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.
Highlights
Diffusion tensor imaging is a tool to evaluate diffusion properties in white matter (Basser, 1995; Pierpaoli et al, 1996) in living subjects, both qualitatively and quantitatively (Pierpaoli and Basser, 1996)
Post mortem interval (PMI) was not correlated with the fractional anisotropy (FA) of the genu or body of the callosum, in the controls, the values were clustered near the values for the splenium
These findings suggest that the correlation between PMI and FA did not account for the reduction seen in the body or genu of the callosum of the subjects with amyotrophic lateral sclerosis (ALS)
Summary
Diffusion tensor imaging is a tool to evaluate diffusion properties in white matter (Basser, 1995; Pierpaoli et al, 1996) in living subjects, both qualitatively and quantitatively (Pierpaoli and Basser, 1996). Many studies have described changes of white matter diffusion parameters in patients with amyotrophic lateral sclerosis (ALS) (Ellis et al, 1999) which are thought to be caused by loss of integrity of axons undergoing degeneration (Song et al, 2003). ALS patients with low FA of the corticospinal tract have shorter survival and more rapid progression (Agosta et al, 2010; Menke et al, 2012). Tissue changes thought to account for changes in diffusion measures in ALS patients are based on animal models that caused reduction in FA values by experimental manipulations that cause axonal degeneration or demyelination (Song et al, 2003; Thiessen et al, 2013).
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