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Karalija, N., Papenberg, G., Wåhlin, A., Johansson, J., Andersson, M., Axelsson, J., . . . Nyberg, L. (2019). C957T-mediated Variation in Ligand Affinity Affects the Association between C-11-raclopride Binding Potential and Cognition. Journal of cognitive neuroscience, 31(2), 314-325
Open this publication in new window or tab >>C957T-mediated Variation in Ligand Affinity Affects the Association between C-11-raclopride Binding Potential and Cognition
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2019 (English)In: Journal of cognitive neuroscience, ISSN 0898-929X, E-ISSN 1530-8898, Vol. 31, no 2, p. 314-325Article in journal (Refereed) Published
Abstract [en]

The dopamine (DA) system plays an important role in cognition. Accordingly, normal variation in DA genes has been found to predict individual differences in cognitive performance. However, little is known of the impact of genetic differences on the link between empirical indicators of the DA system and cognition in humans. The present work used PET with C-11-raclopride to assess DA D2-receptor binding potential (BP) and links to episodic memory, working memory, and perceptual speed in 179 healthy adults aged 64-68 years. Previously, the T-allele of a DA D2-receptor single-nucleotide polymorphism, C957T, was associated with increased apparent affinity of C-11-raclopride, giving rise to higher BP values despite similar receptor density values between allelic groups. Consequently, we hypothesized that C-11-raclopride BP measures inflated by affinity rather than D2-receptor density in T-allele carriers would not be predictive of DA integrity and therefore prevent finding an association between C-11-raclopride BP and cognitive performance. In accordance with previous findings, we show that C-11-raclopride BP was increased in T-homozygotes. Importantly, C-11-raclopride BP was only associated with cognitive performance in groups with low or average ligand affinity (C-allele carriers of C957T, n = 124), but not in the high-affinity group (T-homozygotes, n = 55). The strongest C-11-raclopride BP-cognition associations and the highest level of performance were found in C-homozygotes. These findings show that genetic differences modulate the link between BP and cognition and thus have important implications for the interpretation of DA assessments with PET and C-11-raclopride in multiple disciplines ranging from cognitive neuroscience to psychiatry and neurology.

Place, publisher, year, edition, pages
MIT Press, 2019
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-155630 (URN)10.1162/jocn_a_01354 (DOI)000454429400011 ()30407135 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationRagnar Söderbergs stiftelseTorsten Söderbergs stiftelseThe Swedish Brain FoundationVästerbotten County Council
Available from: 2019-01-28 Created: 2019-01-28 Last updated: 2019-01-28Bibliographically approved
Salami, A., Garrett, D. D., Wåhlin, A., Rieckmann, A., Papenberg, G., Karalija, N., . . . Nyberg, L. (2019). Dopamine D2/3 Binding Potential Modulates Neural Signatures of Working Memory in a Load-Dependent Fashion.. Journal of Neuroscience, 39(3), 537-547
Open this publication in new window or tab >>Dopamine D2/3 Binding Potential Modulates Neural Signatures of Working Memory in a Load-Dependent Fashion.
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2019 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 39, no 3, p. 537-547Article in journal (Refereed) Published
Abstract [en]

Dopamine (DA) modulates corticostriatal connections. Studies in which imaging of the DA system is integrated with functional imaging during cognitive performance have yielded mixed findings. Some work has shown a link between striatal DA (measured by PET) and fMRI activations, whereas others have failed to observe such a relationship. One possible reason for these discrepant findings is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. Moreover, a potential DA–BOLD association may be modulated by task performance. We studied 155 (104 normal-performing and 51 low-performing) healthy older adults (43% females) who underwent fMRI scanning while performing a working memory (WM) n-back task along with DA D2/3 PET assessment using [11C]raclopride. Using multivariate partial-least-squares analysis, we observed a significant pattern revealing positive associations of striatal as well as extrastriatal DA D2/3 receptors to BOLD response in the thalamo–striatal–cortical circuit, which supports WM functioning. Critically, the DA–BOLD association in normal-performing, but not low-performing, individuals was expressed in a load-dependent fashion, with stronger associations during 3-back than 1-/2-back conditions. Moreover, normal-performing adults expressing upregulated BOLD in response to increasing task demands showed a stronger DA–BOLD association during 3-back, whereas low-performing individuals expressed a stronger association during 2-back conditions. This pattern suggests a nonlinear DA–BOLD performance association, with the strongest link at the maximum capacity level. Together, our results suggest that DA may have a stronger impact on functional brain responses during more demanding cognitive tasks.

