The relationship between diffusion heterogeneity and microstructural changes in high-grade gliomas using Monte Carlo simulations.

PURPOSE: Diffusion-weighted imaging (DWI) may aid accurate tumor grading. Decreased diffusivity and increased diffusion heterogeneity measures have been observed in high-grade gliomas using the non-monoexponential models for DWI. However, DWI measures concerning tissue characteristics in terms of pathophysiological and structural changes are yet to be established. Thus, this study aims to investigate the relationship between the diffusion measurements and microstructural changes in the presence of high-grade gliomas using a three-dimensional Monte Carlo simulation with systematic changes of microstructural parameters. METHODS: Water diffusion was simulated in a microenvironment along with changes associated with the presence of high-grade gliomas, including increases in cell density, nuclear volume, extracellular volume (VFex), and extracellular tortuosity (λex), and changes in membrane permeability (Pmem). DWI signals were simulated using a pulsed gradient spin-echo sequence. The sequence parameters, including the maximum gradient strength and diffusion time, were set to be comparable to those of clinical scanners and advanced human MRI systems. The DWI signals were fitted using the gamma distribution and diffusional kurtosis models with b-values up to 6000 and 2500 s/mm2, respectively. RESULTS: The diffusivity measures (apparent diffusion coefficients (ADC), Dgamma of the gamma distribution model and Dapp of the diffusional kurtosis model) decreased with increases in cell density and λex, and a decrease in Pmem. These diffusivity measures increased with increases in nuclear volume and VFex. The diffusion heterogeneity measures (σgamma of the gamma distribution model and Kapp of the diffusional kurtosis model) increased with increases in cell density or nuclear volume at the low Pmem, and a decrease in Pmem. Increased σgamma was also associated with an increase in VFex. CONCLUSION: Among simulated microstructural changes, only increases in cell density at low Pmem or decreases in Pmem corresponded to both the decreased diffusivity and increased diffusion heterogeneity measures. The results suggest that increases in cell density at low Pmem or decreases in Pmem may be associated with the diffusion changes observed in high-grade gliomas.

Estimating Nephron Number from Biopsies: Impact on Clinical Studies.

BACKGROUND: Accumulating evidence supports an association between nephron number and susceptibility to kidney disease. However, it is not yet possible to directly measure nephron number in a clinical setting. Recent clinical studies have used glomerular density from a single biopsy and whole kidney cortical volume from imaging to estimate nephron number and single nephron glomerular filtration rate. However, the accuracy of these estimates from individual subjects is unknown. Furthermore, it is not clear how sample size or biopsy location may influence these estimates. These questions are critical to study design, and to the potential translation of these tools to estimate nephron number in individual subjects. METHODS: We measured the variability in estimated nephron number derived from needle or virtual biopsies and cortical volume in human kidneys declined for transplantation. We performed multiple needle biopsies in the same kidney, and examined the three-dimensional spatial distribution of nephron density by magnetic resonance imaging. We determined the accuracy of a single-kidney biopsy to predict the mean nephron number estimated from multiple biopsies from the same kidney. RESULTS: A single needle biopsy had a 15% chance and virtual biopsy had a 60% chance of being within 20% of the whole-kidney nephron number. Single needle biopsies could be used to detect differences in nephron number between large cohorts of several hundred subjects. CONCLUSIONS: The number of subjects required to accurately detect differences in nephron number between populations can be predicted on the basis of natural intrakidney variability in glomerular density. A single biopsy is insufficient to accurately predict nephron number in individual subjects.

Image analysis techniques to map pyramids, pyramid structure, glomerular distribution, and pathology in the intact human kidney from 3-D MRI.

