Conventional and quantitative MRI in a novel feline model of demyelination and endogenous remyelination.

BACKGROUND: The feeding of irradiated food to healthy adult cats results in widespread, noninflammatory demyelination of the central nervous system (CNS); a return to a normal diet results in endogenous remyelination with functional recovery. This recently discovered, reversible disease might provide a compelling clinical neuroimaging model system for the development and testing of myelin-directed MRI methods as well as future remyelination therapies. PURPOSE: Identify the noninvasive imaging characteristics of this new disease model and determine whether it features measurable changes on conventional and quantitative MRI. STUDY TYPE: Pilot study. ANIMAL MODEL: Ten adult cats at various stages of demyelinating disease induced by an irradiated diet (35-55 kGy), and during recovery following a return to a normal diet. FIELD STRENGTH/SEQUENCE: Conventional (T2 -weighted) and quantitative (diffusion tensor, magnetization transfer) at 3T. ASSESSMENT: MRI of the brain, optic nerves, and cervical spinal cord; a subset of diseased cats was euthanized for comparative histopathology. STATISTICAL TESTS: Descriptive statistics. RESULTS: Disease produced T2 prolongation, progressing from patchy to diffuse throughout most of the cerebral white matter (eventually involving U-fibers) and spinal cord (primarily dorsal columns, reminiscent of subacute combined degeneration but without evidence of B12 deficiency). Magnetization transfer parameters decreased by 50-53% in cerebral white matter and by 25-30% in optic nerves and spinal cord dorsal columns. Fractional diffusion anisotropy decreased by up to 20% in pyramidal tracts, primarily driven by increased radial diffusivity consistent with axon preservation. Histopathology showed scattered myelin vacuolation of major white matter tracts as well as many thin myelin sheaths consistent with remyelination in the recovery phase, which was detectable on magnetization transfer imaging. DATA CONCLUSION: Feline irradiated diet-induced demyelination features noninvasively imageable and quantifiable demyelination and remyelination of the CNS. It is therefore a compelling clinical neuroimaging model system. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1304-1311.

Removal of cerebrospinal fluid partial volume effects in quantitative magnetization transfer imaging using a three-pool model with nonexchanging water component.

PURPOSE: Parameters of the two-pool model describing magnetization transfer (MT) in macromolecule-rich tissues may be significantly biased in partial volume (PV) voxels containing cerebrospinal fluid (CSF). The purpose of this study was to develop a quantitative MT (qMT) method that provides indices insensitive to CSF PV averaging. THEORY AND METHODS: We propose a three-pool MT model, in which PV macro-compartment is modeled as an additional nonexchanging water pool. We demonstrate the feasibility of model parameter estimation from several MT-weighted spoiled gradient echo datasets. We validated the three-pool model in numerical, phantom, and in vivo studies. RESULTS: PV averaging with the free water compartment reduces all qMT parameters, most significantly affecting macromolecular proton fraction (MPF) and cross-relaxation rate. Monte-Carlo simulations confirmed stability of the three-pool model fit. Unlike the standard two-pool model, the three-pool model qMT parameters were not affected by PV averaging in simulations and phantom studies. The three-pool model fit allowed CSF PV correction in brain PV voxels and resulted in good correlation with standard two-pool model parameters in non-PV voxels. CONCLUSION: Quantitative MT imaging based on a three-pool model with a non-exchanging water component yields a set of CSF-insensitive qMT parameters, which may improve MPF-based assessment of myelination in structures strongly affected by CSF PV averaging such as brain gray matter.

Analysis and correction of biases in cross-relaxation MRI due to biexponential longitudinal relaxation.

PURPOSE: Cross-relaxation imaging (CRI) is a family of quantitative magnetization transfer techniques that utilize images obtained with off-resonance saturation and longitudinal relaxation rate (R1) maps reconstructed by the variable flip angle (VFA) method. It was demonstrated recently that a significant bias in an apparent VFA R1 estimation occurs in macromolecule-rich tissues due to magnetization transfer (MT)-induced biexponential behavior of longitudinal relaxation of water protons. The purpose of this article is to characterize theoretically and experimentally the resulting bias in the CRI maps and propose methods to correct it. THEORY: The modified CRI algorithm is proposed, which corrects for such biases and yields accurate parametric bound pool fraction f, cross-relaxation rate k, and R1 maps. Additionally, an analytical correction procedure is introduced to recalculate previously obtained parameter values. RESULTS: The systematic errors due to unaccounted MT-induced biexponential relaxation can be characterized as an overestimation of R1, f, and k, with a relative bias comparable with the magnitude of f. The phantom and human in vivo experiments demonstrate that both proposed modified CRI and analytical correction approaches significantly improve the accuracy of the CRI method. CONCLUSION: The accuracy of the CRI method can be considerably improved by taking into account the contribution of MT-induced biexponential longitudinal relaxation into variable flip angle R1 measurements.

