Progressive Tau Accumulation in Alzheimer Disease: 2-Year Follow-up Study

Abstract

Tau PET enables in vivo visualization and quantitation of tau accumulation in Alzheimer disease (AD). In cross-sectional tau PET studies, tau burden reflects disease severity and phenotypic variation. We investigated longitudinal changes in cortical tau accumulation and their association with cognitive decline in patients with AD. Methods: We enrolled 107 participants (45 amyloid-β-negative cognitively unimpaired [CU-], 7 amyloid-β-positive cognitively unimpaired [CU+], 31 with prodromal AD [mild cognitive impairment; MCI+], and 24 with AD dementia [DEM+]) who completed 2 baseline PET scans (¹⁸F-flortaucipir and ¹⁸F-florbetaben), MRI, and neuropsychologic tests. All participants underwent the same assessments after 2 y. After correcting for partial-volume effect, we created SUV ratio (SUVR) images. By using a linear mixed-effect model, we investigated the changes in SUVR across time within each group. We also investigated a correlation between the progression of tau accumulation and cognitive decline. Results: In contrast to no change in global cortical SUVR in the CU- and CU+ groups during the 2-y period, global cortical SUVR increased by 0.06 (2.9%) in the MCI+ group and 0.19 (8.0%) in the DEM+ group at follow-up. The MCI+ group was associated with additional tau accumulation predominantly in the medial and inferior temporal cortices, whereas the DEM+ group showed increases in the lateral temporal cortex. Progressive tau accumulation occurred in the diffuse cortical areas in the MCI+ patients who developed dementia and the DEM+ patients who showed deterioration of global cognition, whereas there was only a small increase of additional tau accumulation in the lateral temporal cortex in those who did not show worsening of cognition. Deterioration of global cognition and language functions was associated with progression of diffuse tau accumulation in the association neocortex. Conclusion: Progressive tau accumulation occurs in prodromal AD and DEM patients in the cortical areas at different levels of tau accumulation. Progression of cognitive dysfunction may be related to the additional tau accumulation in regions of higher Braak stage. ¹⁸F-flortaucipir PET is an imaging biomarker for monitoring the progression of AD.

Keywords: 18F-flortaucipir; Alzheimer disease; longitudinal study; positron emission tomography; tau.

FIGURE 1.

Examples of ¹⁸F-flortaucipir PET SUVR images created with cerebellar crus as reference region and their longitudinal changes in PVE-corrected SUVR obtained at baseline and follow-up. (A) Examples of spatially normalized PET images uncorrected for PVE, with ¹⁸F-florbetaben and ¹⁸F-flortaucipir SUVR and MMSE scores presented below the images. (B) ¹⁸F-flortaucipir SUVR measured in global cortical gray matter and composite regions corresponding to different Braak stages. B = baseline; F = follow-up; G/A = sex/age; A and T = global cortical SUVR of ¹⁸F-florbetaben or ¹⁸F-flortaucipir PET, respectively; COR and UNC = SUVR with and without PVE correction, respectively.

FIGURE 2.

Longitudinal changes in PVE-corrected ¹⁸F-flortaucipir SUVR obtained with cerebellar crus as reference region. Regional changes and their statistical significance are shown at top. Horizontal bars in leftward (green) and rightward (red) directions represent P values in log scale with decrease and increase of regional uptake at follow-up, respectively. Vertical blue dotted lines represent cutoff P value of 0.05 (−log₁₀P = 1.3), and asterisks represent regions that survived correction for multiple comparisons. Surface-based analyses of longitudinal changes are shown at bottom. Mean increases in cortical ¹⁸F-flortaucipir SUVR (left) and cortical areas with significantly increased uptake at follow-up compared with those at baseline (right) are displayed on cortical surface. Only vertices that survived correction for multiple comparisons are displayed. For simplicity, negative changes are not displayed.

FIGURE 3.

Longitudinal changes in PVE-corrected ¹⁸F-flortaucipir SUVR obtained with cerebellar crus as reference region in MCI patients who progressed or did not progress to dementia and in AD patients who showed or did not show progression of cognitive dysfunction. (A) In VOI-based analysis, color bars represent P values in log scale, and horizontal bars in leftward (green) and rightward (red) directions represent P values in log scale with decrease and increase of regional uptake at follow-up, respectively. Vertical blue dotted lines represent cutoff P value of 0.05 (−log₁₀P = 1.3), and asterisks represent regions that survived correction for multiple comparisons. (B) In surface-based analysis, only vertices that survived correction for multiple comparisons are displayed. For simplicity, negative changes are not displayed. npMCI+ = MCI+ who did not progress to dementia; pMCI+ = MCI+ who progressed to dementia; npDEM+ = DEM+ who did not show progression; pDEM+ = DEM+ who showed progression.