Associations Between Cortical Iron Accumulation and Memory in Patients With Amnestic Mild Cognitive Impairment and in Cognitively Normal Individuals

Abstract

Background and purpose: Brain iron accumulation is recognized as a cause and therapeutic target in Alzheimer's disease (AD). We investigated the differences in both volume and iron accumulation between cognitively normal (CN) older adults and patients with amnestic mild cognitive impairment (aMCI). Additionally, we assessed which combination of these measures best explains the group differences in visual and verbal memory performance.

Materials and methods: We retrospectively analyzed data from 48 patients with aMCI and 33 age-matched CN individuals. Structural differences were investigated using voxel-based comparisons of T1-weighted magnetic resonance images. Differences in iron accumulation were investigated using voxel-based comparisons of quantitative susceptibility mapping (QSM) images. Subsequently, significant clusters from these voxel-based analyses (amygdala, posterior cingulate cortex, precuneus, lateral occipital cortex, and pericalcarine cortex) were entered into a stepwise regression to predict verbal and visual memory scores, while accounting for age, sex, and education as covariates.

Results: In comparison to CN, patients with aMCI had significantly lower scores in both verbal and visual memory tests (p < 0.001). The T1-weighted voxel-based morphometry (VBM) results showed significant hippocampal atrophy in the aMCI group relative to CN individuals. The QSM-VBM results showed increased iron accumulation in the amygdala, posterior cingulate cortex, precuneus, lateral occipital cortex, and pericalcarine cortex (FWE-corrected p < 0.05). Lower hippocampal volume (B = 2015.91, SE = 469.61, p < 0.001) and higher posterior cingulate cortex susceptibility (B = -189.63 SE = 89.11, p = 0.037) were significant predictors of verbal memory. For visual memory, higher lateral occipital susceptibility (B = -659. 96, SE = 253.03, p = 0.011) was significant imaging predictor.

Conclusions: These results suggest that iron accumulates in regions where atrophy has not yet occurred, suggesting that iron may serve as an earlier imaging marker of neurodegeneration compared to volume atrophy. Further studies are needed to investigate the longitudinal relationship between brain volume and iron accumulation during cognitive decline.

Keywords: iron; memory; mild cognitive impairment; quantitative susceptibility mapping.

FIGURE 1

Overview of (A) QSM processing and (B) voxel‐based analysis of T1 volume and QSM.

FIGURE 2

Patterns of GM atrophy (A) and iron accumulation (B) in patients with aMCI versus NC group. The results are shown on a 3D surface render (top) and overlaid on representative axial, coronal, and sagittal slices (bottom). Statistical significance of p < 0.05, corrected for multiple comparisons using few, are used. (A) T1‐VBM results: significant atrophy in the hippocampus in aMCI compared to NC group. (B) QSM‐VBM results: increased iron accumulation (noted as higher positive QSM values) in the amygdala/hippocampus, precuneus, posterior cingulate cortex, lateral occipital cortex, and pericalcarine cortex. Abbreviations: aMCI, amnestic mild cognitive impairment; CN, cognitively normal; GM, gray matter; QSM‐VBM, quantitative susceptibility mapping‐voxel‐based morphometry.

FIGURE 3

Correlation between the specific memory scores and the regional susceptibilities.