Apparent Diffusion Coefficient Of Water Research Articles

Magnetic resonance imaging of tumor response to stroma-modifying pegvorhyaluronidase alpha (PEGPH20) therapy in early-phase clinical trials

Pre-clinical and clinical studies have shown that PEGPH20 depletes intratumoral hyaluronic acid (HA), which is linked to high interstitial fluid pressures and poor distribution of chemotherapies. 29 patients with metastatic advanced solid tumors received quantitative magnetic resonance imaging (qMRI) in 3 prospective clinical trials of PEGPH20: HALO-109-101 (NCT00834704), HALO-109-102 (NCT01170897), and HALO-109-201 (NCT01453153). Apparent Diffusion Coefficient of water (ADC), T1, ktrans, vp, ve, and iAUC maps were computed from qMRI acquired at baseline and ≥ 1 time point post-PEGPH20. Tumor ADC and T1 decreased, while iAUC, ktrans, vp, and ve increased, on day 1 post-PEGPH20 relative to baseline values. This is consistent with HA depletion leading to a decrease in tumor extracellular water content and an increase in perfusion, permeability, extracellular matrix space, and vascularity. Baseline parameter values predictive of pharmacodynamic responses were: ADC > 1.46 × 10−3 mm2/s (Balanced Accuracy (BA) = 72%, p < 0.01), T1 > 0.54 s (BA = 82%, p < 0.01), iAUC < 9.2 mM-s (BA = 76%, p < 0.05), ktrans < 0.07 min−1 (BA = 72%, p = 0.2), ve < 0.17 (BA = 68%, p < 0.01), and vp < 0.02 (BA = 60%, p < 0.01). A low ve at baseline was moderately predictive of response in any parameter (BA = 65.6%, p < 0.01 averaged across patients). These qMRI biomarkers are potentially useful for guiding patient pre-selection and post-treatment follow-up in future clinical studies of PEGPH20 and other tumor stroma-modifying anti-cancer therapies.

Characterization of a Novel Packaged Hydrogel Wound Dressing by 2.35 T Magnetic Resonance Imaging

Hydrogel wound dressing makes easier the treatment of patients suffering from difficult wounds. A new process for the manufacturing of a sterile, packaged hydrogel wound dressing, based on an interpenetrating structure of calcium alginate, agar, and polyvinylpyrrolidone, was recently developed. The new formulation overtakes some previous technologies’ drawbacks expressing a better resistance to mechanical deformations compared to products on the market. In this work, the 2.35 T proton density, spin-lattice relaxation time, spin-spin relaxation time, phase-coherence relaxation, and water apparent diffusion coefficient analysis in the new hydrogel and several alternative formulations, including a commercial one (Neoheal®), are reported. Specifically, the combination of agar, acting as a thermolabile forming agent, with calcium alginate and γ irradiated polyvinylpyrrolidone, acting, respectively, as physical, and chemical crosslinking agents with an irreversible (temperature independent) effect, have been investigated. The new hydrogel formulation brings a qualitative improvement in its handling due to its increased mechanical stiffness when compared to the commercial hydrogel reference. This comes together with a reduced water content (100 vs. 112 for proton density in arbitrary units) and swelling capacity (88% vs. 124%) but with improved water mobility (1.42 vs. 1.34 × 10−3 mm2 s−1 for the apparent diffusion coefficient).

NIMG-01. PREDICTING POST-STEREOTACTIC RADIOTHERAPY MAGNETIC RESONANCE IMAGE OUTCOMES OF BREAST CANCER METASTASES TO THE BRAIN

