Earlier detection of tumor treatment response using magnetic resonance diffusion imaging with oscillating gradients

An improved method for detecting early changes in tumors in response to treatment, based on a modification of diffusion-weighted magnetic resonance imaging, has been demonstrated in an animal model. Early detection of therapeutic response in tumors is important both clinically and in pre-clinical assessments of novel treatments. Noninvasive imaging methods that can detect and assess tumor response early in the course of treatment, and before frank changes in tumor morphology are evident, are of considerable interest as potential biomarkers of treatment efficacy. Diffusion-weighted magnetic resonance imaging is sensitive to changes in water diffusion rates in tissues that result from structural variations in the local cellular environment, but conventional methods mainly reflect changes in tissue cellularity and do not convey information specific to microstructural variations at sub-cellular scales. We implemented a modified imaging technique using oscillating gradients of the magnetic field for evaluating water diffusion rates over very short spatial scales that are more specific for detecting changes in intracellular structure that may precede changes in cellularity. Results from a study of orthotopic 9L gliomas in rat brains indicate that this method can detect changes as early as 24 h following treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea, when conventional approaches do not find significant effects. These studies suggest that diffusion imaging using oscillating gradients may be used to obtain an earlier indication of treatment efficacy than previous magnetic resonance imaging methods.     

Comparison of diffusion tensor,dynamic susceptibility contrast MRI and Tc-Tetrofosmin brain SPECT for the detection of recurrent high-grade glioma

Introduction

Treatment induced necrosis is a relatively frequent finding in patients treated for high-grade glioma. Differentiation by imaging modalities between glioma recurrence and treatment induced necrosis is not always straightforward. This is a comparative study of diffusion tensor imaging (DTI), dynamic susceptibility contrast MRI and ^99mTc-Tetrofosmin brain single-photon emission computed tomography (SPECT) for differentiation of recurrent glioma from treatment induced necrosis.

Methods

A prospective study was made of 30 patients treated for high-grade glioma who had suspected recurrent tumor on follow-up MRI. All had been treated by surgical resection of the tumor followed by standard postoperative radiotherapy with chemotherapy. No residual tumor had been found on brain imaging immediately after the initial treatment. All the patients were studied with dynamic susceptibility contrast brain MRI and, within a week, ^99mTc-Tetrofosmin brain SPECT.

Results

Both ^99mTc-Tetrofosmin brain SPECT and dynamic susceptibility contrast MRI could discriminate between tumor recurrence and treatment induced necrosis with 100% sensitivity and 100% specificity. An apparent diffusion coefficient (ADC) ratio cut-off value of 1.27 could differentiate recurrence from treatment induced necrosis with 65% sensitivity and 100% specificity and a fractional anisotropy (FA) ratio cut-off value of 0.47 could differentiate recurrence from treatment induced necrosis with 57% sensitivity and 100% specificity. A significant correlation was demonstrated between ^99mTc-Tetrofosmin uptake ratio and rCBV (P = 0.003).

Conclusions

Dynamic susceptibility contrast MRI and brain SPECT with ^99mTc-Tetrofosmin had the same accuracy and may be used to detect recurrent tumor following treatment for glioma. DTI also showed promise for the detection of recurrent tumor, but was inferior to both dynamic susceptibility contrast MRI and brain SPECT.     

Prediction of gene therapy-induced tumor size changes by the vascularity changes measured using dynamic contrast-enhanced MRI

