Microstructural Alterations in Hippocampal Subfields Mediate Age-Related Memory Decline in Humans.

Hamsanandini Radhakrishnan,Shauna M Stark,Craig E L Stark

doi:10.3389/fnagi.2020.00094

Abstract

Aging, even in the absence of clear pathology of dementia, is associated with cognitive decline. Neuroimaging, especially diffusion-weighted imaging, has been highly valuable in understanding some of these changes in live humans, non-invasively. Traditional tensor techniques have revealed that the integrity of the fornix and other white matter tracts significantly deteriorates with age, and that this deterioration is highly correlated with worsening cognitive performance. However, traditional tensor techniques are still not specific enough to indict explicit microstructural features that may be responsible for age-related cognitive decline and cannot be used to effectively study gray matter properties. Here, we sought to determine whether recent advances in diffusion-weighted imaging, including Neurite Orientation Dispersion and Density Imaging (NODDI) and Constrained Spherical Deconvolution, would provide more sensitive measures of age-related changes in the microstructure of the medial temporal lobe. We evaluated these measures in a group of young (ages 20–38 years old) and older (ages 59–84 years old) adults and assessed their relationships with performance on tests of cognition. We found that the fiber density (FD) of the fornix and the neurite density index (NDI) of the fornix, hippocampal subfields (DG/CA3, CA1, and subiculum), and parahippocampal cortex, varied as a function of age in a cross-sectional cohort. Moreover, in the fornix, DG/CA3, and CA1, these changes correlated with memory performance on the Rey Auditory Verbal Learning Test (RAVLT), even after regressing out the effect of age, suggesting that they were capturing neurobiological properties directly related to performance in this task. These measures provide more details regarding age-related neurobiological properties. For example, a change in fiber density could mean a reduction in axonal packing density or myelination, and the increase in NDI observed might be explained by changes in dendritic complexity or even sprouting. These results provide a far more comprehensive view than previously determined on the possible system-wide processes that may be occurring because of healthy aging and demonstrate that advanced diffusion-weighted imaging is evolving into a powerful tool to study more than just white matter properties.

Highlights

Decades of research have shown that, even outside of overt pathology or dementia, aging is associated with cognitive decline, such as decreases in processing speed, poorer divided attention, and episodic memory impairments (Johnson, 1997; Schacter et al, 1997; Glisky, 2007; Eckert, 2011)
With connectivity-based fixel enhancement (CFE) statistics, we found that the fiber density (FD) of the fornix was significantly lower in the older adults (t = 5.959; p < 0.0001) and that FD decreased linearly with age in the older adults alone (R2 = 0.3638, p = 0.0023; Figure 2C)
These changes were correlated with poorer Rey Auditory Verbal Learning Test (RAVLT) performance, suggesting that age-related microstructural deterioration of the fornix may play a role in age-related cognitive decline

Summary

Introduction

Decades of research have shown that, even outside of overt pathology or dementia, aging is associated with cognitive decline, such as decreases in processing speed, poorer divided attention, and episodic memory impairments (Johnson, 1997; Schacter et al, 1997; Glisky, 2007; Eckert, 2011). Human imaging studies have shown that the hippocampal volume decreases after the age of 70 at a rate of approximately 1.5% a year (Jack et al, 1998; Raz et al, 2005) This reduction could be due to synaptic size reduction (Petralia et al, 2014), microglia decrease (Sharaf et al, 2013), demyelination (Peters, 2002; Kövari et al, 2004) and/or other changes in connectivity (Fjell et al, 2016). Aging results in axonal degeneration of the fornix and other white matter pathways, due to loss of myelinated fibers and alterations in the myelin sheath (Peters et al, 2010; Salvadores et al, 2017). New neuroimaging techniques may prove to be valuable tools for investigating these age-related alterations in vivo in the human brain

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