In Vivo MRI Mapping of Brain Iron Deposition across the Adult Lifespan

Abstract

Disruption of iron homeostasis as a consequence of aging is thought to cause iron levels to increase, potentially promoting oxidative cellular damage. Therefore, understanding how this process evolves through the lifespan could offer insights into both the aging process and the development of aging-related neurodegenerative brain diseases. This work aimed to map, in vivo for the first time with an unbiased whole-brain approach, age-related iron changes using quantitative susceptibility mapping (QSM)--a new postprocessed MRI contrast mechanism. To this end, a full QSM standardization routine was devised and a cohort of N = 116 healthy adults (20-79 years of age) was studied. The whole-brain and ROI analyses confirmed that the propensity of brain cells to accumulate excessive iron as a function of aging largely depends on their exact anatomical location. Whereas only patchy signs of iron scavenging were observed in white matter, strong, bilateral, and confluent QSM-age associations were identified in several deep-brain nuclei--chiefly the striatum and midbrain-and across motor, premotor, posterior insular, superior prefrontal, and cerebellar cortices. The validity of QSM as a suitable in vivo imaging technique with which to monitor iron dysregulation in the human brain was demonstrated by confirming age-related increases in several subcortical nuclei that are known to accumulate iron with age. The study indicated that, in addition to these structures, there is a predilection for iron accumulation in the frontal lobes, which when combined with the subcortical findings, suggests that iron accumulation with age predominantly affects brain regions concerned with motor/output functions.

Significance statement: This study used a whole--brain imaging approach known as quantitative susceptibility mapping (QSM) to provide a novel insight into iron accumulation in the brain across the adult lifespan. Validity of the method was demonstrated by showing concordance with ROI analysis and prior knowledge of iron accumulation in subcortical nuclei. We discovered that, beyond these regions, there is extensive involvement of the frontal lobes that has been missed by past ROI analyses. Broadly speaking, therefore, the motor system selectively accumulates iron with age. The results offer insights into the aging process, but also offer a new approach to studying the role of iron dysregulation in the evolution of age-related neurodegenerative diseases.

Keywords: aging; brain iron; magnetic susceptibility; neurodegenerative diseases.

Figure 1.

Summary steps of the processing pipeline (QSM calculation, spatial standardization, and analysis) for the in vivo study of brain iron. The numbering indicates the order of procedural steps.

Figure 2.

Standardized (to MNI152 space) 3T QSM of a 51-year-old subject. Dark regions reflect the strong paramagnetism returned by metallic species such as tissue iron. Globus pallidus, striatum, substantia nigra, and red nucleus are the most salient features in the QSM contrast; the cortex also displays some QSM contrast. Each panel's left side represents the true left hemisphere.

Figure 3.

Regions of interest overlaid onto the studywise average QSM template (A) and the relative variance map (B) across 116 healthy subjects. Areas of extreme QSM dispersion (dark on B) arise from poor spatial standardization and other sources of error.

Figure 4.

Bilateral and confluent landscape of iron deposition across the adult lifespan. Thresholded (p_FWE < 0.005) statistical map for the cluster-enhanced linear relationship between QSM and age in 116 healthy subjects (20–79 years old). Results were standardized to the MNI152 space and overlaid onto the MNI-normalized QSM study template. Left on the figure represents the true left.

Figure 5.

Demonstration of aging-driven QSM elevation in healthy subjects with no previous history of hypertension (or other vascular risks). A, Thresholded (p_FWE < 0.05) statistical results for the comparison of 15 elderly subjects (age: 70 ± 5 years) without a diagnosis of hypertension versus 15 healthy young subjects (age: 27 ± 4 years). B, Results (p_FWE < 0.005) for the whole-brain age regression on 116 subjects (same as in Fig. 4). Note that the statistical comparison between hypertensive and age-matched subjects with no apparent vascular risks was completely negative.

Figure 6.

Regional plots for left/right average, median QSM values as a function of age for nine deep-brain nuclei: substantia nigra, dentate nucleus, red nucleus, globus pallidus, caudate nucleus, putamen, thalamus, hippocampus, and amygdala (from greatest to lowest average QSM; Table 1). Dark circles/light squares denote female/male subjects, respectively. Linear functions were fitted to the data (thick continuous line) whether the QSM–age Pearson correlation test returned significant p values (Table 1). The thinner lines represent the simultaneous prediction bounds of the 95% confidence intervals for the linear fits.