We studied the changes of tumor size after gene therapy treatment and its relationship with the changes of vascular volume as measured by dynamic contrast-enhanced magnetic resonance imaging (MRI), to investigate whether the vascular changes is predictive of tumor regression. The study was carried out using a spontaneously regressing rat tumor model (C6 Glioma grown subcutaneously in rats). Three rats were treated with recombinant adenoviruses expressing three genes, mouse interleukin 1-alpha (IL1-alpha), mouse interferon gamma (IFN-gamma), and human transforming growth factor beta (TGF-beta), one from each kind. Two rats were treated with saline as controls. Longitudinal studies were performed to monitor the changes of tumor volume (based on T(2)-weighted images) and the vascular volume (based on dynamic contrast enhanced images). In untreated animals, tumor regression was preceded by several days with a decrease in vascular volume. When the tumor growth was perturbed by expression of mouse IL-1alpha, the increase in vascular volume was correlated with the continuing growth in size, and the decrease in vascular volume was predictive of the onset of tumor regression. As new advances in immunotherapy in cancer treatment emerge, the ability to determine the efficacy of therapy as early as possible will enable optimization of treatment regiments. The vascularity changes measured by dynamic MRI may provide a means to serve for this purpose.     

Repeatability of echo-planar-based diffusion measurements of the human prostate at 3 T

Echo-planar-based diffusion-weighted imaging (DWI) of the prostate is increasingly being suggested as a viable technique, complementing information derived from conventional magnetic resonance imaging methods for use in tissue discrimination. DWI has also been suggested as a potentially useful tool in the assessment of tumor response to treatment. In this study, the repeatability of apparent diffusion coefficient (ADC) values obtained from both DWI and diffusion tensor imaging (DTI) has been assessed as a precursor to determining the magnitude of treatment-induced changes required for reliable detection. The repeatability values of DWI and DTI were found to be similar, with ADC values repeatable to within 35% or less over a short time period of a few minutes and a longer time period of a month. Fractional anisotropy measurements were found to be less repeatable (between 26% and 71%), and any changes duly recorded in longitudinal studies must therefore be treated with a degree of caution.     

Promise and pitfalls of quantitative imaging in oncology clinical trials

Quantitative imaging using computed tomography, magnetic resonance imaging and positron emission tomography modalities will play an increasingly important role in the design of oncology trials addressing molecularly targeted, personalized therapies. The advent of molecularly targeted therapies, exemplified by antiangiogenic drugs, creates new complexities in the assessment of response. The Quantitative Imaging Network addresses the need for imaging modalities which can accurately and reproducibly measure not just change in tumor size but changes in relevant metabolic parameters, modulation of relevant signaling pathways, drug delivery to tumor and differentiation of apoptotic cell death from other changes in tumor volume. This article provides an overview of the applications of quantitative imaging to phase 0 through phase 3 oncology trials. We describe the use of a range of quantitative imaging modalities in specific tumor types including malignant gliomas, lung cancer, head and neck cancer, lymphoma, breast cancer, prostate cancer and sarcoma. In the concluding section, we discuss potential constraints on clinical trials using quantitative imaging, including complexity of trial conduct, impact on subject recruitment, incremental costs and institutional barriers. Strategies for overcoming these constraints are presented.     

Combined imaging biomarkers for therapy evaluation in glioblastoma multiforme: correlating sodium MRI and F-18 FLT PET on a voxel-wise basis

We evaluate novel magnetic resonance imaging (MRI) and positron emission tomography (PET) quantitative imaging biomarkers and associated multimodality, serial-time-point analysis methodologies, with the ultimate aim of providing clinically feasible, predictive measures for early assessment of response to cancer therapy. A focus of this work is method development and an investigation of the relationship between the information content of the two modalities. Imaging studies were conducted on subjects who were enrolled in glioblastoma multiforme (GBM) therapeutic clinical trials. Data were acquired, analyzed and displayed using methods that could be adapted for clinical use. Subjects underwent dynamic [¹⁸F]fluorothymidine (F-18 FLT) PET, sodium (²³Na) MRI and 3-T structural MRI scans at baseline (before initiation of therapy), at an early time point after beginning therapy and at a late follow-up time point after therapy. Sodium MRI and F-18 FLT PET images were registered to the structural MRI. F-18 FLT PET tracer distribution volumes and sodium MRI concentrations were calculated on a voxel-wise basis to address the heterogeneity of tumor physiology. Changes in, and differences between, these quantities as a function of scan timing were tracked.     

