Microstructural Changes across Different Clinical Milestones of Disease in Amyotrophic Lateral Sclerosis

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.

Apathy Is Correlated with Widespread Diffusion Tensor Imaging (DTI) Impairment in Amyotrophic Lateral Sclerosis

“…Microstructural alterations in the CC found in our ALS population were similar to those reported in other cohorts of ALS patients [ 59 , 60 ]. Similar to previous studies, we performed a TBSS analysis of DTI data, a hypothesis-free technique which is capable of detecting structural changes over the whole brain and therefore highlights the structural process of disease spreading across WM fibers known to connect motor areas [ 59 , 60 , 63 ]. Structural neuroimaging evidence of CC damage seems to provide, in vivo , the same neuropathological signatures of neurodegeneration widely reported in both animal models [ 64 ] and autopsied patients [ 65 ].…”

“…A voxel-based TBSS approach was used for the group analysis of DTI data [ 38 ]. DTI data sets were processed with the Functional MRI of the Brain (FMRIB) Software Library (FSL) software package ( http://www.fmrib.ox.ac.uk/fsl ), according to methods used in our previous studies [ 59 , 60 ]. Preprocessing included eddy current and motion correction and brain-tissue extraction.…”

Region‐specific atrophy of precentral gyrus in patients with amyotrophic lateral sclerosis

“…32 The hypothesis that ALSrelated pathology starts focally and progressively spreads through the anatomy of the motor system towards extramotor areas has been corroborated in several studies. 12,33,34 However, the region-specific alterations in PrCG has not yet been clearly elucidated. In this study, local atrophy of PrCG in ALS at a late stage was much more widespread than patients at an early stage, indicating that surface area atrophy starts locally and spreads to other areas in PrCG as time progresses.…”

ALS biomarkers for therapy development: State of the field and future directions

“…Cross‐sectional DTI studies in ALS show widespread white matter changes in ALS subjects compared with healthy volunteers, and these changes correlate with upper motor neuron signs, ALSFRS‐R scores, verbal fluency, and the estimated rate of functional decline between the reported date of symptom onset and the date of scanning . Longitudinal DTI studies in ALS show more focal pathology, involving the corticospinal tract, corpus callosum, and posterior limb of the internal capsule in some studies, and other studies have shown more diffuse changes, including the cerebellum and the temporal and parietal lobes .…”