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.

• Authors: Dietmar Rudolf Thal, Thomas G Beach, Michelle Zanette, Johan Lilja, Kerstin Heurling, Aruna Chakrabarty, Azzam Ismail, Gill Farrar, Christopher Buckley, Adrian P L Smith
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 136 Issue 4 Pg. 557-567 (10 2018) ISSN: 1432-0533 [Electronic] Germany
• PMID: 30123935 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• APP protein, human
• Amyloid beta-Protein Precursor
• Aniline Compounds
• Benzothiazoles
• Radiopharmaceuticals
• flutemetamol

Topics

• Aged
• Aged, 80 and over
• Alzheimer Disease (diagnostic imaging, metabolism)
• Amyloid beta-Protein Precursor (metabolism)
• Aniline Compounds
• Autopsy
• Benzothiazoles
• Brain (pathology)
• Caudate Nucleus (diagnostic imaging)
• Cerebral Cortex (diagnostic imaging)
• Disease Progression
• Female
• Humans
• Male
• Middle Aged
• Plaque, Amyloid (diagnostic imaging, metabolism)
• Pons (diagnostic imaging, metabolism)
• Predictive Value of Tests
• Radiopharmaceuticals