Single‐ and double‐Diffusion encoding MRI for studying ex vivo apparent axon diameter distribution in spinal cord white matter

Anaby, Debbie; Morozov, Darya; Seroussi, Inbar; Hametner, Simon; Sochen, Nir; Cohen, Yoram

doi:10.1002/nbm.4170

Cited by 12 publications

(7 citation statements)

References 93 publications

(281 reference statements)

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“…As discussed above, TDR is sensitive to the volume weighted distribution of axons, and therefore the mean diameter calculated from electron microscopy might not be the best quantity for comparison, nevertheless, there is a clear trend, as illustrated in Figure 9. The trends of TDR are also consistent with previous MRI correlates of axon diameter, both using diffusion data as well as relaxometry 30,75–77 .…”

Section: Discussionsupporting

confidence: 88%

Optimisation and Pre-clinical Demonstration of Temporal Diffusion Ratio for Imaging Restricted Diffusion

Warner

Palombo

Cruz

et al. 2022

Preprint

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Temporal Diffusion Ratio (TDR) is a recently proposed dMRI technique (Dell'Acqua, 2019) which provides contrast between areas with restricted diffusion and areas either without restricted diffusion or with length scales too small for characterisation. Hence, it has a potential for mapping pore sizes, in particular large axon diameters or other cellular structures. TDR employs the signal from two dMRI acquisitions obtained with the same, large, b-value but with different diffusion times and gradient settings. TDR is advantageous as it employs standard acquisition sequences, does not make any assumptions on the underlying tissue structure and does not require any model fitting, avoiding issues related to model degeneracy. This work for the first time optimises the TDR diffusion sequences in simulation for a range of different tissues and scanner constraints. We extend the original work (which considers substrates containing cylinders) by additionally considering the TDR signal obtained from spherical structures, representing cell soma in tissue. Our results show that contrasting an acquisition with short gradient duration and short diffusion time with an acquisition with long gradient duration and long diffusion time improves the TDR contrast for a wide range of pore configurations. Additionally, in the presence of Rician noise, computing TDR from a subset (50% or fewer) of the acquired diffusion gradients rather than the entire shell as proposed originally further improves the contrast. In the last part of the work the results are demonstrated experimentally on rat spinal cord. In line with simulations, the experimental data shows that optimised TDR improves the contrast compared to non-optimised TDR. Furthermore, we find a strong correlation between TDR and histology measurements of axon diameter. In conclusion, we find that TDR has great potential and is a very promising alternative (or potentially complement) to model-based approaches for mapping pore sizes and restricted diffusion in general.

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Section: Discussionsupporting

confidence: 88%

Optimisation and Pre-clinical Demonstration of Temporal Diffusion Ratio for Imaging Restricted Diffusion

Warner

Palombo

Cruz

et al. 2022

Preprint

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“…There have been several recent reports estimating non-parametric cell size distributions in biological tissues using diffusion MRIbased methods. [42][43][44][45] Deriving the cell size distribution within a voxel or region would potentially improve both the sensitivity and specificity of IMPULSED for assessing cell size changes. However, one important point should be kept in mind: the more complicated the signal model becomes, the higher SNR that is required to obtain stable fittings.…”

Section: Specificity Of Impulsed Methods For Assessing T Cell Infiltramentioning

confidence: 99%

MRI of tumor T cell infiltration in response to checkpoint inhibitor therapy

Jiang

Dudzinski

Beckermann

et al. 2020

J Immunother Cancer

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BackgroundImmune checkpoint inhibitors, the most widespread class of immunotherapies, have demonstrated unique response patterns that are not always adequately captured by traditional response criteria such as the Response Evaluation Criteria in Solid Tumors or even immune-specific response criteria. These response metrics rely on monitoring tumor growth, but an increase in tumor size and/or appearance after starting immunotherapy does not always represent tumor progression, but also can be a result of T cell infiltration and thus positive treatment response. Therefore, non-invasive and longitudinal monitoring of T cell infiltration are needed to assess the effects of immunotherapies such as checkpoint inhibitors. Here, we proposed an innovative concept that a sufficiently large influx of tumor infiltrating T cells, which have a smaller diameter than cancer cells, will change the diameter distribution and decrease the average size of cells within a volume to a degree that can be quantified by non-invasive MRI.MethodsWe validated our hypothesis by studying tumor response to combination immune-checkpoint blockade (ICB) of anti-PD-1 and anti-CTLA4 in a mouse model of colon adenocarcinoma (MC38). The response was monitored longitudinally using Imaging Microstructural Parameters Using Limited Spectrally Edited Diffusion (IMPULSED), a diffusion MRI-based method which has been previously shown to non-invasively map changes in intracellular structure and cell sizes with the spatial resolution of MRI, in cell cultures and in animal models. Tumors were collected for immunohistochemical and flow cytometry analyzes immediately after the last imaging session.ResultsImmunohistochemical analysis revealed that increased T cell infiltration of the tumors results in a decrease in mean cell size (eg, a 10% increase of CD3+ T cell fraction results a ~1 µm decrease in the mean cell size). IMPULSED showed that the ICB responders, mice with tumor volumes were less than 250 mm3 or had tumors with stable or decreased volumes, had significantly smaller mean cell sizes than both Control IgG-treated tumors and ICB non-responder tumors.ConclusionsIMPULSED-derived cell size could potentially serve as an imaging marker for differentiating responsive and non-responsive tumors after checkpoint inhibitor therapies, a current clinical challenge that is not solved by simply monitoring tumor growth.

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“…Still, it might be possible for advanced diffusion encoding schemes to estimate more complex characteristics of axons in tissue. Some recent studies have also characterized the distribution of axon diameter as a single representative value ( Veraart et al, 2020 ), while other recent studies have looked to estimate the distribution of axon diameters ( Anaby et al, 2019 ; Romascano et al, 2020 ). Since intra- and extra-axonal water diffusion is sensitive to different measures of axon diameter (see the Appendix ), and given the near linear dependence of Δ D e⊥ on axon size and the near quadratic dependence of Δ D i⊥ , it may be possible to incorporate multiple oscillating gradient, pulsed gradient and/or double diffusion encoding schemes to estimate parameters like the variance of the axon diameter distribution, extra-axonal volume fraction, and/or g-ratio, ( Ianu et al, 2017 ; Kakkar et al, 2018 ; Shemesh, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

A simple estimate of axon size with diffusion MRI

Harkins

Beaulieu

et al. 2021

NeuroImage

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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, Δ D ⊥ . 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 Δ D ⊥ with effective axon diameter increased with the difference in diffusion time of both oscillating and pulsed gradient diffusion sequences.

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Single‐ and double‐Diffusion encoding MRI for studying ex vivo apparent axon diameter distribution in spinal cord white matter

Cited by 12 publications

References 93 publications

Optimisation and Pre-clinical Demonstration of Temporal Diffusion Ratio for Imaging Restricted Diffusion

Optimisation and Pre-clinical Demonstration of Temporal Diffusion Ratio for Imaging Restricted Diffusion

MRI of tumor T cell infiltration in response to checkpoint inhibitor therapy

A simple estimate of axon size with diffusion MRI

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