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Diffusion basis spectrum imaging (DBSI) models diffusion-weighted magnetic resonance imaging (MRI) signals as a combination of discrete anisotropic diffusion tensors and a spectrum of isotropic diffusion tensors. Here, we report the histopathological correlates of DBSI in the biopsied brain tissue of a patient with an inflammatory demyelinating lesion typical of multiple sclerosis (MS). Increased radial diffusivity (marker of demyelination), decreased fiber fraction (apparent axonal density), elevated nonrestricted isotropic fraction (marker of vasogenic edema), but unchanged axial diffusivity (marker of integrity of residual axons) seen in the lesion appeared consistent with histopathological findings of inflammatory demyelination with relative axonal sparing. Our report supports the application of DBSI as a biomarker in human studies of MS.

Diffusion basis spectrum imaging (DBSI) combines discrete anisotropic diffusion tensors and the spectrum of isotropic diffusion tensors to model the underlying multiple sclerosis (MS) pathologies. We used clinical MS subtypes as a surrogate of underlying pathologies to assess DBSI as a biomarker of pathology in 55 individuals with MS. Restricted isotropic fraction (reflecting cellularity) and fiber fraction (representing apparent axonal density) were the most important DBSI metrics to classify MS using brain white matter lesions. These DBSI metrics outperformed lesion volume. When analyzing the normal-appearing corpus callosum, the most significant DBSI metrics were fiber fraction, radial diffusivity (reflecting myelination), and nonrestricted isotropic fraction (representing edema). This study provides preliminary evidence supporting the ability of DBSI as a potential noninvasive biomarker of MS neuropathology., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Despite 253,000 spinal cord injury (SCI) patients in the United States, little is known about how SCI affects brain networks. Spinal MRI provides only structural information with no insight into functional connectivity. Resting-state functional MRI (RS-fMRI) quantifies network connectivity through the identification of resting-state networks (RSNs) and allows detection of functionally relevant changes during disease. Given the robust network of spinal cord afferents to the brain, we hypothesized that SCI produces meaningful changes in brain RSNs. RS-fMRIs and functional assessments were performed on 10 SCI subjects. Blood oxygen-dependent RS-fMRI sequences were acquired. Seed-based correlation mapping was performed using five RSNs: default-mode (DMN), dorsal-attention (DAN), salience (SAL), control (CON), and somatomotor (SMN). RSNs were compared with normal control subjects using false-discovery rate-corrected two way t tests. SCI reduced brain network connectivity within the SAL, SMN, and DMN and disrupted anti-correlated connectivity between CON and SMN. When divided into separate cohorts, complete but not incomplete SCI disrupted connectivity within SAL, DAN, SMN and DMN and between CON and SMN. Finally, connectivity changed over time after SCI: the primary motor cortex decreased connectivity with the primary somatosensory cortex, the visual cortex decreased connectivity with the primary motor cortex, and the visual cortex decreased connectivity with the sensory parietal cortex. These unique findings demonstrate the functional network plasticity that occurs in the brain as a result of injury to the spinal cord. Connectivity changes after SCI may serve as biomarkers to predict functional recovery following an SCI and guide future therapy.