Abstract BACKGROUND Stereotactic radiosurgery (SRS) is a cornerstone in the management of Breast Cancer Metastases to the Brain (BCMB). While control rates are high following SRS, radiation necrosis is a rare but potentially devastating long-term toxicity. There is a clinical need for automated/semi-automated methods to assess tumor response and optimize the RT plans for local control with minimal long-term toxicity. Multiparametric MRI (mpMRI), particularly Apparent Diffusion Coefficient of water (ADC) maps, contain information that is mechanistically relatable to voxel-level tumor response to RT. We report a deep learning-based approach to predict post-SRS ADC maps, FLAIR, T2-weighted (T2W), T1-weighted unenhanced (T1W) and contrast-enhanced (T1WCE) images, from pre-SRS T1W, T1WCE, T2W and FLAIR images, ADC maps, and the delivered RT dose map. These “forward models” will enable the radiation oncologist to simulate radiologic outcomes and iteratively optimize RT plans for local control with minimal toxicity. METHODS We trained a variant of the pix2pix Generative Adversarial Network (GAN) on MRI and RT dose map data from 18 BCMB patients treated with stereotactic radiation with confirmed controlled and locally recurrent metastases. Patients were treated with stereotactic radiation dose of 1-40 Gy between 2013-2019. RESULTS On test data from 6 BCMB patients, the trained forward model predicted post-SRS ADC values within the Gross Tumor Volume (GTV) that were broadly in agreement with ground truth post-SRS ADC maps. In agreement with expectations, the forward model also predicts increasing post-RT ADC within the GTV with increasing simulated RT doses in the range of 1-71 Gy. We have also explored an inverse model to predict the RT dose map required to produce “prescribed” post-SRS ADC values within the GTV. CONCLUSIONS We envision that the forward models will assist the radiation oncologist in initial RT dose plan optimization, while the inverse model may be useful for daily RT plan optimization.

Physically implausible signals as a quantitative quality assessment metric in prostate diffusion-weighted MR imaging.

To provide a quantitative assessment of diffusion-weighted MR images of the prostate through identification of PIDS which clearly represents artifacts in the data. We calculated the percentage and distribution of PIDS in prostate DWI and compare the amount of PIDS between mpMRI images obtained with and without an endorectal coil. This IRB approved retrospective study (from 03/03/2014 to 03/10/2020), included 40 patients scanned with endorectal coil (ERC) and 40 without ER coil (NERC). PIDS contains any voxel where: (1) the diffusion signal increases despite an increase in b-value; and/or (2) apparent diffusion coefficient (ADC) is more than 3.0 μm2/ms (the ADC of pure water at 37 °C and it is physically implausible for any material to have a higher ADC). PIDS for transition zone (TZ) and peripheral zone (PZ) was calculated using an in-house MATLAB program. DWI images were quantitatively inspected for noise, motion, and distortion. T-test was used to compare the difference between PIDS levels in ERC versus NERC and ANOVA to compare the PIDS levels in the anatomic zones. The images were evaluated by a fellowship-trained radiologist in Abdominal Imaging with more than 10years of experience in reading prostate MRI. This was tested only in prostate in this study. 80 patients (58 ± 8years old, 80 men) were evaluated. The percentage of voxels exhibiting PIDS was 17.1 ± 8.1% for the ERC cohort and 22.2 ± 15.5% for the NERC cohort. PIDS for NERC versus ERC were not significantly different (p = 0.14). The apex and base showed similar percentages of PIDS in ERC (p = 0.30) and NERC (p = 0.86). The mid (13.8 ± 8.6%) in ERC showed lower values (p = 0.02) of PIDS compared to apex (19.9 ± 11.1%) and base (17.5 ± 8.3%). PIDS maps provide a spatially resolved quantitative quality assessment for prostate DWI. Average PIDS over the entire prostate were similar for the ERC and NERC cohorts, and did not differ significantly across prostate zones. However, for many of the patients, PIDS was focally much higher in specific prostate zones. PIDS assessment can guide Radiologist's evaluation of images and the development of improved DWI sequences.

Comparing imaging biomarkers of cerebral edema after TBI in young adult male and female rats

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. Cerebral edema following TBI is known to play a critical role in injury severity and prognosis. In the current study we used multimodal magnetic resonance imaging (MRI) to assess cerebral edema 24 h after unilateral contusive TBI in male and female rats. We then directly quantified brain water content in the same subjectsex vivo.We found that both males and females had similarly elevated T2 values after TBI compared with sham controls. Apparent diffusion coefficient (ADC) was more variable than T2 and did not show significant injury effects in males or females. Brain water was elevated in male TBI rats compared with sham controls, but there was no difference between female TBI and sham groups. Notably, MRI biomarkers of edema were more closely correlated with brain water in male rats; female rats did not show any relationship between brain water and T2 or ADC. These observations raise questions about the interpretation of radiological findings traditionally interpreted as edema in female TBI patients. A better understanding of sex differences and similarities in the pathophysiology of post-traumatic edema is needed to help improve patient management and the development of effective treatment strategies for men and women.

Differentiation of carcinosarcoma from endometrial carcinoma on magnetic resonance imaging using deep learning.

