Alterations In Tissue Microstructure Research Articles

Diffusion MRI approaches for investigating microstructural complexity in a rat model of traumatic brain injury

Our study explores the potential of conventional and advanced diffusion MRI techniques including diffusion tensor imaging (DTI), and single-shell 3-tissue constrained spherical deconvolution (SS3T-CSD) to investigate complex microstructural changes following severe traumatic brain injury in rats at a chronic phase. Rat brains after sham-operation or lateral fluid percussion (LFP) injury were scanned ex vivo in a 9.4 T scanner. Our region-of-interest-based approach of tensor-, and SS3T-CSD derived fixel-, 3-tissue signal fraction maps were sensitive to changes in both white matter (WM) and grey matter (GM) areas. Tensor-based measures, such as fractional anisotropy (FA) and radial diffusivity (RD), detected more changes in WM and GM areas as compared to fixel-based measures including apparent fiber density (AFD), peak FOD amplitude and primary fiber bundle density, while 3-tissue signal fraction maps revealed distinct changes in WM, GM, and phosphate-buffered saline (PBS) fractions highlighting the complex tissue microstructural alterations post-trauma. Track-weighted imaging demonstrated changes in track morphology including reduced curvature and average pathlength distal from the primary lesion in severe TBI rats. In histological analysis, changes in the diffusion MRI measures could be associated to decreased myelin density, loss of myelinated axons, and increased cellularity, revealing progressive microstructural alterations in these brain areas five months after injury. Overall, this study highlights the use of combined conventional and advanced diffusion MRI measures to obtain more precise insights into the complex tissue microstructural alterations in chronic phase of severe brain injury.

Comparison of Diffusion Tensor Imaging Metrics in Normal-Appearing White Matter to Cerebrovascular Lesions and Correlation with Cerebrovascular Disease Risk Factors and Severity.

Alterations in tissue microstructure in normal-appearing white matter (NAWM), specifically measured by diffusion tensor imaging (DTI) fractional anisotropy (FA), have been associated with cognitive outcomes following stroke. The purpose of this study was to comprehensively compare conventional DTI measures of tissue microstructure in NAWM to diverse vascular brain lesions in people with cerebrovascular disease (CVD) and to examine associations between FA in NAWM and cerebrovascular risk factors. DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were measured in cerebral tissues and cerebrovascular anomalies from 152 people with CVD participating in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). Ten cerebral tissue types were segmented including NAWM, and vascular lesions including stroke, periventricular and deep white matter hyperintensities, periventricular and deep lacunar infarcts, and perivascular spaces (PVS) using T1-weighted, proton density-weighted, T2-weighted, and fluid attenuated inversion recovery MRI scans. Mean DTI metrics were measured in each tissue region using a previously developed DTI processing pipeline and compared between tissues using multivariate analysis of covariance. Associations between FA in NAWM and several CVD risk factors were also examined. DTI metrics in vascular lesions differed significantly from healthy tissue. Specifically, all tissue types had significantly different MD values, while FA was also found to be different in most tissue types. FA in NAWM was inversely related to hypertension and modified Rankin scale (mRS). This study demonstrated the differences between conventional DTI metrics, FA, MD, AD, and RD, in cerebral vascular lesions and healthy tissue types. Therefore, incorporating DTI to characterize the integrity of the tissue microstructure could help to define the extent and severity of various brain vascular anomalies. The association between FA within NAWM and clinical evaluation of hypertension and disability provides further evidence that white matter microstructural integrity is impacted by cerebrovascular function.

102 Insights Into the Molecular Underpinnings of Disrupted Mammary Development and Function Arising from Late-Gestation Heat Stress