Quantitative MR imaging of two-pool magnetization transfer model parameters in myelin mutant shaking pup.

Magnetization transfer (MT) imaging quantitatively assesses cerebral white matter disease through its sensitivity to macromolecule-bound protons including those associated with myelin proteins and lipid bilayers. However, traditional MT contrast measured by the MT ratio (MTR) lacks pathologic specificity as demyelination, axon loss, inflammation and edema all impact MTR, directly and/or indirectly through multiple covariances among imaging parameters (particularly MTR with T(1)) and tissue features (e.g. axon loss with demyelination). In this study, more complex modeling of MT phenomena ("quantitative" MT or qMT) was applied to a less complex disease model (the myelin mutant shaking [sh] pup, featuring hypomyelination but neither inflammation nor axon loss) in order to eliminate the covariances on both sides of the MR-pathology "equation" and characterize these important relationships free from the usual confounds. qMT measurements were acquired longitudinally in 6 sh pups and 4 age-matched controls ranging from 3 to 21 months of age and compared with histology. The qMT parameter, bound pool fraction (f), was the most distinctive between diseased and control animals; both f and longitudinal relaxation rate R(1) tracked myelination with normal aging, whereas MTR did not--presumably owing to counterbalancing MT and R(1) effects. qMT imaging provides a more accurate and potentially more specific non-invasive tissue characterization.

Differing Patterns of Altered Slow-5 Oscillations in Healthy Aging and Ischemic Stroke.

The 'default-mode' network (DMN) has been investigated in the presence of various disorders, such as Alzheimer's disease and Autism spectrum disorders. More recently, this investigation has expanded to include patients with ischemic injury. Here, we characterized the effects of ischemic injury in terms of its spectral distribution of resting-state low-frequency oscillations and further investigated whether those specific disruptions were unique to the DMN, or rather more general, affecting the global cortical system. With 43 young healthy adults, 42 older healthy adults, 14 stroke patients in their early stage (<7 days after stroke onset), and 16 stroke patients in their later stage (between 1 to 6 months after stroke onset), this study showed that patterns of cortical system disruption may differ between healthy aging and following the event of an ischemic stroke. The stroke group in the later stage demonstrated a global reduction in the amplitude of the slow-5 oscillations (0.01-0.027 Hz) in the DMN as well as in the primary visual and sensorimotor networks, two 'task-positive' networks. In comparison to the young healthy group, the older healthy subjects presented a decrease in the amplitude of the slow-5 oscillations specific to the components of the DMN, while exhibiting an increase in oscillation power in the task-positive networks. These two processes of a decrease DMN and an increase in 'task-positive' slow-5 oscillations may potentially be related, with a deficit in DMN inhibition, leading to an elevation of oscillations in non-DMN systems. These findings also suggest that disruptions of the slow-5 oscillations in healthy aging may be more specific to the DMN while the disruptions of those oscillations following a stroke through remote (diaschisis) effects may be more widespread, highlighting a non-specificity of disruption on the DMN in stroke population. The mechanisms underlying those differing modes of network disruption need to be further explored to better inform our understanding of brain function in healthy individuals and following injury.

Implication of the Slow-5 Oscillations in the Disruption of the Default-Mode Network in Healthy Aging and Stroke.

