MRI relaxometry is sensitive to a variety of tissue characteristics in a complex manner, which makes it both attractive and challenging for characterizing tissue. This article reviews the most common ...water proton relaxometry measures, T1, T2, and T2*, and reports on their development and current potential to probe the composition and microstructure of brain tissue. The development of these relaxometry measures is challenged by the need for suitably accurate tissue models, as well as robust acquisition and analysis methodologies. MRI relaxometry has been established as a tool for characterizing neural tissue, particular with respect to myelination, and the potential for further development exists.
•MRI relaxometry is sensitive to brain tissue microstructure.•Each of T1, T2, and T2∗ relaxometry can be used.•Tissue models, acquisition methods, and analysis methods are important.
Comprising ~20 % of the volume, water is a key determinant of the mechanical behavior of cortical bone. It essentially exists in two general compartments: within pores and bound to the matrix. The ...amount of pore water—residing in the vascular-lacunar-canalicular space—primarily reflects intracortical porosity (i.e., open spaces within the matrix largely due to Haversian canals and resorption sites) and as such is inversely proportional to most mechanical properties of bone. Movement of water according to pressure gradients generated during dynamic loading likely confers hydraulic stiffening to the bone as well. Nonetheless, bound water is a primary contributor to the mechanical behavior of bone in that it is responsible for giving collagen the ability to confer ductility or plasticity to bone (i.e., allows deformation to continue once permanent damage begins to form in the matrix) and decreases with age along with fracture resistance. Thus, dehydration by air-drying or by solvents with less hydrogen bonding capacity causes bone to become brittle, but interestingly, it also increases stiffness and strength across the hierarchical levels of organization. Despite the importance of matrix hydration to fracture resistance, little is known about why bound water decreases with age in hydrated human bone. Using
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H nuclear magnetic resonance (NMR), both bound and pore water concentrations in bone can be measured ex vivo because the proton relaxation times differ between the two water compartments, giving rise to two distinct signals. There are also emerging techniques to measure bound and pore water in vivo with magnetic resonance imaging (MRI). The NMR/MRI-derived bound water concentration is positively correlated with both the strength and toughness of hydrated bone and may become a useful clinical marker of fracture risk.
This paper introduces a multi-compartment model for microscopic diffusion anisotropy imaging. The aim is to estimate microscopic features specific to the intra- and extra-neurite compartments in ...nervous tissue unconfounded by the effects of fibre crossings and orientation dispersion, which are ubiquitous in the brain. The proposed MRI method is based on the Spherical Mean Technique (SMT), which factors out the neurite orientation distribution and thus provides direct estimates of the microscopic tissue structure. This technique can be immediately used in the clinic for the assessment of various neurological conditions, as it requires only a widely available off-the-shelf sequence with two b-shells and high-angular gradient resolution achievable within clinically feasible scan times. To demonstrate the developed method, we use high-quality diffusion data acquired with a bespoke scanner system from the Human Connectome Project. This study establishes the normative values of the new biomarkers for a large cohort of healthy young adults, which may then support clinical diagnostics in patients. Moreover, we show that the microscopic diffusion indices offer direct sensitivity to pathological tissue alterations, exemplified in a preclinical animal model of Tuberous Sclerosis Complex (TSC), a genetic multi-organ disorder which impacts brain microstructure and hence may lead to neurological manifestations such as autism, epilepsy and developmental delay.
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•The Spherical Mean Technique (SMT) has enabled us to recover the microscopic diffusion process in brain tissue.•This paper introduces a multi-compartment model, which provides estimates of neurite density and intrinsic diffusivity.•These microscopic diffusion-based features are unconfounded by fibre crossings and orientation dispersion.•SMT requires only an off-the-shelf diffusion sequence with two b-shells achievable on standard clinical scanners.•Demonstrator applications: human normative database of the novel biomarkers; preclinical mouse study for the detection of tuberous sclerosis (TSC).
Myelin abnormalities are increasingly being recognized as an important component of a number of neurologic developmental disorders. The integration of many signaling pathways and cell types are ...critical for correct myelinogenesis. The PI3-K and mechanistic target of rapamycin (mTOR) pathways have been found to play key roles. mTOR is found within two distinct complexes, mTORC1 and mTORC2. mTORC1 activity has been shown to play a major role during myelination, while the role of mTORC2 is not yet well understood. To determine the role of mTORC2 signaling in myelinogenesis, we generated a mouse lacking the critical mTORC2 component Rictor in oligodendrocyte precursors (OPCs). Targeted deletion of Rictor in these cells decreases and delays the expression of myelin related proteins and reduces the size of cerebral white matter tracts. This is developmentally manifest as a transient reduction in myelinated axon density and g-ratio. OPC cell number is reduced at birth without detectable change in proliferation with proportional reductions in mature oligodendrocyte number at P15. The total number of oligodendrocytes as well as extent of myelination, does improve over time. Adult conditional knock-out (CKO) animals do not demonstrate a behavioral phenotype likely due in part to preserved axonal conduction velocities. These data support and extend prior studies demonstrating an important but transient contribution of mTORC2 signaling to myelin development.
