Source Of Contrast Research Articles

Use of Magnetization Transfer Contrast MRI to Detect Early Molecular Pathology in Alzheimer's Disease

The purpose of this study was to determine if magnetization transfer contrast (MTC) imaging could be used to detect early macromolecular accumulation in a mouse model of early Alzheimer's disease. We obtained MTC images at 9.4 T at three different age points in the Tg2576 mouse model of Alzheimer's disease. The Tg2576 mouse exhibits increased amyloid beta deposition that eventually progresses into amyloid beta plaque formation, increased hyper-phosphorylated tau but does not exhibit neurodegeneration. Our results show an increase in the MTC signal that predates plaque formation and reported learning and memory deficits in the Tg2576 mouse. This increase in the MTC signal was reversed in a model of antioxidant therapy. MTC magnetic resonance imaging can be used to detect early macromolecular changes in the Tg2576 mouse model of Alzheimer's disease. The source of the MTC contrast is likely complex and warrants further investigation in additional preclinical models that represent early and late stage Alzheimer's disease pathologies.

Motility imaging via optical coherence phase microscopy enables label-free monitoring of tissue growth and viability in 3D tissue-engineering scaffolds

As the field of tissue engineering continues to progress, there is a deep need for non-invasive, label-free imaging technologies that can monitor tissue growth and health within thick three-dimensional (3D) constructs. Amongst the many imaging modalities under investigation, optical coherence tomography (OCT) has emerged as a promising tool, enabling non-destructive in situ characterization of scaffolds and engineered tissues. However, the lack of optical contrast between cells and scaffold materials using this technique remains a challenge. In this communication, we show that mapping the optical phase fluctuations resulting from cellular viability and motility allows for the distinction of live cells from their surrounding scaffold environment. Motility imaging was performed via a common-path optical coherence phase microscope (OCPM), an OCT modality that has been shown to be sensitive to nanometer-level fluctuations. More specifically, we examined the development of human adipose-derived stem cells and/or murine pre-osteoblasts within two distinct scaffold systems, commercially available alginate sponges and custom-microfabricated poly(d, l-lactic-co-glycolic acid) fibrous scaffolds. Cellular motility is demonstrated as an endogenous source of contrast for OCPM, enabling real-time, label-free monitoring of 3D engineered tissue development.

Intravital Confocal and Two-Photon Imaging of Dual-Color Cells and Extracellular Matrix Mimics

We report our efforts in identifying optimal scanning laser microscope parameters to study cells in three-dimensional culture. For this purpose we studied contrast of extracellular matrix (ECM) mimics, as well as signal attenuation, and bleaching of red and green fluorescent protein labeled cells. Confocal backscattering, second harmonic generation (SHG), and autofluorescence were sources of contrast in ECM mimics. All common ECM mimics exhibit contrast observable with confocal reflectance microscopy. SHG imaging on collagen I based hydrogels provides high contrast and good optical penetration depth. Agarose is a useful embedding medium because it allows for large optical penetration and exhibits minimal autofluorescence. We labeled breast cancer cells' outline with DsRed2 and nucleus with enhanced green fluorescent protein (eGFP). We observed significant difference both for the bleaching rates of eGFP and DsRed2 where bleaching is strongest during two-photon excitation (TPE) and smallest during confocal imaging. But for eGFP the bleaching rate difference is smaller than for DsRed2. After a few hundred microns depth in a collagen I hydrogel, TPE fluorescence of DsRed2 becomes twice as strong compared to confocal imaging. In fibrin and agarose gels, the imaging depth will need to be beyond 1 mm to notice a TPE advantage.

Confocal microscopy in the diagnosis of melanoma

Melanoma is the most deadly form of skin cancer of melanocytic origin. The tumor has a high malignant potential and early metastasis. Prognosis is directly linked to the stage of the disease. Diagnosing thin melanoma at an early stage offers patients their best chance for survival. The crucial innovation in the early recognition of melanoma was the development of in vivo examination of the skin in high-resolution, by confocal microscopy. Confocal microscopy and its modifications provides a ?virtual biopsy?, owing to melanosomes and melanin, which are a source of endogenous contrast. Confocal scanning laser microscopy (CSLM) provides visualization of microanatomical structures and cellular detail in real time (pigmented keratinocytes, melanocytes, melanosomes and melanophages) in the epidermis, dermoepidermal junction and superficial dermis at a resolution equivalent to the resolution of conventional microscopes.

