White Matter Degeneration Pathways Associated with Tau Deposition in Alzheimer’s Disease

Abstract

BackgroundThe dynamics of white matter (WM) changes are understudied in Alzheimer’s disease (AD). Leveraging tau deposition measured from Tau‐PET, our goal was to study the association between tau and white matter health using NODDI from multi‐shell diffusion MRI (dMRI). Specifically, we focused on the Neurite Density Index (NDI) from NODDI, which in WM captures the signal from axons.MethodWe identified 251 participants (126 cognitively normal, 58 MCI, 67 dementia) from the Mayo ADRC and Mayo Clinic Study of Aging with Aβ‐PET, Tau‐PET, and multi‐shell dMRI who were Aβ‐positive (mean age of 77 years and 55% male). We limited to Aβ‐positive participants because Aβ deposition accelerates tau deposition. For Tau‐PET, we estimated SUVRs from three regions corresponding to Braak I/II, III/IV, and V/VI (Figure 1.a). To understand the associations between Tau‐PET SUVRs at three Braak regions and NDIs at 30 candidate WM tracts, we implemented three analyses methods ‐ Pearson correlation, linear regression, and multilayer perceptron machine learning regression.ResultHigher tau burden in all three Braak regions was associated with lower neurite density in 10 significant WM tracts (Table 1). Interestingly, uncinate fasciculus (UNC) was found significantly associated with all three Braak regions. All three analysis methods consistently showed differential involvement of WM pathways for Braak staging such as ‐ Cingulum adjoining Hippocampus (CGH) for Braak I/II regions, Medial Temporal WM (MTWM) for Braak III/IV regions, and Inferior Occipital WM (IOWM) for Braak V/VI regions (Figure 1.b). The linear regression and machine learning regression models also suggested that WM measurements reflected 18‐35% of variance due to tau depositionConclusionWe found that CGH and UNC WM were the most impacted ROIs associated with Braak I/II regions as expected. UNC, directly connecting anterior temporal lobes to the orbitofrontal cortex, was a key WM tract identified as important for all Braak I‐VI regions and warrants further investigation in the study of AD progression. This study highlights the significant impact tau deposition may have on WM. This work also demonstrates the feasibility of using NODDI as an informative supplementary imaging modality for monitoring AD progression.

The Alzheimer Disconnectome

“…There are some potentially important implications in the study of Tian et al 7 First, these findings provide further support for the increasing evidence of white matter disruption in degenerative dementia. 5,6 Although future work would be needed to determine how much of the white matter changes are secondary effects of gray matter degeneration, there is growing evidence of primary pathology in myelin and oligodendrocytes in Alzheimer disease.…”

“…In this edition of Neurology ®, Tian and co-authors 7 have brought together these advances on tau and white matter imaging. They sought to study the association between tau deposition, measured with flortaucipir PET, and white matter health, using a diffusion magnetic resonance imaging (dMRI) metric as a proxy for axonal density, called the neurite density index (NDI).…”

“…The only cognitive evaluation performed was the Short Test of Mental Status, which was transformed to a Mini Mental State Examination (MMSE) score. Tian et al 7 selected flortaucipir standard uptake value ratios (SUVRs) from 3 regions corresponding to Braak stages I (early AD), III/IV (mid-stage), and V/VI (late-stage) and evaluated associations between these SUVRs and NDIs in 29 candidate white matter tracts. The investigators found that white matter integrity declined with increasing Braak tau deposition, most consistently for the uncinate fasciculus and the cingulum adjoining the hippocampus.…”