PurposeTo verify whether deep learning can be used to differentiate between carcinosarcomas (CSs) and endometrial carcinomas (ECs) using several magnetic resonance imaging (MRI) sequences.Material and methodsThis retrospective study included 52 patients with CS and 279 patients with EC. A deep-learning model that uses convolutional neural networks (CNN) was trained with 572 T2-weighted images (T2WI) from 42 patients, 488 apparent diffusion coefficient of water maps from 33 patients, and 539 fat-saturated contrast-enhanced T1-weighted images from 40 patients with CS, as well as 1612 images from 223 patients with EC for each sequence. These were tested with 9-10 images of 9-10 patients with CS and 56 images of 56 patients with EC for each sequence, respectively. Three experienced radiologists independently interpreted these test images. The sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUC) for each sequence were compared between the CNN models and the radiologists.ResultsThe CNN model of each sequence had sensitivity 0.89-0.93, specificity 0.44-0.70, accuracy 0.83-0.89, and AUC 0.80-0.94. It also showed an equivalent or better diagnostic performance than the 3 readers (sensitivity 0.43-0.91, specificity 0.30-0.78, accuracy 0.45-0.88, and AUC 0.49-0.92). The CNN model displayed the highest diagnostic performance on T2WI (sensitivity 0.93, specificity 0.70, accuracy 0.89, and AUC 0.94).ConclusionsDeep learning provided diagnostic performance comparable to or better than experienced radiologists when distinguishing between CS and EC on MRI.

Utilizing Radiation Dose Maps to Predict Local Failure Following Stereotactic Radiation of Brain Metastases

Radiologic images have long been used clinically to assess tumor response to therapies, with a significant thrust in recent years to develop methods for predicting tumor response to therapy from radiologic images. Magnetic resonance imaging (MRI) of the apparent diffusion coefficient of water (ADC) in the tumor has been mechanistically linked to tumor cell density and viability. Post-radiation tumor ADC can arguably serve as an objective metric of tumor response to radiation treatment (RT). Here we hypothesize that the post-RT tumor ADC map can be predicted from spatially co-registered pre-RT multiparameter MRI (mpMRI) images and the delivered RT dose map. The overarching goal of this work is to provide a method to predict the RT dose map that will optimize local control.We retrospectively examined 19 patients with breast cancer metastases to the brain (BCMB) who were treated with stereotactic radiation from 2013 to 2019. All patients had confirmed local recurrence. Subjects received a median dose of 21 Gy (range 15-30 Gy) in 1-5 fractions. T1-weighted unenhanced (T1W), T1-weighted contrast-enhanced (T1WCE), T2-weighted (T2W), Fluid-Attenuated Inversion Recovery (FLAIR) scans and ADC maps were acquired on all subjects before SRS, an average of 78 (15-158) days after SRS, and an average of 303 (54-831) days after SRS. Intensity-calibrated images from 11 subjects were used to train a forward model of the general form: ADCpostRT = f(RT Dose Map, T1WpreRT, T1WCEpreRT, T2WpreRT, FLAIRpreRT, ADCpreRT).A significant univariable correlation was observed between the pixelwise change in tumor ADC (first post-SRS scan vs. pre-SRS scan) and the pixelwise RT dose (Table). A multivariable forward model with 13 fitted parameters that related ADCpostRT to an exponential function of the RT dose map with additional exponential terms involving ADCpreRT, T1WpreRT, T1W-CEpreRT, T2WpreRT, and FLAIRpreRT could predict ADCpostRT maps that were visually similar to the corresponding measured ADCpostRT maps (mean structural similarity index measure = 0.96).We have demonstrated the feasibility of predicting post-RT ADC maps from pre-RT mpMRI images and the delivered RT dose maps. Further studies are underway to improve the forward model as well as to train a conditional Generative Adversarial Network (cGAN)-based inverse model. The ultimate study objective is to investigate whether the inverse model can predict the RT dose map that will yield a target post-RT ADC map in BCMB.

Protecting the Brain During Pediatric DKA Treatment.