We describe a novel imaging method to assess central nervous system pathology called "Diffusion Basis Spectrum Imaging" (DBSI). Diffusion tensor imaging (DTI) has been widely used to estimate axonpathology and demyelination. However, in the settings of acute inflammation and chronic tissue loss asare common in multiple sclerosis, DTI signals can lead to false interpretations. DBSI is a computationallynovel method that separates isotropic from anisotropic components in imaging voxels. Isotropicdiffusion is believed to reflect inflammatory components (cells, edema), as well as intrinsic cells andextracellular space. DBSI enables the measurement of axial and radial diffusivities within the anisotropiccomponents of imaging voxels, which reflect the integrity of axon fibers and myelin, respectively., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Many brain diseases have been linked to abnormal oxygen metabolism and blood perfusion; nevertheless, there is still a lack of robust diagnostic tools for directly imaging cerebral metabolic rate of oxygen (CMRO(2)) and cerebral blood flow (CBF), as well as the oxygen extraction fraction (OEF) that reflects the balance between CMRO(2) and CBF. This study employed the recently developed in vivo (17)O MR spectroscopic imaging to simultaneously assess CMRO(2), CBF and OEF in the brain using a preclinical middle cerebral arterial occlusion mouse model with a brief inhalation of (17)O-labeled oxygen gas. The results demonstrated high sensitivity and reliability of the noninvasive (17)O-MR approach for rapidly imaging CMRO(2), CBF and OEF abnormalities in the ischemic cortex of the MCAO mouse brain. It was found that in the ischemic brain regions both CMRO(2) and CBF were substantially lower than that of intact brain regions, even for the mildly damaged brain regions that were unable to be clearly identified by the conventional MRI. In contrast, OEF was higher in the MCAO affected brain regions. This study demonstrates a promising (17)O MRI technique for imaging abnormal oxygen metabolism and perfusion in the diseased brain regions. This (17)O MRI technique is advantageous because of its robustness, simplicity, noninvasiveness and reliability: features that are essential to potentially translate it to human patients for early diagnosis and monitoring of treatment efficacy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Globoid-cell leukodystrophy (GLD) is an inherited demyelinating disease caused by the deficiency of the lysosomal enzyme galactosylceramidase (GALC). A previous study in the murine model of GLD (twitcher) demonstrated a dramatic synergy between CNS-directed adeno-associated virus 2/5 (AAV2/5) gene therapy and myeloreductive bone marrow transplantation (BMT). However, the mechanism by which these two disparate therapeutic approaches synergize is not clear. In addition, the therapeutic efficacy may have been limited since the CNS-directed gene therapy was restricted to the forebrain and thalamus. In the current study, intrathecal and intracerebellar injections were added to the therapeutic regimen and the mechanism of synergy between BMT and gene therapy was determined. Although AAV2/5 alone provided supraphysiological levels of GALC activity and reduced psychosine levels in both the brain and spinal cord, it significantly increased CNS inflammation. Bone marrow transplantation alone provided essentially no GALC activity to the CNS and did not reduce psychosine levels. When AAV2/5 is combined with BMT, there are sustained improvements in motor function and the median life span is increased to 123 d (range, 92-282 d) compared with 41 d in the untreated twitcher mice. Interestingly, addition of BMT virtually eliminates both the disease and AAV2/5-associated inflammatory response. These data suggest that the efficacy of AAV2/5-mediated gene therapy is limited by the associated inflammatory response and BMT synergizes with AAV2/5 by modulating inflammation.

Acute necrotizing encephalopathy and acute disseminated encephalomyelitis are 2 rare types of acute postinfectious encephalopathy in children. Acute necrotizing encephalopathy is characterized by multiple symmetric lesions in the thalami, putamena, cerebral and cerebellar white matter, and brainstem. Acute disseminated encephalomyelitis is an immune-mediated demyelinating central nervous system disorder that predominantly affects the white matter. Diffusion magnetic resonance imaging is sensitive to measuring water diffusion in the central nervous system in human and animal models. Recent studies have demonstrated that by using an analytical approach to directional diffusivity-derived parameters, the axial diffusivity and the radial diffusivity, one can assess the extent of axonal or myelin injury in the central nervous system white matter. We applied directional diffusivity to acute necrotizing encephalopathy, acute disseminated encephalomyelitis, and control subjects correlating with neuropathology findings. In acute necrotizing encephalopathy, axonal injury without demyelination, noted on biopsy samples of brain tissue, was suggested by a decreased apparent diffusion coefficient, unchanged fractional anisotropy, and decreased axial and radial diffusivity. In acute disseminated encephalomyelitis, an increased apparent diffusion coefficient, decreased fractional anisotropy, unchanged axial diffusivity, and markedly increased radial diffusivity compatible with active inflammatory demyelination were noted, consistent with tissue biopsy sample neuropathology. In conclusion, diffusion tensor parameters can potentially depict more microstructural changes than conventional magnetic resonance imaging in postinfectious encephalopathy in children., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Noise is a major concern in many important imaging applications. To improve data signal-to-noise ratio (SNR), experiments often focus on collecting low-frequency k-space data. This article proposes a new scheme to enable extended k-space sampling in these contexts. It is shown that the degradation in SNR associated with extended sampling can be effectively mitigated by using statistical modeling in concert with anatomical prior information. The method represents a significant departure from most existing anatomically constrained imaging methods, which rely on anatomical information to achieve super-resolution. The method has the advantage that less accurate anatomical information is required relative to super-resolution approaches. Theoretical and experimental results are provided to characterize the performance of the proposed scheme.