Abstract Exposure to heat stress during a dairy cow’s dry period disrupts mammary gland remodeling impairing milk production during the subsequent lactation. The dry period coincides with late gestation, and Intrauterine hyperthermia affects offspring growth, physiology, and performance into adulthood. This presentation will highlight histological and molecular adaptations of the mammary gland under heat stress, emphasizing the carry-over effects in the dam and her progeny. Pregnant dams were either cooled (CL, fans and water soakers) or heat-stressed (HS, lack of access to cooling devices) in a free-stall setting during the dry period (~46 d) in summer. Heifers gestated under maternal heat stress or cooling (in utero heat stressed, IUHS vs. in utero cooled, IUCL) were euthanized at birth or weaning, or were followed until the first lactation to collect mammary tissue for histological, proteomics, and methylation analyses. In the dam’s mammary gland, 251 proteins and 224 phosphorylated proteins were differentially abundant in HS compared to CL. Top functions were related to immune function, inflammation, amino acid metabolism, reactive oxygen species production, tissue remodeling, and stress response. Intrauterine hyperthermia derailed mammary gland development inducing alterations in the size and weight of the whole udder and parenchyma and fat pad mass. Epithelial structures within the parenchyma of IUHS heifers were significantly underdeveloped, with reduced proliferative capacity. These early-life alterations in tissue microstructure persist through the first lactation, evidenced by IUHS mammary glands with smaller alveoli and fewer mammary epithelial cells that exhibited reduced proliferation capacity. Further, in utero hyperthermia epigenetically programed the udder. Over 130 differentially methylated genes were identified in the IUHS mammary gland with roles in development, innate immune defense, cell signaling, and transcription and translation. These studies provide insights into the molecular underpinnings of disrupted mammary structure and function arising from prior exposure to dry period/late-gestation heat stress, which led to lower milk yields of the dam and her offspring.

Combined Assessment of Diffusion Parameters and Cerebral Blood Flow Within Basal Ganglia in Early Parkinson's Disease.

Diffusion tensor imaging (DTI) is a sensitive tool for detecting brain tissue microstructural alterations in Parkinson’s disease (PD). Abnormal cerebral perfusion patterns have also been reported in PD patients using arterial spin labeling (ASL) MRI. In this study we aimed to perform a combined DTI and ASL assessment in PD patients within the basal ganglia, in order to test the relationship between microstructural and perfusion alterations. Fifty-two subjects participated in this study. Specifically, 26 PD patients [mean age (SD) = 66.7 (8.9) years, 21 males, median (IQR) Modified Hoehn and Yahr = 1.5 (1–1.6)] and twenty-six healthy controls [HC, mean age (SD) = 65.2 (7.5), 15 males] were scanned with 1.5T MRI. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) maps were derived from diffusion-weighted images, while cerebral blood flow (CBF) maps were computed from ASL data. After registration to Montreal Neurological Institute standard space, FA, MD, AD, RD and CBF median values were extracted within specific regions of interest: substantia nigra, caudate, putamen, globus pallidus, thalamus, red nucleus and subthalamic nucleus. DTI measures and CBF were compared between the two groups. The relationship between diffusion parameters and CBF was tested with Spearman’s correlations. False discovery rate (FDR)-corrected p-values lower than 0.05 were considered significant, while uncorrected p-values <0.05 were considered a trend. No significant FA, MD and RD differences were observed. AD was significantly increased in PD patients compared with HC in the putamen (p = 0.005, pFDR = 0.035). No significant CBF differences were found between PD patients and HC. Diffusion parameters were not significantly correlated with CBF in the HC group, while a significant correlation emerged for PD patients in the caudate nucleus, for all DTI measures (with FA: r = 0.543, pFDR = 0.028; with MD: r = −0.661, pFDR = 0.002; with AD: r = −0.628, pFDR = 0.007; with RD: r = −0.635, pFDR = 0.003). This study showed that DTI is a more sensitive technique than ASL to detect alterations in the basal ganglia in the early phase of PD. Our results suggest that, although DTI and ASL convey different information, a relationship between microstructural integrity and perfusion changes in the caudate may be present.

Susceptibility Perturbation MRI Maps Tumor Infiltration into Mesorectal Lymph Nodes.

