Age-related magnetic susceptibility changes in deep grey matter and cerebral cortex of normal young and middle-aged adults depicted by whole brain analysis

Abstract

Background: Iron accumulates in brain tissue in healthy subjects during aging. Our goal was to conduct a detailed analysis of iron deposition patterns in the cerebral deep grey matter and cortex using region-based and whole-brain analyses of brain magnetic susceptibility. Methods: Brain MRI was performed in 95 healthy individuals aged between 21 and 58 years on a 3T scanner. MRI protocol included T1-weighted (T1W) magnetization-prepared rapid acquisition with gradient echo images and 3D flow-compensated multi-echo gradient-echo images for quantitative susceptibility mapping (QSM). In the region-based analysis, QSM and T1W images entered an automated multi-atlas segmentation pipeline and regional mean bulk susceptibility values were calculated. The whole-brain analysis included a non-linear transformation of QSM images to the standard MNI template. For the whole-brain analysis voxel-wise maps of linear regression slopes β and P values were calculated. Regional masks of cortical voxels with a significant association between susceptibility and age were created and further analyzed.Results: In cortical regions, the highest increase of susceptibility values with age was found in areas involved in motor functions (precentral and postcentral areas, premotor cortex), in cognitive processing (prefrontal cortex, superior temporal gyrus, insula, precuneus), and visual processing (occipital gyri, cuneus, posterior cingulum, fusiform, calcarine and lingual gyrus). Thalamic susceptibility increased until the fourth decade and decreased thereafter with the exception of the pulvinar where susceptibility increase was observed throughout the adult lifespan. Deep grey matter structures with the highest increase of susceptibility values with age included the red nucleus, putamen, substantia nigra, dentate nucleus, external globus pallidus, caudate nucleus, and the subthalamic nucleus in decreasing order.Conclusions: Accumulation of iron in basal ganglia follows a linear pattern whereas in the thalamus, pulvinar, precentral cortex, and precuneus, it follows a quadratic or exponential pattern. Age-related changes of iron content are different in the pulvinar and the rest of the thalamus as well as in internal and external globus pallidus. In the cortex, areas involved in motor and cognitive functions and visual processing show the highest iron increase with aging. We suggest that the departure from normal patterns of regional brain iron trajectories during aging may be helpful in the detection of subtle neurodegenerative and neuroinflammatory processes.

Oxidative Stress Markers in Cerebrospinal Fluid of Newly Diagnosed Multiple Sclerosis Patients and Their Link to Iron Deposition and Atrophy

“…Healthy controls (HC) for brain MRI were recruited from the general community [ 15 ]. The controls were free of neurologic or other medical disorders affecting brain health and had a normal neurological examination.…”

“…MRI examination was performed and processed as previously published [ 15 ]: Magnetization Prepared Rapid Gradient-Echo (MPRAGE, TE: 2.96 ms, TI 900 ms TR: 2300 ms, spatial resolution: 1 × 1 × 1 mm), gradient-echo (GRE, 6 TEs: 4.5–29.5 ms, evenly spaced, TR: 33 ms, spatial resolution: 0.94 × 0.94 × 0.94 mm), and Fluid-Attenuated Inversion Recovery (FLAIR, TE 397 ms, TI 1800 ms, TR 5000 ms, spatial resolution 1 × 1 × 1 mm) pulse sequences were acquired on a 3T MRI scanner (Siemens Skyra 3T, Siemens Healthcare, Erlangen, Germany) with a 20 channel head coil.…”

Cerebral Iron Deposition in Neurodegeneration

“…Fe accumulation with age predominantly takes place in basal ganglia and other brain regions concerned with motor functions. During adult lifespan, the steepest accumulation is observed in the red nucleus, substantia nigra (SN), and putamen [7,8]. Whole-brain MRI studies showed that, in addition to the deep gray matter, precentral, prefrontal, and occipital cortices involved in motor, cognitive, and visual function also accumulate iron with aging [7,9] (Table 1).…”

“…During adult lifespan, the steepest accumulation is observed in the red nucleus, substantia nigra (SN), and putamen [7,8]. Whole-brain MRI studies showed that, in addition to the deep gray matter, precentral, prefrontal, and occipital cortices involved in motor, cognitive, and visual function also accumulate iron with aging [7,9] (Table 1). Glial cells (astrocytes, oligodendrocytes, microglia) contain higher Fe concentrations than neurons whereby astrocytes are the primary Fe homeostatic cells in the central nervous system.…”

“…Aging ↑ serum ferritin [53] ↑ Fe in red nucleus, putamen, substantia nigra, dentate nucleus, globus pallidus, caudate nucleus, subthalamic nucleus, cortex [7] Fe remains stable in oligodendroglia; Fe accumulates in astrocytes and dystrophic microglia in cortex and deep gray matter [12] Fe bound to ferritin in cytoplasm of microglia and astrocytes and to neuromelanin in neurons [12,28] AceruloplasMinemia ↑ Fe in liver, pancreas, retina ↑ serum ferritin, ↓ transferrin saturation [54,55] ↑ Fe in putamen, caudate, lateral, habenular, and pulvinar thalamic nuclei, red nucleus, dentate nucleus, inner cortical layers, hippocampus, mammillary bodies, superior and inferior colliculi [56,57] ↑ Fe in astrocytes, neurons [58][59][60] Fe stored in ferritin/ hemosiderin in lysosomal dense bodies and cytoplasmic inclusions [61,62] Hereditary Ferritinopathy ↑ Fe in liver, kidney, skin, muscle ↓ serum ferritin [63][64][65] ↑ Fe in globus pallidus, substantia nigra, dentate nucleus, putamen, thalamus, caudate, deep cortical layers [66][67][68] ↑ Fe in nuclei and cytoplasm of microglia, oligodendroglia, neurons, and also extracellularly [64,69] Fe stored in inclusion bodies consisting of abnormal ferritin aggregates [69,70] Pantothenate Kinase-Associated Neurodegeneration -↑ Fe in globus pallidus, substantia nigra [71][72][73][74] ↑ Fe in astrocytes, neurons, perivascular macrophages, iron dust in neuropil [75,76] Fe stored in cytoplasmic inclusions co-localized with ferritin [75] Mitochondrial Membrane Protein-Associated Neurodegeneration -↑ Fe in globus pallidus, substantia nigra, putamen, caudate [77,78] ↑ Fe in perivascular macrophages, astrocytes, neurons…”