Microstructure of White Matter, Probed With Diffusion MRI Modeling, Reveals Distinct Correlations Between Intra‐ vs Extra‐Cellular Spaces and Tau Load

Abstract

AbstractBackgroundIn Alzheimer’s disease, pathological phosphorylation of tau protein destabilizes microtubules affecting the neural cytoskeleton organization (Kolarova et al., 2012). In this study, we investigated correlates of Alzheimer’s tau pathology and white matter (WM) microstructure using diffusion MRI (dMRI) advanced models to detect tau‐related tissue changes and their trends across brain regions.MethodTen cognitively impaired subjects (age:70±7,M/F:6/4,MMSE:27.8,CI) and 11 cognitive unimpaired (age:62.4±9,M/F:1/10,CU) were recruited in the context of the COSCODE research project (Ribaldi et al., 2021). Tau standardized uptake value ratio (SUVR) was assessed from 18F‐flortaucipir PET in entorhinal, lateral‐occipital, inferior‐temporal cortex, and amygdala (reference: cerebellar crus; Mishra et al., 2017). dMRI scans were collected at 7T. WM microstructure analysis included: diffusion tensor (DTI), kurtosis tensor imaging (DKI, Jensen and Helpern, 2010), and a biophysical model of WM microstructure (WMTI‐Watson, Fig.1, Jespersen, et al., 2018). Mean values for each diffusion metric were calculated in WM ROIs of the JHU atlas (Mori et al. 2005) and correlated to tau across CI subjects (statistical significance: p<0.05).ResultCorrelation analysis showed a systematic disconnect between diffusion metrics parallel and perpendicular to the axons: RD (and MD) correlated positively with tau, while AD negatively. Similarly, RK (and MK) correlated negatively, while AK positively (Fig. 2). Higher diffusivities and lower kurtosis (perpendicular to axons) are associated with less complex tissue, while lower diffusivities and higher kurtosis (parallel to axons) are associated with a more tortuous and heterogeneous environment. The biophysical model showed that higher diffusivity in the extra‐cellular space (De,//, De, ⊥ ) was associated with higher tau, while axonal density (f) and within‐axon diffusivity (Da) correlated negatively.ConclusionThe significant correlations between tau and FA, RD, MD, RK and MK, are consistent with neurodegeneration. The positive correlation of De,//, De, ⊥ and negative correlation of f to tau confirms the axonal loss and the increase of extracellular diffusivity. Interestingly, the negative correlation of tau to water diffusivity within the axons (Da) could be explained by microtubules breakdown and intra‐axonal deposition of neurofibrillary tangles that impede water diffusion. These evidences of dMRI microstructure correlation with tau SUVR may be useful to detect the in‐vivo neurodegeneration.