The most feared complication when treating diabetic ketoacidosis (DKA) is sudden onset of neurologic deterioration, which may include central herniation. Clinical brain swelling complicates 0.5% to 1% of pediatric DKA episodes, and when it occurs, permanent morbidity and mortality are common. However, children in DKA are known to have subclinical brain edema.1 Factors that lead to clinical edema and neurologic abnormalities are not clear. The key issue is to determine the best way to manage these patients, who are dehydrated, severely hyperglycemic, and may have hypo or hypernatremia and severe acidosis.In this issue of Pediatrics, Glaser et al2 provide clinically helpful and reassuring findings in a comparison of 4 intravenous infusion protocols, with varying sodium concentrations and differing rates of rehydration.2,3 There was no difference in rates of neurologic dysfunction or clinically apparent brain swelling in any of the groups.1,2 Even more reassuring, there were no significant differences in these outcomes among those whose serum sodium remained stable or increased versus those whose sodium fell during the first 12 hours of therapy. An important clinical lesson is that this study prospectively demonstrated that rehydration over 1.5 to 2 days does not increase the risk of neurologic injury.2Prevention of DKA is difficult because just over half of episodes are the initial presentation of diabetes.3 Assessment of sensorium can be challenging because headache, throat pain, difficulty waking, and cooperation in infants and younger children can be difficult to judge. The primary study from which Glaser used data included 1389 episodes of DKA in 1255 children. There were 48 episodes (3.5%) when the Glasgow Coma Score was &lt;14 for 2 assessments, and clinically apparent brain injury occurred in 12 episodes (0.9%).3 However, they did not find a significant difference in depression of Glasgow Coma Score or in clinically apparent brain injury among the 4 rehydration protocols.2,3Neuroimaging with MRI and apparent diffusion coefficient (ADC) of water, diffusion weighted images, and spectroscopy reveal that DKA is associated with increased water content in brain tissues supplied by the anterior and middle cerebral arteries with increased perfusion; however, the mean ADCs are abnormally elevated. This differs from what would be predicted by the osmotic disequilibrium theory because the ratio of extracellular volume to total tissue volume determines in part the ADC and should decrease.4,5 Clinical features that were significantly associated with severity of ADC increases during DKA were hypocarbia and elevated serum urea nitrogen but not glucose, sodium, or osmolality.6–8Previous studies with serial neuroimaging of children receiving faster versus slower rehydration during DKA did not differ significantly in the risk of brain edema.9 This previous work, also conducted by Glaser, helped to establish the foundation for this current study to assess different strategies for rehydration.What other pathophysiology occurs that might lead to neurologic injury and brain edema? The brain autoregulates blood flow to meet metabolic needs across a wide range of blood pressure but cerebral blood flow is highly responsive to partial pressure carbon dioxide (paco2). Acute hyperventilation causes vasoconstriction and severe hypocarbia can cause brain ischemia. Although the hypocarbia during DKA causes a compensatory respiratory alkalosis to increase blood pH, the cerebrospinal fluid (CSF) pH typically is normal before treatment. As blood ketosis decreases and the blood paco2 increases, the CSF becomes acidotic. It is important to remember that administration of bicarbonate exacerbates the CSF acidosis associated with DKA treatment. Likewise, a sudden relative increase in paco2 will increase intracranial pressure and CSF acidosis. Airway manipulation should include targeting the child’s baseline paco2 rather than normal values.The current state-of-the-art method to prevent neurologic abnormalities and clinical brain swelling in DKA is not dependent on specific fluid administration but instead on earlier recognition and treatment to avoid profound acidosis and hyperventilation. Current imaging data do not implicate rehydration regimens or changes in blood glucose or sodium with progression to clinical brain edema. The astute clinician will need to rehydrate carefully while paying attention to neurologic status, sustained ventilation, and acid–base status to protect the brain from worsening edema.

Effects of Sex and Age on Fat Fraction, Diffusion-Weighted Image Signal Intensity and Apparent Diffusion Coefficient in the Bone Marrow of Asymptomatic Individuals: A Cross-Sectional Whole-Body MRI Study.

We aimed to describe the relationships between the relative fat fraction (%FF), muscle-normalized diffusion-weighted (DW) image signal intensity and water apparent diffusion coefficient (ADC), sex and age for normal bone marrow, in the normal population. Our retrospective cohort consisted of 100 asymptomatic individuals, equally divided by sex and 10-year age groups, who underwent whole-body MRI at 1.5 T for early cancer detection. Semi-automated segmentation of global bone marrow volume was performed using the DW images and the resulting segmentation masks were projected onto the ADC and %FF maps for extraction of parameter values. Differences in the parameter values between sexes at age ranges were assessed using the Mann–Whitney and Kruskal–Wallis tests. The Spearman correlation coefficient r was used to assess the relationship of each imaging parameter with age, and of %FF with ADC and normalized DW signal intensity values. The average %FF of normal bone marrow was 65.6 ± 7.2%, while nSIb50, nSIb900 and ADC were 1.7 ± 0.5, 3.2 ± 0.9 and 422 ± 67 μm2/s, respectively. The bone marrow %FF values increased with age in both sexes (r = 0.63 and r = 0.64, respectively, p < 0.001). Values of nSIb50 and nSIb900 were higher in younger women compared to men of the same age groups (p < 0.017), but this difference decreased with age. In our cohort of asymptomatic individuals, the values of bone marrow relative %FF, normalized DW image signal intensity and ADC indicate higher cellularity in premenopausal women, with increasing bone marrow fat with aging in both sexes.

