Pathology of callosal damage in ALS: An ex-vivo, 7 T diffusion tensor MRI study

Abstract

ObjectivesThe goal of this study was to better understand the changes in tissue microstructure that underlie white matter diffusion changes in ALS patients.MethodsDiffusion tensor imaging was carried out in postmortem brains of 4 ALS patients and two subjects without neurological disease on a 7 T MRI scanner using steady-state free precession sequences. Fractional anisotropy (FA) was measured in the genu, body, and splenium of the corpus callosum in formalin-fixed hemispheres. FA of the body and genu was expressed as ratio to FA of the splenium, a region unaffected in ALS. After imaging, tissue sections of the same segments of the callosum were stained for markers of different tissue components. Coded image fields were rated for pathological changes by blinded raters.ResultsThe FA body/FA splenium ratio was reduced in ALS patients compared to controls. Patchy areas of myelin pallor and cells immunostained for CD68, a microglial-macrophage marker, were only observed in the body of the callosum of ALS patients. Blinded ratings showed increased CD68 + microglial cells in the body of the corpus callosum in ALS patients, especially those with C9orf72 mutations, and increased reactive astrocytes throughout the callosum.ConclusionReduced FA of the corpus callosum in ALS results from complex changes in tissue microstructure. Callosal segments with reduced FA had large numbers of microglia-macrophages in addition to loss of myelinated axons and astrogliosis. Microglial inflammation contributed to reduced FA in ALS, and may contribute to a pro-inflammatory state, but further work is needed to determine their role.

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

“…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 ]. Interestingly, executive and behavioral dysfunctions have been shown to be associated mainly with a degeneration of the anterior part of CC (e.g., genu) in several cohorts of ALS patients [ 63 , 65 ] as well as in FTLD phenotypes, in support of the existence of a frontotemporal lobar degeneration continuum [ 66 ].…”

“…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 ]. Interestingly, executive and behavioral dysfunctions have been shown to be associated mainly with a degeneration of the anterior part of CC (e.g., genu) in several cohorts of ALS patients [ 63 , 65 ] as well as in FTLD phenotypes, in support of the existence of a frontotemporal lobar degeneration continuum [ 66 ]. Moreover, among associative WM tracts in the frontal lobe, the anterior cingulum bundle is adjacent to the motor cortex, and its microstructural damage in ALS has been hypothesized to be related to the pattern of corticofugal disease spreading [ 67 , 68 ].…”

Occasional essay: Upper motor neuron syndrome in amyotrophic lateral sclerosis

“…Interhemispheric motor cortical fibres in the central corpus callosum (figure 1) are consistently involved in ALS,106–108 especially in PLS 109 110. DTI changes correlate with clinical and transcortical magnetic stimulation studies of UMN involvement,107 109 111 and Wallerian degeneration with microglial infiltration has been suggested as a correlate of these white matter tract MRI changes 112 113…”

Telomere length and advanced diffusion MRI as biomarkers for repetitive mild traumatic brain injury in adolescent rats

“…DWI is a safe and clinically relevant imaging modality that may also be a useful biomarker of mTBI pathophysiology ( Jeter et al, 2013 ; Shultz et al, 2017 ). While conventional imaging techniques that assess for macroscopic abnormalities typically fail to find any evidence of change, initial studies investigating DWI measures suggest that these may be sensitive indicators of the pathophysiological changes that occur after an mTBI ( Dimou and Lagopoulos, 2014 ; Dodd et al, 2014 ; Lancaster et al, 2016 ; Shenton et al, 2012 ; Xiong et al, 2014 ), including both oxidative stress ( Back et al, 2011 ) and inflammation ( Cardenas et al, 2017 ).…”