MR imaging can leverage a wide variety of intrinsic contrast mechanisms to provide detailed information regarding the anatomy, function, physiology, and metabolism of biological tissues. However, because of low sensitivity, many experiments that reveal higher-order structure and function have been limited due to inherent trade-offs between data acquisition time, signal-to-noise ratio, and resolution. This paper describes the further development of a statistical framework for MR image reconstruction which helps to mitigate these effects. Specifically, we advocate the collection of high-resolution multi-modal MR imaging data, and utilize the correlation between features in these different images to reduce noise while maintaining resolution. The proposed approach is illustrated with joint reconstruction of relaxometry and spectroscopic imaging data in a mouse model of stroke.

Magnetic resonance spectroscopic imaging has been recognized for a long time as a powerful tool for biochemical imaging. However, its practical utility is still rather limited due to poor spatial resolution, low signal-to-noise ratio, and long data acquisition times. In this work, we propose a new technique that enables reconstruction of metabolite maps with high spatial resolution. This technique uses a statistical model to incorporate known anatomical boundaries for edge-preserving noise filtering. This statistical reconstruction scheme makes it possible to use very noisy data, thereby enabling the collection of high-resolution data in a reasonable amount of time. We illustrate the performance of this method with images of the N-acetyl-L-aspartate distribution from an in vivo mouse brain.

Disruption of oligodendrocyte lineage progression is implicated in the white-matter injury that occurs in cerebral palsy. We have previously published a model in rabbits consistent with cerebral palsy. Little is known of normal white-matter development in perinatal rabbits. Using a multidimensional approach, we defined the relationship of oligodendrocyte lineage progression and functional maturation of axons to structural development of selected cerebral white-matter tracts as determined by diffusion tensor imaging (DTI). Immunohistochemical studies showed that late oligodendrocyte progenitors appear at gestational age 22 [embryonic day 22 (E22)], whereas immature oligodendrocytes appear at E25, and both increase rapidly with time (approximately 13 cells/mm2/d) until the onset of myelination. Myelination began at postnatal day 5 (P5) (E36) in the internal capsule (IC) and at P11 in the medial corpus callosum (CC), as determined by localization of sodium channels and myelin basic protein. DTI of the CC and IC showed that fractional anisotropy (FA) increased rapidly between E25 and P1 (E32) (11% per day) and plateaued (<5% per day) after the onset of myelination. Postnatal maturation of the compound action potential (CAP) showed a developmental pattern similar to FA, with a rapid rise between E29 and P5 (in the CC, 18% per day) and a slower rise from P5 to P11 (in the CC, <5% per day). The development of immature oligodendrocytes after E29 coincides with changes in FA and CAP area in both the CC and IC. These findings suggest that developmental expansion of immature oligodendrocytes during the premyelination period may be important in defining structural and functional maturation of the white matter.

