AXONAL DENSITY AND MYELIN INTEGRITY IN COGNITIVE DECLINE: A DIFFUSIONAL KURTOSIS IMAGING STUDY

Abstract

Age-related changes in brain white matter have been associated with cognitive decline and Alzheimer's disease. Here, with advanced biophysical modeling of Diffusional Kurtosis Imaging (DKI) data (Fig. 1), we test the hypothesis that cognitively intact older adults who demonstrate cognitive decline over 15 months (i.e. “Decliners”) already demonstrate a more pronounced loss of axonal density and myelin integrity at baseline compared to matched controls (i.e. “Controls”). 69 cognitively intact older adults underwent neuropsychological testing and MRI (Siemens 3T TIM Trio), with a subset (n=39) completing the same procedures at follow-up 14.8 ± 3.3 months later. Of these subjects, 6 demonstrated declines on cognitive testing, i.e. “Decliners” had ≦-0.5 z-score decline in memory and at least 1 other UDS test normed for age). 12 “Controls” were selected to match these “Decliners;” these groups did not differ on baseline neuropsychological performance or several other health variables (Table 1). DKI protocol: 2.5 mm3 voxels, 3 b-values (0, 1000, 2000 s/mm2), 64 directions, 1 average. DKI data were processed using Diffusional Kurtosis Estimator to derive metrics of axonal density (i.e. axonal water fraction [AWF]) and myelin integrity (i.e. extra-axonal diffusivity in the radial direction [De_radial]). Voxelwise analysis of AWF and De_radial were performed with tract-based spatial statistics in FSL (5,000 permutations and threshold-free cluster enhancement to correct for familywise error). Using FSL's randomise, we tested whether these groups differed in AWF and De_radial, covarying for age. Contrary to the expected “accelerated aging” effect of pronounced loss of axonal density (↓ AWF) and myelin integrity (↑ De_radial) in Decliners, we found higher AWF in Decliners versus Controls along the corpus callosum and in the right temporal lobe (p<0.05), and lower De_radial in Decliners versus Controls (p=0.07) in the genu of the corpus callosum (Fig. 2). These results suggest that individuals at greatest risk for cognitive decline may demonstrate greater axonal density for enhanced inter-hemispheric processing and compensatory scaffolding in the right temporal lobe. This finding is one of the first diffusion MRI-based studies to corroborate the well-established compensation theories of cognitive aging described in the fMRI and cognitive neuroscience literature. Panel A: The WM model assumes that in highly aligned WM tracts, diffusion occurs in non- exchanging compartments: the intra-axonal space (red) and the extra-axonal (blue) space. Panel B: Diffusion parallel to the direction of axons is measured by the metrics extra-axonal diffusivity, axial (De,||) and intra-axonal diffusivity (Daxon). Panel C: A cross-sectional image of a fiber bundle with myelinated axons. Panel D: Diffusion perpendicular to the axons is measured by the metric extra-axonal diffusivity, radial (De,⊥).