Reduced structural connectivity within a prefrontal-motor-subcortical network in amyotrophic lateral sclerosis.

BACKGROUND: To investigate white matter structural connectivity changes associated with amyotrophic lateral sclerosis (ALS) using network analysis and compare the results with those obtained using standard voxel-based methods, specifically Tract-based Spatial Statistics (TBSS). METHODS: MRI data were acquired from 30 patients with ALS and 30 age-matched healthy controls. For each subject, 85 grey matter regions (network nodes) were identified from high resolution structural MRI, and network connections formed from the white matter tracts generated by diffusion MRI and probabilistic tractography. Whole-brain networks were constructed using strong constraints on anatomical plausibility and a weighting reflecting tract-averaged fractional anisotropy (FA). RESULTS: Analysis using Network-based Statistics (NBS), without a priori selected regions, identified an impaired motor-frontal-subcortical subnetwork (10 nodes and 12 bidirectional connections), consistent with upper motor neuron pathology, in the ALS group compared with the controls (P = 0.020). Reduced FA in three of the impaired network connections, which involved fibers of the corticospinal tract, correlated with rate of disease progression (P ≤ 0.024). A novel network-tract comparison revealed that the connections involved in the affected network had a strong correspondence (mean overlap of 86.2%) with white matter tracts identified as having reduced FA compared with the control group using TBSS. CONCLUSION: These findings suggest that white matter degeneration in ALS is strongly linked to the motor cortex, and that impaired structural networks identified using NBS have a strong correspondence to affected white matter tracts identified using more conventional voxel-based methods.

Executive deficits, not processing speed relates to abnormalities in distinct prefrontal tracts in amyotrophic lateral sclerosis.

Cognitive impairment in amyotrophic lateral sclerosis is characterized by deficits on tests of executive function; however, the contribution of abnormal processing speed is unknown. Methods are confounded by tasks that depend on motor speed in patients with physical disability. Structural and functional magnetic resonance imaging studies have revealed multi-system cerebral involvement, with evidence of reduced white matter volume and integrity in predominant frontotemporal regions. The current study has two aims. First, to investigate whether cognitive impairments in amyotrophic lateral sclerosis are due to executive dysfunction or slowed processing speed using methodology that accommodates motor disability. This is achieved using a dual-task paradigm and tasks that manipulate stimulus presentation times and do not rely on response motor speed. Second, to identify relationships between specific cognitive impairments and the integrity of distinct white matter tracts. Thirty patients with amyotrophic lateral sclerosis and 30 age- and education-matched control subjects were administered an experimental dual-task procedure that combined a visual inspection time task and digit recall. In addition, measures of executive function (including letter fluency) and processing speed (visual inspection time and rapid serial letter identification) were administered. Integrity of white matter tracts was determined using region of interest analyses of diffusion tensor magnetic resonance imaging data. Patients with amyotrophic lateral sclerosis did not show impairments on tests of processing speed, but executive deficits were revealed once visual inspection time was combined with digit recall (dual-task) and in letter fluency. In addition to the corticospinal tracts, significant differences in fractional anisotropy and mean diffusivity were found between groups in a number of prefrontal and temporal white matter tracts including the anterior cingulate, anterior thalamic radiation, uncinate fasciculus and hippocampal portion of the cingulum bundles. Significant differences also emerged in the anterior corona radiata as well as in white matter underlying the superior, medial and inferior frontal gyri and the temporal gyri. Dual-task performance significantly correlated with fractional anisotropy measures in the middle frontal gyrus white matter and anterior corona radiata. Letter fluency indices significantly correlated with fractional anisotropy measures of the inferior frontal gyrus white matter and corpus callosum in addition to the corticospinal tracts and mean diffusivity measures in the white matter of the superior frontal gyrus. The current study demonstrates that cognitive impairment in amyotrophic lateral sclerosis is not due to generic slowing of processing speed. Moreover, different executive deficits are related to distinct prefrontal tract involvement in amyotrophic lateral sclerosis with dual-task impairment associating with dorsolateral prefrontal dysfunction and letter fluency showing greater dependence on inferolateral prefrontal dysfunction.

Quantitative tractography and tract shape modeling in amyotrophic lateral sclerosis.

PURPOSE: To investigate brain-wide white matter structural changes associated with amyotrophic lateral sclerosis (ALS) using an automatic single seed point tractography-based segmentation method, probabilistic neighborhood tractography (PNT), which provides quantitative measures of both tract integrity and shape. MATERIALS AND METHODS: Diffusion MRI data were acquired from 30 patients with ALS (ALS Functional Rating Scale-Revised score > 20) and 30 matched controls. PNT was used to segment 12 major projection, commissural and association fibers, and assess differences in how the shape of an individual subject's tract compares to that of a predefined reference tract, in addition to providing tract-average mean diffusivity (〈D〉) and fractional anisotropy (FA) data. RESULTS: Across all 12 tracts, group-averaged 〈D〉 was larger, while group-averaged FA was equal to or smaller in value for patients than controls. These differences were significant for right cingulum 〈D〉, and left and right corticospinal tract (CST) 〈D〉 and FA (P-values 6 × 10(-5) to 0.03). Tract shape modeling indicated that there were significantly greater topological differences from the reference tract in left and right CST, and right uncinate fasciculus (P-values 0.02 to 0.04) for patients than controls. The rate of disease progression was significantly negatively correlated with bilateral CST FA (P-values 0.01 to 0.02). CONCLUSION: ALS, although particularly affecting CST, is associated with subtle changes in white matter tract integrity and shape in several other major fibers within the brain. Correlations between CST integrity and disease progression rate suggest that quantitative tractography may provide useful biomarkers of disease evolution in ALS.