Phase 3 Trial of Flutemetamol Labeled With Radioactive Fluorine 18 Imaging and Neuritic Plaque Density

Abstract

In vivo imaging of brain β-amyloid, a hallmark of Alzheimer disease, may assist in the clinical assessment of suspected Alzheimer disease. OBJECTIVE To determine the sensitivity and specificity of positron emission tomography imaging with flutemetamol injection labeled with radioactive fluorine 18 to detect β-amyloid in the brain using neuropathologically determined neuritic plaque levels as the standard of truth. DESIGN, SETTING, AND PARTICIPANTS Open-label multicenter imaging study that took place at dementia clinics, memory centers, and hospice centers in the United States and England from June 22, 2010, to November 23, 2011. Participants included terminally ill patients who were 55 years or older with a life expectancy of less than 1 year. INTERVENTIONS Flutemetamol injection labeled with radioactive fluorine 18 (Vizamyl; GE Healthcare) administration followed by positron emission tomography imaging and subsequent brain donation. MAIN OUTCOMES AND MEASURES Sensitivity and specificity of flutemetamol injection labeled with radioactive fluorine 18 positron emission tomography imaging for brain β-amyloid. Images were reviewed without and with computed tomography scans and classified as positive or negative for β-amyloid by 5 readers who were blind to patient information. In patients who died, neuropathologically determined neuritic plaque levels were used to confirm scan interpretations and determine sensitivity and specificity. RESULTS Of 176 patients with evaluable images, 68 patients (38%) died during the study, were autopsied, and had neuritic plaque levels determined; 25 brains (37%) were β-amyloid negative; and 43 brains (63%) were β-amyloid positive. Imaging was performed a mean of 3.5 months (range, 0 to 13 months) before death. Sensitivity without computed tomography was 81% to 93% (median, 88%). Median specificity was 88%, with 4 of 5 of the readers having specificity greater than 80%. When scans were interpreted with computed tomography images, sensitivity and specificity improved for most readers but the differences were not significant. The area under the receiver operating curve was 0.90. There were no clinically meaningful findings in safety parameters. CONCLUSIONS AND RELEVANCE This study showed that flutemetamol injection labeled with radioactive fluorine 18 was safe and had high sensitivity and specificity in an end-of-life population. In vivo detection of brain β-amyloid plaque density may increase diagnostic accuracy in cognitively impaired patients.

Quantitation of PET signal as an adjunct to visual interpretation of florbetapir imaging

“…PET imaging ligands including Pittsburgh compound B ( 11 C-PIB) [2], 18 F-florbetaben [3], 18 F-flutemetamol [4] and 18 F-florbetapir [5] have been developed for estimation of cortical beta amyloid (Aβ) neuritic plaque deposition, a hallmark pathology, and a required element for the evaluation of neuropathological changes in patients with Alzheimer's disease (AD) [6]. As shown by their respective package inserts/summaries of product characteristics, as well as the published literature [7][8][9], reader accuracy in the pivotal trials for the 18 F-labeled agents averaged close to 90% for discriminating patients found at autopsy to have no or sparse neuritic plaques (amyloid-negative, Aβ−) from those found to have moderate to frequent plaques (amyloid-positive, Aβ+). However, as might be expected, within each of these development programs, there were individual readers with sensitivity or specificity values below the average, and in some with values below 80%.…”

Effect of Amyloid Imaging on the Diagnosis and Management of Patients with Cognitive Decline: Impact of Appropriate Use Criteria

“…The advent of positron emission tomography (PET) imaging agents such as Pittsburgh compound B [5], 18 F-florbetaben [6], 18 F-flutemetamol [7], and florbetapir F 18 [8,9], which bind to fibrillar β-amyloid (Aβ), has made it possible to estimate, in living patients, the density of neuritic amyloid plaques [10,11,12,13,14]. Because neuritic plaques are a required component of a pathological diagnosis of AD, PET-derived information regarding neuritic plaque density could be of value in the diagnosis of patients with cognitive impairment.…”

Amyloid Imaging: Poised for Integration into Medical Practice

“…The 2 false-negative cases became positive when CT was used to help with the anatomic details. The remaining 2 false-negative cases were borderline [32]. An additional study aimed to determine the ability of flutemetamol to detect amyloid by PET imaging in different phases of amyloid deposition and found that this approach detects a positive signal in advanced phases of amyloid deposition (phase [4][5].…”