Cortical Iron Accumulation as an Imaging Marker for Neurodegeneration in Clinical Cognitive Impairment Spectrum: A Quantitative Susceptibility Mapping Study

Abstract

Objective Cortical iron deposition has recently been shown to occur in Alzheimer’s disease (AD). In this study, we aimed to evaluate how cortical gray matter iron, measured using quantitative susceptibility mapping (QSM), differs in the clinical cognitive impairment spectrum. Materials and Methods This retrospective study evaluated 73 participants (mean age ± standard deviation, 66.7 ± 7.6 years; 52 females and 21 males) with normal cognition (NC), 158 patients with mild cognitive impairment (MCI), and 48 patients with AD dementia. The participants underwent brain magnetic resonance imaging using a three-dimensional multi-dynamic multi-echo sequence on a 3-T scanner. We employed a deep neural network (QSMnet+) and used automatic segmentation software based on FreeSurfer v6.0 to extract anatomical labels and volumes of interest in the cortex. We used analysis of covariance to investigate the differences in susceptibility among the clinical diagnostic groups in each brain region. Multivariable linear regression analysis was performed to study the association between susceptibility values and cognitive scores including the Mini-Mental State Examination (MMSE). Results Among the three groups, the frontal ( P < 0.001), temporal ( P = 0.004), parietal ( P = 0.001), occipital ( P < 0.001), and cingulate cortices ( P < 0.001) showed a higher mean susceptibility in patients with MCI and AD than in NC subjects. In the combined MCI and AD group, the mean susceptibility in the cingulate cortex (β = -216.21, P = 0.019) and insular cortex (β = -276.65, P = 0.001) were significant independent predictors of MMSE scores after correcting for age, sex, education, regional volume, and APOE4 carrier status. Conclusion Iron deposition in the cortex, as measured by QSMnet+, was higher in patients with AD and MCI than in NC participants. Iron deposition in the cingulate and insular cortices may be an early imaging marker of cognitive impairment related neurodegeneration.

The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases

“…This suggests that iron elevation, which is yet to be toxic, may occur prior to the tau pathology burden [19]. Moreover, studies show cortical accumulation of iron in Braak IV stage regions in MCI comparable to that observed in AD, further suggesting an earlier involvement of iron in disease pathogenesis [21].…”

“…Parallelly, exposure to Aβ was shown to elicit iron homeostatic changes in astrocytes [39], and single-cell RNA sequencing revealed ferroptosis genes to be significantly dysregulated in AD entorhinal cortex astrocytes [40], suggesting that AD-related iron dysregulation may be a dynamic process involving multiple cell types throughout disease progression. This could be a possible explanation for the lack of MRI iron level differences observed in MCI versus AD patients [21,31], as well as the persistence of iron cognition correlations without bulk changes in regional iron levels in AD patients, as will be discussed in more depth in the following sections [18,22].…”

“…Iron imbalance in AD-affected brains is thought to be a widespread pathological phenomenon affecting several brain areas. Increased levels of iron are found in the whole cortex, including frontal, temporal, parietal, occipital, insular, and cingulate cortices [18][19][20][21], where temporal and occipital lobes are often found with a prominent burden [20,22] (Figure 2). Subcortical regions, most consistently in the caudate nucleus and the putamen, are observed with higher iron burden, which are reported to be more closely associated with disease progression defined by advanced cognitive impairment and duration of disease [18,20,23,24].…”

“…Evaluating Aβ-CSF-positive cognitively unimpaired versus impaired AD patients, quantitative susceptibility mapping (QSM) values of the cortical and inferior temporal gyrus (ITG), as well as their tau-SUVR uptake levels were found to be increased, with a negative correlation between the QSM signal in the ITG and global cognition, as quantified by the mini-mental state examination (MMSE) [19]. In longitudinal, post-mortem, and observational studies, MMSE was associated with or predicted with increased iron levels in the ITG, cingulate cortex, insular cortex, right angular gyrus, supramarginal gyrus, lateral occipital cortex, parietal operculum cortex, left frontal operculum cortex, and the inferior frontal gyrus [18,19,21]. Associations with the Montreal cognitive assessment (MoCA) scores were also observed in the right angular gyrus, supramarginal gyrus, lateral occipital cortex, superior temporal gyrus, and frontal cortices [18].…”

Cortical Iron Deposition Is Multicausal, and Therefore Cannot Serve as a Biomarker for Early Cognitive Impairment

“…We read with interest, the article by Kim et al [ 1 ] on a retrospective magnetic resonance imaging (MRI) study of cortical iron deposition (CID) in 158 patients with mild cognitive impairment (MCI), 48 with Alzheimer’s disease (AD), and 73 with normal cognition, measured using neuronal network-based quantitative susceptibility mapping (QSMnet). Susceptibility in the frontal, temporal, parietal, occipital, and cingulate cortices was higher in patients with MCI and AD than that in the controls [ 1 ]. Susceptibility in the cingulate and insular cortices was found to be an independent predictor of Mini Mental Status Examination [ 1 ].…”