Tl-weighted MRI image of a metastatic lesion in L3. The lesion margins are well-defined because of the intrinsic contrast of the low signal intensity of the lesion against the high signal intensity of the residual marrow fat. The fat-suppressed T2-weighted image of the same spine (B) shows greater contrast and a correspondingly greater extent of involvement of the vertebral body by tumor. Accordingly, decisions about the image acquisition technique affect the accuracy and precision of dimensional measurements. (Courtesy of Synarc, Inc., with permission.)

Figure 4 Image acquisition dictates the scope of image analysis possible. Delineating the margins of a lesion for dimensional measurements depends on image contrast and spatial resolution. (A) Tl-weighted MRI image of a metastatic lesion in L3. The lesion margins are well-defined because of the intrinsic contrast of the low signal intensity of the lesion against the high signal intensity of the residual marrow fat. The fat-suppressed T2-weighted image of the same spine (B) shows greater contrast and a correspondingly greater extent of involvement of the vertebral body by tumor. Accordingly, decisions about the image acquisition technique affect the accuracy and precision of dimensional measurements. (Courtesy of Synarc, Inc., with permission.)

Other imaging markers provide information about the biochemical composition of tissues. In contrast to biochemical markers assayed in serum, urine, or other body fluids, compositional imaging markers map the spatial distribution of tissue constituents, and can in some cases quantify steady-state tissue concentrations of certain constituents. Bone mineral density measured with DXA is an example of this class of marker used in the study of osteoporosis. In neurodegenerative diseases, such as Alzheimer's disease and multiple sclerosis,

Figure 5 Computer-assisted image analysis. (A) CT image of a liver containing several metastatic lesions and the orthogonal dimensions (cross-product = 3.0 cm2) of one lesion in the right lobe. (B) Computerized segmentation of the lesions to measure their volumes. However, because of improper thresholding several lesions are not detected and the volumes of the ones that are identified are underestimated. (C) Reader-corrected segmentation allowing accurate volume quantification. Optimal performance in image analysis thus comes from integrating expert judgment from the clinical-trials radiologist with the computing power of the measurement algorithm. (Courtesy of Synarc, Inc., with permission.)

Figure 5 Computer-assisted image analysis. (A) CT image of a liver containing several metastatic lesions and the orthogonal dimensions (cross-product = 3.0 cm2) of one lesion in the right lobe. (B) Computerized segmentation of the lesions to measure their volumes. However, because of improper thresholding several lesions are not detected and the volumes of the ones that are identified are underestimated. (C) Reader-corrected segmentation allowing accurate volume quantification. Optimal performance in image analysis thus comes from integrating expert judgment from the clinical-trials radiologist with the computing power of the measurement algorithm. (Courtesy of Synarc, Inc., with permission.)

MR spectroscopy and spectroscopic imaging of n-acetylaspartate, an amino acid specific in the brain to neuronal tissue, combined with spectroscopic measurements of myo-inositol, a glial marker, can greatly increase the sensitivity and specificity of brain atrophy measurements (Fig. 10). Coronary calcification score using electron-beam computed tomography (CT) or spiral multislice (multirow detector) CT is a compositional marker shown to be an earlier and

Figure 6 Diffusion-weighted MRI in an experimental RIF-1 tumor in a rodent model. Diffusion-weighted MRI allows delineation of the necrotic center (higher apparent diffusion coefficient [ADC]) compared to surrounding viable tissue (lower ADC). Correlation with histological sectioning suggests the role of diffusion-weighted MRI as a "noninvasive biopsy." (Courtesy of K. Helmer, Worcester Polytechnic Institute.) (See color insert.)

ADC map derived from diffusion weighted MR1 Histology

Figure 6 Diffusion-weighted MRI in an experimental RIF-1 tumor in a rodent model. Diffusion-weighted MRI allows delineation of the necrotic center (higher apparent diffusion coefficient [ADC]) compared to surrounding viable tissue (lower ADC). Correlation with histological sectioning suggests the role of diffusion-weighted MRI as a "noninvasive biopsy." (Courtesy of K. Helmer, Worcester Polytechnic Institute.) (See color insert.)

Figure 7 Diffusion-tensor MRI. Vector map showing the preferred orientation of white-matter tracts in the human brain from a diffusion-tensor imaging examination. The color map shows the orientation of the tracts in a medial-lateral (red), anterior-posterior (green), and through plane (blue) composite. (Courtesy of M. Moseley, Synarc, Inc. and Sanford University.) (See color insert.)

