Performance of [¹⁸F]flutemetamol amyloid imaging against the neuritic plaque component of CERAD and the current (2012) NIA‐AA recommendations for the neuropathologic diagnosis of Alzheimer's disease

Abstract

IntroductionPerformance of the amyloid tracer [18F]flutemetamol was evaluated against three pathology standard of truth (SoT) measures including neuritic plaques (CERAD “original” and “modified” and the amyloid component of the 2012 NIA-AA guidelines).MethodsAfter [18F]flutemetamol imaging, 106 end-of-life patients who died underwent postmortem brain examination for amyloid plaque load. Blinded positron emission tomography scan interpretations by five independent electronically trained readers were compared with pathology measures.ResultsBy SoT, sensitivity and specificity of majority image interpretations were, respectively, 91.9% and 87.5% with “original CERAD,” 90.8% and 90.0% with “modified CERAD,” and 85.7% and 100% with the 2012 NIA-AA criteria.DiscussionThe high accuracy of either CERAD criteria suggests that [18F]flutemetamol predominantly reflects neuritic amyloid plaque density. However, the use of CERAD criteria as the SoT can result in some false-positive results because of the presence of diffuse plaques, which are accounted for when the positron emission tomography read is compared with the 2012 NIA-AA criteria.

Neuropathological correlates of amyloid PET imaging in Down syndrome

“…The discovery and application of carbon-11 labeled Pittsburgh Compound-B (PiB) (Klunk et al, 2004) and related fluorine-18 labeled amyloid PET ligands Florbetapir (Amyvid) (Clark et al, 2011;Wong et al, 2010), Florbetaben (Neuraceq) (Sabri et al, 2015), and Flutemetamol (Vizamyl) (Vandenberghe et al, 2010) has allowed for detection and quantification of amyloid burden in brains of living subjects. Recent clinical pathological studies reported that neuritic Aβ plaques are primarily responsible for binding of amyloid PET ligands in AD, supported by a high correspondence between antemortem amyloid PET retention levels and region-matched frequencies of neuritic plaques determined postmortem (Clark et al, 2012;Curtis et al, 2015;Hatsuta et al, 2015;Sabri et al, 2015;Salloway et al, 2017). While cortical Aβ plaques can be present in subjects with amyloid PET retention below detection levels, these are typically nonneuritic and diffuse (Cairns, 2011;Ikonomovic et al, 2012).…”

“…While cortical Aβ plaques can be present in subjects with amyloid PET retention below detection levels, these are typically nonneuritic and diffuse (Cairns, 2011;Ikonomovic et al, 2012). However, a recent clinical-pathological study demonstrated several cases that were amyloid-PET positive, but postmortem analysis revealed insufficient amounts of cortical neuritic plaques marked by Bielschowsky silver histology (Salloway et al, 2017). These false positive cases had significant amounts of cortical diffuse Aβ plaques detected immunohistochemically, suggesting that both diffuse and neuritic Aβ plaques can contribute to amyloid PET signal (Ikonomovic et al, 2016;Ikonomovic, Fantoni, Farrar, & Salloway, 2018).…”

Signs and Artifacts in Amyloid PET

“…cal β-amyloid plaques in living human subjects (11,(21)(22)(23). Additionally, premortem amyloid PET results demonstrated high correlation with postmortem disease assessed using a modification of the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) criteria (11,(24)(25)(26)(27). Negative amyloid scans were prespecified to correspond with none to sparse neuritic plaque counts according to CERAD, and positive scans were prespecified to correspond with moderate to frequent counts.…”

Cerebrospinal fluid levels of synaptic and neuronal integrity correlate with gray matter volume and amyloid load in the precuneus of cognitively intact older adults

“…[ 18 F]‐flutemetamol (Vizamyl, GE Healthcare) is a widely used amyloid‐PET ligand which predominantly binds to neuritic amyloid plaques (Salloway et al . ). In a subset of asymptomatic subjects, neurodegeneration is present, as measured by volumetric magnetic resonance imaging (MRI), [ 18 F]‐fluoro‐deoxy‐glucose‐PET or by means of CSF levels of t‐tau and phosphorylated tau (p‐tau) (Sperling et al .…”

“…The asymptomatic phase of AD is defined as evidence of brain amyloid load, assessed by reduced cerebrospinal fluid (CSF) levels of amyloid-b 1-42 or through a positive amyloid positron emission tomography (PET) scan (Sperling et al 2011(Sperling et al , 2014. [ 18 F]flutemetamol (Vizamyl, GE Healthcare) is a widely used amyloid-PET ligand which predominantly binds to neuritic amyloid plaques (Salloway et al 2017). In a subset of asymptomatic subjects, neurodegeneration is present, as measured by volumetric magnetic resonance imaging (MRI), [ 18 F]-fluoro-deoxy-glucose-PET or by means of CSF levels of t-tau and phosphorylated tau (p-tau) (Sperling et al 2011(Sperling et al , 2014Mattsson et al 2017;Gordon et al 2018).…”