MRI assessment of drug-induced fluid accumulation in humans: validation of the technology

PURPOSE: The purpose of this study was to evaluate the feasibility of using proton and sodium magnetic resonance imaging (MRI) to detect fluid accumulation produced by fludrocortisone and nifedipine - two drugs known to cause salt/water retention by different mechanisms. MATERIALS AND METHODS: Twelve young healthy male subjects were randomly assigned to one of two groups and treated with either fludrocortisone or nifedipine for 14 or 25 days, respectively. The change in sodium MRI, as well as in proton T(2) value and T(1)-weighted signal intensity in the calf following postural change [referred to here as 'postural delta signal'(PDS)], was evaluated before, during and after drug administration. The changes in MRI PDS were compared to conventional physiological parameters, including body weight, calf volume and pitting edema. RESULTS: When compared to the baseline pretreatment values, the subjects treated with fludrocortisone showed a 5.5% increase in sodium MRI PDS (P=.01), a 2-ms increase in proton T(2) PDS of the gastrocnemius muscle (P=.06) and a body weight gain of 2.3% (P=.001) within 1 week. In the nifedipine-treated subjects, the sodium MRI PDS increased by 6% versus baseline (P=.03), while the proton T(2) PDS of the gastrocnemius muscle increased by 3.7 ms (P=.01), associated with a 0.5% weight gain (P=.55), within 3 weeks. No significant changes were noted in the T(1)-weighed images following postural change. Measurements of calf circumference, volume and pitting edema did not show consistent changes associated with the drug administration. CONCLUSION: The postural change in sodium MRI and proton T(2) signals provides a sensitive method for detecting the fluid accumulation produced by fludrocortisone and nifedipine. The MRI results are consistent with treatment-induced increases in extracellular fluid volume and correlate well with the observed weight gain. These findings support the potential utility of MRI for the evaluation of medication-induced fluid retention.     

White matter changes in multiple sclerosis: correlation of q-space diffusion MRI and 1H MRS

OBJECTIVE: To explore the diagnostic usefulness of high b-value diffusion magnetic resonance brain imaging ("q-space" imaging) in multiple sclerosis (MS). More specifically, we aimed at evaluating the ability of this methodology to identify tissue damage in the so-called normal-appearing white matter (NAWM). DESIGN: In this study we examined the correlation between q-space diffusion imaging and magnetic resonance spectroscopy (MRS)-based two-dimensional 1H chemical shift imaging. Eight MS patients with different degree of disease severity and seven healthy subjects were scanned in a 1.5-T magnetic resonance imaging (MRI) scanner. The MRI protocol included diffusion tensor imaging (DTI) (with bmax of 1000 s/mm2), high b-value diffusion-weighted imaging (with bmax of 14,000 s/mm2) and 2D chemical shift imaging. The high b-value data set was analyzed using the q-space methodology to produce apparent displacement and probability maps. RESULTS: We found that the q-space diffusion displacement and probability image intensities correlated well with N-acetylaspartate levels (r=.61 and .54, respectively). Furthermore, NAWM that was abnormal on MRS was also found to be abnormal using q-space diffusion imaging. In these areas, the q-space displacement values increased from 3.8+/-0.2 to 4.6+/-0.6 microm (P<.02), the q-space probability values decreased from 7.4+/-0.3 to 6.8+/-0.3 (P<.002), while DTI revealed only a small, but still significant, reduction in fractional anisotropy values from 0.40+/-0.02 to 0.37+/-0.02 (P<.05). CONCLUSION: High b-value diffusion imaging can detect tissue damage in the NAWM of MS patients. Despite the theoretical limitation of this method, in practice it provides additional information which is clinically relevant for detection of tissue damage not seen in conventional imaging techniques.     

