Time-dependent diffusivity and kurtosis in phantoms and patients with head and neck cancer.

PURPOSE: To assess the reliability of measuring diffusivity, diffusional kurtosis, and cellular-interstitial water exchange time with long diffusion times (100-800 ms) using stimulated-echo DWI. METHODS: Time-dependent diffusion MRI was tested on two well-established diffusion phantoms and in 5 patients with head and neck cancer. Measurements were conducted using an in-house diffusion-weighted STEAM-EPI pulse sequence with multiple diffusion times at a fixed TE on three scanners. We used the weighted linear least-squares fit method to estimate time-dependent diffusivity, D ( t ) $$ D(t) $$ , and diffusional kurtosis, K ( t ) $$ K(t) $$ . Additionally, the Kärger model was used to estimate cellular-interstitial water exchange time ( τ ex $$ {\tau}_{ex} $$ ) from K ( t ) $$ K(t) $$ . RESULTS: Diffusivity measured by time-dependent STEAM-EPI measurements and commercial SE-EPI showed comparable results with R2 above 0.98 and overall 5.4 ± 3.0% deviation across diffusion times. Diffusional kurtosis phantom data showed expected patterns: constant D $$ D $$ and K $$ K $$  = 0 for negative controls and slow varying D $$ D $$ and K $$ K $$ for samples made of nanoscopic vesicles. Time-dependent diffusion MRI in patients with head and neck cancer found that the Kärger model could be considered valid in 72% ± 23% of the voxels in the metastatic lymph nodes. The median cellular-interstitial water exchange time estimated for lesions was between 58.5 ms and 70.6 ms. CONCLUSIONS: Based on two well-established diffusion phantoms, we found that time-dependent diffusion MRI measurements can provide stable diffusion and kurtosis values over a wide range of diffusion times and across multiple MRI systems. Moreover, estimation of cellular-interstitial water exchange time can be achieved using the Kärger model for the metastatic lymph nodes in patients with head and neck cancer.

Reproducibility of the Standard Model of diffusion in white matter on clinical MRI systems.

Estimating intra- and extra-axonal microstructure parameters, such as volume fractions and diffusivities, has been one of the major efforts in brain microstructure imaging with MRI. The Standard Model (SM) of diffusion in white matter has unified various modeling approaches based on impermeable narrow cylinders embedded in locally anisotropic extra-axonal space. However, estimating the SM parameters from a set of conventional diffusion MRI (dMRI) measurements is ill-conditioned. Multidimensional dMRI helps resolve the estimation degeneracies, but there remains a need for clinically feasible acquisitions that yield robust parameter maps. Here we find optimal multidimensional protocols by minimizing the mean-squared error of machine learning-based SM parameter estimates for two 3T scanners with corresponding gradient strengths of 40and80mT/m. We assess intra-scanner and inter-scanner repeatability for 15-minute optimal protocols by scanning 20 healthy volunteers twice on both scanners. The coefficients of variation all SM parameters except free water fraction are ≲10% voxelwise and 1-4% for their region-averaged values. As the achieved SM reproducibility outcomes are similar to those of conventional diffusion tensor imaging, our results enable robust in vivo mapping of white matter microstructure in neuroscience research and in the clinic.

Improved Task-based Functional MRI Language Mapping in Patients with Brain Tumors through Marchenko-Pastur Principal Component Analysis Denoising.

