MRI and histological analysis of beta‐amyloid plaques in both human Alzheimer's disease and APP/PS1 transgenic mice

Abstract

Purpose: To investigate the relationship between MR image contrast associated with beta-amyloid (A␤) plaques and their histology and compare the histopathological basis of image contrast and the relaxation mechanism associated with A␤ plaques in human Alzheimer's disease (AD) and transgenic APP/PS1 mouse tissues. Materials and Methods:With the aid of the previously developed histological coil, T* 2 -weighted images and R* 2 parametric maps were directly compared with histology stains acquired from the same set of Alzheimer's and APP/ PS1 tissue slices. Results:The electron microscopy and histology images revealed significant differences in plaque morphology and associated iron concentration between AD and transgenic APP/PS1 mice tissue samples. For AD tissues, T* 2 contrast of A␤-plaques was directly associated with the gradation of iron concentration. Plaques with significantly less iron load in the APP/PS1 animal tissues are equally conspicuous as the human plaques in the MR images. Conclusion:These data suggest a duality in the relaxation mechanism where both high focal iron concentration and highly compact fibrillar beta-amyloid masses cause rapid proton transverse magnetization decay. For human tissues, the former mechanism is likely the dominant source of R* 2 relaxation; for APP/PS1 animals, the latter is likely the major cause of increased transverse proton relaxation rate in A␤ plaques. The data presented are essential for understanding the histopathological underpinning of MRI measurement associated with A␤ plaques in humans and animals. THE FORMATION OF amyloid-beta (A␤) plaques is a neuropathological hallmark and a cardinal feature of Alzheimer's disease (AD). APP/PS1 transgenic mouse models that mimic the formation of human A␤ plaques in the mouse brain are widely used as an animal model for AD investigations. The development of an imaging technology capable of visualizing and quantifying A␤ plaques in animal models and in the AD brain is critically important for translational, preclinical and clinical research. The ability to delineate A␤ plaques with MRI has been demonstrated ex vivo with human brain samples (1) and in vivo with the mouse model (2-4). Understanding the histological basis of MRI contrast associated with A␤ plaques is essential in this endeavor. To achieve this goal, it is necessary to correlate MRI results with histological stains, which has been technologically challenging because of the limitations in co-registration of planar histology tissue samples with MR images. A prior study involving the innovation of a histological coil has addressed this long-standing difficulty (5). The ability to directly image histological samples is possible when using the developed histological radiofrequency (RF) coil design. Consequently, MR images and histology data from the same tissue sample can be directly overlaid and compared without uncertainties of co-registration between the two imaging modalities. The goal of the current study is to use this novel technology to (i) further optimize the m...

Cortical phase changes in Alzheimer's disease at 7T MRI: A novel imaging marker

“…Similar patterns have been described in studies of AD transgenic mice and postmortem human AD cases, and were attributed to the presence of amyloid plaques using histological confirmation [11][12][13][14][15][16][17][18][19]. It has been proposed that the visualization on MRI of plaques in humans and mice is based on the fact that these deposits colocalize with iron, which gives rise to magnetic susceptibility effects on T2*-weighted images over volumes that are much larger than the actual size of amyloid plaques [17,[19][20][21][22][23][24]. An alternative method to measure these susceptibility changes in the brain is to measure the relative phase in regions of interest (ROIs), because it has been shown that this is a reliable indicator of the iron content in the brain [25][26][27][28].…”

“…These features included hypointense foci and diffuse granular patterns of less distinct hypointense foci in the cerebral cortex [10]. Similar patterns have been described in studies of AD transgenic mice and postmortem human AD cases, and were attributed to the presence of amyloid plaques using histological confirmation [11][12][13][14][15][16][17][18][19]. It has been proposed that the visualization on MRI of plaques in humans and mice is based on the fact that these deposits colocalize with iron, which gives rise to magnetic susceptibility effects on T2*-weighted images over volumes that are much larger than the actual size of amyloid plaques [17,[19][20][21][22][23][24].…”

Comparison of Histological Techniques to Visualize Iron in Paraffin-embedded Brain Tissue of Patients with Alzheimer’s Disease

“…Earlier studies showed plaques using this method on 60-to 100-µm free-floating sections (LeVine 1997;Meadowcroft et al 2009) and iron-containing microglia in multiple sclerosis brains (LeVine 1997). No results of iron in layers IV/V have been reported using this method.…”

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…Iron elevation in AD brains, first demonstrated in 1953 [99], is a consistently reported finding [99][100][101][102][103][104][105][106][107][108]. Neuronal iron deposition causes oxidative stress via the Fenton reaction, which might contribute to elevated oxidative stress observed in the AD brain [109].…”