Dataset Information

Validation of an electronic image reader training programme for interpretation of [18F]flutemetamol ?-amyloid PET brain images.

ABSTRACT: An electronic training programme (ETP) was developed for interpretation of images during routine clinical use of the PET amyloid imaging agent [F]flutemetamol injection (VIZAMYL). This study was carried out to validate the ETP.Five nuclear medicine technologists (NMTs) and five readers previously inexperienced in amyloid image interpretation were required to self-train using the ETP and pass a test to participate. A total of 305 [F]flutemetamol PET images were then tested as the validation set, following preassessment and reorientation (where required) by one of five NMTs. Next, a new set of readers blinded to clinical information independently assessed all 305 images. Images had been acquired in previous studies from patients representing the full spectrum of cognitive capacity. When available, a standard of truth determined by histopathology or clinical history was used to derive sensitivity and specificity for image interpretation from this validation set. Randomly selected images (n=29) were read in duplicate to measure intrareader reproducibility. Images were read first without, and subsequently with anatomic images, if available.All NMTs and all readers scored 100% on the qualifying test. The interpretation of 135 cases without anatomic image support resulted in sensitivity ranging from 84% to 94% (majority 94%, median 92%) and specificity ranging from 77% to 96% (majority 92%, median 81%). Inter-reader agreement was very high, with most ? scores more than 0.8. Intrareader reproducibility ranged from 93 to 100%.The self-guided ETP effectively trained new amyloid PET image readers to accurately and reproducibly interpret [F]flutemetamol PET images.

SUBMITTER: Buckley CJ

PROVIDER: S-EPMC5318150 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Validation of an electronic image reader training programme for interpretation of [18F]flutemetamol β-amyloid PET brain images.

Buckley Christopher J CJ Sherwin Paul F PF Smith Adrian P L AP Wolber Jan J Weick Sharon M SM Brooks David J DJ

Nuclear medicine communications 20170301 3

<h4>Objectives</h4>An electronic training programme (ETP) was developed for interpretation of images during routine clinical use of the PET amyloid imaging agent [F]flutemetamol injection (VIZAMYL). This study was carried out to validate the ETP.<h4>Materials and methods</h4>Five nuclear medicine technologists (NMTs) and five readers previously inexperienced in amyloid image interpretation were required to self-train using the ETP and pass a test to participate. A total of 305 [F]flutemetamol PE ...[more]

PMID: 27984539

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Project description:Background[18F]flutemetamol PET scanning provides information on brain amyloid load and has been approved for routine clinical use based upon visual interpretation as either negative (equating to none or sparse amyloid plaques) or amyloid positive (equating to moderate or frequent plaques). Quantitation is however fundamental to the practice of nuclear medicine and hence can be used to supplement amyloid reading methodology especially in unclear cases.MethodsA total of 2770 [18F]flutemetamol images were collected from 3 clinical studies and 6 research cohorts with available visual reading of [18F]flutemetamol and quantitative analysis of images. These were assessed further to examine both the discordance and concordance between visual and quantitative imaging primarily using thresholds robustly established using pathology as the standard of truth. Scans covered a wide range of cases (i.e. from cognitively unimpaired subjects to patients attending the memory clinics). Methods of quantifying amyloid ranged from using CE/510K cleared marked software (e.g. CortexID, Brass), to other research-based methods (e.g. PMOD, CapAIBL). Additionally, the clinical follow-up of two types of discordance between visual and quantitation (V+Q- and V-Q+) was examined with competing risk regression analysis to assess possible differences in prediction for progression to Alzheimer's disease (AD) and other diagnoses (OD).ResultsWeighted mean concordance between visual and quantitation using the autopsy-derived threshold was 94% using pons as the reference region. Concordance from a sensitivity analysis which assessed the maximum agreement for each cohort using a range of cut-off values was also estimated at approximately 96% (weighted mean). Agreement was generally higher in clinical cases compared to research cases. V-Q+ discordant cases were 11% more likely to progress to AD than V+Q- for the SUVr with pons as reference region.ConclusionsQuantitation of amyloid PET shows a high agreement vs binary visual reading and also allows for a continuous measure that, in conjunction with possible discordant analysis, could be used in the future to identify possible earlier pathological deposition as well as monitor disease progression and treatment effectiveness.

