Toward Quantification: Microstructure and Magnetic Resonance Fingerprinting.

Quantitative magnetic resonance imaging (MRI) is a long-standing challenge. We advocate that the origin of the problem is the simplification applied in commonly used models of the MRI signal relation to the target parameters of biological tissues. Two research fields are briefly reviewed as ways to respond to the challenge of quantitative MRI, both experiencing an exponential growth right now. Microstructure MRI strives to build physiology-based models from cells to signal and, given the signal, back to the cells again. Magnetic resonance fingerprinting aims at efficient simultaneous determination of multiple signal parameters. The synergy of these yet disjoined approaches promises truly quantitative MRI with specific target-oriented diagnostic tools rather than universal imaging methods.

MR evaluation of vessel size imaging of human gliomas: Validation by histopathology.

PURPOSE: To compare the vessel size and the cerebral blood volume in human gliomas with histopathology. Vessel size imaging (VSI) is a dynamic susceptibility contrast method for the assessment of the vessel size in normal and pathological tissue. Previous publications in rodents showed a satisfactory conformity with the vessel size derived from histopathology. To assess the clinical value, further, the progression-free interval was determined and correlated. MATERIALS AND METHODS: Twenty-five gliomas (WHO grade °II [n = 10], °III [n = 3], °IV [n = 12]) were prospectively included and received a stereotaxic biopsy after VSI. The vessel size and the cerebral blood volume (CBV) were calculated in regions of interest at the tumor edge and correlated with the vessel size measured by histopathology. RESULTS: Both VSI and CBV showed a good correlation with the vessel size in histopathology (up to r = 0.84, P < 0.001, and r = 0.62, P < 0.001, respectively). Slope and offset of the linear regression (y = 0.77x + 0.36 µm) suggest that the size of normal capillaries is overestimated with VSI, while for grossly enlarged vessels an underestimation occurs. Both VSI and CBV were negatively correlated with the progression-free interval (r = -0.57, P = 0.008, and r = -0.50, P = 0.025, respectively). CONCLUSION: The correlation between VSI and vessel size from histopathology is in good accordance with the animal studies. The overestimation of small capillary sizes is also known from the animal trials. Vessel size and CBV showed similar results, both for the correlation with the histopathological vessel size and the progression-free interval.

Correlation of dynamic contrast-enhanced MRI perfusion parameters with angiogenesis and biologic aggressiveness of rectal cancer: Preliminary results.

PURPOSE: To investigate whether quantitative parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) are correlated with angiogenesis and biologic aggressiveness of rectal cancer. MATERIALS AND METHODS: A total of 46 patients with rectal cancer underwent DCE-MRI. Using a two-compartmental model, quantitative parameters (K(trans) , kep , ve , and iAUC) were calculated from the whole-transverse region of interest (ROI) and high K(trans) area ROI of entire tumors. Histological specimens were analyzed for tumor size; T/N stage; lymphatic, vascular, perineural invasion; expression of epidermal growth factor receptor (EGFR); and KRAS gene mutations. Tumor angiogenesis was evaluated based on the microvessel density (MVD) and the expression level of the vascular endothelial growth factor. Correlations of the DCE-MRI parameters with histological markers and angiogenesis were determined using Student's t-test and analysis of variance (ANOVA). RESULTS: The mean kep from high K(trans) area ROIs showed a significantly positive correlation with MVD (P = 0.030, r = 0.514, R(2) = 0.264). The mean kep from the whole-transverse ROIs showed a significant inverse correlation with T stage (T1 vs. T2-4, P = 0.021). EGFR-positive cancer displayed higher mean K(trans) (P = 0.045) and kep (P = 0.038) than EGFR-negative cancer in whole-transverse ROIs. CONCLUSION: These preliminary results suggest that the determination of kep of high K(trans) area permits the noninvasive estimation of tumor angiogenesis in rectal cancer and that DCE-MRI parameters can be used as imaging biomarkers to predict the biologic aggressiveness of the tumor and patient prognosis.

Blood tracer kinetics in the arterial tree.