Noninvasive characterization of lymph node involvement in cancer is an enduring onerous challenge. In rectal cancer, pathologic lymph node status constitutes the most important determinant of local recurrence and overall survival, and patients with involved lymph nodes may benefit from preoperative chemo and/or radiotherapy. However, knowledge of lymph node status before surgery is currently hampered by limited imaging accuracy. Here, we introduce Susceptibility-Perturbation MRI (SPI) as a novel source of contrast to map malignant infiltration into mesorectal lymph nodes. SPI involves multigradient echo (MGE) signal decays presenting a nonmonoexponential nature, which we show is sensitive to the underlying microstructure via susceptibility perturbations. Using numerical simulations, we predicted that the large cell morphology and the high cellularity of tumor within affected mesorectal lymph nodes would induce signature SPI decays. We validated this prediction in mesorectal lymph nodes excised from total mesorectal excision specimens of patients with rectal cancer using ultrahigh field (16.4 T) MRI. SPI signals distinguished benign from malignant nodal tissue, both qualitatively and quantitatively, and our histologic analyses confirmed cellularity and cell size were the likely underlying sources for the differences observed. SPI was then adapted to a clinical 1.5 T scanner, added to patients' staging protocol, and compared with conventional assessment by two expert radiologists. Nonmonoexponential decays, similar to those observed in the ex vivo study, were demonstrated, and SPI classified lymph nodes more accurately than standard high-resolution T2-weighted imaging assessment. These findings suggest this simple, yet highly informative, method can improve rectal cancer patient selection for neoadjuvant therapy. SIGNIFICANCE: These findings introduce an MRI methodology tailored to detect magnetic susceptibility perturbations induced by subtle alterations in tissue microstructure.

High-Spatial-Resolution Diffusion MRI in Parkinson Disease: Lateral Asymmetry of the Substantia Nigra

Background Motor symptoms in Parkinson disease (PD) have exhibited lateral asymmetry, suggesting asymmetric neuronal loss in the substantia nigra (SN). Diffusion MRI may be able to help confirm tissue microstructural alterations in the substantia nigra to probe for the presence of asymmetry. Purpose To investigate lateral asymmetry in the SN of patients with PD by using diffusion MRI with both Gaussian and non-Gaussian models. Materials and Methods In this cross-sectional study conducted from March 2015 to March 2017, 27 participants with PD and 27 age-matched healthy control (HC) participants, all right handed, underwent MRI at 3.0 T. High-spatial-resolution diffusion images were acquired with a reduced field of view by using seven b values up to 3000 sec/mm2. A continuous-time random-walk (CTRW) non-Gaussian diffusion model was used to produce anomalous diffusion coefficient (Dm) and temporal (α) and spatial (β) diffusion heterogeneity indexes followed by a Gaussian diffusion model to yield an apparent diffusion coefficient (ADC). Individual or linear combinations of diffusion parameters in the SN were unilaterally and bilaterally compared between the PD and HC groups. Results In the bilateral comparison between the PD and HC groups, differences were observed in β (0.67 ± 0.06 [standard deviation] vs 0.64 ± 0.04, respectively; P = .016), ADC (0.48 μm2/msec ± 0.08 vs 0.53 μm2/msec ± 0.06, respectively; P = .03), and the combination of CTRW parameters (P = .02). In the unilateral comparison, differences were observed in all diffusion parameters on the left SN (P < .03), but not on the right (P > .20). In a receiver operating characteristic (ROC) analysis to delineate left SN abnormality in PD, the combination of Dm, α, and β produced the best sensitivity (sensitivity, 0.78); the combination of Dm and β produced the best specificity (specificity, 0.85); and the combination of α and β produced the largest area under the ROC curve (area under the ROC curve, 0.73). Conclusion These results suggest that quantitative diffusion MRI is sensitive to brain tissue changes in participants with Parkinson disease and provide evidence of substantia nigra lateral asymmetry in this disease. © RSNA, 2019 Online supplemental material is available for this article.

Quantitative diagnosis of tissue microstructure with wide-field high spatial frequency domain imaging.

Non-contact and minimally invasive endoscopic optical imaging is an invaluable diagnostic tool for tissue examination and cancer screening. The point sampling techniques with high sensitivity to the tissue microenvironment are time consuming and often not affordable in clinics. There is a major clinical need for a large field-of-view (FOV) rapid screening method to highlight subtle tissue microstructural alterations. To address this unmet need, we have developed High Spatial Frequency Domain Imaging (HSFDI)-a non-contact imaging modality that spatially maps the tissue microscopic scattering structures over a large field of view (>1cm2). Based on an analytical reflectance model of sub-diffusive light from forward-peaked highly scattering media, HSFDI quantifies the spatially-resolved parameters of the light scattering phase function (i.e., the backscattering probability and the light spreading length) from the reflectance of structured light modulated at high spatial frequencies. Enhanced signal to noise ratio (SNR) is achieved at even ultra-high modulation frequencies with single snapshot multiple frequency demodulation (SSMD). The variations in tissue microstructures, including the strength of the background (pudding) refractive index fluctuation and the prominent scattering structure (plum) morphology, can then be inferred. After validation with optical phantoms, measurements of fresh ex vivo tissue samples revealed significant contrast and differentiation of the phase function parameters between different types and disease states (normal, inflammatory, and cancerous) of tissue whereas tissue absorption and reduced scattering coefficients only show modest changes. HSFDI may provide wide-field images of microscopic structural biomarkers unobtainable with either diffuse light imaging or point-based optical sampling. Potential clinical applications include the rapid screening of excised tissue and the noninvasive examination of suspicious lesions during operation.