Project description:The deposition of the amyloid β-protein (Aβ) in senile plaques is one of the histopathological hallmarks of Alzheimer's disease (AD). Aβ-plaques arise first in neocortical areas and, then, expand into further brain regions in a process described by 5 phases. Since it is possible to identify amyloid pathology with radioactive-labeled tracers by positron emission tomography (PET) the question arises whether it is possible to distinguish the neuropathological Aβ-phases with amyloid PET imaging. To address this question we reassessed 97 cases of the end-of-life study cohort of the phase 3 [18F]flutemetamol trial (ClinicalTrials.gov identifiers NCT01165554, and NCT02090855) by combining the standardized uptake value ratios (SUVRs) with pons as reference region for cortical and caudate nucleus-related [18F]flutemetamol-retention. We tested them for their prediction of the neuropathological pattern found at autopsy. By defining threshold levels for cortical and caudate nucleus SUVRs we could distinguish different levels of [18F]flutemetamol uptake termed PET-Aβ phase estimates. When comparing these PET-Aβ phase estimates with the neuropathological Aβ-phases we found that PET-Aβ phase estimate 0 corresponded with Aβ-phases 0-2, 1 with Aβ-phase 3, 2 with Aβ-phase 4, and 3 with Aβ-phase 5. Classification using the PET-Aβ phase estimates predicted the correct Aβ-phase in 72.16% of the cases studied here. Bootstrap analysis was used to confirm the robustness of the estimates around this association. When allowing a range of ± 1 phase for a given Aβ-phase correct classification was given in 96.91% of the cases. In doing so, we provide a novel method to convert SUVR-levels into PET-Aβ phase estimates that can be easily translated into neuropathological phases of Aβ-deposition. This method allows direct conclusions about the pathological distribution of amyloid plaques (Aβ-phases) in vivo. Accordingly, this method may be ideally suited to detect early preclinical AD-patients, to follow them with disease progression, and to provide a more precise prognosis for them based on the knowledge about the underlying pathological phase of the disease.

Project description:Background: Blood biomarkers may aid in recruitment to clinical trials of Alzheimer's disease (AD) modifying therapeutics by triaging potential trials participants for amyloid positron emission tomography (PET) or cerebrospinal fluid (CSF) A? and tau tests. Objective: To discover a plasma proteomic signature associated with CSF and PET measures of AD pathology. Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) based proteomics were performed in plasma from participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD, recruited to the Amsterdam Dementia Cohort, stratified by CSF Tau/A?42 (n = 50). Technical replication and independent validation were performed by immunoassay in plasma from SCD, MCI, and AD participants recruited to the Amsterdam Dementia Cohort with CSF measures (n = 100), MCI participants enrolled in the GE067-005 study with [18F]-Flutemetamol PET amyloid measures (n = 173), and AD, MCI and cognitively healthy participants from the EMIF 500 study with CSF A?42 measurements (n = 494). Results: 25 discovery proteins were nominally associated with CSF Tau/A?42 (P < 0.05) with associations of ficolin-2 (FCN2), apolipoprotein C-IV and fibrinogen ? chain confirmed by immunoassay (P < 0.05). In the GE067-005 cohort, FCN2 was nominally associated with PET amyloid (P < 0.05) replicating the association with CSF Tau/A?42. There were nominally significant associations of complement component 3 with PET amyloid, and apolipoprotein(a), apolipoprotein A-I, ceruloplasmin, and PPY with MCI conversion to AD (all P < 0.05). In the EMIF 500 cohort FCN2 was trending toward a significant relationship with CSF A?42 (P ? 0.05), while both A1AT and clusterin were nominally significantly associated with CSF A?42 (both P < 0.05). Conclusion: Associations of plasma proteins with multiple measures of AD pathology and progression are demonstrated. To our knowledge this is the first study to report an association of FCN2 with AD pathology. Further testing of the proteins in larger independent cohorts will be important.

Project description:BACKGROUND:A long dynamic scanning protocol may be required to accurately measure longitudinal changes in amyloid load. However, such a protocol results in a lower patient comfort and scanning efficiency compared to static scans. A compromise can be achieved by implementing dual-time-window protocols. This study aimed to optimize these protocols for quantitative [18F]flutemetamol and [18F]florbetaben studies. METHODS:Rate constants for subjects across the Alzheimer's disease spectrum (i.e., non-displaceable binding potential (BPND) in the range 0.02-0.77 and 0.02-1.04 for [18F]flutemetamol and [18F]florbetaben, respectively) were established based on clinical [18F]flutemetamol (N?=?6) and [18F]florbetaben (N?=?20) data, and used to simulate tissue time-activity curves (TACs) of 110?min using a reference tissue and plasma input model. Next, noise was added (N?=?50) and data points corresponding to different intervals were removed from the TACs, ranging from 0 (i.e., 90-90?=?full-kinetic curve) to 80 (i.e., 10-90) minutes, creating a dual-time-window. Resulting TACs were fitted using the simplified reference tissue method (SRTM) to estimate the BPND, outliers (??1.5?×?BPND max) were removed and the bias was assessed using the distribution volume ratio (DVR?=?BPND?+?1). To this end, acceptability curves, which display the fraction of data below a certain bias threshold, were generated and the area under those curves were calculated. RESULTS:[18F]Flutemetamol and [18F]florbetaben data demonstrated an increased bias in amyloid estimate for larger intervals and higher noise levels. An acceptable bias (??3.1%) in DVR could be obtained with all except the 10-90 and 20-90-min intervals. Furthermore, a reduced fraction of acceptable data and most outliers were present for these two largest intervals (maximum percentage outliers 48 and 32 for [18F]flutemetamol and [18F]florbetaben, respectively). CONCLUSIONS:The length of the interval inversely correlates with the accuracy of the BPND estimates. Consequently, a dual-time-window protocol of 0-30 and 90-110?min (=maximum of 60?min interval) allows for accurate estimation of BPND values for both tracers. [18F]flutemetamol: EudraCT 2007-000784-19, registered 8 February 2007, [18F]florbetaben: EudraCT 2006-003882-15, registered 2006.

