Early detection of amyloid load using 18F-florbetaben PET

Abstract

Background A low amount and extent of Aβ deposition at early stages of Alzheimer’s disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using 18F-florbetaben PET. Quantitative thresholds for the early (SUVRearly) and established (SUVRestab) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition. Methods The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition (“gray zone”), and subjects with established Aβ pathology. Results SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the “gray zone” or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology. Conclusions This study supports the utility of using two cutoffs for amyloid PET abnormality defining a “gray zone”: a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention. Trial registration Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov (NCT00928304, NCT00750282, NCT01138111, NCT02854033) and EudraCT (2014-000798-38).

Multi-method investigation of factors influencing amyloid onset and impairment in three cohorts

“…This observation, coupled with similarities in DVR/SUVR rates, suggest amyloid accumulation rates are ostensibly consistent between individuals and predictable once underlying amyloid burden sufficiently exceeds the amyloid PET detection limit. Below this threshold, the interpretation of DVR/SUVR gradually transitions from being due to amyloid to being due to stochastic measurement error, which is consistent with PET detection physics, the concept of subthreshold amyloid 46 and supports previous work proposing two thresholds 47 to define three interpretation zones: undetectable amyloid, transition, and confidently A+. It follows that EAOA derived from DVR/SUVR values in these different zones will have similar interpretation such that EAOA is more meaningful in the A+ range and becomes less interpretable as reference DVR/SUVR decreases below the A+ threshold.…”

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

“…In this study, only 1 out of 13 subjects (7.7%) with less than 36 CL was visually tau positive while 21 out 30 subjects (80%) with greater than 83 CL of amyloid showed 18 F-PI-2620 accumulation based on visual assessment. Additionally, similar bivariate associations between amyloid-beta and tau have been reported for other PET tracers: 18 F-florbetaben and 18 F-flortaucipir [ 25 ], 18 F-NAV4694 and 18 F-MK6240 [ 30 ], 11C-PiB and 18 F-flortaucipir [ 31 ], and 18 F-florbetapir and 18 F-flortaucipir [ 5 ]. Tau deposition was predominantly present in the mesial temporal, fusiform gyrus, and inferior temporal cortex and less frequent in the occipital and parietal cortices, as expected in the population included in this study.…”

“…3 Scatter plots of the 18 F-PI-2620 SUVR versus amyloid-beta 18 F-florbetaben CLs. Red and blue lines represent 18 F-PI-2620 SUVR and 18 F-florbetaben CL positivity cutoffs, respectively, derived from previous publications [ 14 , 25 ]. Solid dots correspond to those subjects that underwent 1-year follow-up 18 F-PI-2620 PET scans …”

“…Finally, the CL values were calculated (CL =153.4 · SUVR − 154.9) [ 24 ]. The in-house implementation of the standard CL analysis was previously validated using data freely accessible at the GAAIN website ( http://www.gaain.org ) [ 25 ].…”

“…The percent of tau-positive scans by visual assessment was calculated for low amyloid-beta load subjects (CL<36) based on previously published CL cutoffs [ 25 ] and elevated amyloid-beta load subjects (CL > 36) split in two parts with an equal number of subjects (CL 36–83 CL, CL>83). Percent of tau-positive cases for the different levels of amyloid-beta were compared statistically using the chi-squared test for trend in proportions.…”