Intelligent Design of Nano-Scale Molecular Imaging Agents

Visual representation and quantification of biological processes at the cellular and subcellular levels within living subjects are gaining great interest in life science to address frontier issues in pathology and physiology. As intact living subjects do not emit any optical signature, visual representation usually exploits nano-scale imaging agents as the source of image contrast. Many imaging agents have been developed for this purpose, some of which exert nonspecific, passive, and physical interaction with a target. Current research interest in molecular imaging has mainly shifted to fabrication of smartly integrated, specific, and versatile agents that emit fluorescence or luminescence as an optical readout. These agents include luminescent quantum dots (QDs), biofunctional antibodies, and multifunctional nanoparticles. Furthermore, genetically encoded nano-imaging agents embedding fluorescent proteins or luciferases are now gaining popularity. These agents are generated by integrative design of the components, such as luciferase, flexible linker, and receptor to exert a specific on–off switching in the complex context of living subjects. In the present review, we provide an overview of the basic concepts, smart design, and practical contribution of recent nano-scale imaging agents, especially with respect to genetically encoded imaging agents.

Advancing Optical Imaging for Breast Margin Assessment: An Analysis of Excisional Time, Cautery, and Patent Blue Dye on Underlying Sources of Contrast

Breast conserving surgery (BCS) is a recommended treatment for breast cancer patients where the goal is to remove the tumor and a surrounding rim of normal tissue. Unfortunately, a high percentage of patients return for additional surgeries to remove all of the cancer. Post-operative pathology is the gold standard for evaluating BCS margins but is limited due to the amount of tissue that can be sampled. Frozen section analysis and touch-preparation cytology have been proposed to address the surgical needs but also have sampling limitations. These issues represent an unmet clinical need for guidance in resecting malignant tissue intra-operatively and for pathological sampling. We have developed a quantitative spectral imaging device to examine margins intra-operatively. The context in which this technology is applied (intra-operative or post-operative setting) is influenced by time after excision and surgical factors including cautery and the presence of patent blue dye (specifically Lymphazurin™, used for sentinel lymph node mapping). Optical endpoints of hemoglobin ([THb]), fat ([β-carotene]), and fibroglandular content via light scattering (<µs’>) measurements were quantified from diffuse reflectance spectra of lumpectomy and mastectomy specimens using a Monte Carlo model. A linear longitudinal mixed-effects model was used to fit the optical endpoints for the cautery and kinetics studies. Monte Carlo simulations and tissue mimicking phantoms were used for the patent blue dye experiments. [THb], [β-carotene], and <µs’> were affected by <3.3% error with <80 µM of patent blue dye. The percent change in [β-carotene], <µs’>, and [β-carotene]/<µs’> was <14% in 30 minutes, while percent change in [THb] was >40%. [β-carotene] and [β-carotene]/<µs’> were the only parameters not affected by cautery. This work demonstrates the importance of understanding the post-excision kinetics of ex-vivo tissue and the presence of cautery and patent blue dye for breast tumor margin assessment, to accurately interpret data and exploit underling sources of contrast.

Nanometer to micrometer scaled inhomogeneous etching of bulk metallic glasses by ion sputtering

In order to faithfully investigate the microscopic and mesoscopic structures of bulk metallic glass (BMG) materials, inhomogeneous contrast in nanometer to micrometer scale in BMG specimens has been throughoutly studied by transmission electron microscopy (TEM), atomic force microscopy (AFM) and scanning electron microscopy (SEM). It is found that ion-milling induced surface roughening and pattern formation are the source of the inhomogeneous contrast in TEM images of BMG samples. Additionally, high resolution TEM and X-ray energy dispersive spectroscopy investigations rule out structure or composition changes in the specimens. The dynamic roughening process during ion-milling as well as saturated pattern sizes are revealed from Zr-, Cu-, Fe- and Mg-based BMGs. The understanding of this inhomogeneous etching in BMG specimens is critical for recently intensive TEM studies on microscopic and mesoscopic inhomogeneities of BMGs.

