Advanced measures of cortical microstructural change and associations with cognitive and blood‐based biomarkers in autosomal dominant Alzheimer’s disease

Abstract

AbstractBackgroundIn Alzheimer’s disease (AD), dysfunction and loss of cortical neurons occurs prior to symptom onset. Diffusion tensor imaging, measuring mean diffusivity (MD), provides a metric of microscopic change but lacks specificity for different underlying microstructural processes. We used Neurite Orientation Dispersion and Density Imaging (NODDI) to investigate specific cortical microstructural features across the disease course in autosomal dominant AD (ADAD).MethodSixty‐three ADAD family members (36 mutation carriers) (Table 1) underwent T1w and multi‐shell diffusion MRI (dMRI). Cortical thickness and cortical MD were estimated, with NODDI providing measures of tissue fraction (TF), neurite density index (NDI) and orientation dispersion index (ODI) (a proxy measure of dendritic complexity). Imaging metrics were sampled across six cortical regions of interest (ROIs) known to be particularly vulnerable to early neurodegeneration. Associations between dMRI measures and 1) disease stage as measured by estimated years to onset (EYO), 2) AD blood biomarkers, and 3) cognitive measures were assessed.ResultAcross mutation carriers, ODI (Figure 1) and TF (Figure 2) demonstrated negative associations (p<0.05) with EYO in most ROIs, while MD demonstrated positive correlations. Most associations remained after adjusting for cortical thickness. The association between ODI and EYO in the supramarginal gyrus also remained after adjustment for MD (p = 0.002). In presymptomatic carriers, EYO appeared most prominently associated with ODI (p<0.05 in 3/6 regions). ODI, TF and MD showed widespread associations with MMSE and CDR sum of boxes. TF was negatively, and MD positively, associated with serum NfL across ROIs, but for ODI this was only the case in the supramarginal gyrus. ptau181 demonstrated significant associations with ODI in the supramarginal (p = 0.0089) and inferior parietal (p = 0.033) cortices, and with MD in the entorhinal cortex (p = 0.015).ConclusionCortical dendritic complexity (modelled by ODI) and cortical tissue fraction decrease, while overall diffusivity increases as individuals approach symptom onset. ODI appears to be the metric most closely associated with presymptomatic disease stage, possibly reflecting early dendritic pruning, and is associated with ptau – a measure of early pathology – while MD and TF may be more sensitive to later larger scale changes, given their associations with serum NfL and cognitive measures.