Increased retention of tau PET ligand [18F]-AV1451 in Alzheimer's Disease Psychosis

Abstract

Psychosis in Alzheimer's disease (AD) represents a distinct disease subtype with a more rapid progression of illness evidenced by an increased velocity of cognitive decline and a hastened mortality. Previous biomarker and post-mortem studies have implicated tau neuropathology as a possible mediator of the accelerated decline in AD psychosis. Tau positron emission tomography (PET) neuroimaging provides the opportunity to evaluate tau pathology in-vivo, so that clinical symptomatology can be correlated with disease pathology. [¹⁸F]-AV1451 (Flortaucipir) is a PET ligand with high affinity for insoluble paired-helical filaments (PHFs) of hyperphosphorylated tau. In order to determine whether the development of psychosis and worsened prognosis in AD is associated with an increased burden of tau pathology that can be identified with tau imaging, we identified subjects within the Alzheimer's disease neuroimaging initiative (ADNI) who had [¹⁸F]-AV1451 imaging at baseline and became psychotic over the course of the study (N = 17) and matched them 1:3 for gender, age, and education to subjects who had [¹⁸F]-AV1451 imaging at baseline and did not become psychotic (N = 50). We compared baseline [¹⁸F]-AV1451 retention, in addition to cognitive and functional baseline and longitudinal change, in those who became psychotic over the course of participation in ADNI with those who did not. Results suggest that increases in tau pathology in frontal, medial temporal, and occipital cortices, visualized with [¹⁸F]-AV1451 binding, are associated with psychosis and a more rapid cognitive and functional decline.

Fig. 1. ¹⁸F-AV-1451 SUVR uptake for AD + P and AD − P groups.

Cortical uptake of ¹⁸F-AV-1451 tracer in the form of SUVR referenced to whole cerebellum cortex for each group in the study: AD + P and AD − P. Top row displays lateral planes of the brain, middle row superior and inferior planes, and bottom row medial planes. SUVR standardized uptake value ratio, AD + P Alzheimer´s disease with Psychotic symptoms, AD − P Alzheimer´s disease without Psychotic symptoms.

Fig. 2. Voxelwise contrast of ¹⁸F-AV-1451 SUVR uptake between AD + P and AD − P groups.

Contrast voxel-wise maps shows brain regions where AD + P had higher ¹⁸F-AV-1451 uptake compared to AD − P. Color wheel represents log10 of p level with threshold p < 10⁻⁴ = 0.0001. Results from multiple comparisons correction using permutations tests (see the “Methods” section) are reported in Supplementary Table 2. AD + P Alzheimer´s disease with Psychotic symptoms, AD − P Alzheimer´s disease without Psychotic symptoms.

Fig. 3. Braak stage-derived ROI analysis of ¹⁸F-AV-1451 uptake between AD + P and AD − P groups.

Figures shows the comparisons in SUVR units referenced to whole cerebellum cortex between AD + P and AD − P. Top row display the GLM results uncorrected for PVE, and bottom row displays the results corrected for PVEs. Statistical contrasts corrected for multiple comparisons using FDR. *p < 0.05, n.s. not significant. Dashed lines represent the Braak-derived stage thresholds as provided in reference [66]. SUVR standardized uptake value ratio, AD + P Alzheimer´s disease with Psychotic symptoms, AD − P Alzheimer´s disease without Psychotic symptoms, GLM general linear model, PVE partial volume effects, FDR false discovery rate. .

Fig. 4. Cognitive trajectories by group.

This figure shows the mean annualized rate change (ARC) in cognition by group (AD − P vs. AD + P). A Shows the mean ARC for CDR-SB for each group; note that for the case of CDR-SB, higher scores correspond to greater longitudinal functional impairment. B Shows the mean ARC for MMSE for each group; note that for the case of MMSE, lower scores correspond to greater cognitive decline. Error bars represent the standard error of the mean (SEM). AD − P Alzheimer´s disease without Psychotic symptoms, AD + P Alzheimer´s disease with Psychotic symptoms, CDR-SB Clinical Dementia Rating–Sum of Boxes, MMSE Mini Mental State Examination, ARC annualized rate change.