Kidney pathologies are often highly heterogeneous. To comprehensively understand kidney structure and pathology, it is critical to develop tools to map tissue microstructure in the context of the whole, intact organ. Magnetic resonance imaging (MRI) can provide a unique, three-dimensional view of the kidney and allows for measurements of multiple pathological features. Here, we developed a platform to systematically render and map gross and microstructural features of the human kidney based on three-dimensional MRI. These features include pyramid number and morphology as well as the associated medulla and cortex. In a subset of these kidneys, we also mapped individual glomeruli and glomerular volumes using cationic ferritin-enhanced MRI to report intrarenal heterogeneity in glomerular density and size. Finally, we rendered and measured regions of nephron loss due to pathology and individual glomerular volumes in each pyramidal unit. This work provides new tools to comprehensively evaluate the kidney across scales, with potential applications in anatomic and physiological research, transplant allograft evaluation, biomarker development, biopsy guidance, and therapeutic monitoring. These image rendering and analysis tools could eventually impact the field of transplantation medicine to improve longevity matching of donor allografts and recipients and reduce discard rates through the direct assessment of donor kidneys.NEW & NOTEWORTHY We report the application of cutting-edge image analysis approaches to characterize the pyramidal geometry, glomerular microstructure, and heterogeneity of the whole human kidney imaged using MRI. This work establishes a framework to improve the detection of microstructural pathology to potentially facilitate disease monitoring or transplant evaluation in the individual kidney.

Beyond the tubule: pathological variants of LRP2, encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease.

Pathogenic variants in the LRP2 gene, encoding the multiligand receptor megalin, cause a rare autosomal recessive syndrome: Donnai-Barrow/Facio-Oculo-Acoustico-Renal (DB/FOAR) syndrome. Because of the rarity of the syndrome, the long-term consequences of the tubulopathy on human renal health have been difficult to ascertain, and the human clinical condition has hitherto been characterized as a benign tubular condition with asymptomatic low-molecular-weight proteinuria. We investigated renal function and morphology in a murine model of DB/FOAR syndrome and in patients with DB/FOAR. We analyzed glomerular filtration rate in mice by FITC-inulin clearance and clinically characterized six families, including nine patients with DB/FOAR and nine family members. Urine samples from patients were analyzed by Western blot analysis and biopsy materials were analyzed by histology. In the mouse model, we used histological methods to assess nephrogenesis and postnatal renal structure and contrast-enhanced magnetic resonance imaging to assess glomerular number. In megalin-deficient mice, we found a lower glomerular filtration rate and an increase in the abundance of injury markers, such as kidney injury molecule-1 and N-acetyl-ß-d-glucosaminidase. Renal injury was validated in patients, who presented with increased urinary kidney injury molecule-1, classical markers of chronic kidney disease, and glomerular proteinuria early in life. Megalin-deficient mice had normal nephrogenesis, but they had 19% fewer nephrons in early adulthood and an increased fraction of nephrons with disconnected glomerulotubular junction. In conclusion, megalin dysfunction, as present in DB/FOAR syndrome, confers an increased risk of progression into chronic kidney disease.

MR imaging techniques for nano-pathophysiology and theranostics.

The advent of nanoparticle DDSs (drug delivery systems, nano-DDSs) is opening new pathways to understanding physiology and pathophysiology at the nanometer scale. A nano-DDS can be used to deliver higher local concentrations of drugs to a target region and magnify therapeutic effects. However, interstitial cells or fibrosis in intractable tumors, as occurs in pancreatic or scirrhous stomach cancer, tend to impede nanoparticle delivery. Thus, it is critical to optimize the type and size of nanoparticles to reach the target. High-resolution 3D imaging provides a means of "seeing" the nanoparticle distribution and therapeutic effects. We introduce the concept of "nano-pathophysiological imaging" as a strategy for theranostics. The strategy consists of selecting an appropriate nano-DDS and rapidly evaluating drug effects in vivo to guide the next round of therapy. In this article we classify nano-DDSs by component carrier materials and present an overview of the significance of nano-pathophysiological MRI.

Disruptive chemical doping in a ferritin-based iron oxide nanoparticle to decrease r2 and enhance detection with T1-weighted MRI.

