P4‐299: Phosphorylation of Specific Tau Sites Is Associated With Loss of White Matter Integrity in Autosomal Dominant Alzheimer Disease
Year: 2019
Type: article
Study design: Observational Study
Abstract: Hyperphosphorylation of tau leads to conformational changes that destabilize microtubules and hinder axonal transport in Alzheimer disease (AD). Tau can be phosphorylated at multiple positions that vary over AD disease stage and may quantify severity of tau pathology or neurodegeration. We evaluated whether phosphorylation of tau at three sites (pt217, pt181, and pt205) or total tau associated with changes in white matter track (WMT) integrity within autosomal dominant AD(ADAD). ADAD are a younger cohort that exhibit fewer age-related comorbidities making this an ideal cohort to examine AD white matter changes. Cerebrospinal fluid (CSF) and diffusion tensor imaging was obtained from 71 mutation positive and 40 mutation negative participants from the Dominantly Inherited Alzheimer Network (DIAN). CSF p-tau/tau ratio was evaluated on each site by a nanoAcquity UPLC system coupled to a Fusion Tribrid mass spectrometer. Diffusivity maps were calculated to evaluate WMT integrity. A voxel-wise correlation using permutation testing assessed the relationship between diffusivity and phosphorylation site with age included as a covariate. WMT were created by averaging skeletal voxels that overlaid regions of interest. Linear models were constructed for predicting white matter integrity for each WMT individually or amalgamated into a single composite derived from principal component analysis. Variables incorporated into the model include age, amyloid, white matter hyperintensities, precuneus volume, and phosphorylation site. Fractional anisotropy (FA) and radial diffusivity (DR) within callosal fibers correlated with pt205 but not pt217, pt181, or total tau in mutation carriers (p<0.05 corrected). The primary component derived from WMT explained 70% of the variance with top contributors including cingulum, forceps major (FM), and corpus callosum. Linear regression revealed that only pt205 predicted the PCA WMT composite(p=0.005). In WMT individually pt205 significantly predicted FA and DR for the FM (FA p=0.01; DR p=0.037) and PCC (FA p=0.0023; DR p=0.003).
Source: Alzheimer s & Dementia
Institution: Washington University in St. Louis
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4245522995