MRI measures of corpus callosum iron and myelin in early Huntington's disease

Abstract

Increased iron in subcortical gray matter (GM) structures of patients with Huntington's disease (HD) has been suggested as a causal factor in neuronal degeneration. But how iron content is related to white matter (WM) changes in HD is still unknown. For example, it is not clear whether WM changes share the same physiopathology (i.e. iron accumulation) with GM or whether there is a different mechanism. The present study used MRI to examine iron content in premanifest gene carriers (PreHD, n = 25) and in early HD patients (n = 25) compared with healthy controls (n = 50). 3T MRI acquisitions included high resolution 3D T1, EPI sequences for diffusion tensor imaging (DTI) as an indirect measure of tissue integrity, and T2*-weighted gradient echo-planar imaging for MR-based relaxometry (R2*), which provides an indirect measure of ferritin/iron deposition in the brain. Myelin breakdown starts in the PreHD stage, but there is no difference in iron content values. Iron content reduction manifests later, in the early HD stage, in which we found a lower R2* parameter value in the isthmus. The WM iron reduction in HD is temporally well-defined (no iron differences in PreHD subjects and iron differences only in early HD patients). Iron level in callosal WM may be regarded as a marker of disease state, as iron does not differentiate PreHD subjects from controls but distinguishes between PreHD and HD.

Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis

“…Control is age-matched heterozygous KO mice. (2,4, and 8 mo) were studied for 7-8 mo after tamoxifen injection (2-mo-old, n = 10; KO, male = 6 and female = 4; control, male = 4 and female = 6; 4-mo-old, n = 10; KO, male = 5 and female = 5; control, male = 5 and female = 5; 8-mo-old, KO, n = 9, male = 4, female = 5; control, n = 11, male = 6, female = 5; two-way ANOVA test, body weight, 2M control vs. 2M KO: P = 0.9945, 4M control vs. 4M KO: P = 0.9862, 8M control vs. 8M KO P = 0.9922; rotatod performance, 2M control vs. 2M KO: P = 0.9565, 4M control vs. 4M KO: P = 0.9921, 8M control vs. 8M KO P = 0.7701; gripping ability, 2M control vs. 2M KO: P = 1.0000, 4M control vs. 4M KO: P = 0.9962, 8M control vs. 8M KO P = 0.9718).…”

“…Despite its ubiquitous expression in the brain and body, mutant HTT causes selective neuronal degeneration as well as white matter atrophy in the brain (1)(2)(3). The neuronal degeneration is characterized by the preferential loss of neuronal cells in the striatum in the early disease stage and extensive neurodegeneration in a variety of brain regions in later disease stages.…”

Iron accumulation in the basal ganglia in Huntington's disease: cross-sectional data from the IMAGE-HD study

“…Iron increases have also been observed in cortical regions in symptomatic patients at an advanced disease stage (frontal, precentral and paracentral, parietal, cingulate, precuneus cortices) 8. Moreover, reduced iron has been reported in cortical areas (premotor and parietotemporo-occipital cortices) during the early symptomatic stages, and in white matter regions (frontal lobe white matter, and genu and body of corpus callosum), during both early and advanced symptomatic stages 3 8 11 12…”

Postnatal and adult consequences of loss of huntingtin during development: Implications for Huntington's disease

“…These brain abnormalities may therefore represent the consequences of a developmental diathesis induced by aberrant polyglutamine expansion (polyQ) in huntingtin (Htt). These putative developmental sequelae include impairments in the inhibitory GABAergic system (Philpott et al, 2015), oligodendrocyte abnormalities (Gomez-Tortosa et al, 2001; Myers et al, 1991) and white matter micro-architectural changes (Di Paola et al, 2014; Gregory et al, 2015; Phillips et al, 2014), as well as region-specific brain volumetric alterations (Aylward et al, 2013; Nopoulos et al, 2011; Paulsen et al, 2006). In line with these findings, we and other groups have reported significant developmental abnormalities in striatal and cortical neurogenesis in HD mice (Molero et al, 2009; Molina-Calavita et al, 2014).…”