Detection of T2 changes in an early mouse brain tumor

The aim of the study was to determine the effect of early tumor growth on T₂ relaxation times in an experimental glioma model. A 9.4-T magnetic resonance imaging (MRI) system was used for the investigations. An animal model (n=12) of glioma was established using an intracranial inoculation of U87MGdEGFRvIII cells. The imaging studies were performed from Day 10 through Day 13 following tumor inoculation. Tumor blood vessel density was determined using quantitative immunochemistry. Tumor volume was measured daily using MR images. T₂ values of the tumor were measured in five areas across the tumor and calculated using a single exponential fitting of the echo train. The measurements on Days 10 and 13 after tumor inoculation showed a 20% increase in T₂. The changes in T₂ correlated with the size of the tumor. Statistically significant differences in T₂ values were observed between the edge of the tumor and the brain tissue on Days 11, 12 and 13 (P=.014, .008, .001, respectively), but not on Day 10 (P=.364). The results show that T₂-weighted MRI may not detect glioma during an early phase of growth. T₂ increases in growing glioma and varies heterogenously across the tumor.     

A comparative assessment of preclinical chemotherapeutic response of tumors using quantitative non-Gaussian diffusion MRI

BackgroundDiffusion-weighted MRI (DWI) signal attenuation is often not mono-exponential (i.e. non-Gaussian diffusion) with stronger diffusion weighting. Several non-Gaussian diffusion models have been developed and may provide new information or higher sensitivity compared with the conventional apparent diffusion coefficient (ADC) method. However the relative merits of these models to detect tumor therapeutic response is not fully clear.MethodsConventional ADC, and three widely-used non-Gaussian models, (bi-exponential, stretched exponential, and statistical model), were implemented and compared for assessing SW620 human colon cancer xenografts responding to barasertib, an agent known to induce apoptosis via polyploidy. Bayesian Information Criterion (BIC) was used for model selection among all three non-Gaussian models.ResultsAll of tumor volume, histology, conventional ADC, and three non-Gaussian DWI models could show significant differences between control and treatment groups after four days of treatment. However, only the non-Gaussian models detected significant changes after two days of treatment. For any treatment or control group, over 65.7% of tumor voxels indicate the bi-exponential model is strongly or very strongly preferred.ConclusionNon-Gaussian DWI model-derived biomarkers are capable of detecting tumor earlier chemotherapeutic response of tumors compared with conventional ADC and tumor volume. The bi-exponential model provides better fitting compared with statistical and stretched exponential models for the tumor and treatment models used in the current work.     

Diffusion changes in patients with systemic lupus erythematosus

BACKGROUND AND PURPOSE: Systemic lupus erythematosus (SLE) is an autoimmune disease in which almost all the organs are involved. Neuropsychiatric SLE is of one of the major concerns in the clinical evaluation of this disease. Routine magnetic resonance imaging (MRI) findings are often nonspecific or negative. In this study, we explored the use of diffusion tensor imaging in assisting with the diagnosis of SLE. METHODS: Data from 34 SLE patients (age range, 18-73 years) and 29 age-matched volunteers (age range, 29-64 years) were analyzed. MRI was performed on a 1.5-T clinical MR scanner with a quadrature head coil. The average diffusion constant (D(av)) and diffusion anisotropy maps [fractional anisotropy (FA)] were determined on a pixel-by-pixel basis. Regional diffusion measurements were made by region of interest in the genu and splenium of the corpus callosum (CC), anterior and posterior limb of the internal capsule (IC) and frontal lobe and thalamus. The diffusion distribution was fitted to a triple-Gaussian model. The mean of the brain tissue distribution was determined as a mean diffusion constant for the whole brain (BD(av)). Student's t test was used to determine the diffusion difference between SLE patients and control subjects. The SLE patients were separated into two groups according to their MRI results. A P value lower than .05 was considered to be statistically significant. RESULTS: Twenty of the 34 SLE patients with abnormal MRI results showed findings dominated by nonspecific white matter disease. The BD(av) and D(av) values of the frontal lobe, splenium CC and anterior IC were significantly higher in all SLE patients as compared with the control subjects. The SLE patients with normal MRI results also showed higher BD(av) and D(av) values in the frontal lobe, splenium and anterior and posterior limbs of the IC as compared with the control subjects. There was no significant difference in the D(av) values of the thalamus between the SLE patients and the control subjects. The BD(av) value in the SLE patient group was robustly correlated with the D(av) values of the frontal lobe, splenium and thalamus. These correlations were found to be similarly significant for the SLE patients with normal MRI findings. The diffusion anisotropy measurements showed that splenium CC had the highest FA value in both the control subjects and SLE patients. Overall, SLE patients had lower FA values in the genu and splenium CC as compared with the control subjects. In the group of patients with normal MRI findings, the FA values of the genu and splenium CC as well as the anterior IC were also lower than those in the control subjects. Pearson's correlation statistics revealed robust correlations between the measurements of D(av) and FA values in the SLE patient group. CONCLUSION: Quantitative diffusion imaging and diffusion anisotropy showed early changes in the brains of the SLE patients. Increased BD(av) and D(av) values of the frontal lobe as well as decreased anisotropy in the genu CC and anterior IC may represent preclinical signs of central nervous system involvement of SLE even when the routine MRI findings are negative or nonspecific. Quantitative diffusion analysis may prove to be useful in detecting the initial brain involvement of SLE and may enable monitoring of early disease progression and treatment efficacy.     

