Cortical microstructure in the amyotrophic lateral sclerosis–frontotemporal dementia continuum

Abstract

Objective:We aimed to characterize cortical macro- and micro-structure of behavioral and cognitive changes along the amyotrophic lateral sclerosis (ALS) – frontotemporal dementia (FTD) continuum.Methods:We prospectively recruited 88 participants with a three-Tesla MRI structural and diffusion-weighted imaging sequences: 31 ALS, 20 bvFTD, and 37 cognitively normal controls. ALS participants underwent a comprehensive cognitive and behavioral assessment and were dichotomized in ALS without cognitive or behavioral impairment (ALSno-cbi, n=12) and ALS with cognitive or behavioral impairment (ALScbi, n=19). We computed cortical thickness and cortical mean diffusivity using a surface-based approach and explored the cortical correlates of cognitive impairment with the Edinburgh Cognitive and Behavioral Amyotrophic lateral sclerosis Screen (ECAS).Results:ALSno-cbi and ALScbi groups showed different patterns of reduced cortical thickness and increased cortical mean diffusivity. In the ALSno-cbi group, cortical thinning was mainly restricted to the dorsal motor cortex. In contrast, in the ALScbi group, cortical thinning was observed primarily on fronto-insular and temporal regions bilaterally. There were progressive cortical mean diffusivity changes along the ALSno-cbi, ALScbi, and bvFTD clinical continuum. Importantly, ALS participants with either cognitive or behavioral impairment showed increased cortical mean diffusivity in the prefrontal cortex in the absence of cortical thickness.Conclusions:Cortical mean diffusivity might be a useful biomarker for the study of extra motor cortical neurodegeneration in the ALS-FTD clinical spectrum.Classification of Evidence:This study provides Class III evidence that cortical microstructure correlates with cognitive impairment in the ALS-FTD continuum.

Frontotemporal Pathology in Motor Neuron Disease Phenotypes: Insights From Neuroimaging

“…Clinical observations are widely supported by extra-motor neuroimaging findings. Structural imaging consistently reveals frontotemporal gray and white matter degeneration (14,15,18,(175)(176)(177)(178)(179)(180)(181)(182)(183)(184)(185)(186)(187)(188). Gray matter atrophy has been described in the anterior cingulate, insula, operculum, inferior frontal gyrus, superior temporal gyrus, cerebellum, parietal, and occipital cortex (1,6,7,14,15,20,179,185,(187)(188)(189)(190)(191).…”

“…Structural imaging consistently reveals frontotemporal gray and white matter degeneration (14,15,18,(175)(176)(177)(178)(179)(180)(181)(182)(183)(184)(185)(186)(187)(188). Gray matter atrophy has been described in the anterior cingulate, insula, operculum, inferior frontal gyrus, superior temporal gyrus, cerebellum, parietal, and occipital cortex (1,6,7,14,15,20,179,185,(187)(188)(189)(190)(191). White matter degeneration has been detected in the body of the corpus callosum, inferior longitudinal fasciculus, uncinate fasciculus, cerebellum, inferior frontal, middle temporal, superior temporal, orbitofrontal, occipital, and parietal regions (1, 5-7, 11, 14, 15, 18, 20, 175-191).…”

Cognitive dysfunction in amyotrophic lateral sclerosis: can we predict it?

“…Although, as expected, ALS-FTD patients have shown the most severe atrophy involving widespread frontotemporal cortical areas and subcortical regions (e.g., the caudate nucleus) [ 82 , 83 ], significant GM loss in extensive frontal, temporal, and—to a lesser degree—more posterior cortical brain regions has been observed also in patients with subtle cognitive and/or behavioral impairment [ 82 , 84 ]. Among studies which assessed specifically ALS-cbi patients compared with ALS-cn, greater thinning of inferior frontal, temporal, cingulate, and insular cortices was associated with worse performance in executive, language, verbal fluency, social cognition, and episodic memory task [ 84 , 85 ], in contrast with the focal cortical thinning observed in the dorsal motor cortex of ALS-cn patients [ 86 ]. Reduced volumes of the precuneus [ 87 ] and subcortical structures, including the thalamus and the amygdala [ 88 ], have also been shown in ALS-ci compared with ALS-cn.…”

“…Diffusion tensor imaging (DTI) studies have also demonstrated distinctive microstructural abnormalities of the white matter (WM) in ALS with mild cognitive/behavioral impairment, in terms of diffusivity alterations within extra-motor (i.e., associative) tracts, including the uncinate, cingulum, superior longitudinal fasciculus, and fornix [ 83 , 86 ], correlating with the severity of cognitive and behavioral alterations [ 17 ]. These findings, as well as a recent network-based study correlating the structural disruption of frontal networks with executive dysfunction in ALS patients [ 90 ], support the notion of cognitive impairment in this condition as the result of a “disconnection syndrome” occurring when extra-motor brain WM tracts are pathologically involved.…”

Regional Grey Matter Microstructural Changes and Volume Loss Regarding Disease Duration in Multiple Sclerosis Patients

“…The GM cortical reconstruction process was performed using in-house surface-based approach developed to measure the microstructural changes in neurodegenerative disorders 12,13,35 . We used Freesurfer tools to calculate the midpoint of each individual's cortical surface in order to avoid contamination by adjacent WM and cerebrospinal uid 12,13 .…”