Constrained source space imaging: Application to fast, region‐based functional MRI

A new technique called constrained source space imaging is introduced that holds promise for ultrafast acquisition of functional magnetic resonance imaging data. A sparse set of arbitrarily positioned, coarse voxels is first localized using radiofrequency selective excitation, from which magnetization signals are separated using only the spatial sensitivities of multichannel receiver coils, without the need for k-space encoding using imaging gradients. This method permits very fast acquisitions of targeted magnetization without complex or time-consuming image reconstruction techniques. Furthermore, because the data acquisition is performed without imaging gradients, T2* decays can be densely sampled and processed for contrast enhancement to improve functional magnetic resonance imaging data quality. Here, the constrained source space imaging technique is validated in proof-of-concept form, for a simple functional magnetic resonance imaging motor task using a prototype dual-band stimulated echo acquisition mode excitation to image four voxels at TR = 250 ms. Results demonstrate good voxel signal separation and good characterization of hemodynamic responses in primary motor cortices (M1) and supplementary motor areas through T2* fitting of the measured signals. With further refinement, the constrained source space imaging method has potential utility in a priori ROI-based functional magnetic resonance imaging experiments with TR values under 100 ms. Rapid, multivoxel measurements of other sources of MR signal contrast are also possible.

The Effects of Segmentation and Spatial Geometry on the Tilt Illusion

In the tilt illusion, when the orientation of the center and surround gratings differ by a small angle, the center grating appears to tilt away from the surround orientation (repulsion); however, for a large difference in angle, the center appears to tilt towards the surround orientation (attraction). Orientation perception therefore depends strongly on the context. Changes in two-dimensional configuration or three-dimensional scene geometry may alter the segmentation features between the center and surround, and cause variations in central orientation perception. We first measured the effect of two sources of segmentation information, contrast, and stereo disparity differences, on the strength of the tilt illusion in human observers. We observed: when the center contrast was high, both low-contrast surround and stereo depth segmentation cues reduced the amplitude of both the repulsion and attraction effect, relative to a high-contrast, 2D surround; a higher surround contrast (70%) relative to the center (10%) decreased the repulsion effect but increased both the range and magnitude of the attraction effect. Next, we examined the effect of perceptual grouping behind a 3D occluder ring between the center and surround on perceived central orientation. We observed significantly stronger tilt repulsion effects across occlusion than the condition with a ring at the same plane as the center and surround. We also found that the tilt repulsion is selective for the peripheral location of the surround. These results suggest that scene organization plays a role in central orientation perception.

Magnetization transfer‐based 3D visualization of foot peripheral nerves

To investigate magnetization transfer (MT) effects as a new source of contrast for imaging and tracking of peripheral foot nerves. Two sets of 3D spoiled gradient-echo images acquired with and without a saturation pulse were used to generate MT ratio (MTR) maps of 260 μm in-plane resolution for eight volunteers at 3T. Scan parameters were adjusted to minimize signal loss due to T2 dephasing, and a dedicated coil was used to improve the inherently low signal-to-noise ratio of small voxels. Resulting MTR values in foot nerves were compared with those in surrounding muscle tissue. Average MTR values for muscle (45.5 ± 1.4%) and nerve (21.4 ± 3.1%) were significantly different (P < 0.0001). In general, the difference in MTR values was sufficiently large to allow for intensity-based segmentation and tracking of foot nerves in individual subjects. This procedure was termed MT-based 3D visualization. The MTR serves as a new source of contrast for imaging of peripheral foot nerves and provides a means for high spatial resolution tracking of these structures. The proposed methodology is directly applicable on standard clinical MR scanners and could be applied to systemic pathologies, such as diabetes.

