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.

Psychotic symptoms are associated with elevated tau PET signal in the amygdala independent of Alzheimer’s disease clinical severity and amyloid burden

“…In this sample, there was no difference in amyloid burden in those with psychotic symptoms compared to those without. Previous work has identified elevated tau PET burden across Braak stage regions without correction for disease severity [14]. By adjusting for AD progression (i.e., CDR and amyloid burden) to understand psychosis-specific tau burden that is independent of AD clinical severity, we found evidence of elevated tau in the amygdala, but no evidence of elevated tau across composite Braak stage regions.…”

“…Only one study has investigated living AD patients with tau PET as a potential pathological driver of psychotic symptoms; however the investigators did not correct for clinical severity, and in that study AD patients with psychotic symptoms had worse CDR scores and greater tau burden in Braak stage regions than AD patients without psychotic symptoms. Therefore, it remains unknown if psychotic symptoms in AD is more related to overall disease progression or tau pathology itself [14].…”

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022

“…Tau deposition may also mediate the relationship between NPS and cognitive performance. Tau deposition in frontal, occipital, and medial temporal cortices was associated with psychosis, and accelerated cognitive and functional decline 304 . In MCI participants stratified by Aβ status and the presence or absence of NPS, a greater association between tau deposition and cognition was reported in those with NPS 305 .…”

Global brain activity and its coupling with cerebrospinal fluid flow is related to tau pathology

“…FTP-PET data were acquired from 75-105 minutes post-injection of 10 mCi tracer. FBP-PET and FBB PET data were acquired from the 50-70 minutes post-injection of 10 mCi tracer and from the 90-110 minutes post-injection of 8.1 mCi tracer ( 52, 103, 104 ), respectively (https://adni.loni.usc.edu/wp-content/uploads/2012/10/ADNI3-Procedures-Manual_v3.0_20170627.pdf).…”