The processes of normal aging and aging-related pathologies subject the brain to an active re-organization of its brain networks. Among these, the default-mode network (DMN) is consistently implicated with a demonstrated reduction in functional connectivity within the network. However, no clear stipulation on the underlying mechanisms of the de-synchronization has yet been provided. In this study, we examined the spectral distribution of the intrinsic low-frequency oscillations (LFOs) of the DMN sub-networks in populations of young normals, older subjects, and acute and subacute ischemic stroke patients. The DMN sub-networks were derived using a mid-order group independent component analysis with 117 eyes-closed resting-state functional magnetic resonance imaging (rs-fMRI) sessions from volunteers in those population groups, isolating three robust components of the DMN among other resting-state networks. The posterior component of the DMN presented noticeable differences. Measures of amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) of the network component demonstrated a decrease in resting-state cortical oscillation power in the elderly (normal and patient), specifically in the slow-5 (0.01-0.027 Hz) range of oscillations. Furthermore, the contribution of the slow-5 oscillations during the resting state was diminished for a greater influence of the slow-4 (0.027-0.073 Hz) oscillations in the subacute stroke group, not only suggesting a vulnerability of the slow-5 oscillations to disruption but also indicating a change in the distribution of the oscillations within the resting-state frequencies. The reduction of network slow-5 fALFF in the posterior DMN component was found to present a potential association with behavioral measures, suggesting a brain-behavior relationship to those oscillations, with this change in behavior potentially resulting from an altered network integrity induced by a weakening of the slow-5 oscillations during the resting state. The repeated identification of those frequencies in the disruption of DMN stresses a critical role of the slow-5 oscillations in network disruption, and it accentuates the importance of managing those oscillations in the health of the DMN.

Age-Related Changes in Inter-Network Connectivity by Component Analysis.

Healthy aging is associated with brain changes that reflect an alteration to a functional unit in response to the available resources and architecture. Even before the onset of noticeable cognitive decline, the neural scaffolds underlying cognitive function undergo considerable change. Prior studies have suggested a disruption of the connectivity pattern within the "default-mode" network (DMN), and more specifically a disruption of the anterio-posterior connectivity. In this study, we explored the effects of aging on within-network connectivity of three DMN subnetworks: a posterior DMN (pDMN), an anterior DMN (aDMN), and a ventral DMN (vDMN); as well as between-network connectivity during resting-state. Using groupICA on 43 young and 43 older healthy adults, we showed a reduction of network co-activation in two of the DMN subnetworks (pDMN and aDMN) and demonstrated a difference in between-component connectivity levels. The older group exhibited more numerous high-correlation pairs (Pearson's rho > 0.3, Number of comp-pairs = 46) in comparison to the young group (Number of comp-pairs = 34), suggesting a more connected/less segregated cortical system. Moreover, three component-pairs exhibited statistically significant differences between the two populations. Visual areas V2-V1 and V2-V4 were more correlated in the older adults, while aDMN-pDMN correlation decreased with aging. The increase in the number of high-correlation component-pairs and the elevated correlation in the visual areas are consistent with the prior hypothesis that aging is associated with a reduction of functional segregation. However, the aDMN-pDMN dis-connectivity may be occurring under a different mechanism, a mechanism more related to a breakdown of structural integrity along the anterio-posterior axis.

Characterization of cerebral white matter properties using quantitative magnetic resonance imaging stains.

The image contrast in magnetic resonance imaging (MRI) is highly sensitive to several mechanisms that are modulated by the properties of the tissue environment. The degree and type of contrast weighting may be viewed as image filters that accentuate specific tissue properties. Maps of quantitative measures of these mechanisms, akin to microstructural/environmental-specific tissue stains, may be generated to characterize the MRI and physiological properties of biological tissues. In this article, three quantitative MRI (qMRI) methods for characterizing white matter (WM) microstructural properties are reviewed. All of these measures measure complementary aspects of how water interacts with the tissue environment. Diffusion MRI, including diffusion tensor imaging, characterizes the diffusion of water in the tissues and is sensitive to the microstructural density, spacing, and orientational organization of tissue membranes, including myelin. Magnetization transfer imaging characterizes the amount and degree of magnetization exchange between free water and macromolecules like proteins found in the myelin bilayers. Relaxometry measures the MRI relaxation constants T1 and T2, which in WM have a component associated with the water trapped in the myelin bilayers. The conduction of signals between distant brain regions occurs primarily through myelinated WM tracts; thus, these methods are potential indicators of pathology and structural connectivity in the brain. This article provides an overview of the qMRI stain mechanisms, acquisition and analysis strategies, and applications for these qMRI stains.