D.P.24 Identification of muscle necrosis in mdx mice using optical birefringence imaging

Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy, resulting in muscle degeneration and necrosis. Healthy skeletal muscle has a high degree of birefringence, caused by the regular arrangement of myofibrils. Birefringence decreases when the muscle becomes inflamed or necrotic and this arrangement breaks down. Hence birefringence is usable as a source of image contrast for identifying regions of damage. The mdx mouse is a well-established animal model for DMD. Assessment of the extent of muscle damage and necrosis in these mice is performed by analysis of histological sections, but this requires excision and fixation of the tissue. Optical coherence tomography (OCT) is an imaging modality which uses reflected near-infrared light to provide high resolution (≈10μm) images with a penetration depth of 1–2mm. Early studies on ex vivo tissue have shown OCT’s ability to differentiate between regions of intact myofibers and necrotic lesions. Other studies have demonstrated in vivo imaging deep below the surface by using OCT probes housed within hypodermic needles. Detection of birefringence is also possible using a variant known as polarisation-sensitive OCT (PS-OCT). In birefringent tissue such as muscle this can provide better contrast than regular OCT. In this study, we present a novel, automated, image analysis technique to quantify the birefringence present in a PS-OCT scan. The technique measures the average birefringence of muscle within an area 10×10μm across by 500μm deep. By translating this analysis across the tissue, we created a 2D image for each sample, representing variations in birefringence over the sample. Validated against H&E histology, the technique shows a strong correlation, with regions of low and high birefringence corresponding to areas of necrosis/inflammation and intact myofibers, respectively. This technique has the potential for in vivo assessment of muscle pathology without the need for staining or labelling.

Third harmonic microscopy of intrinsic and induced material anisotropy in dielectric thin films

Third harmonic (TH) microscopy with circularly polarized illumination directly reveals material anisotropy owing to suppression of background optical signals from isotropic media. Because optical thin films and their substrates are expected to be highly isotropic, TH microscopy presents a path to study induced and intrinsic anisotropy in films, providing both insight into laser-induced material modification that precedes damage and feedback about the deposition process. Because nanoscale defects and material strain influence the damage behavior of films, we examined TH sensitivity to similar sources of contrast. We demonstrate imaging of individual 10 nm colloidal gold nanoparticles and 100 mN nanoindentations in fused silica both with signal-to-noise ratio (SNR) ≥ 100∶1. We present TH images (SNR ≥ 210∶1) of sites exposed to femtosecond laser pulses below damage in 100 nm HfO2 films that are barely visible (SNR ≤ 2.3∶1) with Nomarski and polarization imaging, traditional microscopic techniques known to display contrast for material anisotropy. At our detection limit (320 mW, 50 fs, 790 nm, ≈ 106 photomultiplier tube gain), we examined root mean square in the TH image of nascent films that correlated to the film's macrostrain. TH microscopy presents a relatively simple all-optical method to monitor nanoscale anisotropy in thin films during exposure to high-intensity radiation and during deposition.

PP084. Magnetic resonance imaging measurements of T2 relaxation times within contrasting regions of murine placenta is dependent upon blood flow

It has been postulated that reduced placental perfusion as a result of abnormal placental implantation is the initiating event that leads to the maternal symptoms of preeclampsia. To be able to directly measure blood flow and perfusion in the placenta in experimental models of preeclampsia would provide valuable insight into the structural abnormalities of this syndrome. Magnetic resonance imaging (MRI) offers visualization of anatomy and analysis of changes in tissue morphology and function including blood flow and perfusion. The major source of image contrast in MRI comes from the variation in relaxation times between tissues. Previously, human placenta has appeared as fairly homogeneous in studies of T1 and T2 relaxation times, with no internal morphology apparent. The aim of this study was to investigate, using much higher field strengths (11.7Tesla) and much higher resolution than have been used previously, whether structural inhomogeneities in the placenta can be discerned by T2 mapping and whether T2 mapping is capable of detecting structural abnormalities that may affect blood flow in a preeclamptic placenta. Magnetic resonance images were acquired on an anaesthetised C57BL/6JArc mouse placed in a vertical animal probe using a Bruker Avance 11.7Tesla wide-bore spectrometer with micro-imaging probe capable of generating gradients of 0.45T/m. T2 measurements were acquired using an MSME sequence protocol (Bruker MSME-T2-map) with an in-plane resolution of 0.1-0.2mm. Matlab was used to generate R2 (i.e., 1/T2) maps from the acquired data with the T2 values being calculated from selected regions of interest within 5 individual placenta. Additional T2 measurements were acquired on the same slices immediately after blood flow was reduced to zero. Three distinct regions of T2 contrast were discerned in the mouse placenta, likely correlating to the labrynthine, junctional and decidual zones. The contrast between the inner two regions was substantially abrogated when blood flow ceased upon euthanasia of the animal by anaesthetic overdose (p<0.005), whereas the decidual region remained unchanged (p=0.13). These results demonstrate that morphologically distinct regions of the mouse placenta can be detected through the mapping of T2 relaxation times. The contrast between regions is lost when blood flow ceases and the placenta becomes homogeneous in appearance, suggesting that differences in T2 relaxation times across regions of the placenta may be used to non-invasively examine structural abnormalities and blood flow in the placenta of experimental animal models of preeclampsia.

