Microstructural organization of axons in the human corpus callosum quantified by diffusion-weighted magnetic resonance spectroscopy of N-acetylaspartate and post-mortem histology

Abstract

Diffusion-weighted magnetic resonance spectroscopy of brain metabolites offers unique access to compartment-specific microstructural information on neural tissue. Here, we investigated in detail the diffusion characteristics of the neuronal/axonal markers N-acetylaspartate + N-acetyl aspartyl glutamate (tNAA) in a small region of the human corpus callosum at 7 T. The diffusion-weighted spectroscopy data were analyzed by fitting to a model in which information about cross-callosal tract orientation within the spectroscopy volume, obtained from diffusion tensor imaging data, was incorporated. We estimated the microscopic misalignment of axons (σ φ = 18.6° ± 3.0°) in excellent agreement with independent histological results (σ φ = 18.1° ± 4.6°) obtained from microscopic analysis of axonal orientations in the body of the corpus callosum from post-mortem human brain slices. We also robustly quantified the diffusion coefficient of tNAA (0.51 ± 0.06 × 10(-3) mm(2)/s) in axonal cytoplasm, unbiased by the tract curvature. This work supports the notion that microscopic axonal misalignment is a dominant microstructural property in white matter tracts and has a strong impact on the evaluation of tissue microstructure using diffusion information, and should therefore be taken into consideration in the evaluation of white matter microstructure. Additionally, this study enabled robust and unbiased assessment of the cytosolic diffusion coefficient of tNAA, a potential biomarker for axonopathy and neuronal degeneration.

One diffusion acquisition and different white matter models: How does microstructure change in human early development based on WMTI and NODDI?

“…Set #2 is a case where NODDI assumptions are perfectly met: D a = D′ e,|| , relatively high dispersion and a CSF compartment. More general sets #3 and #4 likely represent biologically plausible cases, with some difference in diffusivities, a dispersion in agreement with histological data on corpus callosum (Ronen et al, 2013), and some CSF contamination (for Set #4).…”

“…While initially derived under the hypothesis of perfect axon alignment (Fieremans et al, 2010), it was later argued that, for clinically relevant diffusion times, both the EAS and the IAS can be modeled as Gaussian compartments, with effective parameters corresponding to the long time limit (“tortuosity limit”), whereby the non-Gaussian contribution from the IAS could be approximately neglected for a coplanar fiber dispersion of up to 30° (Fieremans et al, 2011). It should be noted that the angular spread of major white matter tracts such as corpus callosum is estimated at approximately 18° from histology and from diffusion spectroscopy of N -acetylaspartate (Ronen et al, 2013). …”

Orientation dependence of magnetization transfer parameters in human white matter

“…The assumption of a distinct fiber population does not hold for the majority of WM voxels ('crossing fiber problem') (Jones et al, 2013), and even in regions with relatively coherent fiber bundles, such as the corpus callosum, axons are not perfectly parallel but demonstrate some degree of spreading or bending (Choe et al, 2012;Leergaard et al, 2010;Ronen et al, 2014). For adaptation of the lineshape model, we assume that individual fibers consist of cylindrical segments that can be described as wrapping bilayers and introduce a fiber orientation distribution function (fODF) to account for multidirectionality (including fiber crossings and spreading in each main direction).…”

Microanisotropy imaging: quantification of microscopic diffusion anisotropy and orientational order parameter by diffusion MRI with magic-angle spinning of the q-vector

“…Biophysical modeling of WM is a field that has attracted much activity lately [74], and the need to disentangle orientation dispersion from dispersion in compartment size is now obvious [23,75,76]. Isotropic q-MAS DW could be an important tool to help disentangle the two phenomena.…”