Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease

Abstract

Although amyloid plaques and neurofibrillary pathology play important roles in Alzheimer disease (AD), our understanding of AD is incomplete, and the contribution of microglia and iron to neurodegeneration is unknown. High-field magnetic resonance imaging (MRI) is exquisitely sensitive to microscopic iron. To explore iron-associated neuroinflammatory AD pathology, we studied AD and control human brain specimens by (1) performing ultra-high resolution ex vivo 7 Tesla MRI, (2) coregistering the MRI with successive histologic staining for iron, microglia, amyloid beta, and tau, and (3) quantifying the relationship between magnetic resonance signal intensity and histological staining. In AD, we identified numerous small MR hypointensities primarily within the subiculum that were best explained by the combination of microscopic iron and activated microglia (p = 0.025), in contradistinction to the relatively lesser contribution of tau or amyloid. Neuropathologically, this suggests that microglial-mediated neurodegeneration may occur in the hippocampal formation in AD and is detectable by ultra-high resolution MRI.

Family History of Alzheimer’s Disease and Cortical Thickness in Patients With Dementia

“…33 Recent data from an ultrahigh-field MRI postmortem study suggest microscopic iron and activated microglia specifically in the SUB of patients with AD, consistent with spreading neurodegeneration along entorhinal projections to the hippocampus. 34,35 It shows that innovative MRI techniques contribute to our understanding of AD-associated pathology and its subregional effects on medial temporal lobe integrity. Recent animal data show that the SUB is the earliest hippocampal region showing severe neuronal loss in a mice model of AD 36 and that subicular neuron damage could be related to AD through neuroinflammatory pathways.…”

Seven-Tesla MRI and neuroimaging biomarkers for Alzheimer’s disease

“…Microglia are immune cells of the nervous system, and a compelling series of studies has implicated them in the pathogenesis of AD. 22,23,28,29,33,34,59,79,103 In a recent study by Zeineh et al, conspicuous focal hypointensities were found in the hippocampus, and specifically in the subiculum (a peripheral subregion of the hippocampus), in 4 out of 5 advanced AD specimens, but not in any of the controls 102 (Fig. 3).…”

“…3). 102 Standardization of anatomy should facilitate greater ease of communication for further research into atrophy during AD, especially during the early stages of AD when only very specific regions of the hippocampus are involved. With the continuous advancement in imaging hardware and reconstruction software, as well as the use of simultaneous multislice techniques, it is now possible to achieve high in vivo resolutions comparable to the current ex vivo resolutions, in clinically feasible times.…”

Iron chelation in the treatment of neurodegenerative diseases

“…While total cortical iron levels may be unaltered in AD [137], post-mortem MRI and histopathological studies showed that increased iron levels are associated with amyloid-beta (Abeta) plaques [138,139], vessel walls, and microglia [140]. One of the possible sources of iron in AD are microbleeds related to cerebral amyloid angiopathy [141].…”