In Vivo Imaging of Amyloid Deposition in Alzheimer Disease Using the Radioligand ¹⁸F-AV-45 (Flobetapir F 18)

Abstract

Introduction An [18F] labeled PET amyloid (Aβ) imaging agent could facilitate clinical evaluation of late-life cognitive impairment by providing an objective measure for Alzheimer’s disease (AD) pathology. Here we present the results of the first clinical trial with [18F]AV-45 (Florbetapir F 18). Methods An open-label, multicenter, brain imaging, metabolism and safety study of [18F]AV-45 was performed on 16 patients with Alzheimer’s disease (AD: MMSE 19.3 +/− 3.1; Age 75.8 +/− 9.2) and 16 cognitively healthy controls (HC: MMSE 29.8 +/− 0.45; Age 72.5 +/− 11.6 ). Dynamic PET imaging was performed over a period of approximately 90 minutes following 10 mCi injection of the tracer. Standard uptake values (SUV) and cortical to cerebellum SUV ratios (SUVR) were calculated. A simplified reference tissue method was used to generate distribution volume ratio (DVR) parametric maps in a subset of subjects Results Valid PET imaging data were available for 11 AD and 15 HC subjects [18F]AV-45 accumulated in cortical regions expected to be high in amyloid deposition (e.g., precuneus, frontal and temporal cortex) of AD patients; minimal accumulation of tracer was seen in cortical regions of HC subjects. The cortical to cerebellar SUVR values in AD patients showed continual substantial increases through 30 minutes post-administration, reaching a plateau within 50 minutes. The 10 minute period from 50–60 minutes post administration was taken as a representative sample for further analysis. The cortical average SUVR for this period was 1.67 +/− 0.175 for patients with AD vs. 1.25 +/− 0.177 for HC subjects. Spatially normalized DVRs generated from PET dynamic scans were highly correlated with SUVR (r= 0.58–0.88, p<0.005) and were significantly greater for AD patients than for HC subjects in cortical regions, but not in subcortical white matter or cerebellar regions. There were no clinically significant changes in vital signs, ECG or laboratory values. Conclusions [18F]AV-45 was well tolerated and PET imaging showed significant discrimination between AD patients and HC subjects using either a parametric reference region method (DVR) or a simplified SUVR calculated from 10 minutes of scanning 50–60 minutes after [18F]AV-45 administration.

On the early diagnosis of Alzheimer's Disease from multimodal signals: A survey

“…The accumulation of ˇA on the brain is considered a necessary but not sufficient condition to produce the clinical symptoms of MCI and dementia [34]. The presence of these plaques and tangles is eventually accompanied by the damage and death of neurons [3], and in fact, one of the most favourable hypothesis about the origin of AD nowadays is the abnormal deposition of these proteins [35][36][37]. Cerebral hypoperfusion has also been found to be more evident in AD patients than in normal adults, so other hypothesis blaming the vascular and cardiovascular problems to be the cause of this hypoperfusion which in turn could trigger dementia have been developed [38].…”

Amyloid-β imaging with PET in Alzheimer’s disease: is it feasible with current radiotracers and technologies?

“…Since amyloid plaques are, on average, approximately 50 µm in diameter and the spatial resolution of PET is normally in the range of 2 to 3 mm for high-resolution systems and 5 to 7 mm for standard scans, the partial-volume effect should theoretically be factored heavily into amyloid imaging and should not be overlooked [36,37]. And yet Wong et al explicitly state that in a phase I clinical study of florbetapir partial-volume correction was not undertaken in the analysis of data [6]. The reports of other studies on amyloid radiotracers make no mention of partial-volume correction, suggesting that this highly significant effect was also neglected in these studies.…”

“…However, the advent of three new radiotracers, which are currently at various stages of FDA assessment and approval, has brought amyloid imaging to the doorstep of clinical use. Recent clinical studies on florbetapir (AV-45), florbetaben (BAY-94), and flutemetamol (GE-067) claim to have demonstrated an ability to discriminate between AD patients and healthy controls with high degrees of sensitivity and specificity [6][7][8][9][10][11]. However, the theoretical bases of and ubiquitous patterns in the reported data raise a host of lingering questions that should be addressed before these radiotracers are clinically approved.…”

“…et al reported significant correlations between quantitative and semiquantitative measures of overall amyloid burden through imaging and histopathology, but the regional localizations of these amyloid deposits do not seem to agree with pre-existing pathological data [5]. Imaging studies conducted with florbetapir, as well as virtually any other amyloid radiotracer, consistently show the frontal lobe to have one of-if not the-highest standardized uptake values (SUVs) [6,8,9,[11][12][13][14]. This implies a preponderant amyloid burden in the frontal lobe, which is not in line with the findings of in vitro studies.…”

Synthesis and Evaluation of 5-Fluoro-2-aryloxazolo[5,4-b]pyridines as β-Amyloid PET Ligands and Identification of MK-3328

“…Several research programs have engaged in the design and discovery of 18 16,17 and AZD4694 (7). 18 Based on the preclinical and clinical data available, 12À18 we estimated that a successful amyloid imaging agent must have high affinity for β-amyloid plaque (K d < 20 nM) with minimal nonspecific binding in order to provide a large specific signal for plaque detection.…”