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Purpose: Visual interpretation of PET [18F]flutemetamol images relies on systematic review of five brain regions and is considered positive when an elevated signal is observed in at least one region. Amnestic mild cognitive impairment (aMCI) is an early clinical presentation of Alzheimer's disease (AD); hence it is of interest to determine if the pattern of visually read regional positivity between end-of-life (EoL) patients with and without dementia and aMCI patients is different. Methods: A total of 180 EoL patients with and without dementia (mean age 81 years, range 59 to 95 years) and 232 aMCI patients (mean age 71 years, range 53 to 91 years) were scanned following intravenous administration of 185–370 MBq [18F]flutemetamol. Images from both studies were read by two groups of five blinded readers who independently classified each of the five regions as either positive or negative. The majority interpretation made by at least three of the five readers was used as the imaging endpoint and compared with a composite standardized uptake value ratio (SUVR) analysis using a predetermined threshold. Results: Amyloid-positive images from 71 of 106 EoL patients coming to autopsy and from 97 aMCI patients were included. In the images from the EoL patients widespread deposition of amyloid was observed, with 76% of the images positive in all five regions and a further 20% positive in four regions. In the images from the aMCI patients, similar results were observed with 87% of the images positive in five regions and a further 5% positive in four regions. The mean SUVR of these positively read images was 2.24 (range 1.48 to 3.14) and 2.08 (range 1.28 to 3.04) in the autopsy and aMCI groups, respectively. There was 95.3% agreement between the visual reading and SUVR quantitation in the aMCI group and 90.4% agreement in the autopsy group. Conclusion: Patients with aMCI showed a similar distribution of amyloid deposition determined by both visual reading and SUVR to that observed in patients with and without dementia coming to autopsy. Most of the aMCI patients, who are already within the AD continuum, had widespread amyloid deposition in terms of amount and topographical progression. Attempts to observe potential initial signs of amyloid deposition should focus on populations earlier in the dementia spectrum such as patients with subjective cognitive decline or even at-risk subjects with earlier stages of disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A heart-to-mediastinum (H/M) ratio of 1.6 or greater on planar 123I-iobenguane (123I-MIBG) images identifies heart failure patients at low risk of experiencing an adverse cardiac event. This phase-4 study used standardized phantoms to assess the intercamera, intracamera, and interhead variability in H/M ratio determinations from planar cardiac 123I-MIBG imaging using commercially available, dual-head γ-cameras. Methods: A fillable thorax phantom was developed to simulate the typical uptake of 123I-MIBG. The phantom had a nominal H/M ratio of 1.6 on the reference camera. Commercial cameras used in the study were dual-head and capable of 90° configuration for cardiac imaging. The target sample size was 8 units (examples) per camera model. Two imaging technologists independently analyzed planar images of simulated 123I-MIBG uptake from the thorax phantom. H/M was the ratio of the average counts per pixel of the heart and mediastinum regions of interest. The primary endpoint, intercamera variability in H/M ratio from head 1, was determined for each camera model via comparison with the H/M ratio on the reference camera. Only cameras with at least 8 units tested (n ≥ 8) were included in the primary analysis. Intracamera and interhead variability in the H/M ratio were also evaluated. Results: Nine camera models were studied. The mean H/M ratio ranged from 1.342 to 1.677. The primary analysis (6 camera models) using a mixed-model, repeated-measures analysis showed no significant difference in H/M ratio between any camera model and the reference camera. Intracamera variability (head 1) in the H/M ratio among camera models with 8 units or more was high, with SDs ranging from 0.0455 to 0.1193. Interhead variability was low (SDs of the interhead difference, 0.017-0.074). Conclusion: Commonly used γ-cameras produced H/M ratios from simulated 123I-MIBG phantom images that were not significantly different from those on the reference camera. This finding indicates that the results of previous clinical trials of 123I-MIBG, involving many different clinical sites and camera models, are valid. The assessment of the performance of a given camera unit using an 123I planar phantom before H/M results from 123I-MIBG imaging are used for classifying risk in heart failure patients is encouraged. [ABSTRACT FROM AUTHOR]