Quantitative Analysis of Tissue Damage Evolution in Porcine Liver With Interrupted Mechanical Testing Under Tension, Compression, and Shear.

In this study, the damage evolution of liver tissue was quantified at the microstructural level under tensile, compression, and shear loading conditions using an interrupted mechanical testing method. To capture the internal microstructural changes in response to global deformation, the tissue samples were loaded to different strain levels and chemically fixed to permanently preserve the deformed tissue geometry. Tissue microstructural alterations were analyzed to quantify the accumulated damages, with damage-related parameters such as number density, area fraction, mean area, and mean nearest neighbor distance (NND). All three loading states showed a unique pattern of damage evolution, in which the damages were found to increase in number and size, but decrease in NND as strain level increased. To validate the observed damage features as true tissue microstructural damages, more samples were loaded to the above-mentioned strain levels and then unloaded back to their reference state, followed by fixation. The most major damage-relevant features at higher strain levels remained after the release of the external loading, indicating the occurrence of permanent inelastic deformation. This study provides a foundation for future structure-based constitutive material modeling that can capture and predict the stress-state dependent damage evolution in liver tissue.

Diffusion characteristics of the fornix in patients with Alzheimer’s disease

White matter degradation is a major part of the pathogenesis of Alzheimer’s disease (AD). The fornix is the predominant outflow tract from the hippocampus, and alterations to its microstructure in patients with AD are still being explored. Diffusion tensor imaging (DTI) is an in vivo neuroimaging technique that can provide unique information about alterations in tissue microstructure, which can indicate underlying neurobiological process at the microstructural level. In this prospective study, DTI was used to assess and analyze the microstructural features of the fornix in subjects with AD (n = 17), mild cognitive impairment (MCI; n = 12) and healthy controls (n = 17). DTI was performed using Explore DTI software and the FSL package. Within the fornix, patients with AD showed decreased fractional anisotropy values and length of fiber tracts of the fornix relative to healthy controls, but higher mean diffusivity values. MCI subjects showed a trend towards elevated mean diffusivity values in the fornix. The data suggest that DTI provides supporting information on the microstructural alteration of the fornix in patients with AD, and that these diffusion characteristics of the fornix may be helpful for the clinical diagnosis of AD.

Kurtosis analysis of neural diffusion organization

A computational framework is presented for relating the kurtosis tensor for water diffusion in brain to tissue models of brain microstructure. The tissue models are assumed to be comprised of non-exchanging compartments that may be associated with various microstructural spaces separated by cell membranes. Within each compartment the water diffusion is regarded as Gaussian, although the diffusion for the full system would typically be non-Gaussian. The model parameters are determined so as to minimize the Frobenius norm of the difference between the measured kurtosis tensor and the model kurtosis tensor. This framework, referred to as kurtosis analysis of neural diffusion organization (KANDO), may be used to help provide a biophysical interpretation to the information provided by the kurtosis tensor. In addition, KANDO combined with diffusional kurtosis imaging can furnish a practical approach for developing candidate biomarkers for neuropathologies that involve alterations in tissue microstructure. KANDO is illustrated for simple tissue models of white and gray matter using data obtained from healthy human subjects.

Connectivity and tissue microstructural alterations in right and left temporal lobe epilepsy revealed by diffusion spectrum imaging.

