White Matter Microstructure Breakdown in the Motor Neuron Disease Spectrum: Recent Advances Using Diffusion Magnetic Resonance Imaging

Abstract

Motor neuron disease (MND) is a fatal progressive neurodegenerative disorder characterized by the breakdown of the motor system. The clinical spectrum of MND encompasses different phenotypes classified according to the relative involvement of the upper or lower motor neurons (LMN) and the presence of genetic or cognitive alterations, with clear prognostic implications. However, the pathophysiological differences of these phenotypes remain largely unknown. Recently, magnetic resonance imaging (MRI) has been recognized as a helpful in-vivo MND biomarker. An increasing number of studies is applying advanced neuroimaging techniques in order to elucidate the pathophysiological processes and to identify quantitative outcomes to be used in clinical trials. Diffusion tensor imaging (DTI) is a non-invasive method to detect white matter alterations involving the upper motor neuron and extra-motor white matter tracts. According to this background, the aim of this review is to highlight the key role of MRI and especially DTI, summarizing cross-sectional and longitudinal results of different approaches applied in MND. Current literature suggests that DTI is a promising tool in order to define anatomical "signatures" of the different phenotypes of MND and to track in vivo the progressive spread of pathological proteins aggregates.

Keywords: amyotrophic lateral sclerosis; diffusion tensor imaging; fractional anisotropy; magnetic resonance imaging; motor neuron disease; network analysis; structural connectomics.

Figure 1

(A) Whole brain-based spatial statistics (WBSS) of fractional anisotropy (FA) maps at the group level for amyotrophic lateral sclerosis (ALS) patients, primary lateral sclerosis (PLS) patients, and controls. WBSS of FA maps demonstrated multiple clusters of regional FA reductions at p < 0.05 (corrected for multiple comparisons), projectional views. (B) Tractwise fractional anisotropy statistics (TFAS) of FA maps at the group level for ALS patients, PLS patients, and controls. TFAS demonstrated significant regional FA reductions in ALS-related tract systems and in the grand average between ALS patients and controls as well as between PLS patients and controls. No alterations between groups were observed in the reference tract. ^*p < 0.05, ^**p < 0.001. Reproduced with permission from Müller et al. NeuroImage Clinical 2018 (41) (published open-access under a CC BY-NC-ND 4.0 license).

Figure 2

(A) Network topological distance between nodes of stage I, stage I and stage II, stages I, and III and between stages I and IV show a strong ordering effect (p = 0.002). Significance of differences in network topological distances between stages is marked as follows: ^*p < 0.05, ^**p < 0.005. (B) Matrix of mean network topological distances between all four stages. Reproduced with permission from Schmidt et al. NeuroImage 2016 (65) (published open-access under a CC BY-NC-ND 4.0 license).