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. 2021 Jul;48(7):2169-2182.
doi: 10.1007/s00259-020-05174-2. Epub 2021 Feb 22.

Visual assessment of [18F]flutemetamol PET images can detect early amyloid pathology and grade its extent

Lyduine E Collij #  1 , Gemma Salvadó #  2   3 , Mahnaz Shekari  2 , Isadora Lopes Alves  1 , Juhan Reimand  4   5   6 , Alle Meije Wink  1 , Marissa Zwan  4 , Aida Niñerola-Baizán  7 , Andrés Perissinotti  7 , Philip Scheltens  4 , Milos D Ikonomovic  8   9   10 , Adrian P L Smith  11 , Gill Farrar  11 , José Luis Molinuevo  2   3   9   12   13 , Frederik Barkhof  1   14 , Christopher J Buckley  11 , Bart N M van Berckel  15   16 , Juan Domingo Gispert  17   18   19   20   21 ; ALFA study; AMYPAD consortium
Affiliations

Visual assessment of [18F]flutemetamol PET images can detect early amyloid pathology and grade its extent

Lyduine E Collij et al. Eur J Nucl Med Mol Imaging. 2021 Jul.

Abstract

Purpose: To investigate the sensitivity of visual read (VR) to detect early amyloid pathology and the overall utility of regional VR.

Methods: [18F]Flutemetamol PET images of 497 subjects (ALFA+ N = 352; ADC N = 145) were included. Scans were visually assessed according to product guidelines, recording the number of positive regions (0-5) and a final negative/positive classification. Scans were quantified using the standard and regional Centiloid (CL) method. The agreement between VR-based classification and published CL-based cut-offs for early (CL = 12) and established (CL = 30) pathology was determined. An optimal CL cut-off maximizing Youden's index was derived. Global and regional CL quantification was compared to VR. Finally, 28 post-mortem cases from the [18F]flutemetamol phase III trial were included to assess the percentage agreement between VR and neuropathological classification of neuritic plaque density.

Results: VR showed excellent agreement against CL = 12 (κ = .89, 95.2%) and CL = 30 (κ = .88, 95.4%) cut-offs. ROC analysis resulted in an optimal CL = 17 cut-off against VR (sensitivity = 97.9%, specificity = 97.8%). Each additional positive VR region corresponded to a clear increase in global CL. Regional VR was also associated with regional CL quantification. Compared to mCERADSOT-based classification (i.e., any region mCERADSOT > 1.5), VR was in agreement in 89.3% of cases, with 13 true negatives, 12 true positives, and 3 false positives (FP). Regional sparse-to-moderate neuritic and substantial diffuse Aβ plaque was observed in all FP cases. Regional VR was also associated with regional plaque density.

Conclusion: VR is an appropriate method for assessing early amyloid pathology and that grading the extent of visual amyloid positivity could present clinical value.

Keywords: Amyloid PET; Centiloid; Neuropathology; Regional visual read; Sensitivity; [18F]flutemetamol.

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Conflict of interest statement

Lyduine E. Collij; Gemma Salvadó; Mahnaz Shekari; Isadora Lopes Alves; Juhan Reimand; Alle Meije Wink; Marissa Zwan; Aida Niñerola-Baizán & Andrés Perissinotti all report no existing potential conflicts of interest relevant to this article.

Prof. Philip Scheltens received grants from GE Healthcare, Piramal, and Merck, paid to his institution; he has received speaker’s fees paid to the institution Alzheimer Center, VU University Medical Center, Lilly, GE Healthcare, and Roche.

Prof. Frederik Barkhof received payment and honoraria from Bayer-Schering Pharma, Sanofi-Aventis, Genzyme, Biogen-Idec, TEVA, Merck-Serono, Novartis, Roche, Jansen Research, IXICO Ltd., GeNeuro, and Apitope Ltd. for consulting; payment from the Serono Symposia Foundation, IXICOLtd, and MedScape for educational presentations; research support via grants from EU/EFPIA Innovative Medicines Initiative Joint Undertaking (AMYPAD consortium), EuroPOND (H2020), UK MS Society, Dutch MS Society, PICTURE (IMDI-NWO), NIHR UCLH Biomedical Research Centre (BRC), ECTRIMS-MAGNIMS.

