Quantitative MRI of the hippocampus reveals microstructural trajectories of aging and Alzheimer’s disease pathology

TL;DR

This study uses MRI to track microstructural changes in the hippocampus linked to aging and Alzheimer's disease before visible atrophy occurs.

Contribution

The study introduces longitudinal in vivo mapping of hippocampal microstructure to detect early AD pathology and aging effects.

Findings

Microstructural changes like demyelination and iron deposition are early markers of aging and AD.

Quantitative MRI reveals subtle variations in hippocampal regions associated with age and AD risk.

qMRI provides insights into hippocampal health beyond traditional volumetric measures.

Abstract

Hippocampal atrophy, typically measured using volumetry, is a hallmark feature of both normal aging and Alzheimer’s disease (AD). However, the earliest stages of atrophy manifest as microstructural changes in tissue composition rather than macroscopic volume loss. We conducted longitudinal in vivo mapping of hippocampal microstructure in healthy aging and incipient AD, highlighting demyelination, iron deposition, and changes in water content as markers of age and AD risk. A combination of macrostructural and microstructural measures provides a more comprehensive picture of brain health and disease, unlocking unique insights into the pathological state of brain tissue and the impact of AD at a point where therapeutic rescue of the tissue is most likely to be efficacious.

Hippocampal degeneration is a feature of both normal aging and Alzheimer’s disease (AD). Prior to macroscopic degeneration, microstructural changes occur such as demyelination, iron deposition, or subtle atrophy, which can be characterized in vivo using MRI. We topographically mapped measures of microstructure and macrostructure across the unfolded surface of the hippocampus in 224 healthy older adults at risk for AD (aged 57 to 87) and 37 younger adults (aged 18 to 37). We describe three spatial regions of unique structural covariance between four parameters sensitive to microstructural tissue properties (R1, MTsat, R2*, PD) and macrostructure (surface thickness), with high convergence with previous spatial segmentations. We demonstrate both cross-sectional and longitudinal associations of microstructure with healthy aging across the lifespan, AD pathological hallmarks, genetic risk, and cognition. These associations had subtle variations across different spatial areas of the hippocampus. We report associations between age and qMRI measures sensitive to macromolecular concentration (R1, MTsat) and paramagnetic susceptibility (R2*), consistent with mechanisms of demyelination and increased iron deposition as key hallmarks of the aging hippocampus and in presymptomatic stages of AD. qMRI measures did not explain more variance in delayed recall than global PET measures, suggesting variation in cognitive performance in aging and incipient AD is influenced by factors beyond hippocampal microstructure. We demonstrate the utility of quantitative MRI to provide greater insight into hippocampal health compared to typical macrostructural measures through “in vivo histology,” opening a window to understanding neuropathological mechanisms in the earliest stages of age- and disease-related neurodegeneration.

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