778 Poor Sleep Quality is Associated with Reduced Myelination in Patients with Psychotic Disorders

Abstract Introduction Recent studies show that sleep favors oligodendrocyte proliferation and myelination, and sleep loss is associated with alterations in white matter structure and decreased myelination. Psychotic disorders are characterized by disrupted white matter integrity, and abnormal axon and myelin structure. Despite common sleep disturbances in these disorders, little is known about the relationship between sleep quality and white matter findings. A novel in vivo neuroimaging technique that combines diffusion tensor spectroscopy (DTS) and magnetization transfer ratio (MTR) allows separately examining the axon structure and glial function, and myelin content, respectively. Using this method, we examined the association of sleep quality with white matter biology in a sample of patients with psychotic disorders and matched healthy controls. Methods Participants included patients diagnosed with bipolar disorder with psychotic features (euthymic or depressed, n=12) and schizophrenia spectrum disorders (n=9), and age and sex matched healthy controls (n=20). DTS and MTR data was collected from the right prefrontal white matter at 4T. DTS measures included apparent diffusion coefficients of water, NAA, creatine and choline. Sleep quality was measured using Pittsburgh Sleep Quality Index (PSQI). Results PSQI total score was significantly higher in patients. and patient sample included a higher percentage of poor sleepers (PSQI total score&amp;gt;5). In patients, total PSQI score and sleep onset latency were significantly and negatively associated with MTR (F=6.9, p=0.02 and F=9.7, p=0.007, respectively). There was no difference in any DTS measures between groups. Conclusion Our preliminary results show that poor sleep quality is associated with decreased myelin content in the frontal lobe, in patients with psychotic disorders. This finding suggests that sleep loss may be a mediator of white matter alterations in psychosis. Support (if any) This work is supported by National Institute of Mental Health K23MH119322 to Cagri Yuksel

Apparent diffusion coefficient measurement using thin-slice diffusion-weighted magnetic resonance imaging: assessment of measurement errors and repeatability.

We investigated the measurement error and repeatability of the apparent diffusion coefficient (ADC) obtained using thin-slice imaging. Diffusion-weighted images of an ice-water phantom were acquired using 1.5-T and 3.0-T scanners with 1-, 3-, and 5-mm thickness. ADC maps were generated at b = 0 and 1000mm2/s using five consecutive scans. Measurement errors were assessed with accuracy and precision. Repeatability was assessed using the within-subject coefficient of variation. The ADC accuracy of both scanners agreed with the ADC of water at 0°C. At 1-mm, precisions were 2.9% and 8.4% for the 3.0-T and 1.5-T scanners, respectively. The repeatabilities of 1-mm thickness were 1.3% and 3.4% in the 3.0-T and 1.5-T scanners, respectively. The 3.0-T scanner showed acceptable measurement errors and moderate repeatability compared with Quantitative Imaging Biomarkers Alliance recommendation. A 3.0-T scanner can be used for reliable ADC measurement, even with a 1-mm thickness at a reasonable scan time.

Docetaxel chemotherapy response in PC3 prostate cancer mouse model detected by rotating frame relaxations and water diffusion.

MRI is a common method of prostate cancer diagnosis. Several MRI-derived markers, including the apparent diffusion coefficient (ADC) based on diffusion-weighted imaging, have been shown to provide values for prostate cancer detection and characterization. The hypothesis of the study was that docetaxel chemotherapy response could be picked up earlier with rotating frame relaxation times TRAFF2 and TRAFF4 than with the continuous wave T1ρ , adiabatic T1ρ , adiabatic T2ρ , T1 , T2 or water ADC. Human PC3 prostate cancer cells expressing a red fluorescent protein were implanted in 21 male mice. Docetaxel chemotherapy was given once a week starting 1 week after cell implantation for 10 randomly selected mice, while the rest served as a control group (n = 11). The MRI consisted of relaxation along a fictitious field (RAFF) in the second (RAFF2) and fourth (RAFF4) rotating frames, T1 and T2 , continuous wave T1ρ , adiabatic T1ρ and adiabatic T2ρ relaxation time measurements and water ADC. MRI was conducted at 7 T, once a week up to 4 weeks from cell implantation. The tumor volume was monitored using T2 -weighted MRI and optical imaging. The histology was evaluated after the last imaging time point. Significantly reduced RAFFn, T1ρ, T2ρ and conventional relaxation times 4 weeks after tumor implantation were observed in the treated tumors compared with the controls. The clearest short- and long-term responses were obtained with T1 , while no clear improvement in response to treatment was detected with novel methods compared with conventional methods or with RAFFn compared with all others. The tumor volume decreased after a two-week time point for the treated group and increased significantly in the control group, which was supported by increasing red fluorescent light emission in the control tumors. Decreased relaxation times were associated with successful chemotherapy outcomes. The results indicate altered relaxation mechanisms compared with higher dose chemotherapies previously published.

