Fixel-based and tensor-derived white matter abnormalities in relation to memory impairment and neurocognitive disorders

Abstract

Aging-related neurocognitive disorders, including Alzheimer's disease (AD) and mild cognitive impairment (MCI), have been characterised by altered brain white matter (WM), relying widely on diffusion tensor imaging (DTI). DTI's limited accuracy in assessing crossing fibres prompted novel methods that distinguish fibres crossing through same voxel-spaces, such as fixel-based analysis (FBA), highlighting subtle macrostructural and microstructural alterations in AD and MCI. We examined the FBA and DTI's specificity in determining WM features relevant to memory in the neurocognitive aging spectrum. Diffusion-weighted images were analysed in 560 participants with various neurocognitive diagnoses from the Alzheimer's Disease Neuroimaging Initiative (F:297; mean age: 73.2 ± 8). Verbal memory was measured in 488 participants using the Rey Auditory Verbal Learning Test. FBA-derived measures of fibre density (FD), fibre-bundle cross-section (FC), and their combination (FDC), DTI fractional anisotropy (FA) and mean diffusivity (MD) were examined in relation to diagnoses and memory scores, controlling for age, sex, and intracranial volume. MCI and AD groups significantly differed from controls, with lower FD and FDC in the fornix and bilateral fibres extending to the medial temporal lobes (MTL). Memory was positively associated with FD and FDC in the fornix and MTL fibres, and FC in the anterior commissure (AC). Widespread FA reductions and MD increases were observed in AD and MCI and widely associated with memory. Fixel-wise measures highlight fibre tracts that are altered distinctly at the macroscopic and microscopic level in neurocognitive aging, and reveals structures associated with memory performance that are more specifically located than tensor-derived measures.

Keywords: Aging; Alzheimer’s; Fixel-based; Memory; Mild cognitive impairment; White matter.

Fig. 1

Fixel mask overlaid on the white matter fibre orientation distribution template. Note. Displayed using mrview tool in MRTRIX3 [20]

Fig. 2

Scores from selected subtests of the Rey Auditory Verbal Learning Test. Note. AD, Alzheimer’s disease; MCI, mild cognitive impairment; SMC, subjective memory complaint; CN, cognitively normal

Fig. 3

Confirmatory factor analysis (CFA) estimating the memory composite score. Note. Plotted using the R package ‘onyxR’ [36]. AVDEL30MIN, 30-min delay recall; AVDELTOT, recognition

Fig. 4

Fixel-based measures compared across controls and clinical subgroups and associated with memory. Note. Fixels where effect is significant at p_FWE < .05. AD, Alzheimer’s disease; CN, Cognitively normal; FD, fibre density; FDC, combined measure of FD and FC; FC, fibre-bundle cross-section. Red to yellow scales is an increase compared to controls and blue to white a decrease

Fig. 5

Differences in tensor-derived measures across controls and clinical subgroups and association with memory. Note. AD, Alzheimer’s disease; CN, cognitively normal; MCI, mild cognitive impairment; FA, fractional anisotropy; MD, mean diffusivity. The white matter skeleton (white) is plotted on the MNI152 standard space. Tracts associated with memory at p_FWE < .05 are coloured: a and b red-to-yellow for significant increase and dark-to-light blue for significant decrease compared to controls c red-to-yellow for significantly positive FA association and dark-to-light blue for significantly negative MD association