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Fang, X. T., Hultqvist, G., Meier, S. R., Antoni, G., Sehlin, D. & Syvänen, S. (2019). High detection sensitivity with antibody-based PET radioligand for amyloid beta in brain. NeuroImage, 184, 881-888
Open this publication in new window or tab >>High detection sensitivity with antibody-based PET radioligand for amyloid beta in brain
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2019 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 184, p. 881-888Article in journal (Refereed) Published
Abstract [en]

PET imaging of amyloid-beta (A beta) deposits in brain has become an important aid in Alzheimer's disease diagnosis, and an inclusion criterion for patient enrolment into clinical trials of new anti-A beta treatments. Available PET radioligands visualizing A beta bind to insoluble fibrils, i.e. A beta plaques. Levels of prefibrillar A beta forms, e.g. soluble oligomers and protofibrils, correlate better than plaques with disease severity and these soluble species are the neurotoxic form of A beta leading to neurodegeneration. The goal was to create an antibody-based radioligand, recognizing not only fibrillary A beta , but also smaller and still soluble aggregates. We designed and expressed a small recombinant bispecific antibody construct, di-scFv 3D6-8D3, targeting the A beta N-terminus and the transferrin receptor (TfR). Natively expressed at the blood-brain barrier (BBB), TfR could thus be used as a brain-blood shuttle. Di-scFv 3D6-8D3 bound to A beta 1-40 with high affinity and to TfR with moderate affinity. Di-scFv [I-124] 3D6-8D3 was injected in two transgenic mouse models overexpressing human A beta and wild-type control mice and PET scanned at 14, 24 or 72 h after injection. Di-scFv [I-124] 3D6-8D3 was retained in brain of transgenic animals while it was cleared from wild-type lacking A beta . This difference was observed from 24 h onwards, and at 72 h, 18 months old transgenic animals, with high load of A beta pathology, displayed SUVR of 2.2-3.5 in brain while wildtype showed ratios close to unity. A subset of the mice were also scanned with [C-11] PIB. Again wt mice displayed ratios of unity while transgenes showed slightly, non-significantly, elevated SUVR of 1.2, indicating improved sensitivity with novel di-scFv [I-124] 3D6-8D3 compared with [C-11] PIB. Brain concentrations of di-scFv [I-124] 3D6-8D3 correlated with soluble A beta (p < 0.0001) but not with total A beta, i.e. plaque load (p = 0.34). We have successfully created a small bispecific antibody-based radioligand capable of crossing the BBB, subsequently binding to and visualizing intrabrain A beta in vivo. The radioligand displayed better sensitivity compared with [C-11] PIB, and brain concentrations correlated with soluble neurotoxic A beta aggregates.

Keywords
Alzheimer's disease, Amyloid beta, PET, Antibody-based radioligand, Transferrin receptor, Brain
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-332464 (URN)10.1016/j.neuroimage.2018.10.011 (DOI)000449385000075 ()30300753 (PubMedID)
Funder
Swedish Research Council, 2012-1593Swedish Research Council, 2017-02413
Available from: 2017-10-27 Created: 2017-10-27 Last updated: 2019-01-15Bibliographically approved
Coenen, H. H., Gee, A. D., Adam, M., Antoni, G., Cutler, C. S., Fujibayashi, Y., . . . Windhorst, A. D. (2019). Open letter to journal editors on: International Consensus Radiochemistry Nomenclature Guidelines. CLINICAL AND TRANSLATIONAL IMAGING, 7(1), 61-63
Open this publication in new window or tab >>Open letter to journal editors on: International Consensus Radiochemistry Nomenclature Guidelines
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2019 (English)In: CLINICAL AND TRANSLATIONAL IMAGING, ISSN 2281-5872, Vol. 7, no 1, p. 61-63Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
SPRINGER-VERLAG ITALIA SRL, 2019
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-378235 (URN)10.1007/s40336-018-00310-3 (DOI)000458743500008 ()
Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved
Jonasson, M., Wall, A., Chiotis, K., Leuzy, A., Eriksson, J., Antoni, G., . . . Lubberink, M. (2019). Optimal timing of tau pathology imaging and automatic extraction of a reference region using dynamic [18F]THK5317 PET.. NeuroImage: Clinical, 22, Article ID 101681.
Open this publication in new window or tab >>Optimal timing of tau pathology imaging and automatic extraction of a reference region using dynamic [18F]THK5317 PET.
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2019 (English)In: NeuroImage: Clinical, ISSN 0353-8842, E-ISSN 2213-1582, Vol. 22, article id 101681Article in journal (Refereed) Published
Abstract [en]