Label-Free Imaging of Basement Membranes Differentiates Normal, Precancerous, and Cancerous Colonic Tissues by Second-Harmonic Generation Microscopy

Since changes in the basement membranes are the critical indicators for differentiating normal, precancerous, and cancerous colonic tissues, direct visualization of these warning signs is essential for the early diagnosis and treatment of colonic cancer. Here, we present that second harmonic generation (SHG) microscopy can probe the changes of basement membranes in different colonic cancer stages. Our results also show the capability of using the quantitative analyses of images for quantifying these changes in different cancer stages. These results suggest that SHG microscopy has the potential in label-freely imaging the changes of basement membranes for effectively distinguishing between normal, precancerous, and cancerous colonic tissues. To our knowledge, this is the first demonstration of the dynamics of basement membrane changes in different colonic cancer stages using entirely intrinsic source of contrast.

Analysis of the BOLD characteristics in pass‐band bSSFP fMRI

Balanced steady-state free precession (bSSFP) has been proposed as an alternative method to acquire the blood oxygenation level dependent contrast. Particularly, pass-band bSSFP functional magnetic resonance imaging (fMRI) is believed to utilize the T2 sensitivity of bSSFP in a relatively wide and flat off-resonance frequency band of the bSSFP profile. The method has a potential to provide higher signal to noise ratio (SNR) efficiency with reduced imaging artifacts compared to conventional approaches. Previous experimental results suggested that the level of the functional contrast and its characteristics are significantly influenced by the sequence parameters. However, few of these contrast characteristics have been investigated systematically. In this study, a computer simulation was performed to investigate the sources of functional contrast and the influence of scan parameters on the functional contrast to elucidate the contrast characteristics of pass-band bSSFP fMRI. Experiments were performed to validate the simulation results.

The γ parameter of the stretched-exponential model is influenced by internal gradients: Validation in phantoms

In this paper, we investigate the image contrast that characterizes anomalous and non-Gaussian diffusion images obtained using the stretched exponential model. This model is based on the introduction of the γ stretched parameter, which quantifies deviation from the mono-exponential decay of diffusion signal as a function of the b-value. To date, the biophysical substrate underpinning the contrast observed in γ maps, in other words, the biophysical interpretation of the γ parameter (or the fractional order derivative in space, β parameter) is still not fully understood, although it has already been applied to investigate both animal models and human brain. Due to the ability of γ maps to reflect additional microstructural information which cannot be obtained using diffusion procedures based on Gaussian diffusion, some authors propose this parameter as a measure of diffusion heterogeneity or water compartmentalization in biological tissues. Based on our recent work we suggest here that the coupling between internal and diffusion gradients provide pseudo-superdiffusion effects which are quantified by the stretching exponential parameter γ. This means that the image contrast of Mγ maps reflects local magnetic susceptibility differences (Δχm), thus highlighting better than T2∗ contrast the interface between compartments characterized by Δχm. Thanks to this characteristic, Mγ imaging may represent an interesting tool to develop contrast-enhanced MRI for molecular imaging.The spectroscopic and imaging experiments (performed in controlled micro-beads dispersion) that are reported here, strongly suggest internal gradients, and as a consequence Δχm, to be an important factor in fully understanding the source of contrast in anomalous diffusion methods that are based on a stretched exponential model analysis of diffusion data obtained at varying gradient strengths g.