Background Functional MRI improves preoperative planning in patients with brain tumors, but task-correlated signal intensity changes are only 2%-3% above baseline. This makes accurate functional mapping challenging. Marchenko-Pastur principal component analysis (MP-PCA) provides a novel strategy to separate functional MRI signal from noise without requiring user input or prior data representation. Purpose To determine whether MP-PCA denoising improves activation magnitude for task-based functional MRI language mapping in patients with brain tumors. Materials and Methods In this Health Insurance Portability and Accountability Act-compliant study, MP-PCA performance was first evaluated by using simulated functional MRI data with a known ground truth. Right-handed, left-language-dominant patients with brain tumors who successfully performed verb generation, sentence completion, and finger tapping functional MRI tasks were retrospectively identified between January 2017 and August 2018. On the group level, for each task, histograms of z scores for original and MP-PCA denoised data were extracted from relevant regions and contralateral homologs were seeded by a neuroradiologist blinded to functional MRI findings. Z scores were compared with paired two-sided t tests, and distributions were compared with effect size measurements and the Kolmogorov-Smirnov test. The number of voxels with a z score greater than 3 was used to measure task sensitivity relative to task duration. Results Twenty-three patients (mean age ± standard deviation, 43 years ± 18; 13 women) were evaluated. MP-PCA denoising led to a higher median z score of task-based functional MRI voxel activation in left hemisphere cortical regions for verb generation (from 3.8 ± 1.0 to 4.5 ± 1.4; P < .001), sentence completion (from 3.7 ± 1.0 to 4.3 ± 1.4; P < .001), and finger tapping (from 6.9 ± 2.4 to 7.9 ± 2.9; P < .001). Median z scores did not improve in contralateral homolog regions for verb generation (from -2.7 ± 0.54 to -2.5 ± 0.40; P = .90), sentence completion (from -2.3 ± 0.21 to -2.4 ± 0.37; P = .39), or finger tapping (from -2.3 ± 1.20 to -2.7 ± 1.40; P = .07). Individual functional MRI task durations could be truncated by at least 40% after MP-PCA without degradation of clinically relevant correlations between functional cortex and functional MRI tasks. Conclusion Denoising with Marchenko-Pastur principal component analysis led to higher task correlations in relevant cortical regions during functional MRI language mapping in patients with brain tumors. © RSNA, 2020 Online supplemental material is available for this article.

Combined diffusion-relaxometry microstructure imaging: Current status and future prospects.

Microstructure imaging seeks to noninvasively measure and map microscopic tissue features by pairing mathematical modeling with tailored MRI protocols. This article reviews an emerging paradigm that has the potential to provide a more detailed assessment of tissue microstructure-combined diffusion-relaxometry imaging. Combined diffusion-relaxometry acquisitions vary multiple MR contrast encodings-such as b-value, gradient direction, inversion time, and echo time-in a multidimensional acquisition space. When paired with suitable analysis techniques, this enables quantification of correlations and coupling between multiple MR parameters-such as diffusivity, T1 , T2 , and T2∗ . This opens the possibility of disentangling multiple tissue compartments (within voxels) that are indistinguishable with single-contrast scans, enabling a new generation of microstructural maps with improved biological sensitivity and specificity.

Training a neural network for Gibbs and noise removal in diffusion MRI.

PURPOSE: To develop and evaluate a neural network-based method for Gibbs artifact and noise removal. METHODS: A convolutional neural network (CNN) was designed for artifact removal in diffusion-weighted imaging data. Two implementations were considered: one for magnitude images and one for complex images. Both models were based on the same encoder-decoder structure and were trained by simulating MRI acquisitions on synthetic non-MRI images. RESULTS: Both machine learning methods were able to mitigate artifacts in diffusion-weighted images and diffusion parameter maps. The CNN for complex images was also able to reduce artifacts in partial Fourier acquisitions. CONCLUSIONS: The proposed CNNs extend the ability of artifact correction in diffusion MRI. The machine learning method described here can be applied on each imaging slice independently, allowing it to be used flexibly in clinical applications.

Assessment of myofiber microstructure changes due to atrophy and recovery with time-dependent diffusion MRI.

Current clinical MRI evaluation of musculature largely focuses on nonquantitative assessments (including T1-, T2- and PD-weighted images), which may vary greatly between imaging systems and readers. This work aims to determine the efficacy of a quantitative approach to study the microstructure of muscles at the cellular level with the random permeable barrier model (RPBM) applied to time-dependent diffusion tensor imaging (DTI) for varying diffusion time. Patients (N = 15, eight males and seven females) with atrophied calf muscles due to immobilization of one leg in a nonweight-bearing cast, were enrolled after providing informed consent. Their calf muscles were imaged with stimulated echo diffusion for DTI, T1-mapping and RPBM modeling. Specifically, After cast removal, both calf muscles (atrophied and contralateral control leg) were imaged with MRI for all patients, with follow-up scans to monitor recovery of the atrophied leg for six patients after 4 and 8 weeks. We compare RPBM-derived microstructural metrics: myofiber diameter, a, and sarcolemma permeability, κ, along with macroscopic anatomical parameters (muscle cross-sectional area, fiber orientation, <θ>, and T1 relaxation). ROC analysis was used to compare parameters between control and atrophied muscle, while the Friedman test was used to evaluate the atrophied muscle longitudinally. We found that the RPBM framework enables measurement of microstructural parameters from diffusion time-dependent DTI, of which the myofiber diameter is a stronger predictor of intramuscular morphological changes than either macroscopic (anatomical) measurements or empirical diffusion parameters. This work demonstrates the potential of RPBM to assess pathological changes in musculature that seem undetectable with standard diffusion and anatomical MRI.