[18F]THK5317 is a PET tracer for in-vivo imaging of tau associated with Alzheimer's disease (AD). This work aimed to evaluate optimal timing for standardized uptake value ratio (SUVR) measures with [18F]THK5317 and automated generation of SUVR-1 and relative cerebral blood flow (R1) parametric images. Nine AD patients and nine controls underwent 90 min [18F]THK5317 scans. SUVR-1 was calculated at transient equilibrium (TE) and for seven different 20 min intervals and compared with distribution volume ratio (DVR; reference Logan). Cerebellar grey matter (MRI) was used as reference region. A supervised cluster analysis (SVCA) method was implemented to automatically generate a reference region, directly from the dynamic PET volume without the need of a structural MRI scan, for computation of SUVR-1 and R1 images for a scan duration matching the optimal timing. TE was reached first in putamen, frontal- and parietal cortex at 22 ± 4 min for AD patients and in putamen at 20 ± 0 min in controls. Over all regions and subjects, SUVR20-40-1 correlated best with DVR-1, R2 = 0.97. High correlation was found between values generated using MRI- and SVCA-based reference (R2 = 0.93 for SUVR20-40-1; R2 = 0.94 for R1). SUVR20-40 allows for accurate semi-quantitative assessment of tau pathology and SVCA may be used to obtain a reference region for calculation of both SUVR-1 and R1 with 40 min scan duration.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Alzheimer's disease, PET, Parametric images, Supervised clustering, Tau imaging
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-382941 (URN)10.1016/j.nicl.2019.101681 (DOI)000470123000005 ()30710871 (PubMedID)
Funder
Swedish Research Council, 05817Stockholm County CouncilGun och Bertil Stohnes StiftelseThe Karolinska Institutet's Research FoundationThe Swedish Brain FoundationSwedish Foundation for Strategic Research EU, FP7, Seventh Framework Programme
Available from: 2019-05-07 Created: 2019-05-07 Last updated: 2019-06-26Bibliographically approved
Persson, J., Szalisznyo, K., Antoni, G., Wall, A., Fällmar, D., Zora, H. & Bodén, R. (2019). Phosphodiesterase 10A levels are related to striatal function in schizophrenia: a combined positron emission tomography and functional magnetic resonance imaging study. European Archives of Psychiatry and Clinical Neuroscience
Open this publication in new window or tab >>Phosphodiesterase 10A levels are related to striatal function in schizophrenia: a combined positron emission tomography and functional magnetic resonance imaging study
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2019 (English)In: European Archives of Psychiatry and Clinical Neuroscience, ISSN 0940-1334, E-ISSN 1433-8491Article in journal (Refereed) Published
Abstract [en]