Keywords
PET, aging, dopamine, fMRI, working memory
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-155492 (URN)10.1523/JNEUROSCI.1493-18.2018 (DOI)000455849400013 ()30478031 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationTorsten Söderbergs stiftelseRagnar Söderbergs stiftelseThe Swedish Brain FoundationVästerbotten County Council
Available from: 2019-01-18 Created: 2019-01-18 Last updated: 2019-02-08Bibliographically approved
de Boer, L., Axelsson, J., Chowdhury, R., Riklund, K., Dolan, R. J., Nyberg, L., . . . Guitart-Masip, M. (2019). Dorsal striatal dopamine D1 receptor availability predicts an instrumental bias in action learning. Proceedings of the National Academy of Sciences of the United States of America, 116(1), 261-270
Open this publication in new window or tab >>Dorsal striatal dopamine D1 receptor availability predicts an instrumental bias in action learning
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2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 1, p. 261-270Article in journal (Refereed) Published
Abstract [en]

Learning to act to obtain reward and inhibit to avoid punishment is easier compared with learning the opposite contingencies. This coupling of action and valence is often thought of as a Pavlovian bias, although recent research has shown it may also emerge through instrumental mechanisms. We measured this learning bias with a rewarded go/no-go task in 60 adults of different ages. Using computational modeling, we characterized the bias as being instrumental. To assess the role of endogenous dopamine (DA) in the expression of this bias, we quantified DA D1 receptor availability using positron emission tomography (PET) with the radioligand [11C]SCH23390. Using principal-component analysis on the binding potentials in a number of cortical and striatal regions of interest, we demonstrated that cortical, dorsal striatal, and ventral striatal areas provide independent sources of variance in DA D1 receptor availability. Interindividual variation in the dorsal striatal component was related to the strength of the instrumental bias during learning. These data suggest at least three anatomical sources of variance in DA D1 receptor availability separable using PET in humans, and we provide evidence that human dorsal striatal DA D1 receptors are involved in the modulation of instrumental learning biases.

Place, publisher, year, edition, pages
National Academy of Sciences, 2019
Keywords
decision making, dopamine, Pavlovian bias, instrumental learning, positron emission tomography
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-155637 (URN)10.1073/pnas.1816704116 (DOI)000454707700042 ()30563856 (PubMedID)
Funder
Swedish Research Council, VR521-2013-2589
Available from: 2019-01-25 Created: 2019-01-25 Last updated: 2019-01-25Bibliographically approved
Rutegård, M., Båtsman, M., Axelsson, J., Brynolfsson, P., Brännström, F., Rutegård, J., . . . Riklund, K. (2019). PET/MRI and PET/CT hybrid imaging of rectal cancer - description and initial observations from the RECTOPET (REctal Cancer trial on PET/MRI/CT) study. Cancer Imaging, 19, Article ID 52.
Open this publication in new window or tab >>PET/MRI and PET/CT hybrid imaging of rectal cancer - description and initial observations from the RECTOPET (REctal Cancer trial on PET/MRI/CT) study
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2019 (English)In: Cancer Imaging, ISSN 1740-5025, E-ISSN 1470-7330, Vol. 19, article id 52Article in journal (Refereed) Published
Abstract [en]

