Evaluation of tau deposition using 18F-PI-2620 PET in MCI and early AD subjects—a MissionAD tau sub-study

Abstract

Background The ability of 18F-PI-2620 PET to measure the spatial distribution of tau pathology in Alzheimer’s disease (AD) has been demonstrated in previous studies. The objective of this work was to evaluate tau deposition using 18F-PI-2620 PET in beta-amyloid positive subjects with a diagnosis of mild cognitive impairment (MCI) or mild AD dementia and characterize it with respect to amyloid deposition, cerebrospinal fluid (CSF) assessment, hippocampal volume, and cognition. Methods Subjects with a diagnosis of MCI due to AD or mild AD dementia and a visually amyloid-positive 18F-florbetaben PET scan (n=74, 76 ± 7 years, 38 females) underwent a baseline 18F-PI-2620 PET, T1-weighted magnetic resonance imaging (MRI), CSF assessment (Aβ42/Aβ40 ratio, p-tau, t-tau) (n=22) and several cognitive tests. A 1-year follow-up 18F-PI-2620 PET scans and cognitive assessments were done in 15 subjects. Results Percentage of visually tau-positive scans increased with amyloid-beta deposition measured in 18F-florbetaben Centiloids (CL) (7.7% (<36 CL), 80% (>83 CL)). 18F-PI-2620 standardized uptake value ratio (SUVR) was correlated with increased 18F-florbetaben CL in several regions of interest. Elevated 18F-PI-2620 SUVR (fusiform gyrus) was associated to high CSF p-tau and t-tau (p=0.0006 and p=0.01, respectively). Low hippocampal volume was associated with increased tau load at baseline (p=0.006 (mesial temporal); p=0.01 (fusiform gyrus)). Significant increases in tau SUVR were observed after 12 months, particularly in the mesial temporal cortex, fusiform gyrus, and inferior temporal cortex (p=0.04, p=0.047, p=0.02, respectively). However, no statistically significant increase in amyloid-beta load was measured over the observation time. The MMSE (Recall score), ADAS-Cog14 (Word recognition score), and CBB (One-card learning score) showed the strongest association with tau deposition at baseline. Conclusions The findings support the hypothesis that 18F-PI-2620 PET imaging of neuropathologic tau deposits may reflect underlying neurodegeneration in AD with significant correlations with hippocampal volume, CSF biomarkers, and amyloid-beta load. Furthermore, quantifiable increases in 18F-PI-2620 SUVR over a 12-month period in regions with early tau deposition are consistent with the hypothesis that cortical tau is associated with cognitive impairment. This study supports the utility of 18F-PI-2620 PET to assess tau deposits in an early AD population. Quantifiable tau load and its corresponding increase in early AD cases could be a relevant target engagement marker in clinical trials of anti-amyloid and anti-tau agents. Trial registration Data used in this manuscript belong to a tau PET imaging sub-study of the elenbecestat MissionAD Phase 3 program registered in ClinicalTrials.gov (NCT02956486; NCT03036280).

Predicting functional decline in aging and Alzheimer’s disease with PET-based Braak staging

“…In 74 Aβ+ CI participants at early symptomatic stages, no associations were observed between [ 18 F]PI2620 signal and baseline or longitudinal FAQ scores, in models with stepwise adjustment for age, sex and Aβ-PET. 44 Meanwhile, baseline [ 18 F]AV1451 signal in different ROIs (bilateral entorhinal cortex, inferior temporal, precuneus, posterior cingulate, supramarginal and the dorsolateral prefrontal) predicted increase in FAQ scores in a sample of 334 CU and 247 CI participants, even with adjustments for age, gender, the interaction of baseline age with time, cognitive measures and Aβ-PET. 45 Here, we add to these findings by showing that a tau-PET staging approach might be useful to predict future functional decline in the Alzheimer’s disease continuum.…”

CenTauR: Towards a Universal Scale and Masks for Standardizing Tau Imaging Studies

“…All participants were assigned a diagnosis of cognitively unimpaired (CU), mild cognitive impairment (MCI) or AD dementia by the entity providing the data. Criteria for assigning participant diagnosis can be found elsewhere [15,[24][25][26][27]. Aβ status (Aβ+ or Aβ-) was defined using either Aβ PET or the Aβ42/Aβ40 ratio in cerebrospinal fluid (CSF).…”

CenTauR: Toward a universal scale and masks for standardizing tau imaging studies

“…All participants were assigned a diagnosis of cognitively unimpaired (CU), mild cognitive impairment (MCI), or AD dementia or other dementia (OD) by the entity providing the data. Criteria for assigning participant diagnosis can be found elsewhere 15,24–27 . Aβ status (Aβ+ or Aβ−) was defined using either Aβ PET or the Aβ42/Aβ40 ratio in cerebrospinal fluid (CSF).…”

“…elsewhere. 15,[24][25][26][27] Aβ status (Aβ+ or Aβ−) was defined using either Aβ PET or the Aβ42/Aβ40 ratio in cerebrospinal fluid (CSF). Analysis of variance was used to determine any significant demographic difference between cohorts.…”