Reduced [¹⁸F]flortaucipir retention in white matter hyperintensities compared to normal-appearing white matter

Recent research has suggested the use of white matter (WM) reference regions for longitudinal tau-PET imaging. However, tau tracers display affinity for the β-sheet structure formed by myelin, and thus WM lesions might influence tracer retention. Here, we explored whether the tau-sensitive tracer [¹⁸F]flortaucipir shows reduced retention in WM hyperintensities (WMH) and how this retention changes over time.

We included 707 participants from the Alzheimer's Disease Neuroimaging Initiative with available [¹⁸F]flortaucipir-PET and structural and FLAIR MRI scans. WM segments and WMH were automatically delineated in the structural MRI and FLAIR scans, respectively. [¹⁸F]flortaucipir standardized uptake value ratios (SUVR) of WMH and normal-appearing WM (NAWM) were calculated using the inferior cerebellar grey matter as reference region, and a 3-mm erosion was applied to the combined NAWM and WMH masks to avoid partial volume effects. Longitudinal [¹⁸F]flortaucipir SUVR changes in NAWM and WMH were estimated using linear mixed models. The percent variance of WM-referenced cortical [¹⁸F]flortaucipir SUVRs explained by longitudinal changes in the WM reference region was estimated with the R² coefficient.

Compared to NAWM, WMH areas displayed significantly reduced [¹⁸F]flortaucipir SUVR, independent of cognitive impairment or Aβ status (mean difference = 0.14 SUVR, p < 0.001). Older age was associated with lower [¹⁸F]flortaucipir SUVR in both NAWM (- 0.002 SUVR/year, p = 0.005) and WMH (- 0.004 SUVR/year, p < 0.001). Longitudinally, [¹⁸F]flortaucipir SUVR decreased in NAWM (- 0.008 SUVR/year, p = 0.03) and even more so in WMH (- 0.02 SUVR/year, p < 0.001). Between 17% and 66% of the variance of longitudinal changes in cortical WM-referenced [¹⁸F]flortaucipir SUVRs were explained by longitudinal changes in the reference region.

[¹⁸F]flortaucipir retention in the WM decreases over time and is influenced by the presence of WMH, supporting the hypothesis that [¹⁸F]flortaucipir retention in the WM is partially myelin-dependent. These findings have implications for the use of WM reference regions for [¹⁸F]flortaucipir-PET imaging.