Project description:BackgroundAlthough amyloid PET of typical Alzheimer's disease (AD) shows diffuse ß-amyloid (Aß) deposition, some patients show focal deposition. The clinical significance of this focal Aß is not well understood. We examined the clinical significance of focal Aß deposition in terms of cognition as well as Aß and tau cerebrospinal fluid (CSF) levels. We further evaluated the order of Aß accumulation by visual assessment.MethodsWe included 310 subjects (125 cognitively unimpaired, 125 mild cognitive impairment, and 60?AD dementia) from 9 referral centers. All patients underwent neuropsychological tests and 18F-flutemetamol (FMM) PET. Seventy-seven patients underwent CSF analysis. Each FMM scan was visually assessed in 10 regions (frontal, precuneus and posterior cingulate, lateral temporal, parietal, and striatum of each hemisphere) and was classified into three groups: No-FMM, Focal-FMM (FMM uptake in 1-9 regions), and Diffuse-FMM (FMM uptake in all 10 regions).Results53/310 (17.1%) subjects were classified as Focal-FMM. The cognitive level of the Focal-FMM group was better than that of Diffuse-FMM group and worse than that of No-FMM group. Among the Focal-FMM group, those who had FMM uptake to a larger extent or in the striatum had worse cognitive levels. Compared to the Diffuse-FMM group, the Focal-FMM group had a less AD-like CSF profile (increased Aß42 and decreased t-tau, t-tau/Aß42). Among the Focal-FMM group, Aß deposition was most frequently observed in the frontal (62.3%) and least frequently observed in the striatum (43.4%) and temporal (39.6%) regions.ConclusionsWe suggest that focal Aß deposition is an intermediate stage between no Aß and diffuse Aß deposition. Furthermore, among patients with focal Aß deposition, those who have Aß to a larger extent and striatal involvement show clinical features close to diffuse Aß deposition. Further longitudinal studies are needed to evaluate the disease progression of patients with focal Aß deposition.

Project description:BACKGROUND:Recently, the block-sequential regularized expectation maximization (BSREM) reconstruction algorithm was commercially introduced (Q.Clear, GE Healthcare, Milwaukee, WI, USA). However, the combination of noise-penalizing factor (β), acquisition time, and administered activity for optimal image quality has not been established for 18F-fluorocholine (FCH). The aim was to compare image quality and diagnostic performance of different reconstruction protocols for patients with prostate cancer being examined with 18F-FCH on a silicon photomultiplier-based PET-CT. Thirteen patients were included, injected with 4 MBq/kg, and images were acquired after 1 h. Images were reconstructed with frame durations of 1.0, 1.5, and 2.0 min using β of 150, 200, 300, 400, 500, and 550. An ordered subset expectation maximization (OSEM) reconstruction with a frame duration of 2.0 min was used for comparison. Images were quantitatively analyzed regarding standardized uptake values (SUV) in metastatic lymph nodes, local background, and muscle to obtain contrast-to-noise ratios (CNR) as well as the noise level in muscle. Images were analyzed regarding image quality and number of metastatic lymph nodes by two nuclear medicine physicians. RESULTS:The highest median CNR was found for BSREM with a β of 300 and a frame duration of 2.0 min. The OSEM reconstruction had the lowest median CNR. Both the noise level and lesion SUVmax decreased with increasing β. For a frame duration of 1.5 min, the median quality score was highest for β 400-500, and for a frame duration of 2.0 min the score was highest for β 300-500. There was no statistically significant difference in the number of suspected lymph node metastases between the different image series for one of the physicians, and for the other physician the number of lymph nodes differed only for one combination of image series. CONCLUSIONS:To achieve acceptable image quality at 4 MBq/kg 18F-FCH, we propose using a β of 400-550 with a frame duration of 1.5 min. The lower β should be used if a high CNR is desired and the higher if a low noise level is important.

Dataset Information

Validation of an electronic image reader training programme for interpretation of [18F]flutemetamol ?-amyloid PET brain images.

Publications

Validation of an electronic image reader training programme for interpretation of [18F]flutemetamol β-amyloid PET brain images.

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