Biological plausibility of single-shell NODDI-DTI in non-demented older adults: associations with plasma biomarkers and follow-up cognition.

Background: White matter (WM) degeneration is increasingly recognized as a major feature of aging and neurodegenerative disorders, such as Alzheimer's disease (AD). NODDI-DTI is a technique that allows the estimation of neurite density index (NDI) and orientation dispersion index (ODI) in white matter from single-shell diffusion tensor imaging. However, it should be interpreted as a tensor-derived approximation and biological support for these metrics is needed. This study aimed to provide multimodal evidence supporting the biological plausibility of NODDI-DTI estimates. Methods: Demographic, clinical and single-shell DWI data from 42 older adults without dementia were obtained from the Alzheimer's Disease Neuroimaging Initiative database. We tested associations between NODDI-DTI metrics by performing (i) an exploratory voxel-wise analysis to characterize the spatial distribution and the percentage of statistically significant associations across the white matter (ii) and a tract-based analyses in a priori AD-vulnerable white matter tracts. Finally, we conducted longitudinal analyses to test whether baseline NODDI-DTI metrics and plasma biomarkers were associated with follow-up Montreal Cognitive Assessment (MoCA) performance. Results: Among the investigated plasma biomarkers, pTau181 was the only biomarker showing widespread significant associations with diffusion metrics, with a substantially more extensive effect for NDI. In the tract-based analyses, higher plasma concentrations of pTau181 were associated mainly with lower NDI in the fornix, inferior fronto-occipital fasciculus and uncinate fasciculus. Higher plasma concentrations of NfL were associated with lower NDI in the fornix, together with opposite ODI effects in the splenium of the corpus callosum and uncinate fasciculus. In the subgroup with follow-up MoCA available, higher baseline ODI in the hippocampal cingulum and higher baseline pTau181 were both independently associated with worse cognitive performance. Conclusions: These findings suggest that NODDI-DTI may represent a biologically plausible and clinically informative approach to study early WM microstructure, with potential prognostic relevance for subsequent cognitive performance, particularly when full multi-shell acquisitions are not feasible or not available.