Magnetic resonance in the era of molecular imaging of cancer

Magnetic resonance imaging (MRI) has played an important role in the diagnosis and management of cancer since it was first developed, but other modalities also continue to advance and provide complementary information on the status of tumors. In the future, there will be a major continuing role for noninvasive imaging in order to obtain information on the location and extent of cancer, as well as assessments of tissue characteristics that can monitor and predict treatment response and guide patient management. Developments are currently being undertaken that aim to provide improved imaging methods for the detection and evaluation of tumors, for identifying important characteristics of tumors such as the expression levels of cell surface receptors that may dictate what types of therapy will be effective and for evaluating their response to treatments. Molecular imaging techniques based mainly on radionuclide imaging can depict numerous, specific, cellular and molecular markers of disease and have unique potential to address important clinical and research challenges. In this review, we consider what continuing and evolving roles will be played by MRI in this era of molecular imaging. We discuss some of the challenges for MRI of detecting imaging agents that report on molecular events, but highlight also the ability of MRI to assess other features such as cell density, blood flow and metabolism which are not specific hallmarks of cancer but which reflect molecular changes. We discuss the future role of MRI in cancer and describe the use of selected quantitative imaging techniques for characterizing tumors that can be translated to clinical applications, particularly in the context of evaluating novel treatments.     

Monitoring chemotherapeutic response in RIF-1 tumors by single-quantum and triple-quantum-filtered (23)Na MRI, (1)H diffusion-weighted MRI and PET imaging

The effects of 5-fluorouracil (5FU, 150 mg/kg, ip) on subcutaneously implanted radiation-induced fibrosarcoma (RIF-1) tumors were monitored by in vivo (1)H MRI to evaluate the water apparent diffusion coefficient (ADC), by single-quantum (SQ) and triple-quantum-filtered (TQF) (23)Na MRI to evaluate compartmental Na(+) content and by positron emission tomography (PET) to evaluate 2-[(18)F]fluoro-2-deoxy-d-glucose (FDG) uptake in the tumor. The MRI experiments were performed on untreated control and treated mice once before and then daily for 3 days after treatment. The PET experiments were performed on separate groups of age- and tumor-volume-matched animals once before and then 3 days after treatment. Tumor volumes significantly decreased in treated animals 2 and 3 days posttreatment. At the same time points, in vivo MRI measurements showed an increase in both total tissue SQ (23)Na signal intensity (SI) and water ADC in treated tumors while control tumors showed no change in these parameters. TQF (23)Na SI and FDG uptake were significantly lower in treated tumors compared with control tumors 3 days after 5FU treatment. The correlated increases in total tissue (23)Na SI and water ADC following chemotherapy reflect an increase in extracellular space, while the lower TQF (23)Na SI and FDG uptake in treated tumors compared with control tumors suggest a shift in tumor metabolism from glycolysis to oxidation and/or a decrease in cell density.     

