Brain intracellular metabolites are freely diffusing along cell fibers in grey and white matter, as measured by diffusion-weighted MR spectroscopy in the human brain at 7 T

Najac, Chloé; Branzoli, Francesca; Ronen, Itamar; Valette, Julien

doi:10.1007/s00429-014-0968-5

Cited by 45 publications

(84 citation statements)

References 47 publications

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“…A more recent animal study further demonstrated the insensitivity of metabolite ADCs to very long and ultra‐long diffusion times ranging from about 80 ms to more than 1 s (Fig. ) , consistent with the human study that used diffusion times ranging from 92 to 712 ms . The ADC measurements were fitted to the two models, and the fitting results were compared with anatomical knowledge of soma, axon, and dendrite diameters .…”

Section: Diffusion Mrs Studies In Brainssupporting

confidence: 74%

“…) , consistent with the human study that used diffusion times ranging from 92 to 712 ms . The ADC measurements were fitted to the two models, and the fitting results were compared with anatomical knowledge of soma, axon, and dendrite diameters . The “neurite” model, but not the “cell body” model, was found to provide biologically valid estimates .…”

Section: Diffusion Mrs Studies In Brainsmentioning

confidence: 63%

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In vivo diffusion MRS investigation of non‐water molecules in biological tissues

Cao¹,

2016

NMR in Biomedicine

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Diffusion MRS of non-water molecules offers great potential in directly revealing various tissue microstructures and physiology at both cellular and subcellular levels. In brain, H diffusion MRS has been demonstrated as a new tool for probing normal tissue microstructures and their pathological changes. In skeletal muscle, H diffusion MRS could characterize slow and restricted intramyocellular lipid diffusion, providing a sensitive marker for metabolic alterations, while P diffusion MRS can measure ATP and PCr diffusion, which may reflect the capacity of cellular energy transport, complementing the information from frequently used P MRS in muscle. In intervertebral disk, H diffusion MRS can directly monitor extracellular matrix integrity by quantifying the mobility of macromolecules such as proteoglycans and collagens. In tumor tissue, C diffusion MRS could probe intracellular glycolytic metabolism, while H diffusion MRS may separate the spectrally overlapped lactate and lipid resonances. In this review, recent diffusion MRS studies of these biologically relevant non-water molecules under normal and diseased conditions will be presented. Technical considerations for diffusion MRS experiments will be discussed. With advances in MRI hardware and diffusion methodology, diffusion MRS of non-water molecules is expected to provide increasingly valuable and biologically specific information on tissue microstructures and physiology, complementing the traditional diffusion MRI of small and ubiquitous water molecules. Copyright © 2016 John Wiley& Sons, Ltd.

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Section: Diffusion Mrs Studies In Brainssupporting

confidence: 74%

Section: Diffusion Mrs Studies In Brainsmentioning

confidence: 63%

In vivo diffusion MRS investigation of non‐water molecules in biological tissues

Cao¹,

2016

NMR in Biomedicine

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“…In this context, DW-MRS offers a unique noninvasive tool to specifically probe each of these cellular compartments and to link the cellular architecture with the macroscopic signal being measured and vice versa. Here we decided to elaborate on our recent finding that metabolite diffusion measured at long diffusion times t d (up to ∼1 s) is fairly stable in the monkey (20) and in the human brain (21), suggesting that metabolites are not significantly confined in subcellular regions or organelles but are instead diffusing in the long fibers typical of neuron and astrocyte morphology. However, because axons, dendrites, and astrocytic processes are not infinite, metabolites should start experiencing long-range structure as t d keeps increasing.…”

Section: Resultsmentioning

confidence: 99%

New paradigm to assess brain cell morphology by diffusion-weighted MR spectroscopy in vivo

Palombo

Ligneul

Najac

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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131

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The brain is one of the most complex organs, and tools are lacking to assess its cellular morphology in vivo. Here we combine original diffusion-weighted magnetic resonance (MR) spectroscopy acquisition and novel modeling strategies to explore the possibility of quantifying brain cell morphology noninvasively. First, the diffusion of cellspecific metabolites is measured at ultra-long diffusion times in the rodent and primate brain in vivo to observe how cell long-range morphology constrains metabolite diffusion. Massive simulations of particles diffusing in synthetic cells parameterized by morphometric statistics are then iterated to fit experimental data. This method yields synthetic cells (tentatively neurons and astrocytes) that exhibit striking qualitative and quantitative similarities with histology (e.g., using Sholl analysis). With our approach, we measure major interspecies difference regarding astrocytes, whereas dendritic organization appears better conserved throughout species. This work suggests that the time dependence of metabolite diffusion coefficient allows distinguishing and quantitatively characterizing brain cell morphologies noninvasively.cell morphology | noninvasive histology | diffusion-weighted NMR spectroscopy | numerical simulations | metabolites T he brain is one of the most complex organs, and it has defined an inexhaustible field of research over the last centuries. Unfortunately, brain's complexity is paralleled by the difficulty in examining it noninvasively. Some fundamental questions regarding morphological modifications of neurons and astrocytes along brain development, aging, or disease, as well as interspecies differences, can only be investigated postmortem using histology, the current gold standard to study cellular morphology. The development of a noninvasive neuroimaging tool to evaluate and monitor brain cell morphology under normal and pathological conditions in vivo would thus represent a major breakthrough.MRI and magnetic resonance spectroscopy (MRS) techniques have opened new doors for examining brain tissues in vivo at both meso-and macroscales. Diffusion-weighted (DW)-MRI and -MRS, which allow the investigation of the diffusion process of endogenous molecules in biological tissues at these scales (1), have made it clear that cell architecture has a critical influence on molecular displacement (2-5). To quantitatively evaluate the impact of cell structure on measured molecular diffusion, mainly two modeling strategies have been developed. The first approach consists in performing numerical simulations of many particles diffusing in arbitrary geometries (e.g., defined by 3D meshes) mimicking "realistic" cell architectures (6-9). Because these realistic geometries are generally built directly from microscopy data rather than being described and generated by a (small) set of parameters, and because simulations are extremely computationally demanding, this approach does not seem adapted to fit experimental data. The second approach consists in simplifying cell architec...

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“…(Palombo et al, 2017) have also demonstrated diffusion of NAA and other metabolites can be modelled as occurring in long, cylindrical fibers, having a D a,‖ of 0.33 µm 2 /ms. The diffusion weighted signals of other metabolites were also fit well by assuming long cylindrical processes (Najac et al, 2016; Najac et al, 2014; Palombo et al, 2017). Since metabolites have differences in molecular size, affinity to charged surfaces, and potential ambiguity in compartment selectivity, the intra-axonal diffusivity of water cannot be unequivocally extrapolated from metabolite diffusivities.…”

Section: Validating Diffusion 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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Brain intracellular metabolites are freely diffusing along cell fibers in grey and white matter, as measured by diffusion-weighted MR spectroscopy in the human brain at 7 T

Cited by 45 publications

References 47 publications

In vivo diffusion MRS investigation of non‐water molecules in biological tissues

In vivo diffusion MRS investigation of non‐water molecules in biological tissues

New paradigm to assess brain cell morphology by diffusion-weighted MR spectroscopy in vivo

Design and Validation of Diffusion MRI Models of White Matter

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