Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease

Abstract

SEE SARAZIN ET AL DOI101093/BRAIN/AWW041 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The advent of the positron emission tomography tracer (18)F-AV1451 provides the unique opportunity to visualize the regional distribution of tau pathology in the living human brain. In this study, we tested the hypothesis that tau pathology is closely linked to symptomatology and patterns of glucose hypometabolism in Alzheimer's disease, in contrast to the more diffuse distribution of amyloid-β pathology. We included 20 patients meeting criteria for probable Alzheimer's disease dementia or mild cognitive impairment due to Alzheimer's disease, presenting with a variety of clinical phenotypes, and 15 amyloid-β-negative cognitively normal individuals, who underwent (18)F-AV1451 (tau), (11)C-PiB (amyloid-β) and (18)F-FDG (glucose metabolism) positron emission tomography, apolipoprotein E (APOE) genotyping and neuropsychological testing. Voxel-wise contrasts against controls (at P < 0.05 family-wise error corrected) showed that (18)F-AV1451 and (18)F-FDG patterns in patients with posterior cortical atrophy ('visual variant of Alzheimer's disease', n = 7) specifically targeted the clinically affected posterior brain regions, while (11)C-PiB bound diffusely throughout the neocortex. Patients with an amnestic-predominant presentation (n = 5) showed highest (18)F-AV1451 retention in medial temporal and lateral temporoparietal regions. Patients with logopenic variant primary progressive aphasia ('language variant of Alzheimer's disease', n = 5) demonstrated asymmetric left greater than right hemisphere (18)F-AV1451 uptake in three of five patients. Across 30 FreeSurfer-defined regions of interest in 16 Alzheimer's disease patients with all three positron emission tomography scans available, there was a strong negative association between (18)F-AV1451 and (18)F-FDG uptake (Pearson's r = -0.49 ± 0.07, P < 0.001) and less pronounced positive associations between (11)C-PiB and (18)F-FDG (Pearson's r = 0.16 ± 0.09, P < 0.001) and (18)F-AV1451 and (11)C-PiB (Pearson's r = 0.18 ± 0.09, P < 0.001). Voxel-wise linear regressions thresholded at P < 0.05 (uncorrected) showed that, across all patients, younger age was associated with greater (18)F-AV1451 uptake in wide regions of the neocortex, while older age was associated with increased (18)F-AV1451 in the medial temporal lobe. APOE ϵ4 carriers showed greater temporal and parietal (18)F-AV1451 uptake than non-carriers. Finally, worse performance on domain-specific neuropsychological tests was associated with greater (18)F-AV1451 uptake in key regions implicated in memory (medial temporal lobes), visuospatial function (occipital, right temporoparietal cortex) and language (left > right temporoparietal cortex). In conclusion, tau imaging-contrary to amyloid-β imaging-shows a strong regional association with clinical and anatomical heterogeneity in Alzheimer's disease. Although preliminary, these results are consistent with and expand upon findings from post-mortem, animal and cerebrospinal fluid studies, and suggest that the pathological aggregation of tau is closely linked to patterns of neurodegeneration and clinical manifestations of Alzheimer's disease.

Keywords: APOE; AV1451 PET; Alzheimer’s disease; cognition; tau.

See Sarazin et al. (doi:10.1093/brain/aww041) for a scientific commentary on this article. The PET tracer [¹⁸F]-AV-1451 allows visualization of tau pathology in living subjects. Ossenkoppele et al. employ the tracer in patients with distinct Alzheimer's disease variants to investigate correlates of tau deposition. Pathological aggregation of tau, but not amyloid-β, is linked to patterns of neurodegeneration and clinical manifestations of Alzheimer’s disease.

Figure 1

¹⁸F-AV1451 uptake in individuals with distinct phenotypes of Alzheimer’s disease. SUVR ¹⁸F-AV1451 images (neurological orientation) in (A) a 59-year-old female (MMSE: 28) with posterior cortical atrophy [note that this a different patient than presented in Ossenkoppele et al. (2015d)]; (B) a 77-year-old female (MMSE: 17) with logopenic variant PPA; (C) a 71-year-old female (MMSE: 23) with amnestic Alzheimer’s disease; (D) a 59-year-old female (MMSE: 27) with non-amnestic Alzheimer’s disease; (E) a 59-year-old male (MMSE: 21) with a behavioural presentation of Alzheimer’s disease, and (F) a 60-year-old female (MMSE: 16) with a corticobasal syndrome affecting the left hemibody.

Figure 2

Tracer uptake patterns in patients with different clinical Alzheimer’s disease variants. (A) Voxelwise contrasts, thresholded at P < 0.05 after family-wise error correction and without covariates, indicating regions in which patients with PCA had greater ¹⁸F-AV1451 (green), reduced ¹⁸F-FDG (red), and elevated ¹¹C-PiB (blue) compared to healthy controls. (B and C) Contrasts for ¹⁸F-AV1451 uptake between amnestic Alzheimer’s disease (B) and logopenic variant PPA (C) patients against healthy controls at P < 0.05 after family-wise error correction and without covariates. In panel D, we binarized the ¹⁸F-AV1451 and ¹⁸F-FDG (P < 0.05 family-wise error corrected) contrasts between patients with PCA and controls, and show in cyan regions where both ¹⁸F-AV1451 and ¹⁸F-FDG differed from controls, and in blue brain regions where only the ¹⁸F-AV1451 contrast was significant. In E, individual ¹⁸F-AV1451 images of five logopenic variant PPA patients are displayed in order of their MMSE scores.

Figure 3

¹⁸F-AV1451 uptake and hemispheric asymmetry in regions of interest. (A) ¹⁸F-AV1451 SUVR values for each Alzheimer’s disease patient and controls in seven bilateral regions of interest. (B) The degree of asymmetric tracer uptake within each region of interest as the percentage difference in SUVR value for left compared to right hemisphere: asymmetry index [%] = 200 × (R − L)/(R + L). Table 2 and Supplementary Table 2 show the group means and differences of ¹⁸F-AV1451 standardized uptake value ratios and asymmetry indices.

Figure 4

Direct region of interest comparisons between PET tracers. Across 16 Alzheimer’s disease patients, regions with greater ¹⁸F-AV1451 uptake were strongly associated with lower ¹⁸F-FDG metabolism (A). Modest, positive associations were also observed between ¹¹C-PiB and ¹⁸F-FDG (B) and between ¹⁸F-AV1451 and ¹¹C-PiB (C).

Figure 5

Patterns of ¹⁸F-AV1451 retention in Alzheimer’s disease associated with age and APOE ϵ4 status. Result from voxelwise linear regression are displayed at P < 0.05 uncorrected for multiple comparisons, without covariates for age (A), and adjusted for global amyloid-β burden for APOE ϵ4 status (B).

Figure 6

Associations between regional ¹⁸F-AV1451 and cognitive performance. Voxelwise contrasts (top; P < 0.05 uncorrected) show associations between increased ¹⁸F-AV1451 retention and worse performance on memory (A), visuospatial (B), and language testing (C). Region of interest analyses (bottom) demonstrate that cognitive impairment was associated with focal rather than global increases in ¹⁸F-AV1451 in regions underlying specific cognitive domains.