Figure 7 Diffusion-tensor MRI. Vector map showing the preferred orientation of white-matter tracts in the human brain from a diffusion-tensor imaging examination. The color map shows the orientation of the tracts in a medial-lateral (red), anterior-posterior (green), and through plane (blue) composite. (Courtesy of M. Moseley, Synarc, Inc. and Sanford University.) (See color insert.)

more precise predictor of cardiac events in asymptomatic patients with atherosclerotic risk factors than any other noninvasive screening method, including stress electrocardiogram (EKG), stress echocardiography, and thallium scintigraphy [11]. T2 relaxation is a compositional MRI marker of collagen content in fibrous tumors, such as fibrosarcoma, desmoid tumor, and neurosarcoma. As mentioned earlier, T2 relaxation can also be used as a measure of collagen organization and content in articular cartilage [10,12]. Proteoglycan content in articular cartilage also can be quantified by MRI in terms of the fixed negative charge density of the glycosaminoglycan moieties. This can be done by quantifying sodium concentration in cartilage using sodium MRI, as sodium is the primary cation in cartilage balancing the negative charge of constituent proteoglycans [13]. Alternatively, proteoglycans can be quantified by measuring the concentration of negatively charged MRI contrast agent, Gd-DTPA2" (through its effect on T1 relaxation) imbibed by cartilage in inverse

Figure 8 Cartilage-T2 mapping with MRI. (Lower panel) Axial T2 relaxation map of the articular cartilage of the patella generated with multiecho MRI at 3T. A focus of decreased T2 relaxation near the ridge is indicative of collagen matrix damage. The graph above shows the T2 profile of a line through this region of articular cartilage. (Courtesy of B. J. Dardzinski, Ph.D., University of Cincinnati College of Medicine.) (See color insert.)

Figure 8 Cartilage-T2 mapping with MRI. (Lower panel) Axial T2 relaxation map of the articular cartilage of the patella generated with multiecho MRI at 3T. A focus of decreased T2 relaxation near the ridge is indicative of collagen matrix damage. The graph above shows the T2 profile of a line through this region of articular cartilage. (Courtesy of B. J. Dardzinski, Ph.D., University of Cincinnati College of Medicine.) (See color insert.)

proportion to the fixed negative charge density of the tissue [14,15] (Fig. 11). Cationic contrast agents have also been shown to shorten articular cartilage T1 in proportion to proteoglycan content [16].

Process-related imaging markers include measures of tissue perfusion, blood volume, and microvascular permeability. These microvascular markers are promising tools in cancer clinical trials, particularly for angiostatic therapies that

Figure 9 Optical coherence tomography of articular cartilage. Optical coherence image (A) and corresponding histological section (B) demonstrates the exquisite spatial resolution of this technique. (Courtesy of Mark Brezinski, with permission.)

Figure 9 Optical coherence tomography of articular cartilage. Optical coherence image (A) and corresponding histological section (B) demonstrates the exquisite spatial resolution of this technique. (Courtesy of Mark Brezinski, with permission.)

halt tumor growth without necessarily reducing lesion size. Markers of perfusion include 99mTc-HMPAO SPECT, various parameters derived with Doppler ultrasound, and changes in T1 to T2* relaxation on dynamic MRI following bolus intravenous injection of Gd-DTPA. Perfusion deficits in stroke patients define

Figure 10 MR spectroscopy in Alzhemimer's disease. Proton MR spectroscopy is a powerful tool for evaluating metabolities in vivo. Measurements are usually made on a single voxel position in the region of interest. The ratio of n-acetylaspartate (NAA) to myo-inositol (mI) concentration (NAA/mI) has been shown to correlate with cognitive abilities in patients with probable Alzheimer's disease and in age-matched controls. (Courtesy of Synarc, Inc. with permission.)

Figure 10 MR spectroscopy in Alzhemimer's disease. Proton MR spectroscopy is a powerful tool for evaluating metabolities in vivo. Measurements are usually made on a single voxel position in the region of interest. The ratio of n-acetylaspartate (NAA) to myo-inositol (mI) concentration (NAA/mI) has been shown to correlate with cognitive abilities in patients with probable Alzheimer's disease and in age-matched controls. (Courtesy of Synarc, Inc. with permission.)

Figure 11 MRI markers of cartilage matrix integrity. (A) Sagittal inversion-recovery image of a knee following intravenous administration of Gd-DTPA shows a region of high signal intensity (arrow) in the patellar cartilage indicative of abnormal uptake of anionic Gd-DTPA, and therefore, local proteoglycan depletion. Cartilage in the trochlear groove (arrowhead) shows low signal intensity indicative of repulsion of Gd-DTPA by negatively charged proteoglycans. (B) Fat-suppressed, T2-weighted image of the same knee prior to Gd-DTPA injection shows a smaller focus of increased signal intensity (arrow) in the same location indicative of local collagen matrix loss. This is associated with subarticular marrow edema in the patella. (From Peterfy CG. The role of MR imaging in clinical research studies. Semin Musculoskelet Radiol 5(4): 365-378, 2001.)