Measurement of cellular-interstitial water exchange time in tumors based on diffusion-time-dependent diffusional kurtosis imaging.

PURPOSE: To assess the feasibility of using diffusion-time-dependent diffusional kurtosis imaging (tDKI) to measure cellular-interstitial water exchange time (τex ) in tumors, both in animals and in humans. METHODS: Preclinical tDKI studies at 7 T were performed with the GL261 glioma model and the 4T1 mammary tumor model injected into the mouse brain. Clinical studies were performed at 3 T with women who had biopsy-proven invasive ductal carcinoma. tDKI measurement was conducted using a diffusion-weighted STEAM pulse sequence with multiple diffusion times (20-800 ms) at a fixed echo time, while keeping the b-values the same (0-3000 s/mm2 ) by adjusting the diffusion gradient strength. The tDKI data at each diffusion time t were used for a weighted linear least-squares fit method to estimate the diffusion-time-dependent diffusivity, D(t), and diffusional kurtosis, K(t). RESULTS: Both preclinical and clinical studies showed that, when diffusion time t ≥ 200 ms, D(t) did not have a noticeable change while K(t) decreased monotonically with increasing diffusion time in tumors and t ≥ 100 ms for the cortical ribbon of the mouse brain. The estimated τex averaged median and interquartile range (IQR) of GL261 and 4T1 tumors were 93 (IQR = 89) ms and 68 (78) ms, respectively. For the cortical ribbon, the estimated τex averaged median and IQR were 41 (34) ms for C57BL/6 and 30 (17) ms for BALB/c. For invasive ductal carcinoma, the estimated τex median and IQR of the two breast cancers were 70 (94) and 106 (92) ms. CONCLUSION: The results of this proof-of-concept study substantiate the feasibility of using tDKI to measure cellular-interstitial water exchange time without using an exogenous contrast agent.

Exploratory study of geometric distortion correction of prostate diffusion-weighted imaging using B0 map acquisition.

BACKGROUND: Evaluation of prostate MRI relies on diffusion-weighted imaging (DWI), commonly distorted by susceptibility artifacts, thereby creating a need for approaches to correct such distortion. PURPOSE: To compare geometric distortion on prostate MRI between standard DWI and a geometric distortion correction method for DWI described as static distortion correction DWI (SDC DWI). STUDY TYPE: Retrospective case study. POPULATION: Thirty patients (ages 31-81 years) undergoing prostate MRI. SEQUENCE: Geometric distortions from echo planar imaging were corrected with the SDC DWI protocol, which first acquires a B0 -field map to estimate geometric distortions. ASSESSMENT: Contours of the prostate were placed on axial T2 -weighted imaging (T2 WI) as an anatomic standard. Pixel shifts and apparent diffusion coefficient (ADC) values were compared between prostate contours applied to the SDC DWI and standard DWI sequences. Detailed characterization of the impact of SDC DWI was performed in three representative patients. STATISTICAL TESTS: One-way analysis of variance (ANOVA) test, Spearman correlation test, and Bland-Altman plots were calculated. RESULTS: There was significantly greater overlap of the SDC DWI prostate region of interest (ROI) with T2 WI than standard DWI with T2 WI (10.56 cm2 ± 3.14, P < 0.05). R2 of ADC values from standard DWI vs. SDC DWI in the 30 patients ranged from 0.02-0.94 (mean 0.60). A patient without susceptibility artifact demonstrated minimal pixel shift ranging from 0.6-1.3 mm and high correlation of ADC values (R2 = 0.89) between SDC DWI and standard DWI. A patient with rectal gas showed greater pixel shift (range: -2.5 to -0.5 mm) and less ADC value correlation (R2 = 0.69). A patient with a pelvic phlebolith adjacent to the prostate showed an even greater pixel shift (range: 10-16 mm) and decreased ADC correlation (R2 = 0.21). DATA CONCLUSION: SDC DWI appears to correct for susceptibility-related pixel shifts in the prostate compared with standard DWI, which may have value for assessing prostate lesions obscured by geometric warping. Level of Evidence 4 Technical Efficacy Stage 1 J. Magn. Reson. Imaging 2019;50:1614-1619.

Validation of surface-to-volume ratio measurements derived from oscillating gradient spin echo on a clinical scanner using anisotropic fiber phantoms.