Imaging Odor-Evoked Activities in the Mouse Olfactory Bulb using Optical Reflectance and Autofluorescence Signals

In the brain, sensory stimulation activates distributed populations of neurons among functional modules which participate to the coding of the stimulus. Functional optical imaging techniques are advantageous to visualize the activation of these modules in sensory cortices with high spatial resolution. In this context, endogenous optical signals that arise from molecular mechanisms linked to neuroenergetics are valuable sources of contrast to record spatial maps of sensory stimuli over wide fields in the rodent brain. Here, we present two techniques based on changes of endogenous optical properties of the brain tissue during activation. First the intrinsic optical signals (IOS) are produced by a local alteration in red light reflectance due to: (i) absorption by changes in blood oxygenation level and blood volume (ii) photon scattering. The use of in vivo IOS to record spatial maps started in the mid 1980's with the observation of optical maps of whisker barrels in the rat and the orientation columns in the cat visual cortex1. IOS imaging of the surface of the rodent main olfactory bulb (OB) in response to odorants was later demonstrated by Larry Katz's group2. The second approach relies on flavoprotein autofluorescence signals (FAS) due to changes in the redox state of these mitochondrial metabolic intermediates. More precisely, the technique is based on the green fluorescence due to oxidized state of flavoproteins when the tissue is excited with blue light. Although such signals were probably among the first fluorescent molecules recorded for the study of brain activity by the pioneer studies of Britton Chances and colleagues3, it was not until recently that they have been used for mapping of brain activation in vivo. FAS imaging was first applied to the somatosensory cortex in rodents in response to hindpaw stimulation by Katsuei Shibuki's group4. The olfactory system is of central importance for the survival of the vast majority of living species because it allows efficient detection and identification of chemical substances in the environment (food, predators). The OB is the first relay of olfactory information processing in the brain. It receives afferent projections from the olfactory primary sensory neurons that detect volatile odorant molecules. Each sensory neuron expresses only one type of odorant receptor and neurons carrying the same type of receptor send their nerve processes to the same well-defined microregions of ˜100μm3 constituted of discrete neuropil, the olfactory glomerulus (Fig. 1). In the last decade, IOS imaging has fostered the functional exploration of the OB5, 6, 7 which has become one of the most studied sensory structures. The mapping of OB activity with FAS imaging has not been performed yet. Here, we show the successive steps of an efficient protocol for IOS and FAS imaging to map odor-evoked activities in the mouse OB.

Imaging Odor-Evoked Activities in the Mouse Olfactory Bulb using Optical Reflectance and Autofluorescence Signals

In the brain, sensory stimulation activates distributed populations of neurons among functional modules which participate to the coding of the stimulus. Functional optical imaging techniques are advantageous to visualize the activation of these modules in sensory cortices with high spatial resolution. In this context, endogenous optical signals that arise from molecular mechanisms linked to neuroenergetics are valuable sources of contrast to record spatial maps of sensory stimuli over wide fields in the rodent brain.Here, we present two techniques based on changes of endogenous optical properties of the brain tissue during activation. First the intrinsic optical signals (IOS) are produced by a local alteration in red light reflectance due to: (i) absorption by changes in blood oxygenation level and blood volume (ii) photon scattering. The use of in vivo IOS to record spatial maps started in the mid 1980's with the observation of optical maps of whisker barrels in the rat and the orientation columns in the cat visual cortex1. IOS imaging of the surface of the rodent main olfactory bulb (OB) in response to odorants was later demonstrated by Larry Katz's group2. The second approach relies on flavoprotein autofluorescence signals (FAS) due to changes in the redox state of these mitochondrial metabolic intermediates. More precisely, the technique is based on the green fluorescence due to oxidized state of flavoproteins when the tissue is excited with blue light. Although such signals were probably among the first fluorescent molecules recorded for the study of brain activity by the pioneer studies of Britton Chances and colleagues3, it was not until recently that they have been used for mapping of brain activation in vivo. FAS imaging was first applied to the somatosensory cortex in rodents in response to hindpaw stimulation by Katsuei Shibuki's group4.The olfactory system is of central importance for the survival of the vast majority of living species because it allows efficient detection and identification of chemical substances in the environment (food, predators). The OB is the first relay of olfactory information processing in the brain. It receives afferent projections from the olfactory primary sensory neurons that detect volatile odorant molecules. Each sensory neuron expresses only one type of odorant receptor and neurons carrying the same type of receptor send their nerve processes to the same well-defined microregions of ˜100μm3 constituted of discrete neuropil, the olfactory glomerulus (Fig. 1). In the last decade, IOS imaging has fostered the functional exploration of the OB5, 6, 7 which has become one of the most studied sensory structures. The mapping of OB activity with FAS imaging has not been performed yet.Here, we show the successive steps of an efficient protocol for IOS and FAS imaging to map odor-evoked activities in the mouse OB.