PurposeThe role of hybrid imaging using F-18-fluoro-2-deoxy-D-glucose positron-emission tomography (FDG-PET), computed tomography (CT) and magnetic resonance imaging (MRI) to improve preoperative evaluation of rectal cancer is largely unknown. To investigate this, the RECTOPET (REctal Cancer Trial on PET/MRI/CT) study has been launched with the aim to assess staging and restaging of primary rectal cancer. This report presents the study workflow and the initial experiences of the impact of PET/CT on staging and management of the first patients included in the RECTOPET study.MethodsThis prospective cohort study, initiated in September 2016, is actively recruiting patients from Region Vasterbotten in Sweden. This pilot study includes patients recruited and followed up until December 2017. All patients had a biopsy-verified rectal adenocarcinoma and underwent a minimum of one preoperative FDG-PET/CT and FDG-PET/MRI examination. These patients were referred to the colorectal cancer multidisciplinary team meeting at Umea University Hospital. All available data were evaluated when making management recommendations. The clinical course was noted and changes consequent to PET imaging were described; surgical specimens underwent dedicated MRI for anatomical matching between imaging and histopathology.ResultsTwenty-four patients have so far been included in the study. Four patients were deemed unresectable, while 19 patients underwent or were scheduled for surgery; one patient was enrolled in a watch-and-wait programme after restaging. Consequent to taking part in the study, two patients were upstaged to M1 disease: one patient was diagnosed with a solitary hepatic metastasis detected using PET/CT and underwent metastasectomy prior to rectal cancer surgery, while one patient with a small, but metabolically active, lung nodulus experienced no change of management. PET/MRI did not contribute to any recorded change in patient management.ConclusionsThe RECTOPET study investigating the role of PET/CT and PET/MRI for preoperative staging of primary rectal cancer patients will provide novel data that clarify the value of adding hybrid to conventional imaging, and the role of PET/CT versus PET/MRI.Trial registrationNCT03846882.

Place, publisher, year, edition, pages
BMC, 2019
Keywords
Rectal neoplasm, Rectal tumour, Staging, Lymph nodes, Tumour deposits, PET, CT, FDG-PET, CT, PET
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-161991 (URN)10.1186/s40644-019-0237-1 (DOI)000477054900002 ()31337428 (PubMedID)
Available from: 2019-08-13 Created: 2019-08-13 Last updated: 2019-08-13Bibliographically approved
Sandgren, K., Johansson, L., Axelsson, J., Jonsson, J., Ögren, M., Ögren, M., . . . Widmark, A. (2019). Radiation dosimetry of [Ga-68]PSMA-11 in low-risk prostate cancer patients. EJNMMI Physics, 6, Article ID 2.
Open this publication in new window or tab >>Radiation dosimetry of [Ga-68]PSMA-11 in low-risk prostate cancer patients
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2019 (English)In: EJNMMI Physics, ISSN 2197-7364, E-ISSN 2191-219X, Vol. 6, article id 2Article in journal (Refereed) Published
Abstract [en]

Background: 68Ga-labeled Glu-NH-CO-NH-Lys(Ahx)-HBED-CC ([68Ga]PSMA-11) has been increasingly used to image prostate cancer using positron emission tomography (PET)/computed tomography (CT) both during diagnosis and treatment planning. It has been shown to be of clinical value for patients both in the primary and secondary stages of prostate cancer. The aim of this study was to determine the effective dose and organ doses from injection of [68Ga]PSMA-11 in a cohort of low-risk prostate cancer patients.

Methods: Six low-risk prostate cancer patients were injected with 133–178 MBq [68Ga]PSMA-11 and examined with four PET/CT acquisitions from injection to 255 min post-injection. Urine was collected up to 4 h post-injection, and venous blood samples were drawn at 45 min, 85 min, 175 min, and 245 min post-injection. Kidneys, liver, lungs, spleen, salivary and lacrimal glands, and total body where delineated, and cumulated activities and absorbed organ doses calculated. The software IDAC-Dose 2.1 was used to calculate absorbed organ doses according to the International Commission on Radiological Protection (ICRP) publication 107 using specific absorbed fractions published in ICRP 133 and effective dose according to ICRP Publication 103. We also estimated the absorbed dose to the eye lenses using Monte Carlo methods.

Results: [68Ga]PSMA-11 was rapidly cleared from the blood and accumulated preferentially in the kidneys and the liver. The substance has a biological half-life in blood of 6.5 min (91%) and 4.4 h (9%). The effective dose was calculated to 0.022 mSv/MBq. The kidneys received approximately 40 mGy after an injection with 160 MBq [68Ga]PSMA-11 while the lacrimal glands obtained an absorbed dose of 0.12 mGy per administered MBq. Regarding the eye lenses, the absorbed dose was low (0.0051 mGy/MBq).

