Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by degeneration of upper motor neurons (UMN) arising from the motor cortex in the brain and lower motor neurons (LMN) in the brainstem and spinal cord. Cerebral changes create differences in brain activity captured by functional magnetic resonance imaging (fMRI), including the spontaneous and simultaneous activity occurring between regions known as the resting state networks (RSNs). Progressive neurodegeneration as observed in ALS may lead to a disruption of RSNs which could provide insights into the disease process. Previous studies have reported conflicting findings of increased, decreased, or unaltered RSN functional connectivity in ALS and do not report the contribution of UMN changes to RSN connectivity. We aimed to bridge this gap by exploring two networks, the default mode network (DMN) and the sensorimotor network (SMN), in 21 ALS patients and 40 age-matched healthy volunteers. An UMN score dichotomized patients into UMN+ and UMN- groups. Subjects underwent resting state fMRI scan on a high field MRI operating at 4.7 tesla. The DMN and SMN changes between subject groups were compared. Correlations between connectivity and clinical measures such as the ALS Functional Rating Scale—Revised (ALSFRS-R), disease progression rate, symptom duration, UMN score and finger tapping were assessed. Significant group differences in resting state networks between patients and controls were absent, as was the dependence on degree of UMN burden. However, DMN connectivity was increased in patients with greater disability and faster progression rate, and SMN connectivity was reduced in those with greater motor impairment. These patterns of association are in line with literature supporting loss of inhibitory interneurons.

The purpose of this study was to investigate whether textures computed from T1‐weighted (T1W) images of the corticospinal tract (CST) in amyotrophic lateral sclerosis (ALS) are associated with degenerative changes evaluated by diffusion tensor imaging (DTI). Nineteen patients with ALS and 14 controls were prospectively recruited and underwent T1W and diffusion‐weighted magnetic resonance imaging. Three‐dimensional texture maps were computed from T1W images and correlated with the DTI metrics within the CST. Significantly correlated textures were selected and compared within the CST for group differences between patients and controls using voxel‐wise analysis. Textures were correlated with the patients' clinical upper motor neuron (UMN) signs and their diagnostic accuracy was evaluated. Voxel‐wise analysis of textures and their diagnostic performance were then assessed in an independent cohort with 26 patients and 13 controls. Results showed that textures autocorrelation, energy, and inverse difference normalized significantly correlated with DTI metrics (p < .05) and these textures were selected for further analyses. The textures demonstrated significant voxel‐wise differences between patients and controls in the centrum semiovale and the posterior limb of the internal capsule bilaterally (p < .05). Autocorrelation and energy significantly correlated with UMN burden in patients (p < .05) and classified patients and controls with 97% accuracy (100% sensitivity, 92.9% specificity). In the independent cohort, the selected textures demonstrated similar regional differences between patients and controls and classified participants with 94.9% accuracy. These results provide evidence that T1‐based textures are associated with degenerative changes in the CST.

Research in amyotrophic lateral sclerosis (ALS) suggests that executive dysfunction, a prevalent cognitive feature of the disease, is associated with abnormal structural connectivity and white matter integrity. In this exploratory study, we investigated the white matter constructs of executive dysfunction, and attempted to detect structural abnormalities specific to cognitively impaired ALS patients. Eighteen ALS patients and 22 age and education matched healthy controls underwent magnetic resonance imaging on a 4.7 Tesla scanner and completed neuropsychometric testing. ALS patients were categorized into ALS cognitively impaired (ALSci, n = 9) and ALS cognitively competent (ALScc, n = 5) groups. Tract-based spatial statistics and connectomics were used to compare white matter integrity and structural connectivity of ALSci and ALScc patients. Executive function performance was correlated with white matter FA and network metrics within the ALS group. Executive function performance in the ALS group correlated with global and local network properties, as well as FA, in regions throughout the brain, with a high predilection for the frontal lobe. ALSci patients displayed altered local connectivity and structural integrity in these same frontal regions that correlated with executive dysfunction. Our results suggest that executive dysfunction in ALS is related to frontal network disconnectivity, which potentially mediates domain-specific, or generalized cognitive impairment, depending on the degree of global network disruption. Furthermore, reported co-localization of decreased network connectivity and diminished white matter integrity suggests white matter pathology underlies this topological disruption. We conclude that executive dysfunction in ALSci is associated with frontal and global network disconnectivity, underlined by diminished white matter integrity. Hum Brain Mapp 38:1249-1268, 2017. © 2016 Wiley Periodicals, Inc.

ObjectiveTo evaluate cerebral degenerative changes in ALS and their correlates with survival using 3D texture analysis.MethodsA total of 157 participants were included in this analysis from four neuroimaging studies. Voxel‐wise texture analysis on T1‐weighted brain magnetic resonance images (MRIs) was conducted between patients and controls. Patients were divided into long‐ and short‐survivors using the median survival of the cohort. Neuroanatomical differences between the two survival groups were also investigated.ResultsWhole‐brain analysis revealed significant changes in image texture (FDR P < 0.05) bilaterally in the motor cortex, corticospinal tract (CST), insula, basal ganglia, hippocampus, and frontal regions including subcortical white matter. The texture of the CST correlated (P < 0.05) with finger‐ and foot‐tapping rate, measures of upper motor neuron function. Patients with a survival below the media of 19.5 months demonstrated texture change (FDR P < 0.05) in the motor cortex, CST, basal ganglia, and the hippocampus, a distribution which corresponds to stage 4 of the distribution TDP‐43 pathology in ALS. Patients with longer survival exhibited texture changes restricted to motor regions, including the motor cortex and the CST.InterpretationWidespread gray and white matter pathology is evident in ALS, as revealed by texture analysis of conventional T1‐weighted MRI. Length of survival in patients with ALS is associated with the spatial extent of cerebral degeneration.

BackgroundWe investigated cerebral degeneration and neurochemistry in patients with amyotrophic lateral sclerosis (ALS) using magnetic resonance spectroscopy (MRS).MethodsWe prospectively studied 65 patients and 43 age-matched healthy controls. Participants were recruited from 4 centers as part of a study in the Canadian ALS Neuroimaging Consortium. All participants underwent single-voxel proton MRS using a protocol standardized across all sites. Metabolites reflecting neuronal integrity (total N-acetyl aspartyl moieties [tNAA]) and gliosis (myo-inositol [Ino]), as well as creatine (Cr) and choline (Cho), were quantified in the midline motor cortex and midline prefrontal cortex. Comparisons were made between patients with ALS and healthy controls. Metabolites were correlated with clinical measures of upper motor neuron dysfunction, disease progression rate, and cognitive performance.ResultsIn the motor cortex, tNAA/Cr, tNAA/Cho, and tNAA/Ino ratios were reduced in the ALS group compared with controls. Group differences in tNAA/Cr and tNAA/Cho in the prefrontal cortex displayed reduced ratios in ALS patients; however, these were not statistically significant. Reduced motor cortex ratios were associated with slower foot tapping rate, whereas only motor tNAA/Ino was associated with finger tapping rate. Disease progression rate was associated with motor tNAA/Cho. Verbal fluency, semantic fluency, and digit span forwards and backwards were associated with prefrontal tNAA/Cr.ConclusionsThis study demonstrates that cerebral degeneration in ALS is more pronounced in the motor than prefrontal cortex, that multicenter MRS studies are feasible, and that motor tNAA/Ino shows promise as a potential biomarker.