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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]

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) Aβ 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/Aβ 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 [ 18 F]-Flutemetamol PET amyloid measures ( n = 173), and AD, MCI and cognitively healthy participants from the EMIF 500 study with CSF Aβ 42 measurements ( n = 494). Results: 25 discovery proteins were nominally associated with CSF Tau/Aβ 42 ( P < 0.05) with associations of ficolin-2 (FCN2), apolipoprotein C-IV and fibrinogen β 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/Aβ 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 Aβ 42 ( P ≈ 0.05), while both A1AT and clusterin were nominally significantly associated with CSF Aβ 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.

A heart-to-mediastinum (H/M) ratio of 1.6 or greater on planar 123 I-iobenguane ( 123 I-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 123 I-MIBG imaging using commercially available, dual-head γ-cameras. Methods: A fillable thorax phantom was developed to simulate the typical uptake of 123 I-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 123 I-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 123 I-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 123 I-MIBG, involving many different clinical sites and camera models, are valid. The assessment of the performance of a given camera unit using an 123 I planar phantom before H/M results from 123 I-MIBG imaging are used for classifying risk in heart failure patients is encouraged., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)