Iron in Frontotemporal Lobar Degeneration: A New Subcortical Pathological Pathway?

Abstract

Introduction: Brain iron homeostasis dysregulation has been widely related to neurodegeneration. In particular, human haemochromatosis protein (HFE) is involved in iron metabolism, and HFE H63D polymorphism has been related to the risk of amyotrophic lateral sclerosis and Alzheimer's disease. Recently, iron accumulation in the basal ganglia of frontotemporal lobar degeneration (FTLD) patients has been described. Objective: To explore the relationship between HFE genetic variation and demographic, clinical and imaging characteristics in a large cohort of FTLD patients. Methods: A total of 110 FTLD patients underwent neuropsychological and imaging evaluation and blood sampling for HFE polymorphism determination. HFE H63D polymorphism was considered in the present study. Two imaging approaches were applied to evaluate the effect of HFE genetic variation on brain atrophy, namely voxel-based morphometry and region of interest-based probabilistic approach (SPM8; Wellcome Trust Centre for Neuroimaging). Results: FTLD patients carrying the D* genotype (H/D or D/D) showed greater atrophy in the basal ganglia, bilaterally, compared to H/H carriers (x, y, z: -22, -4, 0; T = 3.45; cluster size: 33 voxels, x, y, z: 24, 4, -2; T = 3.38; cluster size: 36 voxels). The former group had even more pronounced behavioural symptoms, as defined by the Frontal Behavioural Inventory total scores. Conclusions: Our data suggest that H63D polymorphism could represent a disease-modifying gene in FTLD, fostering iron deposition in the basal ganglia. This suggests a new possible mechanism of FTLD-associated neurodegeneration.

Iron-regulatory genes are associated with Neuroimaging measures in HIV infection

“…To our knowledge, this study represents the first to associate genes involved in iron metabolism, transport and/or regulation with neuroimaging measures in the context of HIV infection, and one of very few studies examining these associations in All associations that survived the first level of multiple-testing correction for number of haplotype blocks evaluated (p < 0.00135) are shown; the single SNP that survived both levels of correction (for 37 haplotype blocks and 21 neuroimaging measures, p < 6.43e-5) is shown in bold Abbreviations: GM, gray matter; WM, white matter; BG, basal ganglia; Cr, creatine; CSF, cerebrospinal fluid; NAA, N-acetylaspartate; SLC11A1, natural resistance-associated macrophage protein 1; BMP6, bone-morphogenetic protein 6, ACO1, cytoplasmic aconitase; FXN, frataxin; FTMT, mitochondrial ferritin; OR, odds ratio; MAF, minor allele frequency humans more broadly. Although iron dysregulation has been consistently linked to neurodegenerative disorders, few studies have investigated the contribution of variation in ironrelated genes to metabolic or structural brain characteristics (Gebril et al 2011;Jahanshad et al 2012;Gazzina et al 2016). Furthermore, five SNP associations that we observed in this diverse population of HIV+ individuals remained significant following p value adjustment for multiple statistical tests, including adjustment for the number of distinct haplotypes and neuroimaging measures that were evaluated.…”

“…Lastly, SNPs in at least three genes were associated with changes in regional brain volumes. Iron excess has been associated with brain atrophy in other neurological and systemic disorders (Gazzina et al 2016;Chai et al 2015). Therefore, these SNPs may modulate the risk of regional (e.g., subcortical) brain atrophy, which is commonly observed in HIV+ individuals and associated with NCI (Nir et al 2014).…”

7T MRI for neurodegenerative dementias in vivo: a systematic review of the literature

“…Findings from histological studies suggest that changes in iron deposition and distribution may also play a key role in AD pathology 54. Disorders of iron homeostasis have also been postulated in PD and related disorders55 and FTD 56…”

Reduced white matter MRI transverse relaxation rate in cognitively normal H63D-HFE human carriers and H67D-HFE mice

“…The H63D mutation and its interaction with other HFE mutations and neurodegenerative disorders remain under investigation (Nandar et al 2014; Ali-Rahmani et al 2014b; Xia et al 2015; Mariani et al 2013; Pulliam et al 2003; Gazzina et al 2015). The MRI data presented here demonstrate that there is an HFE genome related reduction in transverse R 2 in H63D human and H67D mouse carriers compared to WT-HFE controls.…”