Although iron is crucial for neuronal functioning, many aspects of cerebral iron biology await clarification. The ability to quantify specific iron forms in the living brain would open new avenues ...for diagnosis, therapeutic monitoring, and understanding pathogenesis of diseases. A modality that allows assessment of brain tissue composition in vivo, in particular of iron deposits or myelin content on a submillimeter spatial scale, is magnetic resonance imaging (MRI). Multimodal strategies combining MRI with complementary analytical techniques ex vivo have emerged, which may lead to improved specificity. Interdisciplinary collaborations will be key to advance beyond simple correlative analyses in the biological interpretation of MRI data and to gain deeper insights into key factors leading to iron accumulation and/or redistribution associated with neurodegeneration.
Emerging MRI techniques are progressing towards a means for the quantification of iron concentration or myelin content over the scale of a whole brain at submillimeter resolutions both ex vivo and in vivo.Complementary techniques borrowed from analytical chemistry and solid-state physics can help in the specification and quantification of iron forms in the brain.Multiparametric imaging approaches yielding quantitative information on both iron and myelin content may provide useful biomarkers to assess white matter integrity in clinical studies that use iron chelation therapy for diseases associated with iron deposition.
Recent years have seen a growing interest in relating MRI measurements to the structural-biophysical properties of white matter fibers. The fiber g-ratio, defined as the ratio between the inner and ...outer radii of the axon myelin sheath, is an important structural property of white matter, affecting signal conduction. Recently proposed modeling methods that use a combination of quantitative-MRI signals, enable a measurement of the fiber g-ratio in vivo. Here we use an MRI-based g-ratio estimation to observe the variance of the g-ratio within the corpus callosum, and evaluate sex and age related differences.
To estimate the g-ratio we used a model (Stikov et al., 2011; Duval et al., 2017) based on two different WM microstructure parameters: the relative amounts of myelin (myelin volume fraction, MVF) and fibers (fiber volume fraction, FVF) in a voxel. We derived the FVF from the fractional anisotropy (FA), and estimated the MVF by using the lipid and macromolecular tissue volume (MTV), calculated from the proton density (Mezer et al., 2013). In comparison to other methods of estimating the MVF, MTV represents a stable parameter with a straightforward route of acquisition. To establish our model, we first compared histological MVF measurements (West et al., 2016) with the MRI derived MTV. We then implemented our model on a large database of 92 subjects (44 males), aged 7 to 81, in order to evaluate age and sex related changes within the corpus callosum.
Our results show that the MTV provides a good estimation of MVF for calculating g-ratio, and produced values from the corpus callosum that correspond to those found in animals ex vivo and are close to the theoretical optimum, as well as to published in vivo data. Our results demonstrate that the MTV derived g-ratio provides a simple and reliable in vivo g-ratio-weighted (GR*) measurement in humans. In agreement with theoretical predictions, and unlike other tissue parameters measured with MRI, the g-ratio estimations were found to be relatively stable with age, and we found no support for a significant sexual dimorphism with age.
•g-ratio is calculated using 1-PD in the corpus callosum of 92 subjects ages 6-81.•g-ratio was found to vary along the corpus callosum.•g-ratio shows little change with age.•we found no sexual dimorphism in the development of g-ratio with age.
•Monte Carlo simulations of diffusion MRI suggest a simple metric of axon diameter-the change in the radial apparent diffusion coefficient estimated at different diffusion times, ΔD⊥.•ΔD⊥ increased ...with effective mean axon diameter, and was relatively independent of extra-axonal volume fraction, g-ratio, myelin water exchange, and the free diffusion coefficient of water.•The slope of ΔD⊥ increased with the difference in effective diffusion time of the diffusion encoding waveforms.•Both extra- and intra-axonal water can contribute to ΔD⊥, providing sensitivity to small and large axon diameters, respectively.
