Postmortem MRI and histology demonstrate differential iron accumulation and cortical myelin organization in early- and late-onset Alzheimer's disease

Abstract

Previous MRI studies reported cortical iron accumulation in early-onset (EOAD) compared to late-onset (LOAD) Alzheimer disease patients. However, the pattern and origin of iron accumulation is poorly understood. This study investigated the histopathological correlates of MRI contrast in both EOAD and LOAD. T2*-weighted MRI was performed on postmortem frontal cortex of controls, EOAD, and LOAD. Images were ordinally scored using predefined criteria followed by histology. Nonlinear histology-MRI registration was used to calculate pixel-wise spatial correlations based on the signal intensity. EOAD and LOAD were distinguishable based on 7T MRI from controls and from each other. Histology-MRI correlation analysis of the pixel intensities showed that the MRI contrast is best explained by increased iron accumulation and changes in cortical myelin, whereas amyloid and tau showed less spatial correspondence with T2*-weighted MRI. Neuropathologically, subtypes of Alzheimer's disease showed different patterns of iron accumulation and cortical myelin changes independent of amyloid and tau that may be detected by high-field susceptibility-based MRI.

Gray matter T1‐w/T2‐w ratios are higher in Alzheimer's disease

“…Another possibility is remyelination (Peters, ), which has also been suggested by a recent study by Bulk et al (). Using a combined post mortem T2*w MRI with histology, the authors showed an unexpected increase in cortical myelin staining in late stage AD (Bulk et al, ). The increase in myelin density did show a more disorganized cortical myelin architecture compared to controls.…”

“…Note however, that Bulk et al (2018), and multiple other studies (Ayton et al, 2019;Connor, Snyder, Beard, Fine, & Mufson, 1992;Ward, Zucca, Duyn, Crichton, & Zecca, 2014;Zecca, Youdim, Riederer, Connor, & Crichton, 2004), also demonstrated increased iron accumulation in AD. T2-w sequences are known to be highly sensitive to iron deposits, and so the T1-w/T2-w ratio may reflect the presence of both processes (Dusek, Dezortova, & Wuerfel, 2013).…”

“…Possibly, adequate intracortical myelin plasticity may initially compensate for the subcortical transmission delays along WM subcortical fibers, but eventually during the disease course significant intracortical oligodendrocyte deficits develop. Note however, that Bulk et al (), and multiple other studies (Ayton et al, ; Connor, Snyder, Beard, Fine, & Mufson, ; Ward, Zucca, Duyn, Crichton, & Zecca, ; Zecca, Youdim, Riederer, Connor, & Crichton, ), also demonstrated increased iron accumulation in AD. T2‐w sequences are known to be highly sensitive to iron deposits, and so the T1‐w/T2‐w ratio may reflect the presence of both processes (Dusek, Dezortova, & Wuerfel, ).…”

Treating Alzheimer's disease by targeting iron

“…Iron levels in the brain accumulate with age (Aquino et al, 2009), which may engender risk of disease. In AD, cortical iron levels are elevated beyond the already high levels that occur during age, as measured by various methods in post-mortem tissue (Andrasi, Farkas, Scheibler, Reffy, & Bezur, 1995;Bulk et al, 2017;Bulk et al, 2018;Collingwood et al, 2005;Connor, Menzies, St Martin, & Mufson, 1992;De Reuck et al, 2014;Duce et al, 2010;Galazka-Friedman et al, 2011;Goodman, 1953;Hallgren & Sourander, 1960;Smith et al, 2010;Smith, Harris, Sayre, & Perry, 1997;van Duijn et al, 2017).…”

Testing relationships between multimodal modes of brain structural variation and age, sex and polygenic scores for neuroticism in children and adolescents

“…Although cholesterol in myelin is a major determinant of T1-weighted signal intensity 69,70 , so in part is iron, water content and dendrite density [71][72][73] . While cortical GM intensity corresponds closely with histologically based myelin profiles 74 , GWC is microstructurally complex and a product of GM and WM.…”