Diffusion MRI detects basal forebrain cholinergic abnormalities in the 3xTg-AD mouse model of Alzheimer's disease

Degeneration of the basal forebrain (BF) is detected early in the course of Alzheimer's disease (AD). Reduction in the number of BF cholinergic (ChAT) neurons associated with age-related hippocampal cholinergic neuritic dystrophy is described in the 3xTg-AD mouse model; however, no prior diffusion MRI (dMRI) study has explored the presence of BF alterations in this model. Here we investigated the ability of diffusion MRI (dMRI) to detect abnormalities in BF microstructure for the 3xTg-AD mouse model, along with related pathology in the hippocampus (HP) and white matter (WM) tracks comprising the septo-hippocampal pathway. 3xTg-AD and normal control (NC) mice were imaged in vivo using the specific dMRI technique known as diffusional kurtosis imaging (DKI) at 2, 8, and 15 months of age, and 8 dMRI parameters were measured at each time point. Our results revealed significant lower dMRI values in the BF of 2 months-old 3xTg-AD mice compared with NC mice, most likely related to the increased number of ChAT neurons seen in this AD mouse model at this age. They also showed significant age-related dMRI changes in the BF of both groups between 2 and 8 months of age, mainly a decrease in fractional anisotropy and axial diffusivity, and an increase in radial kurtosis. These dMRI changes in the BF may be reflecting the complex aging and pathological microstructural changes described in this region. Group differences and age-related changes were also observed in the HP, fimbria (Fi) and fornix (Fx). In the HP, diffusivity values were significantly higher in the 2 months-old 3xTg-AD mice, and the HP of NC mice showed a significant increase in axial kurtosis after 8 months, reflecting a normal pattern of increased fiber density complexity, which was not seen in the 3xTg-AD mice. In the Fi, mean and radial diffusivity values were significantly higher, and fractional anisotropy, radial kurtosis and kurtosis fractional anisotropy were significantly lower in the 2 months-old 3xTg-AD mice. The age trajectories for both NC and TG mice in the Fi and Fx were similar between 2 and 8 months, but after 8 months there was a significant decrease in diffusivity metrics associated with an increase in kurtosis metrics in the 3xTg-AD mice. These later HP, Fi and Fx dMRI changes probably reflect the growing number of dystrophic neurites and AD pathology progression in the HP, accompanied by WM disruption in the septo-hippocampal pathway. Our results demonstrate that dMRI can detect early cytoarchitectural abnormalities in the BF, as well as related aging and neurodegenerative changes in the HP, Fi and Fx of the 3xTg-AD mice. Since DKI is widely available on clinical scanners, these results also support the potential of the considered dMRI parameters as in vivo biomarkers for AD disease progression.     

The clinical application of whole-body diffusion-weighted imaging in the early assessment of chemotherapeutic effects in lymphoma: the initial experience

At present, accurate assessment of therapeutic efficacy at the early stage of treatment is still a challenge for radiologists. As a new non-radiation whole body imaging technology, Whole body-diffusion weighted imaging (WB-DWI) had shown promising application prospects in therapeutic assessment, which confirmed by many premier animal studies. Here we report that in the chemotherapeutic assessment of malignant non-Hodgkin's lymphoma, WB-DWI can not only detect the morphological change of solid infiltrated lesion as the convention (such as CT, PET, etc.) but also provide information about the growth and decline process of tumor cells in the lesion combining with the dynamic changes of apparent diffusion coefficient (ADC) value, which is sooner than the morphological changes.     

