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.

Keywords: Amyloid PET; Amyloid β-protein; Imaging; Neuropathological staging; [18F]Flutemetamol.

Conflict of interest statement

DRT received consultancies from Covance Laboratories (UK) and GE-Healthcare (UK), and collaborated with Novartis Pharma Basel (Switzerland), Probiodrug (Germany), and Janssen Pharmaceutical Companies (Belgium). TGB received a consultancy from GE-Healthcare (UK). MZ, GF, CB, APLS are employees of GE-Healthcare (UK, USA). JL and KH were employees of GE-Healthcare (Sweden). JL is currently employee of Hermes Medical Solutions (Sweden). AC and AI received personal fees from GE-Healthcare via the University of Leeds.

Figures

Fig. 1

Boxplot diagrams describing the relationship between the pathologically determined Aβ-phases and the cortical SUVR (SUVRcort) (a), the caudate nucleus SUVR (SUVRcaud) (b), the added cortical and caudate SUVRs (SUVRcort + caud) (c), the PET-stage of Aβ-pathology distribution according to Hanseeuw [15] (PET amyloid stage) (d), and the PET estimate of the pathological Aβ-phase (PET-Aβ phase estimate) (e). Note that the SUVR-based PET-Aβ phase estimates allowed detection of all Aβ-phase 3, 4 and 5 cases as well as of single Aβ-phase 1/2 cases (e) whereas Aβ-phase 1, 2 and most Aβ-phase 3 cases were rated as amyloid negative by visual analysis (d). The boxes contain the 50% of cases lying in the 2nd and 3rd quartile. The bars indicate the median. The whiskers display the 1.5-times interquartile range. Stars or circles indicate outliers. The individual data of the cases depicted here are provided in Suppl. Tab. 1. n = 97 cases

Fig. 2

SUVR-based protocol for determination of PET-Aβ phase estimates and its link to the pathologically determined phases of Aβ-plaque deposition [36]. Although Aβ-phases 1 and 2 cannot be detected by [18F]flutemetamol PET, cases in Aβ-phase 3 can be identified within one group, i.e. PET-Aβ phase estimate 1, cases in Aβ-phases 4 and 5, respectively, in two further groups, i.e. PET-Aβ phase estimates 2 and 3. The red mark in the schematic representation of the Aβ-phases covers the area in which newly developed plaques in a given phase will develop. This does not mean that the entire red marked field is filled up with Aβ-plaques but that the first small groups of plaques in a given phase of Aβ-depositions can be found there. SUVRCortex(pons) = SUVRcort; SUVRNCaudatus(pons) = SUVRcaud. Picture elements of this figure were taken from a previously published figure [35] and reused with permission