Evaluation of blood supply of different organs relies on labeling blood with a suitable tracer. The tracer kinetics is linear: Tracer concentration at an observation site is a linear response to an input somewhere upstream the arterial flow. The corresponding impulse response functions are currently treated empirically without incorporating the relation to the vascular morphology of an organ. In this work we address this relation for the first time. We demonstrate that the form of the response function in the entire arterial tree is reduced to that of individual vessel segments under approximation of good blood mixing at vessel bifurcations. The resulting expression simplifies significantly when the geometric scaling of the vascular tree is taken into account. This suggests a new way to access the vascular morphology in vivo using experimentally determined response functions. However, it is an ill-posed inverse problem as demonstrated by an example using measured arterial spin labeling in large brain arteries. We further analyze transport in individual vessel segments and demonstrate that experimentally accessible tracer concentration in vessel segments depends on the measurement principle. Explicit expressions for the response functions are obtained for the major middle part of the arterial tree in which the blood flow in individual vessel segments can be treated as laminar. When applied to the analysis of regional cerebral blood flow measurements for which the necessary arterial input is evaluated in the carotid arteries, present theory predicts about 20% underestimation, which is in agreement with recent experimental data.

Therapy monitoring of skeletal metastases with whole-body diffusion MRI.

Current methods of assessing tumor response at skeletal sites with metastatic disease use a combination of imaging tests, serum and urine biochemical markers, and symptoms assessment. These methods do not always enable the positive assessment of therapeutic benefit to be made but instead provide an evaluation of progression, which then guides therapy decisions in the clinic. Functional imaging techniques such as whole-body diffusion magnetic resonance imaging (MRI) when combined with anatomic imaging and other emerging "wet" biomarkers can improve the classification of therapy response in patients with metastatic bone disease. A range of imaging findings can be seen in the clinic depending on the type of therapy and duration of treatment. Successful response to systemic therapy is usually depicted by reductions in signal intensity accompanied by apparent diffusion coefficient (ADC) increases. Rarer patterns of successful treatment include no changes in signal intensity accompanying increases in ADC values (T2 shine-through pattern) or reductions in signal intensity without ADC value changes. Progressive disease results in increases in extent/intensity of disease on high b-value images with variable ADC changes. Diffusion MRI therapy response criteria need to be developed and tested in prospective studies in order to address current, unmet clinical and pharmaceutical needs for reliable measures of tumor response in metastatic bone disease.

Quantitative cerebral blood flow with bolus tracking perfusion MRI: measurements in porcine model and comparison with H(2)(15)O PET.

PURPOSE: We recently presented a method for the quantitative measurement of the arterial input function which allows for determination of absolute cerebral blood flow (CBF) values without adjustable parameters. The aim of the present work is to estimate absolute CBF values by using this new technique and to compare it with the gold standard for cerebral perfusion, H(2)(15)O positron emission tomography. METHODS: Pigs (13) were comparatively investigated by each method performing multiple measurement runs. The reproducibility of both methods was assessed by a voxel-wise correlation of repeated measurements. An intersubject evaluation was performed on median whole-brain CBF estimates. RESULTS: The mean CBF (MRI) was 20±4mL/100g/min for gray matter, the mean CBF (positron emission tomography) was 24±6mL/100g/min for gray and white matter. The reproducibility for MRI correlated with r = 0.85 and P<0.0001, for positron emission tomography with r = 0.76 and P<0.0001. The correlation for the median whole-brain CBF in MRI and positron emission tomography was r = 0.60 and P = 0.04. CONCLUSIONS: The proposed method allows for determination of quantitative CBF without normalization factors. The relatively low estimates of absolute CBF most likely results from the higher age of the pigs as compared to other studies. The intermediate correlation between both methods is caused by physiological intraindividual fluctuations of the CBF and by a limited reproducibility of both methods.

Arterial input function measurements for bolus tracking perfusion imaging in the brain.

Imaging of cerebral perfusion by tracking the first passage of an exogenous paramagnetic contrast agent (termed dynamic susceptibility contrast, MRI) has been used in the clinical practice for about a decade. However, the primary goal of dynamic susceptibility contrast MRI to directly quantify the local cerebral blood flow remains elusive. The major challenge of dynamic susceptibility contrast MRI is to measure the contrast inflow to the brain, i.e., the arterial input function. The measurement is complicated by the limited dynamic range of MRI pulse sequences that are optimized for a good contrast in brain tissue but are suboptimal for a much higher tracer concentration in arterial blood. In this work, we suggest a novel method for direct arterial input function quantification. The arterial input function is measured in the carotid arteries with a dedicated plug-in to the conventional pulse sequence to enable resolution of T(2) on the order of a millisecond. The new technique is compatible with the clinical measurement protocols. Applied to the pig model (N = 13), the method demonstrates robustness of the arterial input function measurement. The cardiac output and cerebral blood volume, obtained without adjustable parameters, agree well with positron emission tomography measurements and values found in the literature.