A diffusion measurement in the short-time surface-to-volume ratio (S/V) limit (Mitra et al., Phys Rev Lett. 1992;68:3555) can disentangle the free diffusion coefficient from geometric restrictions to diffusion. Biophysical parameters, such as the S/V of tissue membranes, can be used to estimate microscopic length scales non-invasively. However, due to gradient strength limitations on clinical MRI scanners, pulsed gradient spin echo (PGSE) measurements are impractical for probing the S/V limit. To achieve this limit on clinical systems, an oscillating gradient spin echo (OGSE) sequence was developed. Two phantoms containing 10 fiber bundles, each consisting of impermeable aligned fibers with different packing densities, were constructed to achieve a range of S/V values. The frequency-dependent diffusion coefficient, D(ω), was measured in each fiber bundle using OGSE with different gradient waveforms (cosine, stretched cosine, and trapezoidal), while D(t) was measured from PGSE and stimulated-echo measurements. The S/V values derived from the universal high-frequency behavior of D(ω) were compared against those derived from quantitative proton density measurements using single spin echo (SE) with varying echo times, and from magnetic resonance fingerprinting (MRF). S/V estimates derived from different OGSE waveforms were similar and demonstrated excellent correlation with both SE- and MRF-derived S/V measures (ρ ≥ 0.99). Furthermore, there was a smoother transition between OGSE frequency f and PGSE diffusion time when using teffS/V=9/64f, rather than the commonly used teff = 1/(4f), validating the specific frequency/diffusion time conversion for this regime. Our well-characterized fiber phantom can be used for the calibration of OGSE and diffusion modeling techniques, as the S/V ratio can be measured independently using other MR modalities. Moreover, our calibration experiment offers an exciting perspective of mapping tissue S/V on clinical systems.

In vivo measurement of membrane permeability and myofiber size in human muscle using time-dependent diffusion tensor imaging and the random permeable barrier model.

The time dependence of the diffusion coefficient is a hallmark of tissue complexity at the micrometer level. Here we demonstrate how biophysical modeling, combined with a specifically tailored diffusion MRI acquisition performing diffusion tensor imaging (DTI) for varying diffusion times, can be used to determine fiber size and membrane permeability of muscle fibers in vivo. We describe the random permeable barrier model (RPBM) and its assumptions, as well as the details of stimulated echo DTI acquisition, signal processing steps, and potential pitfalls. We illustrate the RPBM method on a few pilot examples involving human subjects (previously published as well as new), such as revealing myofiber size derived from RPBM increase after training in a calf muscle, and size decrease with atrophy in shoulder rotator cuff muscle. Finally, we comment on the potential clinical relevance of our results. Copyright © 2016 John Wiley & Sons, Ltd.

In vivo observation and biophysical interpretation of time-dependent diffusion in human white matter.

The presence of micrometer-level restrictions leads to a decrease of diffusion coefficient with diffusion time. Here we investigate this effect in human white matter in vivo. We focus on a broad range of diffusion times, up to 600 ms, covering diffusion length scales up to about 30 µm. We perform stimulated echo diffusion tensor imaging on 5 healthy volunteers and observe a relatively weak time-dependence in diffusion transverse to major fiber tracts. Remarkably, we also find notable time-dependence in the longitudinal direction. Comparing models of diffusion in ordered, confined and disordered media, we argue that the time-dependence in both directions can arise due to structural disorder, such as axonal beads in the longitudinal direction, and the random packing geometry of fibers within a bundle in the transverse direction. These time-dependent effects extend beyond a simple picture of Gaussian compartments, and may lead to novel markers that are specific to neuronal fiber geometry at the micrometer scale.

Universal Sampling Denoising (USD) for noise mapping and noise removal of non-Cartesian MRI.

Random matrix theory (RMT) combined with principal component analysis has resulted in a widely used MPPCA noise mapping and denoising algorithm, that utilizes the redundancy in multiple acquisitions and in local image patches. RMT-based denoising relies on the uncorrelated identically distributed noise. This assumption breaks down after regridding of non-Cartesian sampling. Here we propose a Universal Sampling Denoising (USD) pipeline to homogenize the noise level and decorrelate the noise in non-Cartesian sampled k-space data after resampling to a Cartesian grid. In this way, the RMT approaches become applicable to MRI of any non-Cartesian k-space sampling. We demonstrate the denoising pipeline on MRI data acquired using radial trajectories, including diffusion MRI of a numerical phantom and ex vivo mouse brains, as well as in vivo $T_2$ MRI of a healthy subject. The proposed pipeline robustly estimates noise level, performs noise removal, and corrects bias in parametric maps, such as diffusivity and kurtosis metrics, and $T_2$ relaxation time. USD stabilizes the variance, decorrelates the noise, and thereby enables the application of RMT-based denoising approaches to MR images reconstructed from any non-Cartesian data. In addition to MRI, USD may also apply to other medical imaging techniques involving non-Cartesian acquisition, such as PET, CT, and SPECT.