Near-Infrared Optical Mammography for Breast Cancer Detection with Intrinsic Contrast

Optical methods to detect breast cancer on the basis of its increased opacity have been explored for some time. These methods have matured to a point in which they are capable of quantifying the optical properties of breast tissue and translating them into measures of concentrations of relevant tissue components. In particular, near-infrared spectroscopy has been employed to determine the concentrations of hemoglobin, water, and lipids, as well as oxygen saturation of hemoglobin and optical scattering properties in normal and cancerous breast tissue. Dynamic optical measurements can also identify abnormal hemodynamic patterns associated with breast cancer. We review, in this article, a number of results in the field, which show that cancerous tissue is associated with higher hemoglobin and water concentrations, and a lower lipid concentration with respect to normal breast tissue. Indications that breast cancers are characterized by lower hemoglobin saturation and stronger scattering decay as a function of wavelength are less robust, with variable results reported in the literature. Intrinsic sources of optical contrast associated with breast cancer can also be used to monitor individual response to neoadjuvant therapy.

Phase contrast MRI is an early marker of micrometastatic breast cancer development in the rat brain

The early growth of micrometastatic breast cancer in the brain often occurs through vessel co-option and is independent of angiogenesis. Remodeling of the existing vasculature is an important step in the evolution of co-opting micrometastases into angiogenesis-dependent solid tumor masses. The purpose of this study was to determine whether phase contrast MRI, an intrinsic source of contrast exquisitely sensitive to the magnetic susceptibility properties of deoxygenated hemoglobin, could detect vascular changes occurring independent of angiogenesis in a rat model of breast cancer metastases to the brain. Twelve nude rats were administered 10(6) MDA-MB-231BRL 'brain-seeking' breast cancer cells through intracardiac injection. Serial, multiparametric MRI of the brain was performed weekly until metastatic disease was detected. The results demonstrated that images of the signal phase (area under the receiver operating characteristic curve, 0.97) were more sensitive than T(2)* gradient echo magnitude images (area under the receiver operating characteristic curve, 0.73) to metastatic brain lesions. The difference between the two techniques was probably the result of the confounding effects of edema on the magnitude of the signal. A region of interest analysis revealed that vascular abnormalities detected with phase contrast MRI preceded tumor permeability measured with contrast-enhanced MRI by 1-2 weeks. Tumor size was correlated with permeability (R(2)= 0.23, p < 0.01), but phase contrast was independent of tumor size (R(2)= 0.03). Histopathologic analysis demonstrated that capillary endothelial cells co-opted by tumor cells were significantly enlarged, but less dense, relative to the normal brain vasculature. Although co-opted vessels were vascular endothelial growth factor-negative, vessels within larger tumor masses were vascular endothelial growth factor-positive. In conclusion, phase contrast MRI is believed to be sensitive to vascular remodeling in co-opting brain tumor metastases independent of sprouting angiogenesis, and may therefore aid in preclinical studies of angiogenic-independent tumors or in the monitoring of continued tumor growth following anti-angiogenic therapy. Published 2011. This article is a US Government work and is in the public domain in the USA.