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Noninvasive estimation of mean axon diameter presents a new opportunity to explore white matter plasticity, development, and pathology. Several diffusion-weighted MRI (DW-MRI) methods have been proposed to measure the average axon diameter in white matter, but they typically require many diffusion encoding measurements and complicated mathematical models to fit the signal to multiple tissue compartments, including intra- and extra-axonal spaces. Here, Monte Carlo simulations uncovered a straightforward DW-MRI metric of axon diameter: the change in radial apparent diffusion coefficient estimated at different effective diffusion times, ΔD⊥. Simulations indicated that this metric increases monotonically within a relevant range of effective mean axon diameter while being insensitive to changes in extra-axonal volume fraction, axon diameter distribution, g-ratio, and influence of myelin water. Also, a monotonic relationship was found to exist for signals coming from both intra- and extra-axonal compartments. The slope in ΔD⊥ with effective axon diameter increased with the difference in diffusion time of both oscillating and pulsed gradient diffusion sequences.
Conventional diffusion imaging uses pulsed gradient spin echo (PGSE) waveforms with diffusion times of tens of milliseconds (ms) to infer differences of white matter microstructure. The combined use ...of these long diffusion times with short diffusion times (<10 ms) enabled by oscillating gradient spin echo (OGSE) waveforms can enable more sensitivity to changes of restrictive boundaries on the scale of white matter microstructure (e.g. membranes reflecting the axon diameters). Here, PGSE and OGSE images were acquired at 4.7 T from 20 healthy volunteers aged 20–73 years (10 males). Mean, radial, and axial diffusivity, as well as fractional anisotropy were calculated in the genu, body and splenium of the corpus callosum (CC). Monte Carlo simulations were also conducted to examine the relationship of intra- and extra-axonal radial diffusivity with diffusion time over a range of axon diameters and distributions.
The results showed elevated diffusivities with OGSE relative to PGSE in the genu and splenium (but not the body) in both males and females, but the OGSE-PGSE difference was greater in the genu for males. Females showed positive correlations of OGSE-PGSE diffusivity difference with age across the CC, whereas there were no such age correlations in males. Simulations of radial diffusion demonstrated that for axon sizes in human brain both OGSE and PGSE diffusivities were dominated by extra-axonal water, but the OGSE-PGSE difference nonetheless increased with area-weighted outer-axon diameter. Therefore, the lack of OGSE-PGSE difference in the body is not entirely consistent with literature that suggests it is composed predominantly of axons with large diameter. The greater OGSE-PGSE difference in the genu of males could reflect larger axon diameters than females. The OGSE-PGSE difference correlation with age in females could reflect loss of smaller axons at older ages. The use of OGSE with short diffusion times to sample the microstructural scale of restriction implies regional differences of axon diameters along the corpus callosum with preliminary results suggesting a dependence on age and sex.
•The diffusion time dependence varied along the corpus callosum with significant differences in short versus long diffusion time in the genu and splenium, but no differences in the body.•The short versus long diffusion time differences were similar for both males and females in the splenium, but it was higher in the genu of males, suggesting larger axons.•The short versus long diffusion time diffusivity difference was correlated positively with age only in females, suggesting a preferential loss of smaller axons with aging.•Simulations showed that diffusion time difference of radial diffusivity depends on area-weighted outer axon diameter.
Purpose
Extend fast, two‐dimensional (2D) methods of bound and pore water mapping in bone to arbitrary slice orientation.
Methods
To correct for slice profile artifacts caused by gradient errors of ...half pulse 2D ultra‐short echo time (UTE), we developed a library of predistorted gradient waveforms that can be used to interpolate optimized gradient waveforms for 2D UTE slice selection. We also developed a method to estimate and correct for a bulk phase difference between the two half pulse excitations used for 2D UTE signal excitation. Bound water images were acquired in three healthy subjects with adiabatic inversion recovery prepared 2D UTE, while pore water images were acquired after short‐T2 signals were suppressed with double adiabatic inversion recovery preparation. The repeatability of bound and pore water imaging with 2D UTE was tested by repeating acquisitions after repositioning.
Results
The library‐based interpolation of optimized slice select gradient waveforms combined with the method to estimate bulk phase between two excitations provided compact slice profiles for half pulse excited 2D UTE. Quantitative bound and pore water values were highly repeatable—the pooled SD of bound water across all three subjects was 0.38 mol 1$$ {}^1 $$H/L, while pooled SD of pore water was 0.30 mol 1$$ {}^1 $$H/L.
Conclusion
Fast, quantitative, 2D UTE‐based bound and pore water images can be acquired at arbitrary oblique orientations after correcting for errors in the slice select gradient waveform and bulk phase shift between the two half acquisitions.
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