Pharmacological inhibition of phosphodiesterase 10A (PDE10A) is being investigated as a treatment option in schizophrenia. PDE10A acts postsynaptically on striatal dopamine signaling by regulating neuronal excitability through its inhibition of cyclic adenosine monophosphate (cAMP), and we recently found it to be reduced in schizophrenia compared to controls. Here, this finding of reduced PDE10A in schizophrenia was followed up in the same sample to investigate the effect of reduced striatal PDE10A on the neural and behavioral function of striatal and downstream basal ganglia regions. A positron emission tomography (PET) scan with the PDE10A ligand [11C]Lu AE92686 was performed, followed by a 6 min resting-state magnetic resonance imaging (MRI) scan in ten patients with schizophrenia. To assess the relationship between striatal function and neurophysiological and behavioral functioning, salience processing was assessed using a mismatch negativity paradigm, an auditory event-related electroencephalographic measure, episodic memory was assessed using the Rey auditory verbal learning test (RAVLT) and executive functioning using trail-making test B. Reduced striatal PDE10A was associated with increased amplitude of low-frequency fluctuations (ALFF) within the putamen and substantia nigra, respectively. Higher ALFF in the substantia nigra, in turn, was associated with lower episodic memory performance. The findings are in line with a role for PDE10A in striatal functioning, and suggest that reduced striatal PDE10A may contribute to cognitive symptoms in schizophrenia.

National Category
Psychiatry Neurosciences
Identifiers
urn:nbn:se:uu:diva-392015 (URN)10.1007/s00406-019-01021-0 (DOI)
Available from: 2019-08-28 Created: 2019-08-28 Last updated: 2019-08-28Bibliographically approved
Coenen, H. H., Gee, A. D., Adam, M., Antoni, G., Cutler, C. S., Fujibayashi, Y., . . . Windhorst, A. D. (2019). Status of the 'consensus nomenclature rules in radiopharmaceutical sciences' initiative. Nuclear Medicine and Biology, 71, 19-22
Open this publication in new window or tab >>Status of the 'consensus nomenclature rules in radiopharmaceutical sciences' initiative
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2019 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 71, p. 19-22Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-390341 (URN)10.1016/j.nucmedbio.2019.05.001 (DOI)000475837000003 ()31128474 (PubMedID)
Available from: 2019-08-09 Created: 2019-08-09 Last updated: 2019-08-09Bibliographically approved
Gonzalez, M. A. C., Nordeman, P., Gomez, A. B., Meyer, D. N., Antoni, G., Schou, M. & Szabo, K. J. (2018). [18F]fluoro-benziodoxole: a no-carrier-added electrophilic fluorinating reagent. Rapid, simple radiosynthesis, purification and application for fluorine-18 labelling. Chemical Communications, 54(34), 4286-4289
Open this publication in new window or tab >>[18F]fluoro-benziodoxole: a no-carrier-added electrophilic fluorinating reagent. Rapid, simple radiosynthesis, purification and application for fluorine-18 labelling
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2018 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 54, no 34, p. 4286-4289Article in journal (Refereed) Published
Abstract [en]

Operationally simple radiosynthesis and purification of [F-18]fluoro-benziodoxole was developed starting from a cyclotron produced [F-18]F- precursor, [F-18]TBAF, and tosyl-benziodoxole. The synthetic utility of [F-18]fluoro-benziodoxole was demonstrated by electrophilic fluorocyclization of o-styrilamides proceeding with high RCC (typically 50-90%) and high molar activity (up to 396 GBq mol(-1)).