In vivo imaging of fibrillar β-amyloid deposits may assist clinical diagnosis of Alzheimer's disease (AD), aid treatment selection for patients, assist clinical trials of therapeutic drugs through subject selection, and be used as an outcome measure. A recent phase III trial of [18F]flutemetamol positron emission tomography (PET) imaging in 106 end-of-life subjects demonstrated the ability to identify fibrillar β-amyloid by comparing in vivo PET to post-mortem histopathology. Post-mortem analyses demonstrated a broad and continuous spectrum of β-amyloid pathology in AD and other dementing and non-dementing disease groups. The GE067-026 trial demonstrated 91% sensitivity and 90% specificity of [18F]flutemetamol PET by majority read for the presence of moderate or frequent plaques. The probability of an abnormal [18F]flutemetamol scan increased with neocortical plaque density and AD diagnosis. All dementia cases with non-AD neurodegenerative diseases and those without histopathological features of β-amyloid deposits were [18F]flutemetamol negative. Majority PET assessments accurately reflected the amyloid plaque burden in 90% of cases. However, ten cases demonstrated a mismatch between PET image interpretations and post-mortem findings. Although tracer retention was best associated with amyloid in neuritic plaques, amyloid in diffuse plaques and cerebral amyloid angiopathy best explain three [18F]flutemetamol positive cases with mismatched (sparse) neuritic plaque burden. Advanced cortical atrophy was associated with the seven false negative [18F]flutemetamol images. The interpretation of images from pathologically equivocal cases was associated with low reader confidence and inter-reader agreement. Our results support that amyloid in neuritic plaque burden is the primary form of β-amyloid pathology detectable with [18F]flutemetamol PET imaging. ClinicalTrials.gov NCT01165554. Registered June 21, 2010; NCT02090855. Registered March 11, 2014. [ABSTRACT FROM AUTHOR]

Amyloid imaging is limited by an inconsistent relationship between cerebral cortex amyloid- β (Aβ) plaques and dementia. Autopsy studies suggest that Aβ plaques first appear in the cerebral cortex while subcortical plaques are present only later in the disease course. The presence of abundant plaques in both cortex and striatum is more strongly correlated with the presence of dementia than cortical Aβ plaques alone. Additionally, detection of striatal plaques may allow, for the first time, pathology-based clinical staging of AD. Striatal plaques are reportedly identifiable by amyloid imaging but the accuracy and reliability of striatal amyloid imaging has never been tested against postmortem histopathology. To determine this, we correlated the presence of histopathologically-demonstrated striatal Aβ deposits with a visually positive panel consensus decision of a positive [18F]flutemetamol striatal PET signal in 68 subjects that later came to autopsy. The sensitivity of [18F]flutemetamol PET striatal amyloid imaging, for several defined density levels of histological striatal Aβ deposits, ranged between 69% and 87% while the specificity ranged between 96% and 100%. Sensitivity increased with higher histological density thresholds while the reverse was found for specificity. In general, as compared with PET alone, PET with CT had slightly higher sensitivities but slightly lower specificities. In conclusion, amyloid imaging of the striatum with [18F]flutemetamol PET has reasonable accuracy for the detection of histologically-demonstrated striatal Aβ plaques when present at moderate or frequent densities. Amyloid imaging of the cerebral cortex and striatum together may allow for a more accurate clinicopathological diagnosis of AD and enable pathology-based clinical staging of AD. [ABSTRACT FROM AUTHOR]

Background Amyloid positron emission tomography (PET) has become an important tool to identify amyloid-β (Aβ) pathology in Alzheimer's disease (AD) patients. Here, we determined the diagnostic value of the amyloid PET tracer [ 18 F]flutemetamol in relation to Aβ pathology at autopsy. Methods [ 18 F]flutemetamol PET was carried out in a cohort of 68 patients included in a [ 18 F]flutemetamol amyloid PET imaging end-of-life study (GE067-007). At autopsy, AD pathology was determined and Aβ plaque pathology was classified into phases of its regional distribution (0–5). Results [ 18 F]flutemetamol PET was universally positive in cases with advanced stage postmortem Aβ pathology (Aβ phases 4 and 5). Negative amyloid PET was universally observed in nondemented or non-AD dementia cases with initial Aβ phases 1 and 2, whereas 33.3% of the phase 3 cases were positive. Conclusions [ 18 F]flutemetamol amyloid PET detects primarily advanced stages of Aβ pathology in preclinical and symptomatic AD cases. [ABSTRACT FROM AUTHOR]