Myelin damage, as seen in multiple sclerosis (MS) and other demyelinating diseases, impairs axonal conduction and can also be associated with axonal degeneration. Accurate assessments of these conditions may be highly beneficial in evaluating and selecting therapeutic strategies for patient management. Recently, an analytical approach examining diffusion tensor imaging (DTI) derived parameters has been proposed to assess the extent of axonal damage, demyelination, or both. The current study uses the well-characterized cuprizone model of experimental demyelination and remyelination of corpus callosum in mouse brain to evaluate the ability of DTI parameters to detect the progression of myelin degeneration and regeneration. Our results demonstrate that the extent of increased radial diffusivity reflects the severity of demyelination in corpus callosum of mouse brain affected by cuprizone treatment. Subsequently, radial diffusivity decreases with the progression of remyelination. Furthermore, radial diffusivity changes were specific to the time course of changes in myelin integrity as distinct from axonal injury, which was detected by betaAPP immunostaining and shown to be most extensive prior to demyelination. Radial diffusivity offers a specific assessment of demyelination and remyelination, as distinct from acute axonal damage.

Using magnetic resonance diffusion tensor imaging (DTI), the present study investigates changes in both gray and white matter in the APPsw transgenic mouse (Tg2576), a model of beta-amyloid plaque deposition associated with Alzheimer's disease (AD). DTI analyses were performed in cross-sectional groups of transgene-positive and -negative mice at 8, 12, 16, and 18 months of age to assess the magnitude of water diffusion in gray matter (i.e., Tr(D)) and changes in diffusion in white matter that may be indicative of axonal degeneration (i.e., reduced water diffusion parallel to axonal tracts, lambda(||)) and myelin degradation (i.e., increased water diffusion perpendicular to axonal tracts, lambda(perpendicular)). No appreciable changes in gray or white matter were observed between the APPsw and the age-matched control mice at 8 months of age. Reduced Tr(D) and lambda(||) were observed in gray and white matter, respectively, for the APPsw mice at ages greater than 8 months, which coincides with the time period when appreciable amyloid plaque accumulation was confirmed by ex vivo histopathological studies. The decreases in lambda(||) suggest the presence of axonal injury in multiple white matter tracts of APPsw mice. Unlike lambda(||), lambda(perpendicular) was unaltered between control and APPsw mice in most white matter tracts. However, in the corpus collosum (CC), lambda(perpendicular) increased at 16 and 18 months of age, suggesting the possibility of myelin damage in the CC at these later ages. This work demonstrates the potential for DTI as a noninvasive modality to detect evolving pathology associated with changes in tissue water diffusion properties in brain tissues.

Increasing evidence demonstrates that there is marked damage and dysfunction not only in the gray matter but also in the white matter in Alzheimer's disease (AD). In this study, transgenic mice overexpressing beta-amyloid precursor protein (APP) under control of the platelet-derived growth factor promoter (PDAPP mice) were examined using diffusion tensor magnetic resonance imaging (DTI) to evaluate the extent of white matter injury before and following the development of AD-like pathology. The profile of DTI parameters was significantly different in old PDAPP mice compared to that of old control mice following the development of AD-like pathology. No difference in DTI parameters was observed between the young PDAPP and control mice. Our results suggest that as amyloid beta (Abeta) deposition and levels increase over time in PDAPP mice, these changes lead to primary or secondary white matter injury that can be detected by DTI.

Formalin fixation of tissue is a common laboratory practice. A direct comparison of diffusion tensor imaging (DTI) parameters from mouse brains before (in vivo) and after (ex vivo) formalin fixation is reported herein. Five diffusion indices were examined in a cohort of seven mice: relative anisotropy (RA), directional correlation (DC), trace (Tr(D)), trace-normalized axial diffusivity (D(axially)), and radial diffusivity (D(radially)). Seven regions of interest (ROIs), including five in white matter and two in gray matter, were selected for examination. Consistent with previous findings, a significant decrease of Tr(D) was observed for all ROIs after fixation. However, water diffusion anisotropy, as defined by the indices RA, DC, D(axially), and D(radially), remained unchanged after fixation. Thus, fixation does not appear to alter diffusion anisotropy in the mouse brain. This finding supports the utility of diffusion anisotropy analysis of fixed tissue. The combination of DTI measurements and standard histology may shed light on the microstructural determinants of diffusion anisotropy in normal and disease states., (Copyright 2003 Wiley-Liss, Inc.)

