Estimation of amyloid distribution by [18F]flutemetamol PET predicts the neuropathological phase of amyloid β-protein deposition

Abstract

The deposition of the amyloid β-protein (Aβ) in senile plaques is one of the histopathological hallmarks of Alzheimer’s disease (AD). Aβ-plaques arise first in neocortical areas and, then, expand into further brain regions in a process described by 5 phases. Since it is possible to identify amyloid pathology with radioactive-labeled tracers by positron emission tomography (PET) the question arises whether it is possible to distinguish the neuropathological Aβ-phases with amyloid PET imaging. To address this question we reassessed 97 cases of the end-of-life study cohort of the phase 3 [18F]flutemetamol trial (ClinicalTrials.gov identifiers NCT01165554, and NCT02090855) by combining the standardized uptake value ratios (SUVRs) with pons as reference region for cortical and caudate nucleus-related [18F]flutemetamol-retention. We tested them for their prediction of the neuropathological pattern found at autopsy. By defining threshold levels for cortical and caudate nucleus SUVRs we could distinguish different levels of [18F]flutemetamol uptake termed PET-Aβ phase estimates. When comparing these PET-Aβ phase estimates with the neuropathological Aβ-phases we found that PET-Aβ phase estimate 0 corresponded with Aβ-phases 0-2, 1 with Aβ-phase 3, 2 with Aβ-phase 4, and 3 with Aβ-phase 5. Classification using the PET-Aβ phase estimates predicted the correct Aβ-phase in 72.16% of the cases studied here. Bootstrap analysis was used to confirm the robustness of the estimates around this association. When allowing a range of ± 1 phase for a given Aβ-phase correct classification was given in 96.91% of the cases. In doing so, we provide a novel method to convert SUVR-levels into PET-Aβ phase estimates that can be easily translated into neuropathological phases of Aβ-deposition. This method allows direct conclusions about the pathological distribution of amyloid plaques (Aβ-phases) in vivo. Accordingly, this method may be ideally suited to detect early preclinical AD-patients, to follow them with disease progression, and to provide a more precise prognosis for them based on the knowledge about the underlying pathological phase of the disease.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1897-9) contains supplementary material, which is available to authorized users.

Applications of amyloid, tau, and neuroinflammation PET imaging to Alzheimer's disease and mild cognitive impairment

“…However, there is still a great deal of variability present in the amyloid positivity thresholds derived from this approach (Su et al, 2018). A further limitation of amyloid PET imaging modalities is that there is a lack of concordance with Aβ plaque phases as determined by pathohistological methodology, such as Thal stages PET was unable to accurate predict the target Aβ stages in 27.84% of cases in an end-of-life cohort (Thal et al, 2018). Additionally, an amyloid positivity threshold of a standardised uptake value ratio of 1.5…”

“…A strong discriminative ability of [ 18 F]florbetapir for AD and MCI compared to a cognitively normal status is supported by a number of additional studies (Degenhardt et al, 2016;Johnson et al, 2013;Namiki et al, 2015). However, there is still a great deal of variability present in the amyloid positivity thresholds derived from this approach (Su et al, 2018 PET was unable to accurate predict the target Aβ stages in 27.84% of cases in an end-of-life cohort (Thal et al, 2018). This is due to a range of factors including variability in scanning time, methodology employed during analyses, identified reference regions and regions of interest, attenuation correction, partial volume correction, machines used to scan, and tracer-specific properties.…”

Neuropathological correlates of amyloid PET imaging in Down syndrome

“…Multiple studies of AD, MCI, and aged non-demented controls demonstrated high correspondence between postmortem amyloid pathology and antemortem amyloid PET imaging using [C-11]PiB (Bacskai et al, 2007;Burack et al, 2010;Ikonomovic et al, 2008;Kadir et al, 2011;Kantarci et al, 2012;Sojkova et al, 2011) and related F-18 labeled ligands Florbetapir (Clark et al, 2012) and Flutemetamol (Curtis et al, 2015;Ikonomovic et al, 2016Ikonomovic et al, , 2018Thal et al, 2018). In contrast, little work has been done to elucidate neuropathology substrates of amyloid PET ligands in DS cases.…”

Longitudinal validity of PET‐based staging of regional amyloid deposition

“…Amyloid imaging with positron emission tomography (PET) has become an important diagnostic tool for AD (Villemagne et al, 2011), displaying high sensitivity and specificity by comparison with neuropathological findings (Clark et al, 2012;Sabri, Seibyl, Rowe, & Barthel, 2015;Villeneuve et al, 2015). Recent amyloid PET studies have attempted to characterize and stage the regional amyloid pathology spread in-vivo, either using an a priori distinction between early neocortical and later subcortical amyloid deposition (Cho et al, 2018;Hanseeuw et al, 2018;Thal et al, 2018) or more comprehensive data-driven models including regional deposition differences within both cortical and subcortical areas (Cho et al, 2016;Grothe et al, 2017;Sakr et al, 2019). In our previous work (Grothe et al, 2017) we have developed an in-vivo staging model that adopts a commonly used analytic approach for determining regional staging schemes in neuropathological studies (Braak & Braak, 1991;Josephs et al, 2016;Thal et al, 2002) and is based on the frequency of regionally measured uptake positivity in cognitively normal older participants.…”