Changes in the brain directly following alcohol consumption-a study of healthy male individuals, with the use of proton magnetic resonance spectroscopy (1HMRS) and diffusion (DWI).

To use proton magnetic resonance spectroscopy (1HMRS) and diffusion weighted imaging (DWI) to identify ethanol in the brain directly after consumption, and examine changes in brain metabolite levels and brain microstructure relative to the duration of time following exposure to alcohol. The study involved 44 male volunteers (18-55years). All brain changes were assessed in the frontal lobes, occipital lobes, basal ganglia and cerebellum, however the detailed analyses focused on the frontal lobes. All participants were examined four times, i.e. before and 0.5-hour, 1hour and 2hours after consumption of 150mL pure vodka (60g of ethanol). The highest ethanol levels were identified between 0.5 and 1hour following alcohol intake. There were significant increases in the concentrations of lipids and lactates approximately one hour after alcohol consumption, and the concentration levels were found to normalise during the following two hours. Some statistically insignificant trends of changes were found for tCr, tCho, mI, GABA, Glc, Glx and tNAA. For the DWI and ADC (Apparent Diffusion Coefficient of water) values, the findings showed statistically insignificant decrease and increase, followed by a tendency towards normalisation. Similar associations in changes of metabolite concentrations and DWI and ADC values were found in the other locations investigated in the study. A single dose of alcohol as used in this experiment produces increases in lipids and lactates in brain tissues that appear reversible.

Magnetic resonance spectroscopy extended by oscillating diffusion gradients: Cell-specific anomalous diffusion as a probe for tissue microstructure in human brain

PurposeTo demonstrate that oscillating gradient spin-echo sequences can be combined with diffusion-weighted magnetic resonance spectroscopy even on clinical MR systems to study human brain at short diffusion times to provide apparent diffusion coefficients (ADCs) sensitive to a narrower cellular length scale than pulsed gradient spin-echo sequences at long diffusion time. MethodsMeasurements were performed on a 3T MR system using a semiLaser sequence with diffusion-weighting realized by oscillating and pulsed gradient modules, encoding diffusion times <10 ms and >50 ms, respectively. Metabolite-cycling was included to measure metabolites and water simultaneously. The sequence was tested in a phantom and in a parieto-occipital cerebral region of interest with mixed gray/white matter content of 6 subjects. The water reference was used for phase, frequency, and eddy-current correction as well as motion compensation. ADCs were estimated by 1D sequential and 2D simultaneous fitting. ResultsMeasurements in the phantom established that both sequences yield equal ADCs, independent of diffusion time, as expected for free diffusion. In contrast, averaged metabolite diffusion in vivo was found to be 1.9 times faster at short (8.3 ms) than at long (155 ms) diffusion times. The difference in ADC was found to be statistically significant for the creatines, cholines, N-acetylaspartate, myo-inositol, and glutamate. The water ADC was measured to be 1.3 times larger at short than at long diffusion time. ConclusionIt is demonstrated that application of oscillating gradients in diffusion-weighted MRS is feasible on clinical MR systems to establish the dependence of ADCs on diffusion times in humans. The initial results largely confirm earlier reports for mice’ and rats’ brain at short and long diffusion times. ADCs representing diffusion at short and ultra-short diffusion times are of interest to probe cellular or subcellular changes in disease. The presented methodology may thus open the door for investigation of pathophysiological changes in cell-specific microstructures in human cohorts.

