# Multimodal MRI Reveals Cerebral and Vascular Amyloid‐Driven Myeloarchitectural Disorganization in a Mouse Model of Alzheimer's Disease

## TL;DR

This study uses advanced MRI techniques to detect early signs of Alzheimer's disease in mice by examining brain myelin and amyloid changes.

## Contribution

A novel multimodal MRI framework is introduced to detect amyloid-driven myeloarchitectural changes in Alzheimer's disease models.

## Key findings

- Significant increases in R2* and susceptibility in the hippocampus of AD mice compared to controls.
- Region-specific changes in NOE-sensitive CEST imaging in the hippocampus, corpus callosum, and thalamus of AD mice.
- Strong Aβ plaque presence and elevated iron load in the hippocampi of AD mice confirmed via immunohistochemistry.

## Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder involving a complex interaction of cerebral and vascular amyloid‐beta (Aβ) accumulation, myelin disruption, lipid alterations, and cerebrovascular dysfunction. The early detection and differentiation of these interconnected pathologies remain challenging. To understand the effect of cerebral and vascular Aβ on regional myeloarchitecture and lipid composition, we developed a novel multimodal neuroimaging approach integrating quantitative MRI (qMRI), chemical exchange saturation transfer (CEST) MRI, and immunohistochemistry (IHC). The framework was applied to a 10‐month‐old mouse model exhibiting both cerebral and vascular amyloid pathologies. High‐resolution in vivo MRI was performed using a 9.4 Tesla scanner. The results suggest region‐specific vulnerability to Aβ pathology with significant regional increases in apparent transverse relaxation rate (R2*, p < 0.05; Hedges' g = 1.22) and quantitative susceptibility mapping (χ, p < 0.01; Hedges' g = 1.99) within the hippocampus of ARTE10 mice compared to wild‐type littermates. Multislice CEST‐based Z‐spectra were used with multipool Lorentzian fitting and quantitative T1 longitudinal relaxation maps to obtain nuclear Overhauser enhancement (NOE) weighted apparent exchange‐dependent relaxation (AREX) maps. NOE (−3.5 ppm)‐sensitive CEST imaging contrast showed region‐specific changes in the hippocampus (p < 0.01; Hedges' g = −1.81), corpus callosum (p < 0.01; Hedges' g = −2.39), and thalamus (p < 0.01; Hedges' g = −2.64) of ARTE10 animals relative to WT littermates. Hippocampal Aβ burden, iron load, and myelin density were quantified using immunohistochemistry, suggesting strong Aβ plaque presence and elevated iron load in the hippocampi of ARTE10 mice compared to WT mice. Collectively, our results demonstrate the utility of this multimodal MRI framework in identifying sensitive and specific biomarkers of amyloid‐driven myeloarchitectural and molecular changes. The proposed framework offers a valuable tool for enhancing early detection, understanding different pathophysiological pathways, and facilitating therapeutic monitoring and targeted intervention strategies.

This study investigates the effect of cerebral and vascular (beta‐amyloid) Aβ on regional myeloarchitecture and lipid composition in a murine model of Alzheimer's disease (AD). The study highlights the feasibility of quantitative MRI and chemical exchange saturation transfer (CEST) imaging to identify multiple biophysical mechanisms involved in pathophysiology of AD in vivo.