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-354948 (URN)10.1039/c8cc00526e (DOI)000430935200013 ()29632936 (PubMedID)
Funder
VINNOVASwedish Research Council
Available from: 2018-06-25 Created: 2018-06-25 Last updated: 2018-06-25Bibliographically approved
Olsen, M., Aguilar, X., Sehlin, D., Fang, X. T., Antoni, G., Erlandsson, A. & Syvänen, S. (2018). Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer's Disease. Molecular Imaging and Biology, 20(4), 605-614
Open this publication in new window or tab >>Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer's Disease
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2018 (English)In: Molecular Imaging and Biology, ISSN 1536-1632, E-ISSN 1860-2002, Vol. 20, no 4, p. 605-614Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-beta (A beta) deposition, hyperphosphorylation of tau, and neuroinflammation. Astrocytes, the most abundant glial cell type in the nervous system, respond to neurodegenerative disorders through astrogliosis, i.e., converting to a reactive inflammatory state. The aim of this study was to investigate how in vivo quantification of astrogliosis using positron emission tomography (PET) radioligand deuterium-l-[C-11]deprenyl ([C-11]DED), binding to enzyme monoamine oxidase-B (MAO-B) which is overexpressed in reactive astrocytes during AD, corresponds to expression of glial fibrillary acidic protein (GFAP) and vimentin, i.e., two well-established markers of astrogliosis, during A beta pathology progression. APP(ArcSwe) mice (n = 37) and wild-type (WT) control mice (n = 23), 2-16-month old, were used to investigate biomarkers of astrogliosis. The radioligand, [C-11]DED, was used as an in vivo marker while GFAP, vimentin, and MAO-B were used to investigate astrogliosis and macrophage-associated lectin (Mac-2) to investigate microglia/macrophage activation by immunohistochemistry of the mouse brain. A beta and GFAP levels were also measured with ELISA in brain homogenates. The intrabrain levels of aggregated A beta and reactive astrocytes were found to be elevated in APP(ArcSwe) compared with WT mice. GFAP and vimentin expression increased with age, i.e., with A beta pathology, in the APP(ArcSwe) mice. This was not the case for in vivo marker [C-11]DED that showed elevated binding of the same magnitude in APP(ArcSwe) mice compared with WT mice at both 8 and 16 months. Further, immunohistochemistry indicated that there was limited co-expression of MAO-B and GFAP. MAO-B levels are increased early in A beta pathology progression, while GFAP and vimentin appear to increase later, most likely as a consequence of abundant A beta plaque formation. Thus, [C-11]DED is a useful PET radioligand for the detection of changes in MAO-B at an early stage of AD progression but does not measure the total extent of astrogliosis at advanced stages of A beta pathology.

Place, publisher, year, edition, pages
SPRINGER, 2018
Keywords
PET, Amyloid-beta, Astrocytes, Astrogliosis, MAO-B, GFAP, Vimentin, [C-11]DED
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:uu:diva-361033 (URN)10.1007/s11307-017-1153-z (DOI)000438457800010 ()29297157 (PubMedID)
Funder
The Swedish Brain FoundationGun och Bertil Stohnes Stiftelse
Available from: 2018-09-21 Created: 2018-09-21 Last updated: 2018-09-21Bibliographically approved
Nordeman, P., Yngve, U., Wilking, H., Gustavsson, S. Å., Eriksson, J. & Antoni, G. (2018). Automated GMP-production of α-[11 C]methyl-L-tryptophan using a tracer production system (TPS). Journal of labelled compounds & radiopharmaceuticals, 61(14), 1106-1109
Open this publication in new window or tab >>Automated GMP-production of α-[11 C]methyl-L-tryptophan using a tracer production system (TPS)
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2018 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 61, no 14, p. 1106-1109Article in journal (Refereed) Published
Abstract [en]

The radiosynthesis and GMP validation of [11 C]AMT for human use are described. Three consecutive batches were produced giving 940-3790 MBq (4%-17% RCY, decay corrected, based on [11 C]CO2 ) of the tracer. The molar activity at the end of synthesis was 19 to 35 GBq/μmol, the radiochemical purity was ≥98%, and the enantiomeric purity was >99%. While the synthesis method was automated using a new generation of synthesis equipment, tracer production system developed in house, the method should be readily applicable to other synthesis platforms with minor modifications.