Quantifying T2 relaxation time changes within lesions defined by apparent diffusion coefficient in grey and white matter in acute stroke patients

The apparent diffusion coefficient (ADC) of cerebral water, as measured by diffusion MRI, rapidly decreases in ischaemia, highlighting a lesion in acute stroke patients. The MRI T2 relaxation time changes in ischaemic brain such that T2 in ADC lesions may be informative of the extent of tissue damage, potentially aiding in stratification for treatment. We have developed a novel user-unbiased method of determining the changes in T2 in ADC lesions as a function of clinical symptom duration based on voxel-wise referencing to a contralateral brain volume. The spherical reference method calculates the most probable pre-ischaemic T2 on a voxel-wise basis, making use of features of the contralateral hemisphere presumed to be largely unaffected. We studied whether T2 changes in the two main cerebral tissue types, i.e. in grey matter (GM) and white matter (WM), would differ in stroke.Thirty-eight acute stroke patients were accrued within 9 h of symptom onset and scanned at 3 T for 3D T1-weighted, multi b-value diffusion and multi-echo spin echo MRI for tissue type segmentation, quantitative ADC and absolute T2 images, respectively. T2 changes measured by the spherical reference method were 1.94 ± 0.61, 1.50 ± 0.52 and 1.40 ± 0.54 ms h−1 in the whole, GM, and WM lesions, respectively. Thus, T2 time courses were comparable between GM and WM independent of brain tissue type involved. We demonstrate that T2 changes in ADC-delineated lesions can be quantified in the clinical setting in a user unbiased manner and that T2 change correlated with symptom onset time, opening the possibility of using the approach as a tool to assess severity of tissue damage in the clinical setting.

The Role of Lactate Metabolism in Prostate Cancer Progression and Metastases Revealed by Dual-Agent Hyperpolarized 13C MRSI.

This study applied a dual-agent, 13C-pyruvate and 13C-urea, hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) and multi-parametric (mp) 1H magnetic resonance imaging (MRI) approach in the transgenic adenocarcinoma of mouse prostate (TRAMP) model to investigate changes in tumor perfusion and lactate metabolism during prostate cancer development, progression and metastases, and after lactate dehydrogenase-A (LDHA) knock-out. An increased Warburg effect, as measured by an elevated hyperpolarized (HP) Lactate/Pyruvate (Lac/Pyr) ratio, and associated Ldha expression and LDH activity were significantly higher in high- versus low-grade TRAMP tumors and normal prostates. The hypoxic tumor microenvironment in high-grade tumors, as measured by significantly decreased HP 13C-urea perfusion and increased PIM staining, played a key role in increasing lactate production through increased Hif1α and then Ldha expression. Increased lactate induced Mct4 expression and an acidic tumor microenvironment that provided a potential mechanism for the observed high rate of lymph node (86%) and liver (33%) metastases. The Ldha knockdown in the triple-transgenic mouse model of prostate cancer resulted in a significant reduction in HP Lac/Pyr, which preceded a reduction in tumor volume or apparent water diffusion coefficient (ADC). The Ldha gene knockdown significantly reduced primary tumor growth and reduced lymph node and visceral metastases. These data suggested a metabolic transformation from low- to high-grade prostate cancer including an increased Warburg effect, decreased perfusion, and increased metastatic potential. Moreover, these data suggested that LDH activity and lactate are required for tumor progression. The lactate metabolism changes during prostate cancer provided the motivation for applying hyperpolarized 13C MRSI to detect aggressive disease at diagnosis and predict early therapeutic response.

Dynamics of Sodium Ions and Water in Swollen Superabsorbent Hydrogels as Studied by 23Na‐ and 1H‐NMR

AbstractDynamics of sodium ions and water in swollen superabsorbent polymer (SAP) hydrogels are studied by 23Na‐ and 1H‐NMR, respectively. The apparent diffusion coefficients of water in swollen SAPs, probed by 1H pulsed field gradient NMR, decreases with increasing diffusion time. The degree of hindrance depends on structural and synthesis parameters. It is quantified within a tortuosity model. Based on the results, the swelling degree has the highest impact on the ion mobility, apart from synthesis parameters leading to different levels of physical and chemical crosslinks. 23Na‐NMR relaxation and diffusion reveal the 23Na+ mobility in swollen SAPs. A higher degree of neutralization leads to faster relaxation and to a smaller apparent diffusion coefficient. Surface crosslinking restricts water mobility, but has a smaller impact on the dynamics of sodium ions. The experimental results indicate an influence of SAP structure on the dynamics of ions and water molecules.

Apparent diffusion coefficient changes in human brain during sleep – Does it inform on the existence of a glymphatic system?

