Synopsis

In order to investigate the likely progression of neurodegeneration in amyotrophic lateral sclerosis (ALS) patients, we applied a novel mathematical model to multi-site diffusion MRI data. Our results indicate directional evolution of disease in the corticospinal tracts (CSTs) of ALS patients, in a distal to proximal manner.

Background

Methods

Using one contemporary and two historical ALS data sets comprising diffusion MRI, we defined biomarkers as the mean FA values of white matter (WM) tracts previously studied and implicated in ALS. The objective of this study was to use a novel event-based model to analyse the likely ordering of these biomarkers in the progression of ALS.

The data sets were derived from cross-sectional samples, comprising 87 ALS patients (M/F = 61/26, mean age = 56.3 ± 11.9 years) and 69 matched controls (M/F = 47/22, mean age = 52.8 ± 12.8 years). No ALS patients were classified as having ALS-FTD. FA images were computed and then normalised into MNI space using Advanced Normalization Tools (ANTs) 2.1.0. The resulting maps were then harmonised using the DTI-adapted ComBat software⁵, to reduce unwanted inter-site variability.

For each tract, region of interest (ROI) masks were created from the two JHU DTI-based white-matter tractography atlases⁶ included in FSL 5.0.7. The ROI masks for the corticospinal tracts were created from the JHU white-matter tractography atlas, thresholded at 50%; all other ROI masks were created from the ICBM-DTI-81 atlas. The left and right sides of each tract were considered as separate biomarkers.

To allow the investigation of a directional progression of ALS white matter neurodegeneration, the corticospinal tracts (CSTs) were split in the inferior to superior direction. Two separate divisions were analysed: i) CSTs divided into halves, and ii) CSTs divided into thirds.

Results

The most likely order of progression (Figure 1 (a)) showed that FA changes in the lower aspect of the CSTs occur at an early stage of disease evolution, with changes in the upper aspect occurring soon after. This result was found individually in all three data sets, as well as when combining them.

This pattern of distal to proximal progression was also found when the CSTs were divided into thirds (Figure 1 (b)).

Discussion

This proof-of-principle study shows that data-driven models of ALS progression are feasible, and the diffusion MRI event ordering results suggest robustly that damage to the CSTs occurs distally prior to proximally. Nevertheless, a general important limitation must be discussed: the small sample size may have biased our results. We have tried to address this issue through the use of bootstrapping, and by assessing how the results varied across three separate data sets.

While the CST results were consistent across the entire process, results for other regions such as the corpus callosum were less constant, suggesting that the biomarker ordering in the wider population may diverge from this sequence. In order to generalise these results to the wider spectrum of ALS, future studies on larger data sets are warranted.

Conclusion

Acknowledgements

References

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