To assess directionality of neurodegeneration in vivo using a multimodal neuroimaging approach.

The anatomical directionality of the neurodegenerative process in ALS is still debated; the dying-forward hypothesis proposes top-down damage starting in the precentral gyrus (PCG) and spreading caudally along the corticospinal tract (CST) to the lower motor neurones. In contrast, the dying-back hypothesis argues for bottom-up damage in the periphery as the initial event with subsequent progression in the caudal to cranial direction. 

MRI was performed at 3 Tesla on 78 ALS patients and 13 healthy controls. Parameter estimates reflecting motor neuron damage were derived from several levels of the CST: PCG thickness using FreeSurfer, CST fractional anisotropy (FA) estimates using FSL, and cross-sectional C3 cervical cord area estimates (adjusted for spinal canal area) using Philips on-line software. Comparisons between patients and controls were reported using unpaired t-tests. In order to standardise measures to a common domain, parameter estimates were converted to z-scores, relative to controls. A mixed-effects linear regression model was then applied to determine whether a gradient of tissue damage existed.

There was a trend towards thinner PCG in patients (mean 2.36mm ± SD 0.16 vs 2.45mm ± 0.11, p = 0.077, 95%CI [-0.010, 0.19]) and CST FA was significantly lower in patients compared to controls (0.42 ± 0.03 vs 0.44 ± 0.02, p = 0.007, 95% CI [0.006, 0.036]). There was no significant difference in cervical cord area. A significant decrease in z-scores was identified at the level between CST FA and cervical cord with patients exhibiting more evidence of damage in PCG thickness and CST FA, and relatively  preserved spinal cord area (regression coefficient between CST FA and cord levels: -0.85, 95% CI [-1.25, -0.46] p< 0.001).

This novel multimodal neuroimaging approach provides in vivo evidence to support a top-down neurodegenerative process in ALS.