The role of sleep in brain physiology is poorly understood. Recently rodent studies have shown that the glymphatic system clears waste products from brain more efficiently during sleep compared to wakefulness due to the expansion of the interstitial fluid space facilitating entry of cerebrospinal fluid (CSF) into the brain. Here, we studied water diffusivity in the brain during sleep and awake conditions, hypothesizing that an increase in water diffusivity during sleep would occur concomitantly with an expansion of CSF volume - an effect that we predicted based on preclinical findings would be most prominent in cerebellum. We used MRI to measure slow and fast components of the apparent diffusion coefficient (ADC) of water in the brain in 50 healthy participants, in 30 of whom we compared awake versus sleep conditions and in 20 of whom we compared rested-wakefulness versus wakefulness following one night of sleep-deprivation. Sleep compared to wakefulness was associated with increases in slow-ADC in cerebellum and left temporal pole and with decreases in fast-ADC in thalamus, insula, parahippocampus and striatal regions, and the density of sleep arousals was inversely associated with ADC changes. The CSF volume was also increased during sleep and was associated with sleep-induced changes in ADCs in cerebellum. There were no differences in ADCs with wakefulness following sleep deprivation compared to rested-wakefulness. Although we hypothesized increases in ADC with sleep, our findings uncovered both increases in slow ADC (mostly in cerebellum) as well as decreases in fast ADC, which could reflect the distinct biological significance of fast- and slow-ADC values in relation to sleep. While preliminary, our findings suggest a more complex sleep-related glymphatic function in the human brain compared to rodents. On the other hand, our findings of sleep-induced changes in CSF volume provide preliminary evidence that is consistent with a glymphatic transport process in the human brain.

Biomimetic nano-surfactant stabilizes sub-50 nanometer phospholipid particles enabling high paclitaxel payload and deep tumor penetration

Sub-50 nm nanoparticles feature long circulation and deep tumor penetration. However, at high volume fractions needed for intravenous injection, safe, highly biocompatible phospholipids cannot form such nanoparticles due to the fluidity of phospholipid shells. Here we overcome this challenge using a nano-surfactant, a sterilized 18-amino-acid biomimetic of the amphipathic helical motif abundant in HDL-apolipoproteins. As it induces a nanoscale phase (glass) transition in the phospholipid monolayer, the peptide stabilizes 5–7 nm phospholipid micelles that do not fuse at high concentrations but aggregate into stable micellesomes exhibiting size-dependent penetration into tumors. In mice bearing human Her-2-positive breast cancer xenografts, high-payload paclitaxel encapsulated in 25 nm (diameter) micellesomes kills more cancer cells than paclitaxel in standard clinical formulation, as evidenced by the enhanced apparent diffusion coefficient of water determined by in vivo MR imaging. Importantly, the bio-inertness of this biomimetic nano-surfactant spares the nanoparticles from being absorbed by liver hepatocytes, making them more generally available for drug delivery.

Diffusion-weighted magnetic resonance spectroscopy boosted by simultaneously acquired water reference signals.

To combine the metabolite-cycling technique with diffusion-weighted 1 H-MR spectroscopy and to use the inherent water reference for compensation of motion-related signal loss for improved estimation of metabolite apparent diffusion coefficients (ADCs). Diffusion-weighted spectra of water and metabolites were acquired simultaneously using metabolite-cycling at 3 T. The water information was used for signal correction of phase, frequency, and eddy currents, as well as for compensation of motion-induced signal loss. ADCs were estimated by 2D simultaneous fitting. The quality of ADC restoration was investigated in vitro. Subsequently, the new approach was applied in 13 subjects for enhanced metabolite ADC estimation in gray matter. Metabolite-cycled diffusion 1 H-MRS is suitable to measure metabolite and water ADCs simultaneously. The water reference facilitates signal amplitude restoration, compensating for motion-related artefacts. 2D fitting stabilizes the fitting procedure and allows the estimation of ADCs even for low signal-to-noise metabolites. Use of the motion-compensation scheme leads to estimation of smaller ADCs for virtually all metabolites (44% smaller ADC on average), to a reduction of fitting uncertainties for metabolite ADCs in individual subjects and reduced variance over the cohort (45% smaller SD on average). Using the simultaneously acquired water signal as internal reference allows not only for compensation of phase and frequency fluctuations but also for signal amplitude restoration, and thus improved metabolite ADC estimation. Combination with 2D simultaneous fitting promises access to the diffusion properties even for low signal-to-noise metabolites. The combination of both techniques increases the specificity and sensitivity of estimated metabolite ADC values in the cohort.