Using PET with 18F-AV-45 (florbetapir) to quantify brain amyloid load in a clinical environment

V. Camus 0 1 P. Payoux 0 1 L. Barr 0 1 B. Desgranges 0 1 T. Voisin 0 1 C. Tauber 0 1 R. La Joie 0 1 M. Tafani 0 1 C. Hommet 0 1 G. Chtelat 0 1 K. Mondon 0 1 V. de La Sayette 0 1 J. P. Cottier 0 1 E. Beaufils 0 1 M. J. Ribeiro 0 1 V. Gissot 0 1 E. Vierron 0 1 J. Vercouillie 0 1 B. Vellas 0 1 F. Eustache 0 1 D. Guilloteau 0 1 V. Camus 0 1 : C. Tauber : C. Hommet : K. Mondon : J. P. Cottier : E. Beaufils : M. J. Ribeiro : E. Vierron : J. Vercouillie : D. Guilloteau UMR INSERM U 0 1 -CNRS ERL 0 1 Tours 0 1 France e-mail: 0 1 0 L. Barr Universit de Caen Basse Normandie , Caen, France 1 L. Barr Groupe de Dveloppements Mthodologiques en Tomographie par mission de Positons, CEA/DSV/I2BM/CI-NAPS UMR6232, Caen, France Purpose Positron emission tomography (PET) imaging of brain amyloid load has been suggested as a core biomarker for Alzheimer's disease (AD). The aim of this study was to test the feasibility of using PET imaging with 18F-AV-45 (florbetapir) in a routine clinical environment to differentiate between patients with mild to moderate AD and mild cognitive impairment (MCI) from normal healthy controls (HC). Methods In this study, 46 subjects (20 men and 26 women, mean age of 69.07.6 years), including 13 with AD, 12 with MCI and 21 HC subjects, were enrolled from three academic memory clinics. PET images were acquired over a 10-min period 50 min after injection of florbetapir (mean SD of - radioactivity injected, 259 57 MBq). PET images were assessed visually by two individuals blinded to any clinical information and quantitatively via the standard uptake value ratio (SUVr) in the specific regions of interest, which were defined in relation to the cerebellum as the reference region. Results The mean values of SUVr were higher in AD patients (median 1.20, Q1-Q3 1.16-1.30) than in HC subjects (median 1.05, Q1-Q3 1.04-1.08; p0 0.0001) in the overall cortex and all cortical regions (precuneus, anterior and posterior cingulate, and frontal median, temporal, parietal and occipital cortex). The MCI subjects also showed a higher uptake of florbetapir in the posterior cingulate cortex (median 1.06, Q1-Q3 0.971.28) compared with HC subjects (median 0.95, Q1-Q3 0.821.02; p0 0.03). Qualitative visual assessment of the PET scans showed a sensitivity of 84.6% (95% CI 0.550.98) and a specificity of 38.1% (95% CI 0.180.62) for discriminating AD patients from HC subjects; however, the quantitative assessment of the global cortex SUVr showed a sensitivity of 92.3% and specificity of 90.5% with a cut-off value of 1.122 (area under the curve 0.894). Conclusion These preliminary results suggest that PET with florbetapir is a safe and suitable biomarker for AD that can be used routinely in a clinical environment. However, the low specificity of the visual PET scan assessment could be improved by the use of specific training and automatic or semiautomatic quantification tools. The use of positron emission tomography (PET) imaging with probes that bind specifically to -amyloid and tau aggregates has received increased attention recently because this technique may provide an earlier diagnosis of Alzheimers disease (AD). Currently, AD [1, 2] must reach the dementia stage, in which cognitive and noncognitive symptoms significantly alter activities of daily living, to be clinically diagnosed. However, disease symptoms are considered a consequence of the cumulative burden of brain alterations that may begin to appear years before initial clinical manifestations [3, 4]. Consequently, the new AD diagnostic criteria suggest that the diagnosis of "prodromal AD" (also called the AD predementia stage) [5] or "MCI due to AD pathology" [6] should rely on invivo biomarkers of amyloid pathology, such as PET imaging that uses ligands of amyloid plaques and degenerative neurofibrillary tangles. Among the candidate probes, 11C-labelled tracers have been extensively studied. The PIB compound (N-methyl-[11C]2-(4-methylaminophenyl)-6-hydroxybenzothiazole), a derivative of thioflavin T, was the first to demonstrate the ability to clearly distinguish AD patients from healthy control (HC) subjects [7]. PET imaging with 11C-PIB has also been used to efficiently differentiate patients with mild cognitive impairment (MCI) who have converted to AD from nonconverters [8], and to estimate the decreased amyloid load in patients treated with bapineuzumab [9]. Nevertheless, 11C-PIB uptake is also increased in nondemented elderly subjects [10] and shows a variable level of agreement with other biomarkers, such as cerebrospinal fluid (CSF) dosage of A [11]. Another 11C-labelled, benzoxazole-derived compound, 11C-BF-227, has good neocortical uptake in AD patients [12] and appears to be able to discriminate MCI converters from nonconverters better than voxel-based morphometry using magnetic resonance imaging (MRI) [13, 14]. However, the 20-min radioactive half-life of both 11C-PIB and 11C-BF-227 is a serious barrier to increasing the accessibility of biomarkers for routine clinical purposes, as the use of these markers is limited to centres with an on-site cyclotron. Consequently, 18F-labelled amyloid ligands appear to be the best alternative, as the 110-min half-life of 18F allows the centralized production and locoregional delivery of compounds, similar to other PET radiotracers, such as 18F-FDG. Several clinical studies have been conducted with a new naphthalene family compound, 2-(1-{6-[(2-18F-fluoroethyl) (methyl)amino]-2-naphthyl}ethylidene)malononitrile (18FFDDNP). PET with 18F-FDDNP has demonstrated the ability to discriminate between HC subjects, MCI patients and AD patients [15]. However, 18F-FDDNP has limitations because of its low metabolic stability and its high white matter binding [16]. More recently, the standard uptake value ratio (SUVr) of 18F-labelled PIB (18F-flutemetamol) was observed to be highly correlated with the SUVr of its parent molecule, 11C-PIB [17]. However, another family of 18F-labelled ligands derived from stilbene has been developed, and two compounds belonging to this family (AV-1 and AV-45) display favourable properties for brain amyloid PET imaging. 18F-AV1 (BAY-949172, florbetaben) has brain kinetic characteristics appropriate for clinical use. When studied 90 to 120 min after injection, the level of cortical uptake clearly distinguished 15 AD patients from 15 healthy elderly subjects [18]. A recent phase II study has shown that the visual rating of PET scans with florbetaben has sufficient sensitivity (80%) and specificity (91%) to distinguish AD patients from HC subjects [19]. The last stilbene family derivative, 18F-AV-45 (florbetapir) [20], also has strong affinity for amyloid proteins in AD brain homogenates (ki 103.3 nM) and faster in vivo kinetics [21]. The use of florbetapir in amyloid imaging has recently been validated in an autopsy study [22], and its safety profile allows clinical applications in brain imaging [23]. A pilot study comparing 16 AD patients with 16 HC (...truncated)