High field magnetic resonance microscopy of the human hippocampus in Alzheimer's disease: Quantitative imaging and correlation with iron

Abstract

We report R2 and R2* in human hippocampus from five unfixed post-mortem Alzheimer’s disease (AD) and three age-matched control cases. Formalin-fixed tissues from opposing hemispheres in a matched AD and control were included for comparison. Imaging was performed in a 600 MHz (14T) vertical bore magnet at MR microscopy resolution to obtain R2 and R2* (62 μm × 62 μm in-plane, 80 μm slice thickness), and R1 at 250 μm isotropic resolution. R1, R2 and R2* maps were computed for individual slices in each case, and used to compare subfields between AD and controls. The magnitudes of R2 and R2* changed very little between AD and control, but their variances in the Cornu Ammonis and dentate gyrus were significantly higher in AD compared for controls (p < 0.001). To investigate the relationship between tissue iron and MRI parameters, each tissue block was cryosectioned at 30 μm in the imaging plane, and iron distribution was mapped using synchrotron microfocus X-ray fluorescence spectroscopy. A positive correlation of R2 and R2* with iron was demonstrated. While studies with fixed tissues are more straightforward to conduct, fixation can alter iron status in tissues, making measurement of unfixed tissue relevant. To our knowledge, these data represent an advance in quantitative imaging of hippocampal subfields in unfixed tissue, and the methods facilitate direct analysis of the relationship between MRI parameters and iron. The significantly increased variance in AD compared for controls warrants investigation at lower fields and in-vivo, to determine if this parameter is clinically relevant.

The role of iron in brain ageing and neurodegenerative disorders

“…MRI scans of post-mortem human brains and a mouse model of Alzheimer’s disease show decreases in hippocampal T 2 * MRI, which is sensitive to the magnetic properties of iron 86,87 or its spatial variance, attributed in part to iron in Aβ plaques. 88–90 Although MRI resolution is not sufficient to detect individual plaques, T 2 * abnormalities that result from plaque aggregates might be detected with MRI. When clearly distinguished from potential confounders originating from haem iron, changes in hippocampal T 2 *-weighted MRI might be a valuable accompaniment to morphological changes in the development of a biomarker for the early stages of Alzheimer’s disease.…”

Is early-life iron exposure critical in neurodegeneration?

“…74 Alzheimer disease (AD) has also been associated with disrupted iron metabolism in the brain, and iron accumulates in the rims of amyloid-β (Aβ) plaques 75 and in neurofibrillary tangles. 76 Despite some suggestion of citation bias with respect to iron accumulation in AD, 77 several studies [78][79][80][81] have confirmed that iron levels are elevated in various brain regions in this disease. Cortical accumulation of iron has also been identified in acute relapses of multiple scler osis; paradoxically, however, iron levels decrease in chronic cases.…”

No Genetic Overlap Between Circulating Iron Levels and Alzheimer’s Disease

“…Dysfunctional brain iron homeostasis is believed to play an important role in Alzheimer's disease (AD) [3]. Iron accumulation is seen in the AD postmortem brain [4] and iron content correlates with disease duration and Mini-Mental State Examination (MMSE) score [5,6]. Individuals with mild cognitive impairment (MCI) with high risk of AD, showed higher cortical iron in vivo using MRI (measured using quantitative susceptibility mapping techniques), which spatially co-localized with A␤ plaques and correlated with higher plaque load [7].…”