Feasibility of Accelerated Prostate Diffusion-Weighted Imaging on 0.55 T MRI Enabled With Random Matrix Theory Denoising.

INTRODUCTION: Prostate cancer diffusion weighted imaging (DWI) MRI is typically performed at high-field strength (3.0 T) in order to overcome low signal-to-noise ratio (SNR). In this study, we demonstrate the feasibility of prostate DWI at low field enabled by random matrix theory (RMT)-based denoising, relying on the MP-PCA algorithm applied during image reconstruction from multiple coils. METHODS: Twenty-one volunteers and 2 prostate cancer patients were imaged with a 6-channel pelvic surface array coil and an 18-channel spine array on a prototype 0.55 T system created by ramping down a commercial magnetic resonance imaging system (1.5 T MAGNETOM Aera Siemens Healthcare) with 45 mT/m gradients and 200 T/m/s slew rate. Diffusion-weighted images were acquired with 4 non-collinear directions, for which b = 50 s/mm 2 was used with 8 averages and b = 1000 s/mm 2 with 40 averages; 2 extra b = 50 s/mm 2 were used as part of the dynamic field correction. Standard and RMT-based reconstructions were applied on DWI over different ranges of averages. Accuracy/precision was evaluated using the apparent diffusion coefficient (ADC), and image quality was evaluated over 5 separate reconstructions by 3 radiologists with a 5-point Likert scale. For the 2 patients, we compare image quality and lesion visibility of the RMT reconstruction versus the standard one on 0.55 T and on clinical 3.0 T. RESULTS: The RMT-based reconstruction in this study reduces the noise floor by a factor of 5.8, thereby alleviating the bias on prostate ADC. Moreover, the precision of the ADC in prostate tissue after RMT increases over a range of 30%-130%, with the increase in both signal-to-noise ratio and precision being more prominent for a low number of averages. Raters found that the images were consistently of moderate to good overall quality (3-4 on the Likert scale). Moreover, they determined that b = 1000 s/mm 2 images from a 1:55-minute scan with the RMT-based reconstruction were on par with the corresponding images from a 14:20-minute scan with standard reconstruction. Prostate cancer was visible on ADC and calculated b = 1500 images even with the abbreviated 1:55-minute scan reconstructed with RMT. CONCLUSIONS: Prostate imaging using DWI is feasible at low field and can be performed more rapidly with noninferior image quality compared with standard reconstruction.

Characteristics of the Most Recently Awarded Magnetic Resonance Imaging Patents in the United States.

PURPOSE: To characterize recent magnetic resonance imaging (MRI) technical development and innovation based on data regarding MRI-related patents awarded in 2016. METHODS: The US Patent and Trademark Office website was searched for patents awarded in 2016 and an abstract containing "magnetic resonance." Patent characteristics were summarized. An MRI physicist classified patents' themes. RESULTS: A total of 423 MRI-related patents were awarded in 2016. Among these, 29% had 1 inventor, 24% had 2 inventors, and 47% had ≥2 inventors. Mean interval between patents being filed and awarded was 1389 ± 559days (range: 167-4029). Most common countries of patents' first assignee were USA (40%), Germany (24%), Netherlands (10%), and Japan (10%). In all, 3% included assignees with different countries (most common collaborators USA and Germany). Patents' first assignee had an industry affiliation in 76% vs an academic affiliation in 21% (4% indeterminate); and 3% had industry-academia collaboration. Patents' most common themes were coils (n = 77), sequence design (n = 65), and noncoil scanner hardware (n = 41). These top themes were similar for USA, international, and industry-based patents; however, for academic-based patents, the most common themes were sequence design, reconstruction, and exogenous agents. Less common themes included image analysis, postprocessing, spectroscopy, relaxometry, diffusion, motion correction, radiation therapy, implants, wireless devices, and positron emission tomography-MRI. CONCLUSION: Most MRI-related patents were by non-US inventors. A large majority had industry affiliation; minimal industry-academic collaborationwas observed. Patents from industry and academic inventors had distinct top focuses: hardware and software, respectively. Awarenessofthe most recent years' MRI patents may provide insights into forthcoming clinical translations and help guide ongoing research and entrepreneurism.