Reproducibility of dynamic contrast-enhanced MR imaging. Part II. Comparison of intra- and interobserver variability with manual region of interest placement versus semiautomatic lesion segmentation and histogram analysis.

PURPOSE: To compare the inter- and intraobserver variability with manual region of interest (ROI) placement versus that with software-assisted semiautomatic lesion segmentation and histogram analysis with respect to quantitative dynamic contrast material-enhanced (DCE) MR imaging determinations of the volume transfer constant (K(trans)). MATERIALS AND METHODS: The study was approved by the institutional review board and compliant with HIPAA. The requirement to obtain informed consent was waived. Fifteen DCE MR imaging studies of the female pelvis defined the study group. Uterine fibroids were used as a perfusion model. Three varying types of lesion measurements were performed by five readers on each study by using DCE MR imaging perfusion analysis software with manual ROI placement and a semiautomatic lesion segmentation and histogram analysis solution. Intra- and interreader variability of measurements of K(trans) with the different measurement types was calculated. RESULTS: The overall interobserver variability of K(trans) with manual ROI placement (mean, 28.5% ± 9.3) was reduced by 42.5% when the semiautomatic, software-assisted lesion measurement method was used (16.4% ± 6.2). Whole-lesion measurement showed the lowest interobserver variability with both measurement methods (20.1% ± 4.3 with the manual method vs 10.8% ± 2.6 with the semiautomatic method). The overall intrareader variability with the manual ROI method (7.6% ± 10.6) was not significantly different from that with the semiautomatic method (7.3% ± 10.8), but the intraclass correlation coefficient for intrareader reproducibility improved from 0.86 overall with the manual method to 0.99 with the semiautomatic method. CONCLUSION: A semiautomatic lesion segmentation and histogram analysis approach can provide a significant reduction in interobserver variability for DCE MR imaging measurements of K(trans) when compared with manual ROI methods, whereas intraobserver reproducibility is improved to some extent.

Vessel size imaging reveals pathological changes of microvessel density and size in acute ischemia.

The aim of this study was to test the feasibility of vessel size imaging with precise evaluation of apparent diffusion coefficient and cerebral blood volume and to apply this novel technique in acute stroke patients within a pilot group to observe the microvascular responses in acute ischemic tissue. Microvessel density-related quantity Q and mean vessel size index (VSI) were assessed in 9 healthy volunteers and 13 acute stroke patients with vessel occlusion within 6 hours after symptom onset. Our results in healthy volunteers matched with general anatomical observations. Given the limitation of a small patient cohort, the median VSI in the ischemic area was higher than that in the mirrored region in the contralateral hemisphere (P<0.05). Decreased Q was observed in the ischemic region in 2 patients, whereas no obvious changes of Q were found in the remaining 11 patients. In a patient without recanalization, the VSI hyperintensity in the subcortical area matched well with the final infarct. These data reveal that different observations of microvascular response in the acute ischemic tissue seem to emerge and vessel size imaging may provide useful information for the definition of ischemic penumbra and have an impact on future therapeutic approaches.

On the design of filters for Fourier and oSVD-based deconvolution in bolus tracking perfusion MRI.

OBJECT: Bolus tracking perfusion evaluation relies on the deconvolution of a tracers concentration time-courses in an arterial and a tissue voxel following the tracer kinetic model. The object of this work is to propose a method to design a data-driven Tikhonov regularization filter in the Fourier domain and to compare it to the singular value decomposition (SVD)-based approaches using the mathematical equivalence of Fourier and circular SVD (oSVD). MATERIALS AND METHODS: The adaptive filter is designed using Tikhonov regularization that depends on only one parameter. Using a simulation, such an optimal parameter that minimizes the sum of statistical and systematic error is determined as a function of the first moment difference between the tissue and the arterial curve and the contrast to noise ratios of the input data (CNR( a ) in arteries and CNR( t ) in tissue). The performance of the method is evaluated and compared to oSVD in simulations and measured data. RESULTS: The proposed method yields a smaller flow underestimation especially for high flows when compared to the oSVD approach with constant threshold. However, this improvement comes to the price of an increased uncertainty of the flow values. The translation of the Tikhonov regularization parameter to an adaptive oSVD-threshold is in good agreement with the literature. CONCLUSION: The proposed method is a comprehensive approach for the design of data-driven filters that can be easily adapted to specific needs.