Figure 11 MRI markers of cartilage matrix integrity. (A) Sagittal inversion-recovery image of a knee following intravenous administration of Gd-DTPA shows a region of high signal intensity (arrow) in the patellar cartilage indicative of abnormal uptake of anionic Gd-DTPA, and therefore, local proteoglycan depletion. Cartilage in the trochlear groove (arrowhead) shows low signal intensity indicative of repulsion of Gd-DTPA by negatively charged proteoglycans. (B) Fat-suppressed, T2-weighted image of the same knee prior to Gd-DTPA injection shows a smaller focus of increased signal intensity (arrow) in the same location indicative of local collagen matrix loss. This is associated with subarticular marrow edema in the patella. (From Peterfy CG. The role of MR imaging in clinical research studies. Semin Musculoskelet Radiol 5(4): 365-378, 2001.)

the region of tissue at risk for infarction and offer a potential endpoint for thrombolytic therapy. When combined with diffusion-weighted imaging, the perfusion/diffusion mismatch provides a marker for salvageable tissue. Alzheimer's patients exhibit regional perfusion deficits that have been shown to be predictive of future decline in cognitive ability, providing a method for enriching study populations with rapid progressors. Unfortunately, MRI-derived blood volume and vascular permeability measurements are currently restricted to the brain, where the blood-brain barrier normally restricts extravasation of Gd-DTPA. When this barrier is disrupted by inflammation or tumor neovascularity, Gd-DTPA diffuses into the local interstitium (Fig. 12). Because of its small molecular size, Gd-DTPA readily diffuses out of even normal vessels, precluding accurate estimation of blood volume (a measure of vessel density), permeability surface-area product, or fractional leak rate. These parameters can, however, be determined using macromolecular contrast agents, such as polylysine-chelated or albumin-chelated Gd-DTPA [17,18] (Fig. 13). Although, these macromolecular contrast agents are not currently approved for use in

Figure 12 Permeability mapping of brain tumors with MRI. Source MRI (A) and synthesized permeability map (B) from a low-grade brain tumor (grade II astrocytoma) show no significant difference in permeability between the tumor and healthy tissue. Soruce MRI (C) and permeability map (D) from a grade IV tumor (glioblastoma muliforme) quantitatively reveals a rine of high microvascular permeability, indicative of angiogenesis. (Courtesy of Heidi Roberts, with permission.)

Figure 12 Permeability mapping of brain tumors with MRI. Source MRI (A) and synthesized permeability map (B) from a low-grade brain tumor (grade II astrocytoma) show no significant difference in permeability between the tumor and healthy tissue. Soruce MRI (C) and permeability map (D) from a grade IV tumor (glioblastoma muliforme) quantitatively reveals a rine of high microvascular permeability, indicative of angiogenesis. (Courtesy of Heidi Roberts, with permission.)

humans, a number of companies are actively developing similar contrast agents that could be used for microvascular assessments. These techniques can also be used to evaluate synovium [19] and pre-erosive osteitis in rheumatoid arthritis and ischemic changes in the heart.

Nuclear medicine techniques such as positron emission tomogrpahy (PET) provide exquisite sensitivity for biochemical processes, such as metabolism. Using a radioactive tracer, such as fluorodeoxyglucose (18FDG), the metabolic pathway of glycolysis can be followed and focal regions of tracer accumulation

Figure 13 Identifying neovascularity with macromolecular MRI contrast. Conventional MRI contrast agents leak rapidly from both normal and abnormal extracranial vessels. However, macromolecular contrast media permeate only abnormal vascular walls in areas of inflammation or neovascularity.

can be monitored. An extensive array of novel radiolabeled probes is under development allowing numerous biochemical pathways and processes to be monitored and localized. Hypo- or hypermetabolism can be quantified and related, via multimodality image fusion, to results from other imaging modalities building up a composite picture of tissue dysfunction at a structural, cellular, vascular, and metabolic functional level.

Much of the development of these types of process markers is taking place in the emerging field of molecular imaging. Molecular imaging differs from conventional techniques in that it identifies specific gene products and intracellular processes using picomolar or micromolar quantities of specialized imaging probes. Reporter gene imaging exemplifies this approach and targets cell surface proteins or receptors, or intracellular enzyme activity, such as p53 tumor suppressor gene expression, initiated by therapy. A particularly intriguing aspect of molecular imaging research is the design of activated MR imaging agents. These imaging agents are engineered to remain inactive until "turned on" by specific enzymes, such as caspase or matrix metalloproteinases, to provide early detection of the onset of apoptosis, a cell cluster's transformation into cancer, or some other critical pathophysiological or therapeutic process of interest. Accordingly, molecular imaging shows great promise for clinical trials, provided researchers can figure out how to get these large molecules into cells and how to increase their MR signal potency sufficiently to image small concentrations of probe.

Aside from the theoretical implications of some of these innovations, a number of practical factors must be considered in selecting an imaging marker for a specific purpose in a clinical trial. The following section addresses this.

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