Synopsis

Keywords: Neurodegeneration, Microstructure, amyotrophic lateral sclerosis - ALS

Amyotrophic lateral sclerosis (ALS) is a fatal upper and lower motor neuron degradation disease that leads to progressive myofiber abnormalities (e.g., decreased size and distribution). The relaxivity contrast imaging (RCI) parameter, TRATE (tissue transverse relaxivity at tracer equilibrium), has been shown to decrease during ALS induced myofiber degradation. The goal of this study is to expand a validated computational method to investigate the biophysical basis of TRATE in muscles of ALS patients and to optimize RCI acquisition parameters.

Introduction

Amyotrophic Lateral Sclerosis (ALS) is characterized by loss of spinal and cortical motor neurons, resulting in progressive muscle atrophy. Recently, we proposed the use of relaxivity contrast imaging (RCI) as a novel approach to evaluate ALS progression and provide faster and improved decision-making during clinical trials [1, 2]. RCI is a susceptibility-based dynamic contrast enhanced approach and the derived biomarker termed the tissue transverse relaxivity at tracer equilibrium (TRATE) was found to be highly sensitive to myofiber size, density, geometry, and heterogeneity [3]. Our goal is to further investigate the biophysical basis of TRATE using an established computational approach in the context of myofiber degeneration.

Methods

Computation of MRI signals for 3D tissue structures were carried out using a validated computational strategy termed the finite perturber finite difference method [4,5]. To assure realistic muscle tissue representation, computed RCI data were compared for two input 3D tissue structures obtained from immunofluorescence microscopy and tissue structures modeled as packed elliptical cylinders (Figure 1). The use of elliptical cylinders allows systematic variation that mimic the known histopathologic progression of ALS-induced muscle degeneration. Each myofiber property can be individually adjusted (e.g., diameter, aspect ratio, orientation angle, etc) to systematically characterize their influence on RCI data and capture the heterogeneity observed during disease progression. Additional input parameters including the contrast agent transfer coefficient (K^trans), water diffusion coefficient and pre-contrast T₁ were distinctly chosen to represent values observed in muscle. A multi-echo GRE pulse sequence is modeled to quantify the T₂* and T₁ changes (ΔR₂*(t) and ΔR₁(t)) that occur after the injection of a contrast agent (CA). TRATE values are then computed using ΔR₂*/C_t for the last few averaged time points. Similar to DCE-MRI, the tissue CA concentration (Ct) is computed using ΔR₁/r₁, where r₁ is the CA’s (known) T₁ relaxivity.

Results and Discussion

Example 2D section of the 3D muscle tissue structures from histopathologic data at two time points of ALS progression are illustrated in Figure 1 A-B. The corresponding structures constructed using elliptical cylinders are shown in Figure 1 C-D. By matching the mean fiber diameter and volume fraction measured from quantitative histologic analysis, the elliptical cylinders provide similar ΔR₂*(t) values to that obtained from histopathologic data for both time points. Figure 2 shows TRATE characterization for four different parameters. Figure 2A shows an increase in TRATE values with increasing fiber diameter. The dependence of TRATE on fiber volume fraction is shown in Figure 2B. Mimicking ALS disease progression can be achieved by inducing loss of myofiber diameter and/or volume fraction. Consistent with in vivo observations [1,2], TRATE values decrease with myofiber degradation in both cases. TRATE values were also found to rely on the mean fiber orientation with respect to the main magnetic field B_o (Figure 2C). Except for the case where the fiber aligns with B_o, a given orientational angle yields similar TRATE values as compared to its complementary angle. This can be explained by the symmetrical field perturbation patterns produced by complementary angles which leads to similar standard deviation of the field perturbation and thereby ΔR₂*. Maximum TRATE values are achieved when mean fiber direction is perpendicular to B_o. When the fiber orientation is parallel to B_o the field perturbation outside fibers is zero with only spatially constant field perturbation inside the fibers; hence the relatively small TRATE values for 0o. TRATE and diffusion exhibit an inverse relationship, consistent with diffusion narrowing of field perturbation (Figure 2D).

Conclusion

Results of this study further characterize the biophysical features that contribute to TRATE and can aid in the design and interpretation of ongoing and future in vivo preclinical and clinical studies. Currently the computational model is being trained using preclinical data for optimization of sequence parameters to maximize the sensitivity of TRATE to muscle degenerative changes associated with ALS.

Acknowledgements

NIH/ NINDS R61NS119642-01