Abstract
Neurodegenerative process in amyotrophic lateral sclerosis (ALS) has been proven to involve several cortical and subcortical brain regions within and beyond motor areas. However, how ALS pathology spreads progressively during disease evolution is still unknown. In this cross-sectional study we investigated 54 ALS patients, divided into 3 subsets according to the clinical stage, and 18 age and sex-matched healthy controls, by using tract-based spatial statistics (TBSS) diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) analyses. We aimed to identify white (WM) and gray matter (GM) patterns of disease distinctive of each clinical stage, corresponding to specific clinical milestones. ALS cases in stage 2A (i.e., at diagnosis) were characterized by GM and WM impairment of left motor and premotor cortices and brainstem at ponto-mesenchephalic junction. ALS patients in clinical stage 2B (with impairment of two functional regions) exhibited decreased fractional anisotropy (FA) (p<0.001, uncorrected) and increased mean (MD) and radial diffusivity (RD) (p<0.001, uncorrected) in the left cerebellar hemisphere and brainstem precerebellar nuclei, as well as in motor areas, while GM atrophy (p<0.001, uncorrected) was detected only in the left inferior frontal gyrus and right cuneus. Finally, ALS patients in stage 3 (with impairment of three functional regions) exhibited decreased FA and increased MD and RD (p<0.05, corrected) within WM underneath bilateral pre and postcentral gyri, corpus callosum midbody, long associative tracts and midbrain, while no significant clusters of GM atrophy were observed. Our findings reinforce the hypothesis that the neurodegenerative process propagates along the axonal pathways and develops beyond motor areas from early stages, involving progressively several frontotemporal regions and their afferents and efferents, while the detection of GM atrophy in earlier stages and its disappearance in later stages may be the result of reactive gliosis.
Highlights
Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease characterized by progressive atrophy and weakness of bulbar, limb, and respiratory muscles [1]
Comparing HCs to ALS patients in clinical stage 3, we found decreased fractional anisotropy (FA) and increased MD and radial diffusivity (RD) (p
We found a sequential dissemination of WM pathology from motor toward extra-motor areas across different clinical milestones of ALS, with a widespread pathway that may reflect the underlying mechanisms of spreading of the neurodegenerative process
Summary
Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease characterized by progressive atrophy and weakness of bulbar, limb, and respiratory muscles [1]. To what observed in other neurodegenerative diseases characterized by tau and alfa-sinuclein pathology [17,18,19], there is increasing evidence that in ALS-FTLD spectrum the aggregation of transactive response DNA binding protein 43 KDa (TDP-43) could sequentially disseminate during disease course from a focal site of onset in a prion-like, cell-to-cell manner [20] This hypothesis recalls the clinicopathological observation that motor neurons degeneration in ALS starts focally and spreads from motor domains towards several extra-motor regions along anatomical pathways [2, 3, 21, 22]. The progressive extent and the regional distribution of GM and WM involvement during disease course, a crucial point for assessing ALS pathophysiology, remain still to be elucidated
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