Age-related alterations in axonal microstructure in the corpus callosum measured by high-gradient diffusion MRI

Abstract

Cerebral white matter exhibits age-related degenerative changes during the course of normal aging, including decreases in axon density and alterations in axonal structure. Noninvasive approaches to measure these microstructural alterations throughout the lifespan would be invaluable for understanding the substrate and regional variability of age-related white matter degeneration. Recent advances in diffusion magnetic resonance imaging (MRI) have leveraged high gradient strengths to increase sensitivity toward axonal size and density in the living human brain. Here, we examined the relationship between age and indices of axon diameter and packing density using high-gradient strength diffusion MRI in 36 healthy adults (aged 22-72) in welldefined central white matter tracts in the brain. A recently validated method for inferring the effective axonal compartment size and packing density from diffusion MRI measurements acquired with 300 mT/m maximum gradient strength was applied to the in vivo human brain to obtain indices of axon diameter and density in the corpus callosum, its sub-regions, and adjacent anterior and posterior fibers in the forceps minor and forceps major. The relationships between the axonal metrics, corpus callosum area and regional gray matter volume were also explored. Results revealed a significant increase in axon diameter index with advancing age in the whole corpus callosum. Similar analyses in sub-regions of the corpus callosum showed that age-related alterations in axon diameter index and axon density were most pronounced in the genu of the corpus callosum and relatively absent in the splenium, in keeping with findings from previous histological studies. The significance of these correlations was mirrored in the forceps minor and forceps major, consistent with previously reported decreases in FA in the forceps minor but not in the forceps major with age. Alterations in the axonal imaging metrics paralleled decreases in

Comparative morphology of the corpus callosum across the adult lifespan in chimpanzees (Pan troglodytes) and humans

“…These histological alterations are reflected in the findings of in‐vivo diffusion MRI studies, which report a decrease in anisotropy and an increase in radial diffusion (i.e., orthogonal to the main fiber direction) in the aging corpus callosum (Hasan et al, 2009; Ota et al, 2006; Pietrasik, Cribben, Olsen, Huang, & Malykhin, 2020; Skumlien, Sederevicius, Fjell, Walhovd, & Westerhausen, 2018). In addition, studies using high‐gradient strength‐based mapping of callosal fiber architecture suggest an aging‐associated reduction in axon density (Fan et al, 2019). Morphometric assessment additionally suggests that not only the axonal composition of the corpus callosum is affected in aging, but also its midsagittal size.…”

“…strength-based mapping of callosal fiber architecture suggest an aging-associated reduction in axon density (Fan et al, 2019). Morphometric assessment additionally suggests that not only the axonal composition of the corpus callosum is affected in aging, but also its midsagittal size.…”

Age-Related Deficits in Binocular Vision Are Associated With Poorer Inhibitory Control in Healthy Older Adults

“…Recent studies also highlight the relation between disruption in white matter tracts and age-related decline in sensorimotor and cognitive processing (Fling et al, 2011;Kohama et al, 2012). For example, microstructural changes in the corpus callosum have been found in apparently healthy older adults (Fan et al, 2019), and these changes have been linked with lower performance on various cognitive tasks (Sullivan et al, 2010;Wong et al, 2017;Halliday et al, 2019). It is possible that widespread disruption of white matter, including the corpus callosum, could lead to both reduced stereopsis and inhibitory processing because efficient performance of both tasks relies on activation of distributed cortical networks within and between the hemispheres.…”

Corpus callosum morphology across the lifespan in baboons (Papio anubis): a cross-sectional study of relative mid-sagittal surface area and thickness

“…Secondly, the use of macroanatomical measures of the corpus callosum will not fully capture known age-related alteration on microstructural level. Histological and high-gradient strength diffusion-imaging studies demonstrate a decline in number and density of small myelinated axons (Fan et al, 2019; Hou & Pakkenberg, 2012; Køster et al, 2018) as well as a degeneration of axonal myelin sheaths (Bowley et al, 2010; Peters & Sethares, 2002) in old aged human and other primates. Combined histological and morphological analyses also report that the midsagittal area is a good predictor of the number of myelinated axons in the corpus callosum (Hou & Pakkenberg, 2012; Riise & Pakkenberg, 2011).…”

“…Thus, it appears little surprising that human neuroimaging studies report an association of individual differences in corpus callosum morphology with differences in higher cognitive abilities (e.g., Danielsen et al, 2020; Dunst, Benedek, Koschutnig, Jauk, & Neubauer, 2014; Hulshoff-Pol et al, 2006; Luders et al, 2007; Westerhausen et al, 2018). In the aging brain, however, these functions of the corpus callosum are affected by a progressive degeneration of callosal axons, evidenced by a reduction in number and density of small myelinated axons (Fan et al, 2019; Hou & Pakkenberg, 2012; Køster, Jesper, & Bente, 2018; Lynn et al, 2020). Diffusion MRI studies, likely reflecting these axonal alterations, find a decrease in fractional anisotropy and an increase in radial diffusivity in older age (e.g., Hasan et al, 2009; Ota et al, 2006; Pietrasik, Cribben, Olsen, Huang, & Malykhin, 2020; Skumlien, Sederevicius, Fjell, Walhovd, & Westerhausen, 2018).…”