Conclusion: The effective dose for [68Ga]PSMA-11 is 0.022 mSv/MBq, where the kidneys and lacrimal glands receiving the highest organ dose.

Place, publisher, year, edition, pages
Springer, 2019
Keywords
Radiation dosimetry, [Ga-68]PSMA-11, PSMA, PET-tracer, Prostate cancer, Absorbed dose and effective dose, Glu-NH-CO-NH-Lys(Ahx)-HBED-CC
National Category
Cancer and Oncology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-155760 (URN)10.1186/s40658-018-0239-2 (DOI)000455503100001 ()30631980 (PubMedID)
Available from: 2019-01-28 Created: 2019-01-28 Last updated: 2019-01-28Bibliographically approved
Leffler, K., Axelsson, J., Larsson, A., Häggström, I. & Yu, J. (2019). Sharper Positron Emission Tomography: Intelligent Data Sampling to Promote Accelerated Medical Imaging. In: : . Paper presented at Winter Conference in Statistics 2019 - Machine Learning, March 10-14, 2019, Hemavan, Sweden.
Open this publication in new window or tab >>Sharper Positron Emission Tomography: Intelligent Data Sampling to Promote Accelerated Medical Imaging
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2019 (English)Conference paper, Poster (with or without abstract) (Other academic)
National Category
Probability Theory and Statistics Medical Image Processing
Research subject
Mathematical Statistics
Identifiers
urn:nbn:se:umu:diva-157665 (URN)
Conference
Winter Conference in Statistics 2019 - Machine Learning, March 10-14, 2019, Hemavan, Sweden
Projects
Statistical modelling and intelligent data sampling in MRI and PET measurements for cancer therapy assessment
Funder
Swedish Research Council, 340-2013-534
Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-04-12Bibliographically approved
Papenberg, G., Karalija, N., Salami, A., Andersson, M., Axelsson, J., Riklund, K., . . . Bäckman, L. (2019). The Influence of Hippocampal Dopamine D2 Receptors on Episodic Memory Is Modulated by BDNF and KIBRA Polymorphisms. Journal of cognitive neuroscience, 31(9), 1422-1429
Open this publication in new window or tab >>The Influence of Hippocampal Dopamine D2 Receptors on Episodic Memory Is Modulated by BDNF and KIBRA Polymorphisms
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2019 (English)In: Journal of cognitive neuroscience, ISSN 0898-929X, E-ISSN 1530-8898, Vol. 31, no 9, p. 1422-1429Article in journal (Refereed) Published
Abstract [en]

Episodic memory is a polygenic trait influenced by different molecular mechanisms. We used PET and a candidate gene approach to investigate how individual differences at the molecular level translate into between-person differences in episodic memory performance of elderly persons. Specifically, we examined the interactive effects between hippocampal dopamine D2 receptor (D2DR) availability and candidate genes relevant for hippocampus-related memory functioning. We show that the positive effects of high D2DR availability in the hippocampus on episodic memory are confined to carriers of advantageous genotypes of the brain-derived neurotrophic factor (BDNF, rs6265) and the kidney and brain expressed protein (KIBRA, rs17070145) polymorphisms. By contrast, these polymorphisms did not modulate the positive relationship between caudate D2DR availability and episodic memory.

Place, publisher, year, edition, pages
MIT Press, 2019
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-162391 (URN)10.1162/jocn_a_01429 (DOI)000477974100012 ()31112471 (PubMedID)2-s2.0-85070257740 (Scopus ID)
Available from: 2019-08-20 Created: 2019-08-20 Last updated: 2019-08-20Bibliographically approved
Jakobson Mo, S., Axelsson, J., Jonasson, L., Larsson, A., Ögren, M. J., Ögren, M., . . . Riklund, K. (2018). Dopamine transporter imaging with [18F]FE-PE2I PET and [123I]FP-CIT SPECT – a clinical comparison. EJNMMI Research, 8, Article ID 100.
Open this publication in new window or tab >>Dopamine transporter imaging with [18F]FE-PE2I PET and [123I]FP-CIT SPECT – a clinical comparison
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2018 (English)In: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 8, article id 100Article in journal (Refereed) Published
Abstract [en]

Background: Dopamine transporter (DAT) imaging may be of diagnostic value in patients with clinically suspected parkinsonian disease. The purpose of this study was to compare the diagnostic performance of DAT imaging with positron emission computed tomography (PET), using the recently developed, highly DAT-selective radiopharmaceutical [18F]FE-PE2I (FE-PE2I), to the commercially available and frequently used method with [123I]FP-CIT (FP-CIT) single-photon emission computed tomography (SPECT) in early-stage idiopathic parkinsonian syndrome (PS).