To study the architectural characteristics of white matter (WM) tracts, the directional correlation (DC), defined as the inner product of the major eigenvector of adjacent pixels, was used as a quantitative index to investigate directional similarity in WM tracts. A region-growing algorithm was employed to propagate an area from a seed point as a function of the DC threshold (DCt) to critically evaluate the directional properties of WM tracts. As the DCt was increased, more pixels were excluded from the propagated region as their DC fell below the DCt, and neighboring WM tracts could be distinguished as the area decreased. Taking the DC into account, a systematic classification routine for WM tracts was devised and tested on a mouse brain in vivo. The results show that individual WM tracts possess a high degree of directional similarity, and, by careful choice of the DCt value, the proposed classification algorithm can recognize all possible WM tracts in a given data set., (Copyright 2003 Wiley-Liss, Inc.)

Background: Advanced magnetic resonance imaging (MRI) methods can provide more specific information about various microstructural tissue changes in multiple sclerosis (MS) brain. Quantitative measurement of T1 and T2 relaxation, and diffusion basis spectrum imaging (DBSI) yield metrics related to the pathology of neuroinflammation and neurodegeneration that occurs across the spectrum of MS. Objective: To use relaxation and DBSI MRI metrics to describe measures of neuroinflammation, myelin and axons in different MS subtypes. Methods: 103 participants (20 clinically isolated syndrome (CIS), 33 relapsing-remitting MS (RRMS), 30 secondary progressive MS and 20 primary progressive MS) underwent quantitative T1, T2, DBSI and conventional 3T MRI. Whole brain, normal-appearing white matter, lesion and corpus callosum MRI metrics were compared across MS subtypes. Results: A gradation of MRI metric values was seen from CIS to RRMS to progressive MS. RRMS demonstrated large oedema-related differences, while progressive MS had the most extensive abnormalities in myelin and axonal measures. Conclusion: Relaxation and DBSI-derived MRI measures show differences between MS subtypes related to the severity and composition of underlying tissue damage. RRMS showed oedema, demyelination and axonal loss compared with CIS. Progressive MS had even more evidence of increased oedema, demyelination and axonal loss compared with CIS and RRMS. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the feasibility of diffusion basis spectrum imaging in multiple sclerosis at 7 T and to investigate the pathological substrates of tissue damage in lesions and normal-appearing white matter. To this end, 43 patients with multiple sclerosis (24 relapsing-remitting, 19 progressive), and 21 healthy control subjects were enrolled. White matter lesions were classified in T1-isointense, T1-hypointense and black holes. Mean values of diffusion basis spectrum imaging metrics (fibres, restricted and non-restricted fractions, axial and radial diffusivities and fractional anisotropy) were measured from whole brain white matter lesions and from both lesions and normal appearing white matter of the corpus callosum. Significant differences were found between T1-isointense and black holes (P ranging from 0.005 to <0.001) and between lesions' centre and rim (P < 0.001) for all the metrics. When comparing the three subject groups in terms of metrics derived from corpus callosum normal appearing white matter and T2-hyperintense lesions, a significant difference was found between healthy controls and relapsing-remitting patients for all metrics except restricted fraction and fractional anisotropy; between healthy controls and progressive patients for all metrics except restricted fraction and between relapsing-remitting and progressive multiple sclerosis patients for all metrics except fibres and restricted fractions (P ranging from 0.05 to <0.001 for all). Significant associations were found between corpus callosum normal-appearing white matter fibres fraction/non-restricted fraction and the Symbol Digit Modality Test (respectively, r = 0.35, P = 0.043; r = -0.35, P = 0.046), and between black holes radial diffusivity and Expanded Disability Status Score (r = 0.59, P = 0.002). We showed the feasibility of diffusion basis spectrum imaging metrics at 7 T, confirmed the role of the derived metrics in the characterization of lesions and normal appearing white matter tissue in different stages of the disease and demonstrated their clinical relevance. Thus, suggesting that diffusion basis spectrum imaging is a promising tool to investigate multiple sclerosis pathophysiology, monitor disease progression and treatment response. [ABSTRACT FROM AUTHOR]