Inorganic doping was used to create flexible, paramagnetic nanoparticle contrast agents for in vivo molecular magnetic resonance imaging (MRI) with low transverse relaxivity (r2). Most nanoparticle contrast agents formed from superparamagnetic metal oxides are developed with high r2. While sensitive, they can have limited in vivo detection due to a number of constraints with T2 or T2*-weighted imaging. T1-weighted imaging is often preferred for molecular MRI, but most T1-shortening agents are small chelates with low metal payload or are nanoparticles that also shorten T2 and limit the range of concentrations detectable with T1-weighting. Here we used tungsten and iron deposition to form doped iron oxide crystals inside the apoferritin cavity to form a WFe nanoparticle with a disordered crystal and un-coupled atomic magnetic moments. The atomic magnetic moments were thus localized, resulting in a principally paramagnetic nanoparticle. The WFe nanoparticles had no coercivity or saturation magnetization at 5 K and sweeping up to ± 20,000 Oe, while native ferritin had a coercivity of 3000 Oe and saturation at ± 20,000 Oe. This tungsten-iron crystal paramagnetism resulted in an increased WFe particle longitudinal relaxivity (r1) of 4870 mm(-1) s(-1) and a reduced transverse relaxivity (r2) of 9076 mm(-1) s(-1) compared with native ferritin. The accumulation of the particles was detected with T1-weighted MRI in concentrations from 20 to 400 nm in vivo, both injected in the rat brain and targeted to the rat kidney glomerulus. The WFe apoferritin nanoparticles were not cytotoxic up to 700 nm particle concentrations, making them potentially important for targeted molecular MRI.

Principles and emerging applications of nanomagnetic materials in medicine.

The development of nanometer-scale magnetic materials for biomedical applications spans the interface between the physical sciences and biology. Applications of these materials are rapidly becoming important in medicine and enable targeted therapies and diagnostics. At the same time, specific applications add focus to the development of novel magnetic materials and facilitate a deeper understanding of the physical mechanisms behind their function. This review presents a broad, nontechnical overview of the basis of magnetism in materials at the nanometer scale and describes how these materials are created, characterized, and used. Specific emerging applications in medical diagnostics and therapies are discussed, including cancer cell targeting for thermal ablation, tissue engineering, and three-dimensional noninvasive molecular imaging. Challenges in these fields are discussed, including the toxicity and delivery of magnetic nanomaterials and the sensitivity of imaging and therapeutic techniques. The development of novel nanomagnetic nanomaterials should continue to accelerate as new applications are identified and researchers uncover new mechanisms to increase and modulate magnetism at the nanometer scale.

Water diffusion heterogeneity index in the human brain is insensitive to the orientation of applied magnetic field gradients.

The alpha diffusion-weighted imaging (DWI) method was developed to study heterogeneous water diffusion in the human brain using magnetic resonance imaging (MRI). An advantage of this model is that it does not require an assumption about the shape of the intravoxel distribution of apparent diffusion rates, and it has a calculable relationship to this distribution. The alpha-DWI technique is useful for detecting microstructural tissue changes associated with brain tumor invasion, and may be useful for directing therapy to invading tumor cells. In previous work, alpha-DWI was performed with magnetic field gradients applied along a single direction in order to avoid artificially introducing a source of heterogeneity to the decay. However, it is known that restricted diffusion is anisotropic in the brain, and the alpha-DWI method must take this into account to be complete. In this work the relationship between the applied magnetic field gradients and the fitted stretched-exponential model parameters was studied in the human brain. It was found the distributed diffusion coefficient (DDC) varies with the direction of applied gradients, while the heterogeneity index alpha is relatively direction-insensitive. It is proposed that in clinical use, maps of alpha can be created using diffusion-weighting gradients applied in a single direction that reflect the tissue heterogeneity.

Intravoxel distribution of DWI decay rates reveals C6 glioma invasion in rat brain.

The hypothesis was tested that the intravoxel distribution of water diffusion rates, as measured with a stretched-exponential model of diffusion-weighted imaging (DWI), is a marker of brain tumor invasion. Eight rats underwent intracerebral inoculation of C6 glioma cells. In three rats, cells were labeled with a fluorescent dye for microscopy. One rat was inoculated with a saline solution, and five more rats were imaged without inoculation as controls. Five healthy uninoculated rats were also imaged. DWI was performed 14-15 days after inoculation, with diffusion-weighting factor b = 500 to 6500 sec/mm2, and the resulting signal attenuation was fitted with the stretched-exponential model. The heterogeneity index values were significantly lower (P < 0.05) in the peritumor ROI than in normal gray matter and significantly higher than in normal white matter. The distributed diffusion coefficient values were significantly lower than in normal white matter or normal gray matter. Fluorescence microscopy confirmed the presence of tumors in the peritumor region that could be histologically distinguished from the main tumor mass. There was no change in proton density or T2-weighted images in the peritumor region, making vasogenic edema unlikely as a source of contrast. It is therefore thought that the heterogeneity parameter alpha is a marker of brain tumor invasion.