Early changes in intravoxel incoherent motion MRI parameters can potentially predict response to chemoradiotherapy in rectal cancer: An animal study

Imaging-based approaches for early predicting response of rectal cancer to neoadjuvant chemoradiotherapy remain an ongoing-challenge. In this study, we aimed to monitor the changes of intravoxel incoherent motion (IVIM) MRI parameters during the early post-treatment period in mouse models of human rectal carcinoma, and to test whether these changes relate to the final response. Thirty-two mice with subcutaneous-tumor were randomly divided into control (n = 11), chemoradiotherapy (n = 10) and chemotherapy (n = 11) group. Tumors were monitored by IVIM at day 0, 3, 7, 9 after treatment. The final tumor response was determined by tumor remission-rate and necrosis scores. The results indicated that within 9 days after treatment, D values increased in both treated groups, but remained stable in control group. D values were significantly higher in chemotherapy group at day 7 and in each treated group at day 9 than in control group (day 7, p = 0.004; day 9: p = 0.011 and 0.009, respectively). D* values decreased in treated groups, and showed significantly lower than in control group at day 7 (p < 0.001). There was a strong positive correlation between delta D*% (D*_{day0 – day7}/D*_day0) and tumor remission rate (r = 0.707, p < 0.001), and a mild negative correlation between delta D% and tumor necrosis scores (r = −0.526, p = 0.014). D and D* values in rectal carcinoma xenograft models appeared tendency change during the early post-treatment period. In conclusion, early changes of D and D* values may have potential for predicting the final efficacy of chemoradiotherapy.     

Primary left atrial angiosarcoma: follow-up by magnetic resonance imaging

We report the case of a primary left atrial angiosarcoma followed by MRI over a period of 1 year. The tumor was lobulated, with an initial central hyperintensity on T1-weighted images which disappeared after radiotherapy. Compared with other imaging modalities, MRI offered the most accurate information about the location, extent, and outcome under treatment.     

MR cell size imaging with temporal diffusion spectroscopy

Cytological features such as cell size and intracellular morphology provide fundamental information on cell status and hence may provide specific information on changes that arise within biological tissues. Such information is usually obtained by invasive biopsy in current clinical practice, which suffers several well-known disadvantages. Recently, novel MRI methods such as IMPULSED (imaging microstructural parameters using limited spectrally edited diffusion) have been developed for direct measurements of mean cell size non-invasively. The IMPULSED protocol is based on using temporal diffusion spectroscopy (TDS) to combine measurements of water diffusion over a wide range of diffusion times to probe cellular microstructure over varying length scales. IMPULSED has been shown to provide rapid, robust, and reliable mapping of mean cell size and is suitable for clinical imaging. More recently, cell size distributions have also been derived by appropriate analyses of data acquired with IMPULSED or similar sequences, which thus provides MRI-cytometry. This review summarizes the basic principles, practical implementations, validations, and example applications of MR cell size imaging based on TDS and demonstrates how cytometric information can be used in various applications. In addition, the limitations and potential future directions of MR cytometry are identified including the diagnosis of nonalcoholic steatohepatitis of the liver and the assessment of treatment response of cancers.     

Volumetric q-space imaging by 3D diffusion-weighted MRI

High b-value diffusion magnetic resonance imaging (MRI) enables us to detect far smaller architectures, by using q-space analysis, than the resolution in conventional MRI. Average displacement, one of the q-space parameters, quantitatively reflects architecture size and is very useful in observing small changes in microstructures in vivo (e.g., neurodegeneration, tumor heterogeneity, and others). Diffusion-weighted imaging (DWI) is performed by a two-dimensional (2D) multislice method; however, due to finite slice thickness and slice gap, there is a partial-volume effect that makes it difficult to detect the net q-space signal. On the other hand, three-dimensional (3D) MRI, having the advantages of very thin slice thickness and no slice gap (contiguous slices), allows volumetric evaluation acquired in a small isotropic voxel, as compared to 2D multislice imaging. Little is known about the isotropic high-resolution 3D DWI application to q-space analysis. In this study, we have developed and implemented a high b-value 3D DWI sequence, applied q-space analysis to study the reliability of high b-value 3D DWI and obtained a microscopic analytical map with isotropic high resolution and less contamination.