Focal epilepsy is increasingly recognized as the result of an altered brain network, both on the structural and functional levels and the characterization of these widespread brain alterations is crucial for our understanding of the clinical manifestation of seizure and cognitive deficits as well as for the management of candidates to epilepsy surgery.Tractography based on Diffusion Tensor Imaging allows non-invasive mapping of white matter tracts in vivo. Recently, diffusion spectrum imaging (DSI), based on an increased number of diffusion directions and intensities, has improved the sensitivity of tractography, notably with respect to the problem of fiber crossing and recent developments allow acquisition times compatible with clinical application.We used DSI and parcellation of the gray matter in regions of interest to build whole-brain connectivity matrices describing the mutual connections between cortical and subcortical regions in patients with focal epilepsy and healthy controls. In addition, the high angular and radial resolution of DSI allowed us to evaluate also some of the biophysical compartment models, to better understand the cause of the changes in diffusion anisotropy.Global connectivity, hub architecture and regional connectivity patterns were altered in TLE patients and showed different characteristics in RTLE vs LTLE with stronger abnormalities in RTLE. The microstructural analysis suggested that disturbed axonal density contributed more than fiber orientation to the connectivity changes affecting the temporal lobes whereas fiber orientation changes were more involved in extratemporal lobe changes. Our study provides further structural evidence that RTLE and LTLE are not symmetrical entities and DSI-based imaging could help investigate the microstructural correlate of these imaging abnormalities.

In vivo time-serial multi-modality optical imaging in a mouse model of ovarian tumorigenesis

Identification of the early microscopic changes associated with ovarian cancer may lead to development of a diagnostic test for high-risk women. In this study we use optical coherence tomography (OCT) and multiphoton microscopy (MPM) (collecting both two photon excited fluorescence [TPEF] and second harmonic generation [SHG]) to image mouse ovaries in vivo at multiple time points. We demonstrate the feasibility of imaging mouse ovaries in vivo during a long-term survival study and identify microscopic changes associated with early tumor development. These changes include alterations in tissue microstructure, as seen by OCT, alterations in cellular fluorescence and morphology, as seen by TPEF, and remodeling of collagen structure, as seen by SHG. These results suggest that a combined OCT-MPM system may be useful for early detection of ovarian cancer.

Polarization-gated Spectroscopy (PGS) to Detect Tissue Microstructural Alterations in Esophageal Field Carcinogenesis

Polarization-gated Spectroscopy (PGS) to Detect Tissue Microstructural Alterations in Esophageal Field Carcinogenesis

Subcortical Alterations in Tissue Microstructure Adjacent to Focal Cortical Dysplasia: Detection at Diffusion-Tensor MR Imaging by Using Magnetoencephalographic Dipole Cluster Localization

To determine whether changes at diffusion-tensor magnetic resonance (MR) imaging were present in children with intractable epilepsy and focal cortical dysplasia (FCD) in (a) subcortical white matter subjacent to MR imaging-visible areas of FCD, (b) subcortical white matter beyond the MR imaging-visible abnormality but subjacent to a magnetoencephalographic (MEG) dipole cluster, and (c) deep white matter tracts. The study protocol had institutional research ethics board approval, and written informed consent was obtained. Fifteen children with FCD and intractable epilepsy (mean age, 11.6 years; range, 3.6-18.3 years) underwent diffusion-tensor MR imaging and MEG. Regions of interest were placed in (a) the subcortical white matter subjacent to the MR imaging-visible abnormality, as well as the contralateral side; (b) the subcortical white matter beyond the MR imaging-visible abnormality but subjacent to a MEG dipole cluster, as well as the contralateral side; and (c) deep white matter tracts projecting to or from the MR imaging-visible FCD, as well as the contralateral side. Fractional anisotropy (FA), mean diffusivity, and eigenvalues (lambda(1), lambda(2), lambda(3)) were evaluated. Eleven of 15 children had MEG dipole clusters, and four children had MEG scatter. There were significant differences in FA, mean diffusivity, lambda(2), and lambda(3) of the subcortical white matter subjacent to the MR imaging-visible FCD (P < .001 for all), as well as that beyond the MR imaging-visible FCD but subjacent to a MEG dipole cluster (P = .001, P = .036, P < .001, and P = .002, respectively), compared with the contralateral side. There were also significant differences in FA (P < .001), mean diffusivity (P = .008), lambda(2) (P < .001), and lambda(3) (P = .001) of the deep white matter tracts projecting to or from the MR imaging-visible FCD compared with the contralateral side. With use of MEG dipole clusters to localize the epileptogenic zone, diffusion-tensor imaging can help identify alterations in tissue microstructure beyond the MR imaging-visible FCD.