Characterization of prostate microstructure using water diffusion and NMR relaxation.

For many pathologies, early structural tissue changes occur at the cellular level, on the scale of micrometers or tens of micrometers. Magnetic resonance imaging (MRI) is a powerful non-invasive imaging tool used for medical diagnosis, but its clinical hardware is incapable of reaching the cellular length scale directly. In spite of this limitation, microscopic tissue changes in pathology can potentially be captured indirectly, from macroscopic imaging characteristics, by studying water diffusion. Here we focus on water diffusion and NMR relaxation in the human prostate, a highly heterogeneous organ at the cellular level. We present a physical picture of water diffusion and NMR relaxation in the prostate tissue, that is comprised of a densely-packed cellular compartment (composed of stroma and epithelium), and a luminal compartment with almost unrestricted water diffusion. Transverse NMR relaxation is used to identify fast and slow T 2 components, corresponding to these tissue compartments, and to disentangle the luminal and cellular compartment contributions to the temporal evolution of the overall water diffusion coefficient. Diffusion in the luminal compartment falls into the short-time surface-to-volume (S/V) limit, indicating that only a small fraction of water molecules has time to encounter the luminal walls of healthy tissue; from the S/V ratio, the average lumen diameter averaged over three young healthy subjects is measured to be 217.7±188.7 µm. Conversely, the diffusion in the cellular compartment is highly restricted and anisotropic, consistent with the fibrous character of the stromal tissue. Diffusion transverse to these fibers is well described by the random permeable barrier model (RPBM), as confirmed by the dynamical exponent ϑ = 1/2 for approaching the long-time limit of diffusion, and the corresponding structural exponent p = -1 in histology. The RPBM-derived fiber diameter and membrane permeability were 19.8±8.1 µm and 0.044±0.045 µm/ms, respectively, in agreement with known values from tissue histology and membrane biophysics. Lastly, we revisited 38 prostate cancer cases from a recently published study, and found the same dynamical exponent ϑ = 1/2 of diffusion in tumors and benign regions. Our results suggest that a multi-parametric MRI acquisition combined with biophysical modeling may be a powerful non-invasive complement to prostate cancer grading, potentially foregoing biopsies.

Time-Dependent Diffusion in Prostate Cancer.

OBJECTIVE: Prior studies in prostate diffusion-weighted magnetic resonance imaging (MRI) have largely explored the impact of b-value and diffusion directions on estimated diffusion coefficient D. Here we suggest varying diffusion time, t, to study time-dependent D(t) in prostate cancer, thereby adding an extra dimension in the development of prostate cancer biomarkers. METHODS: Thirty-eight patients with peripheral zone prostate cancer underwent 3-T MRI using an external-array coil and a diffusion-weighted image sequence acquired for b = 0, as well as along 12 noncollinear gradient directions for b = 500 s/mm using stimulated echo acquisition mode (STEAM) diffusion tensor imaging (DTI). For this sequence, 6 diffusion times ranging from 20.8 to 350 milliseconds were acquired. Tumors were classified as low-grade (Gleason score [GS] 3 + 3; n = 11), intermediate-grade (GS 3 + 4; n = 16), and high-grade (GS ≥4 + 3; n = 11). Benign peripheral zone and transition zone were also studied. RESULTS: Apparent diffusion coefficient (ADC) D(t) decreased with increasing t in all zones of the prostate, though the rate of decay in D(t) was different between sampled zones. Analysis of variance and area under the curve analyses suggested better differentiation of tumor grades at shorter t. Fractional anisotropy (FA) increased with t for all regions of interest. On average, highest FA was observed within GS 3 + 3 tumors. CONCLUSIONS: There is a measurable time dependence of ADC in prostate cancer, which is dependent on the underlying tissue and Gleason score. Therefore, there may be an optimal selection of t for prediction of tumor grade using ADC. Controlling t should allow ADC to achieve greater reproducibility between different sites and vendors. Intentionally varying t enables targeted exploration of D(t), a previously overlooked biophysical phenomenon in the prostate. Its further microstructural understanding and modeling may lead to novel diffusion-derived biomarkers.