Brandon J Hall, Étienne Aumont, Seyyed Ali Hosseini, Jaime Fernández Arias, Arnaud Boré, Gleb Bezgin, Lydia Trudel, Tevy Chan, Joseph Therriault, Arthur Macedo, Marcel S. Woo, Delphine Oliva-Lopez, Nesrine Rahmouni, Yansheng Zheng, Stijn Servaes, Jenna Stevenson, Serge Gauthier, Andrea L Benedet, Matthieu Dumont, Jean-Christophe Houde, Gallen Triana-Baltzer, Hartmuth Christian Kolb, Nicholas J Ashton, Henrik Zetterberg, Yasser Iturria Medina, Paolo Vitali, Maxime Descôteaux, Jesse Michael Klostranec, Tharick Pascoal, Pedro Rosa-Neto
BACKGROUND AND OBJECTIVES: Neurofibrillary tangles (NFTs) progressively damage gray matter in Alzheimer disease (AD). Resulting cortical microstructural alterations might not be detectable using macrostructural metrics but may be studied using isotropic water diffusion, as it reflects extracellular free water content. The aim of this study was to examine the effect of NFTs on cortical microstructure by investigating whether cortical free water increases as a function of tau load. We also investigated whether phosphorylated tau in blood plasma also indicated cortical microstructural abnormalities. METHODS: F]AZD4694), tau PET, and plasma phosphorylated tau 217+ (p-tau217) from the Translational biomarkers in Aging and Dementia cohort at McGill University; participants were recruited between 2017 and 2024. We used the Neurite Orientation Dispersion and Density Imaging algorithm to calculate isotropic free water images ("free water"). FreeSurfer was used to calculate cortical thickness in the entorhinal, fusiform, inferior temporal, and middle temporal gyri regions of interest ("meta-ROI"); Automatic Segmentation of Hippocampal Subfields was used to calculate hippocampal volumes. We grouped participants by amyloid PET positivity (A), plasma p-tau217 positivity (T1), and tau PET positivity (T2). We performed voxel-wise correlation analyses between free water and these proteinopathy markers, as well as ROI-based analyses in the meta-ROI. RESULTS: = 0.64). DISCUSSION: In AD-relevant regions, increased free water correlates with tau load independently of macrostructural metrics or amyloid load. Free water may serve as an imaging marker for microstructural changes in gray matter resulting from NFT accumulation, complementary to macrostructural metrics.