Gray matter and white matter changes in non-demented amyotrophic lateral sclerosis patients with or without cognitive impairment: A combined voxel-based morphometry and tract-based spatial statistics whole-brain analysis

Abstract

The phenotypic heterogeneity in amyotrophic lateral sclerosis (ALS) implies that patients show structural changes within but also beyond the motor cortex and corticospinal tract and furthermore outside the frontal lobes, even if frank dementia is not detected. The aim of the present study was to investigate both gray matter (GM) and white matter (WM) changes in non-demented amyotrophic lateral sclerosis (ALS) patients with or without cognitive impairment (ALS-motor and ALS-plus, respectively). Nineteen ALS-motor, 31 ALS-plus and 25 healthy controls (HC) underwent 3D-T1-weighted and 30-directional diffusion-weighted imaging on a 3 T MRI scanner. Voxel-based morphometry and tract-based spatial-statistics analysis were performed to examine GM volume (GMV) changes and WM differences in fractional anisotropy (FA), axial and radial diffusivity (AD, RD, respectively). Compared to HC, ALS-motor patients showed decreased GMV in frontal and cerebellar areas and increased GMV in right supplementary motor area, while ALS-plus patients showed diffuse GMV reduction in primary motor cortex bilaterally, frontotemporal areas, cerebellum and basal ganglia. ALS-motor patients had increased GMV in left precuneus compared to ALS-plus patients. We also found decreased FA and increased RD in the corticospinal tract bilaterally, the corpus callosum and extra-motor tracts in ALS-motor patients, and decreased FA and increased AD and RD in motor and several WM tracts in ALS-plus patients, compared to HC. Multimodal neuroimaging confirms motor and extra-motor GM and WM abnormalities in non-demented cognitively-impaired ALS patients (ALS-plus) and identifies early extra-motor brain pathology in ALS patients without cognitive impairment (ALS-motor).

Regional Dynamics of the Resting Brain in Amyotrophic Lateral Sclerosis Using Fractional Amplitude of Low-Frequency Fluctuations and Regional Homogeneity Analyses

“…This structure is proved to participate in motor as well as in cognitive and behavioural functions and plays an important role in neurodegenerative diseases, including ALS (Strick ete al., 2009; for a review see Gellersen et al, 2017). Functional abnormalities and hypometabolism in the cerebellum are well documented in ALS (Ferrer et al, 2016;Buhour et al, 2017) as well as gray and white matter changes, and proven to correlate with cognitive and behavioural symptoms (Tan et al, 2014;Christidi et al, 2017;Thivard et al, 2007). Clinical motor characteristics and possibly cognitive symptoms could be further explained by the involvement of these fALFF and ReHo changes found in the cerebellum.…”

Neurodegeneration of brain networks in the amyotrophic lateral sclerosis–frontotemporal lobar degeneration (ALS–FTLD) continuum: evidence from MRI and MEG studies

“…More recently, several DTI studies emphasized the significant WM changes in nondemented ALS patients with or without cognitive impairment, explored in the early stages of the disease. [38][39][40] Specifically, the WM abnormalities in the corpus callosum and in the frontotemporal WM tracts, especially in the uncinate and superior longitudinal fasciculi, appeared to be more pronounced in ALS patients with cognitive impairment as compared to those without cognitive impairment, thus revealing more profound alterations in the former group. 39,40 Structural connectivity alterations reflecting neuropathological abnormalities…”

“…29,30,[32][33][34][35][36][37] To note, early extramotor involvement in ALS [18][19][20][21][22][23] and damage of the corticospinal pathway and of the sensorimotor networks in bvFTD 29,30 have been widely recognized. Moreover, since several structural studies have found significant WM extramotor abnormalities in cohorts of ALS patients without profound cognitive decline and explored in relatively early disease stages, 21,[38][39][40] an early damage of extramotor regions in ALS might be a potential marker of clinical symptoms more evident in later disease stages, such as cognitive and behavioral alterations.…”

Assessment of the Corticospinal Tract Profile in Pure Lower Motor Neuron Disease: A Diffusion Tensor Imaging Study

“…A previous study [12] on the CST diffusion profile highlighted the importance of RD in distinguishing between ALS patients and controls on an individual basis. Al-though the great majority of DTI studies on ALS patients showed unchanged AD in CST [5,12,23,[27][28][29][30], a few studies demonstrated an increment [31][32][33] or a decrease [34,35] of this metric within the CST of ALS patients, suggesting that different methodologies, heterogeneity of the cohorts, as well as the intrinsic complexity of UMN alterations can underlie these different results [36].…”