White matter structural network abnormalities underlie executive dysfunction in amyotrophic lateral sclerosis

Abstract

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.

2‐Deoxy‐2‐[18F]fluoro‐d‐glucose positron emission tomography, cortical thickness and white matter graph network abnormalities in brains of patients with amyotrophic lateral sclerosis and frontotemporal dementia suggest early neuronopathy rather than axonopathy

“…Although not all brain regions share abnormalities of reduced glucose metabolic rate (by PET), CT, and strength and number of edges (by WM network Figure 1 Regions of 18 F-FDG PET hypometabolism in ALS-FTD patients. analysis), the following frontal regions do: superior frontal gyrus (dorsolateral, medial, medial orbital and orbital parts), middle frontal gyrus (orbital part), inferior frontal gyrus (orbital and triangular parts), gyrus rectus, supplementary motor area, medial cingulate gyrus, anterior cingulate gyrus, medial and anterior paracingulate gyri, and precentral gyrus.…”

“…PET images were also acquired only for ALS-FTD patients following intravenous administration of 10 mCi (370 MBq) of 18 F-FDG with a 40-min uptake time. Imaging was done on a hybrid PET/computed tomography Siemens Biograph TruePoint scanner.…”

“…The above results implicate degeneration of both GM and WM in the brains of ALS-FTD patients, although in studies that evaluated either type of region independently. In this study, functional 18 F-FDG PET, CT and whole brain WM network (using graph theory) analyses were combined for the same ALS-FTD patient. Graph theory based network analysis, as used here, is a more sophisticated approach than a region of interest or TBSS approach, especially when combined with DTT, because it does not require registration of brain images to atlas/template space (which introduces inaccuracies) and utilizes each patient's own fiber tracts to reconstruct neural connections across different brain regions.…”

“…In this study of patients with ALS-FTD, our goals were to determine from neuroimaging (i) whether neurodegeneration is predominantly a neuronopathy or axonopathy and (ii) how WM connections in frontal and temporal lobes are affected by the neurodegenerative process. It was hypothesized that, compared to neurological controls, in patients with ALS-FTD (i) CT is reduced significantly in both motor and extramotor regions, (ii) 18 F-FDG PET reveals significantly reduced glucose metabolism in the same brain regions where cortical thinning occurs and (iii) fewer WM networks underlie widespread affected cortical regions suggesting that onset of neurodegeneration is primarily a neuronopathy and not an axonopathy.…”

Impaired Structural Network Properties Caused by White Matter Hyperintensity Related to Cognitive Decline

“…Graph theoretical analysis is applied to construct a white matter structural network and provide information on the amount of integrations among brain regions. Nowadays, DTI and graph theoretical analysis have been increasingly applied to explore white matter integrity and structural network topological organization in multiple neurological diseases, including Alzheimer's disease (AD) (19), multiple sclerosis (20), amyotrophic lateral sclerosis (21), and schizophrenia (22). Furthermore, evidence of structural network changes and clinical relevance has already been presented in previous, larger and longitudinal, population-based studies (23)(24)(25).…”