Keywords
[11C]AMT, automation, methyl iodide, positron emission tomography, tracer production system
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-368809 (URN)10.1002/jlcr.3648 (DOI)000453709100011 ()29902836 (PubMedID)
Available from: 2018-12-07 Created: 2018-12-07 Last updated: 2019-01-15Bibliographically approved
Lindström, E., Sundin, A., Trampal, C., Lindsjö, L., Ilan, E., Danfors, T., . . . Lubberink, M. (2018). Evaluation of penalized likelihood estimation reconstruction on a digital time-of-flight PET/CT scanner for 18F-FDG whole-body examinations. Journal of Nuclear Medicine, 59(7), 1152-1158
Open this publication in new window or tab >>Evaluation of penalized likelihood estimation reconstruction on a digital time-of-flight PET/CT scanner for 18F-FDG whole-body examinations
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2018 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 59, no 7, p. 1152-1158Article in journal (Refereed) Published
Abstract [en]

The resolution and quantitative accuracy of PET are highly influenced by the reconstruction method. Penalized-likelihood estimation algorithms allow for fully convergent iterative reconstruction, generating a higher image contrast than ordered-subsets expectation maximization (OSEM) while limiting noise. In this study, a type of penalized reconstruction known as block-sequential regularized expectation maximization (BSREM) was compared with time-of-flight OSEM (TOF OSEM). Various strengths of noise penalization factor β were tested along with various acquisition durations and transaxial fields of view (FOVs) with the aim of evaluating the performance and clinical use of BSREM for 18F-FDG PET/CT, both quantitatively and in a qualitative visual evaluation. Methods: Eleven clinical whole-body 18F-FDG PET/CT examinations acquired on a digital TOF PET/CT scanner were included. The data were reconstructed using BSREM with point-spread function recovery and β-factors of 133, 267, 400, and 533—and using TOF OSEM with point-spread function—for various acquisition times per bed position and various FOVs. Noise level, signal-to-noise ratio (SNR), signal-to-background ratio (SBR), and SUV were analyzed. A masked evaluation of visual image quality, rating several aspects, was performed by 2 nuclear medicine physicians to complement the analysis. Results: The lowest levels of noise were reached with the highest β-factor, resulting in the highest SNR, which in turn resulted in the lowest SBR. A β-factor of 400 gave noise equivalent to TOF OSEM but produced a significant increase in SUVmax (11%), SNR (22%), and SBR (12%). BSREM with a β-factor of 533 at a decreased acquisition duration (2 min/bed position) was comparable to TOF OSEM at a full acquisition duration (3 min/bed position). Reconstructed FOV had an impact on BSREM outcome measures; SNR increased and SBR decreased when FOV was shifted from 70 to 50 cm. The evaluation of visual image quality resulted in similar scores for reconstructions, although a β-factor of 400 obtained the highest mean whereas a β-factor of 267 was ranked best in overall image quality, contrast, sharpness, and tumor detectability. Conclusion: In comparison with TOF OSEM, penalized BSREM reconstruction resulted in an increased tumor SUVmax and an improved SNR and SBR at a matched level of noise. BSREM allowed for a shorter acquisition than TOF OSEM, with equal image quality.

Keywords
FDG, Image Reconstruction, Molecular Imaging, PET/CT, block-sequential regularized expectation maximization, image reconstruction, penalization factor
National Category
Medical and Health Sciences Medical Image Processing
Identifiers
urn:nbn:se:uu:diva-343272 (URN)10.2967/jnumed.117.200790 (DOI)000437237200037 ()29449445 (PubMedID)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-09-18Bibliographically approved
Eriksson, J., Fang, X. T., Hultqvist, G., Olberg, D. E., Antoni, G., Lannfelt, L., . . . Syvänen, S. (2018). [F-18]Tetrazine-trans-cyclooctene mediated labelling of antibodies for PET imaging of amyloid-beta. Paper presented at 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY. European Journal of Nuclear Medicine and Molecular Imaging, 45, S643-S643
Open this publication in new window or tab >>[F-18]Tetrazine-trans-cyclooctene mediated labelling of antibodies for PET imaging of amyloid-beta
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2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S643-S643Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-372958 (URN)000449266206054 ()
Conference
31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY
Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2019-01-24Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-1525-5255

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