Assessment of vascular remodeling under antiangiogenic therapy using DCE-MRI and vessel size imaging.

PURPOSE: To assess vascular remodeling in tumors during two different antiangiogenic therapies with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and vessel size imaging and to evaluate the vessel size index (VSI) as a novel biomarker of therapy response. MATERIALS AND METHODS: In two independent experiments, nude mice bearing human skin squamous cell carcinoma xenografts were treated with a vascular endothelial growth factor (VEGF) inhibitor (bevacizumab) or a multitargeted tyrosine kinase inhibitor (SU11248). Changes in tumor vascularity were assessed by DCE-MRI and vessel size imaging. DCE-MRI data were analyzed applying a two-compartment model (Brix), calculating the parameters Amplitude and k(ep). RESULTS: For both experiments Amplitude decreased significantly in treated tumors while k(ep) did not change significantly. VSI showed controversial results. VSI was significantly increased in SU11248-treated A431 tumors, whereas no changes were found in bevacizumab-treated HaCaT-ras-A-5RT3 tumors. Immunohistology confirmed these results and suggest differences in the maturation of tumor vascularization as a possible explanation. CONCLUSION: DCE-MRI and vessel size imaging provide reliable and supplementing biomarkers of antiangiogenic therapy response. The results of both methods are in excellent agreement with histology. Nevertheless, our results also indicate that vascular remodeling is complex and that a uniform response cannot be expected for different tumors and therapies.

Extraction of the first bolus passage in dynamic susceptibility contrast perfusion measurements.

OBJECT: The processing of dynamic susceptibility contrast perfusion measurements requires an extraction of the first bolus passage of the injected contrast agent. State-of-the-art methods employ the fit of a gamma variate function to the measured data. The use of a gamma variate function is motivated by its shape similarity to the expected relaxation rate time-course during the first bolus passage. However, the quality of this result is strongly influenced by the amount of overlap of the first and second bolus passage. In this work we present an alternative, data-driven method for the extraction of the first bolus passage from a measured relaxation time-course. MATERIALS AND METHODS: By using prior knowledge of the injection function, the measured time-courses can be transformed to time-courses that would occur at a shorter injection duration where the two bolus passages have less overlap. This time-course is found by Tikhonov regularized deconvolution of the measured time-courses with an injection function that bases on the measurement protocol. A minimum search yields the cut-off point at which the first bolus can be extrapolated to zero. The gamma variate fit is performed using Powells algorithm. The proposed approach is compared to the gamma variate fit approach using simulations and an exemplary dataset from one healthy volunteer. RESULTS: The new method performs comparably stable as the gamma variate function fit approach in simulations. Both methods are superior to a simple exponential extrapolation approach. Applied to volunteer data, the new method performs much faster than the gamma variate fit approach. The results obtained from both methods correspond well. CONCLUSION: The new method offers a conceptual understanding of the first bolus passage and yields similar results to the gamma variate function fit approach but performs much faster.

(1)H MR spectroscopy of inflammation, infection and ischemia of the brain.

Different pathologic patterns in multiple sclerosis (MS) are reflected by alterations of metabolites in (1)H MR spectroscopy of the brain. Elevated choline (Cho), lactate (Lac), lipids and macromolecules are reliable markers for acute demyelination regardless of the clinical entity (also in acute disseminated encephalomyelitis). N-acetyl-aspartate (NAA) is a suitable marker for neuronal integrity. It is reduced in acute MS lesions and in normal appearing white matter, even distant to acute and chronic-lesions. Recovery from reduced NAA levels to subnormal values during remyelination, and varying time courses of NAA in normal appearing white matter during relapsing remitting disease indicate the value of this spectroscopic marker for monitoring activity and recovery. Inositol (Ins) is increased in chronic MS lesions being a marker for astrocytic gliosis. In viral disease, Cho and Ins are always increased, whereas a reduction of NAA mostly reflects an advanced or a detoriated clinical state. In bacterial brain abscesses, numerous amino acids, lipids and Lac can be elevated. In ischemia, especially the Lac/NAA in comparison with perfusion and diffusion weighted imaging seems to be a new measure for areas of metabolic need, and may help to better characterise the penumbra of the stroke and the final infarct size.