Determining Amyloid-β Positivity Using ¹⁸F-AZD4694 PET Imaging

Abstract

Amyloid-β deposition into plaques is a pathological hallmark of Alzheimer's disease (AD) appearing years before the onset of symptoms. Although cerebral amyloid-β deposition occurs on a continuum, dichotomization into positive and negative groups has advantages for diagnosis, clinical management and population enrichment for clinical trials. 18F-AZD4694 (also known as 18F-NAV4694) is an amyloid-β imaging ligand with high affinity for amyloid-β plaques. Despite being employed in multiple academic centers, no studies have assessed a quantitative cut-off for amyloid-β positivity using 18F-AZD4694 PET. Methods: We assessed 176 individuals [young adults (n = 22), cognitively unimpaired elderly (n = 89), and cognitively impaired (n = 65)] who underwent amyloid- PET with 18F-AZD4694, lumbar puncture, structural MRI, and genotyping for APOEε4. 18F-AZD4694 values were normalized using the cerebellar grey matter as a reference region. We compared five methods for deriving a quantitative threshold for 18F-AZD4694 PET positivity: comparison with young controls SUVRs values, Receiver Operating Characteristic (ROC) curves based on clinical classification of CU elderly vs AD dementia, ROC curves based on visual Aβ+/Aβ-classification, Gaussian Mixture Modeling and comparison with cerebrospinal fluid measures of amyloid-β, specifically the Aβ42/Aβ40 ratio. Results: We observed good convergence between four methods: ROC curves based on visual classification (optimal cut point: 1.55 SUVR), ROC curves based on clinical classification (optimal cut point: 1.56 SUVR) GaussianMixture Modeling (optimal cut point: 1.55 SUVR) and comparison with CSF measures of amyloid-β (optimal cut point: 1.51 SUVR). Means and 2 standard deviations from young controls resulted in a lower threshold (1.33 SUVR) that did not agree with the other methods and labeled the majority of elderly individuals as Aβ+. Conclusion: Good convergence was obtained between a number of methods for determining an optimal cut-off for 18F-AZD4694 PET positivity. Despite

2020 update on the clinical validity of cerebrospinal fluid amyloid, tau, and phospho-tau as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework

“…Similar cutoffs (based on Youden index for separating participants based on Aβ-status using Amyloid PET) were also reported by Schindler et al [87,88] (CSF Aβ42, 1098 pg/mL; P-tau/ Aβ42, 0.0198; T-tau/Aβ42, 0.211). In addition, the LUMIPULSE® assay, that provides a quantitative result for an analyte within 35 min, demonstrates an Aβ42/Aβ40 cutoff of 0.068 for an AD diagnoses but is also validated against Amyloid PET [89]. These methods are now being standardized to each other in terms of the absolute CSF Aβ42 concentration they deliver [22].…”

Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer’s disease

“…Global Aβ PET used averaged SUVR of the precuneus, cingulate, inferior parietal, medial prefrontal, lateral temporal, and orbitofrontal cortices 37 and positivity was visually de ned by two neurologists blinded to clinical diagnosis. An additional Aβ PET SUVR cutoff value of 1.55 was estimated as previously described 38 . Aβ PET SUVR was also converted to Centiloid units 39 as previously described 38,40 .…”

“…An additional Aβ PET SUVR cutoff value of 1.55 was estimated as previously described 38 . Aβ PET SUVR was also converted to Centiloid units 39 as previously described 38,40 . The PET SUVR cutoff value of 1.55 corresponds to 24 Centiloids.…”

Topographic Distribution of Amyloid-β, Tau, and Atrophy in Patients With Behavioral/Dysexecutive Alzheimer Disease

“…To help circumvent potential biases related to visual classification of PET scans, we additionally used quantitative thresholds to assess positivity for both Aβ and tau. Amyloid-PET positivity was determined using an [ 28 F]AZD4694 SUVR threshold of 1.55 validated through gaussian mixture modeling, receiver operating characteristic (ROC) analyses, comparison with CSF biomarkers, and comparisons with young adults (age < 25). 28 All participants with AD had tau-PET SUVRs above the mean and 2 SD of the CU elderly group 29 in all Braak regions.…”