The role of iron in gray matter degeneration in Huntington's disease: A magnetic resonance imaging study

Abstract

In Huntington's disease, iron accumulation in basal ganglia accompanies neuronal loss. However, if iron content changes with disease progression and how it relates to gray matter atrophy is not clear yet. We explored iron content in basal ganglia and cortex and its relationship with gray matter volume in 77 mutation carriers [19 presymptomatic, 8 with soft symptoms (SS), and 50 early-stage patients) and 73 matched-controls by T2*relaxometry and T1-weighted imaging on a 3T scanner. The ANCOVA model showed that iron accumulates in the caudate in presymptomatic subjects (P = 0.004) and remains relatively stable along disease stages in this nucleus; while increases in putamen and globus pallidus (P < 0.05). Volume instead decreases in basal ganglia, starting from the caudate (P < 0.0001) and extending to the putamen and globus pallidus (P ≤ 0.001). The longer the disease duration and the higher the CAG repeats, the higher the iron accumulation and the smaller the volume. In the cortex, iron decreases in parieto-occipital areas in SS (P < 0.027); extending to premotor and parieto-temporo-occipital areas in patients (P < 0.003); while volume declines in frontoparietal and temporal areas in presymptomatic (P < 0.023) and SS (P < 0.045), and extends throughout the cortex, with the exception of anterior frontal regions, in patients (P < 0.023). There is an inverse correlation between volume and iron levels in putamen, globus pallidus and the anterior cingulate; and a direct correlation in cortical structures (SMA-sensoriomotor and temporo-occipital). Iron homeostasis is affected in the disease; however, there appear to be differences in the role played by iron in basal ganglia and in cortex.

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

“…Our findings are consistent with the available imaging studies on iron concentration in HD using various neuroimaging approaches 3 6–10 12. In these previous studies, greater iron accumulation has been collectively reported in pallidum, putamen and caudate in both pre-HD and symp-HD.…”

“…However, findings have not been fully consistent across studies. For example, Dumas et al 9 (using MFC) found increased iron in pallidum, putamen and caudate in symp-HD but not pre-HD; Jurgens et al 10 (T 2 hypointensities) found increased iron in pre-HD in pallidum but not in putamen or caudate; Rosas et al 8 (field mapping evolution) found increased iron in pallidum and putamen in pre-HD and symp-HD and in caudate in symp-HD only; Vymazal et al 6 (R 2 relaxometry) found increased iron in symp-HD in pallidum but not in putamen or caudate; and Sánchez-Castañeda et al 12 ( relaxometry) found increased iron in pallidum and putamen in pre-HD and symp-HD and in caudate increased iron in pre-HD only. By contrast with the above studies, IMAGE-HD is the first to report increased iron deposition in pallidum, putamen and caudate across both the premanifest and symptomatic stages.…”

“…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…”

Recent imaging advances in neurology

“…In a large HD longitudinal study, changes in several imaging measures such as whole-brain, putamen, ventricular and grey matter volume were predictive of decline in total functional capacity and tracked longitudinal change over 36 months after adjustment with respect to age and CAG length [70]. MRI has also shown that there is an inverse correlation between volume and iron levels in the putamen, pallidus and anterior cingulate cortex, while a direct correlation is present between iron deposits and cortical volume in sensorimotor and temporo-occipital cortex [71]; iron deposits in the corpus callosum could be regarded as a marker of disease state, since iron accumulates only in manifest HD [72]. Longitudinal FA change in putamen has been demonstrated to distinguish between premanifest HD and symptomatic HD after a diagnosis was established [73]; premanifest HD also exhibited a longitudinal reduction in functional connectivity, evaluated with BOLD signal, among an extensive prefrontal and motor network during a working memory task [74].…”

Efficient imaging of midbrain nuclei using inverse double‐echo steady‐state acquisition a)

“…4(a). A second limitation is that quantitative T2* mapping, which shows potential for iron content quantification, [36][37][38] has not been integrated into the iDESS sequence. Nevertheless, we regard this restriction as largely temporary, which by no means preclude further developments to expand our currently qualitative technique to a larger-scale quantitative investigation.…”