Prof. J. L. Molinuevo is currently a full-time employee of Lundbeck and priory has served as a consultant or at advisory boards for the following for-profit companies, or has given lectures in symposia sponsored by the following for-profit companies: Roche Diagnostics, Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, Alector, BioCross, GE Healthcare, ProMIS Neurosciences. He also received research support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking AMYPAD grant agreement n° 115952; the EU/EFPIA Innovative Medicines Initiative Joint Undertaking EPAD grant agreement n° 115736; the EU/EFPIA Innovative Medicines Initiative Joint Undertaking AETIONOMY grant n° 115568; and ‘la Caixa’ Foundation.

Dr. J.D. Gispert has received speaker’s fees from Biogen and Philips. In addition he holds a ‘Ramón y Cajal’ fellowship (RYC-2013-13054) from the Spanish Ministry of Economy and Competitiveness, has received research support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking AMYPAD grant agreement n° 115952, and from Ministerio de Ciencia y Universidades (grant agreement RTI2018-102261).

Prof. BN.M. van Berckel received research support from ZON-MW, AVID radiopharmaceuticals, CTMM and Janssen Pharmaceuticals. BvB is a trainer for Piramal and GE; he receives no personal honoraria.

G Farrar, C Buckley and APL Smith are full-time employees of GE Healthcare.

MD Ikonomovic has received research funding from GE Healthcare.

No other potential conflicts of interest relevant to this article exist.

Figures

Fig. 1
Fig. 1
Visual read against global Centiloid. a Plots shows all 497 subjects ordered by global amyloid burden expressed in Centiloid units. The green line illustrates the CL = 12 cut-off as proposed by La Joie and colleagues (2019) based on post-mortem comparison and by Salvadó and colleagues (2019) based on CSF Aβ42. The red line illustrates the CL = 30 cut-off as previously proposed by Salvadó and colleagues compared to CSF p-tau/Aβ42, which was suggested to indicate the presence of established pathology. Finally, the orange line represents the optimal CL = 17 cut-off according the data-driven ROC analyses of this dataset using the Youden Index. b Centiloid values significantly increase per additional visually positive region. Post hoc analyses showed significant differences between all groups. p < 0.1; *p < 0.05; **p < 0.01; ***p < 0.001
Fig. 2
Fig. 2
Regional visual read against regional quantification. Boxplots represent the regional visual assessment against regional amyloid burden, with quantification expressed in both Centiloid (y-axis left) and SUVR (y-axis right) units. PC/PCC: precuneus/posterior cingulate cortex; SUVR: standardized uptake value ratio; VR: visual read
Fig. 3
Fig. 3
Patterns of visually positive regions. Bar graph represents number of subjects in each visual read group. In total, 10 combinations of regional amyloid positivity were observed. Blue represents the ALFA+ cognitively unimpaired subjects and red represents the ADC clinical cohort. PC/PCC: precuneus/posterior cingulate cortex; VR: visual read
Fig. 4
Fig. 4
Example [18F]flutemetamol images. A series of 10 [18F]flutemetamol scans form the ALFA+ cohort ordered based on Centiloid values are shown. Upper panel illustrates which regions were visually assessed as positive. From top to bottom, axial, coronal, and sagittal images are provided. White arrows highlight specific regional amyloid uptake. Note, that the main differences between VR- (left panel) and early amyloid accumulation (second to fourth panel) can be observed basal frontally on the axial image and in the orbitofrontal and precuneal regions on the sagittal images. PC/PCC: precuneus/posterior cingulate cortex; VR: visual read
Fig. 5
Fig. 5
Visual read false positive cases. PC/PCC: precuneus/posterior cingulate cortex; MFL: midfrontal lobe; ACG: anterior cingulate gyrus; PCG: posterior cingulate gyrus; PRC: precuneus; IPC: inferior parietal cortex; STG: superior temporal gyrus; MTG: middle temporal gyrus; LBD: lewy body dementia; AD: Alzheimer’s dementia
Fig. 6
Fig. 6
Visual read against neuropathological burden measured with mCERADSOT. Boxplots represent the regional visual assessment (x-axis) against regional amyloid neuropathological burden (y-axis). Dotted line represents the cut-off for sparse-to-moderate (mCERADSOT = 1) and the full line the cut-off for moderate-to-frequent neuritic plaques (mCERADSOT > 1.5). MFL: midfrontal lobe; ACG: anterior cingulate gyrus; PCG: posterior cingulate gyrus; PRC: precuneus; IPC: inferior parietal cortex; STG: superior temporal gyrus; MTG: middle temporal gyrus; mCERADSOT: modfied CERAD standard of truth; VR: visual read
See this image and copyright information in PMC

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