Evaluation of diffusion kurtosis imaging in ex vivo hypomyelinated mouse brains

Kelm, Nathaniel D.; West, Kathryn L.; Carson, Robert P.; Gochberg, Daniel F.; Ess, Kevin C.; Does, Mark D.

doi:10.1016/j.neuroimage.2015.09.028

Cited by 74 publications

(98 citation statements)

References 57 publications

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“…Conversely, the correlation between D e,⊥ and g -ratio was significant, while that between AWF and g -ratio was not (although a trend was present). It should be noted that Kelm and colleagues reported no linear correlation between D e,⊥ and myelin metrics extracted from EM in a mouse model of hypomyelination (Kelm et al, 2016). We stress however that there is likely a packing difference between myelinated axons that have become demyelinated and axons that were never myelinated.…”

Section: Discussionmentioning

confidence: 99%

In vivo quantification of demyelination and recovery using compartment-specific diffusion MRI metrics validated by electron microscopy

et al. 2016

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There is a need for accurate quantitative non-invasive biomarkers to monitor myelin pathology in vivo and distinguish myelin changes from other pathological features including inflammation and axonal loss. Conventional MRI metrics such as T2, magnetization transfer ratio and radial diffusivity have proven sensitivity but not specificity. In highly coherent white matter bundles, compartment-specific white matter tract integrity (WMTI) metrics can be directly derived from the diffusion and kurtosis tensors: axonal water fraction, intra-axonal diffusivity, and extra-axonal radial and axial diffusivities. We evaluate the potential of WMTI to quantify demyelination by monitoring the effects of both acute (6 weeks) and chronic (12 weeks) cuprizone intoxication and subsequent recovery in the mouse corpus callosum, and compare its performance with that of conventional metrics (T2, magnetization transfer, and DTI parameters). The changes observed in vivo correlated with those obtained from quantitative electron microscopy image analysis. A 6-week intoxication produced a significant decrease in axonal water fraction (p < 0.001), with only mild changes in extra-axonal radial diffusivity, consistent with patchy demyelination, while a 12-week intoxication caused a more marked decrease in extra-axonal radial diffusivity (p = 0.0135), consistent with more severe demyelination and clearance of the extra-axonal space. Results thus revealed increased specificity of the axonal water fraction and extra-axonal radial diffusivity parameters to different degrees and patterns of demyelination. The specificities of these parameters were corroborated by their respective correlations with microstructural features: the axonal water fraction correlated significantly with the electron microscopy derived total axonal water fraction (ρ = 0.66; p = 0.0014) but not with the g-ratio, while the extra-axonal radial diffusivity correlated with the g-ratio (ρ = 0.48; p = 0.0342) but not with the electron microscopy derived axonal water fraction. These parameters represent promising candidates as clinically feasible biomarkers of demyelination and remyelination in the white matter.

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Section: Discussionmentioning

confidence: 99%

In vivo quantification of demyelination and recovery using compartment-specific diffusion MRI metrics validated by electron microscopy

et al. 2016

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“…D e,⊥ is the diffusivity of the extra-axonal compartment in the radial direction. Both AWF and D e,⊥ have compelling support from validation studies using cuprizone-induced demyelination and hypomyelination knockout models (Falangola et al, 2014; Guglielmetti et al, 2016; Jensen et al, 2017; Kelm et al, 2016). Noteworthy is the ﬁnding of a double dissociation: in the corpus callosum of cuprizone-fed mice, AWF correlates with tissue AWF (measured by electron micro- scopy) but not with the g-ratio (a marker of demyelination), whereas D e,⊥ correlates with the g-ratio but not with tissue AWF (Jelescu et al, 2016).…”

Section: Introductionmentioning

confidence: 93%

Modeling white matter tract integrity in aging with diffusional kurtosis imaging

Benitez

Jensen

Falangola

et al. 2018

Neurobiology of Aging

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Myelin breakdown and neural ﬁber loss occur in aging. This study used white matter tract integrity metrics derived from biophysical modeling using Diffusional Kurtosis Imaging to assess loss of myelin (i.e., extraaxonal diffusivity, radial direction, De,⊥) and axonal density (i.e., axonal water fraction) in cognitively unimpaired older adults. Tract-based spatial statistics and region of interest analyses sought to identify ontogenic differences and age-related changes in white matter tracts using cross-sectional and longitudinal data analyzed with general linear and mixed-effects models. In addition to pure diffusion parameters (i.e., fractional anisotropy, mean diffusivity, mean kurtosis), we found that white matter tract integrity metrics signiﬁcantly differentiated early- from late-myelinating tracts, correlated with age in spatially distinct regions, and identiﬁed primarily extraaxonal changes over time. Percent metric changes were |0.3-0.9|% and |0.0-1.9|% per year using cross-sectional data and longitudinal data, respectively. There was accelerated decline in some late- versus early-myelinating tracts in older age. These results demonstrate that these metrics may inform further study of the transition from age-related changes to neurodegenerative decline.

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“…WMTI has been used in studies of a large variety of conditions, with substantial validation efforts using animal models of altered myelin (Benitez et al, 2013; de Kouchkovsky et al, 2016; Guglielmetti et al, 2016; Hui et al, 2012; Jelescu et al, 2016b; Kamiya et al, 2017; Kelm et al, 2016). …”

Section: Modelsmentioning

confidence: 99%

Design and Validation of Diffusion MRI Models of White Matter

2017

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Diffusion MRI is arguably the method of choice for characterizing white matter microstructure in vivo. Over the typical duration of diffusion encoding, the displacement of water molecules is conveniently on a length scale similar to that of the underlying cellular structures. Moreover, water molecules in white matter are largely compartmentalized which enables biologically-inspired compartmental diffusion models to characterize and quantify the true biological microstructure. A plethora of white matter models have been proposed. However, overparameterization and mathematical fitting complications encourage the introduction of simplifying assumptions that vary between different approaches. These choices impact the quantitative estimation of model parameters with potential detriments to their biological accuracy and promised specificity. First, we review biophysical white matter models in use and recapitulate their underlying assumptions and realms of applicability. Second, we present up-to-date efforts to validate parameters estimated from biophysical models. Simulations and dedicated phantoms are useful in assessing the performance of models when the ground truth is known. However, the biggest challenge remains the validation of the “biological accuracy” of estimated parameters. Complementary techniques such as microscopy of fixed tissue specimens have facilitated direct comparisons of estimates of white matter fiber orientation and densities. However, validation of compartmental diffusivities remains challenging, and complementary MRI-based techniques such as alternative diffusion encodings, compartment-specific contrast agents and metabolites have been used to validate diffusion models. Finally, white matter injury and disease pose additional challenges to modeling, which are also discussed. This review aims to provide an overview of the current state of models and their validation and to stimulate further research in the field to solve the remaining open questions and converge towards consensus.

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Evaluation of diffusion kurtosis imaging in ex vivo hypomyelinated mouse brains

Cited by 74 publications

References 57 publications

In vivo quantification of demyelination and recovery using compartment-specific diffusion MRI metrics validated by electron microscopy

In vivo quantification of demyelination and recovery using compartment-specific diffusion MRI metrics validated by electron microscopy

Modeling white matter tract integrity in aging with diffusional kurtosis imaging

Design and Validation of Diffusion MRI Models of White Matter

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