Methods: Twenty-two patients with a clinical de novo diagnosis of PS and 28 healthy controls (HC) participating in an on-going clinical trial of FE-PE2I were analyzed in this study. Within the trial protocol, participants are clinically reassessed 2 years after inclusion. A commercially available software was used for automatic calculation of FP-CIT-specific uptake ratio (SUR). MRI-based volumes of interest combined with threshold PET segmentation were used for FE-PE2I binding potential relative to non-displaceable binding (BPND) quantification and specific uptake value ratios (SUVR).

Results: PET with FE-PE2I revealed significant differences between patients with a clinical de novo diagnosis of PS and healthy controls in striatal DAT availability (p < 0.001), with excellent accuracy of predicting dopaminergic deficit in early-stage PS. The effect sizes were calculated for FE-PE2I BPND (Glass’s Δ = 2.95), FE-PE2I SUVR (Glass’s Δ = 2.57), and FP-CIT SUR (Glass’s Δ = 2.29). The intraclass correlation (ICC) between FE-PE2I BPND FP-CIT SUR was high in the caudate (ICC = 0.923), putamen (ICC = 0.922), and striatum (ICC = 0.946), p < 0.001. Five of the 22 patients displayed preserved striatal DAT availability in the striatum with both methods. At follow-up, a non-PS clinical diagnosis was confirmed in three of these, while one was clinically diagnosed with corticobasal syndrome. In these patients, FE-PE2I binding was also normal in the substantia nigra (SN), while significantly reduced in the remaining patients. FE-PE2I measurement of the mean DAT availability in the putamen was strongly correlated with BPND in the SN (R = 0.816, p < 0.001). Olfaction and mean putamen DAT availability was correlated using both FE-PE2I BPND and FP-CIT SUR (R ≥ 0.616, p < 0.001).

Conclusion: DAT imaging with FE-PE2I PET yields excellent basic diagnostic differentiation in early-stage PS, at least as good as FP-CIT SPECT.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Parkinson's disease, PET, SPECT, Dopamine transporter (DAT), [F-18]FE-PE2I
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-154944 (URN)10.1186/s13550-018-0450-0 (DOI)000450488800002 ()30443684 (PubMedID)
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-05-07Bibliographically approved
Jonsson, P., Lindmark, L., Axelsson, J., Karlsson, L., Lundberg, L. & Stegmayr, B. (2018). Formation of Blood Foam in the Air Trap During Hemodialysis Due to Insufficient Automatic Priming of Dialyzers. Artificial Organs, 42(5), 533-539
Open this publication in new window or tab >>Formation of Blood Foam in the Air Trap During Hemodialysis Due to Insufficient Automatic Priming of Dialyzers
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2018 (English)In: Artificial Organs, ISSN 0160-564X, E-ISSN 1525-1594, Vol. 42, no 5, p. 533-539Article in journal (Refereed) Published
Abstract [en]

We were encouraged to investigate the reasons for large amounts of foam observed in bloodlines during hemodialysis (HD). Foam was visible in the venous air trap within the Artis Gambro dialysis device. Estimates of the extent of foam were graded (0no foam, 10extensive foam) by two persons that were blind to the type of dialyzer used. Thirty-seven patients were involved in the dialysis procedures. Consecutive dialyses were graded using dialyzers from Fresenius Medical Care (CorDiax dialyzers that were used for high flux HDFX80 and FX100, and for hemodiafiltrationFX1000). The extracorporeal circuit was primed automatically by dialysate using Gambro Artis software 8.15 006 (Gambro, Dasco, Medolla Italy, Baxter, Chicago, IL, USA). The priming volume recommended by the manufacturer was 1100 mL, whereas our center uses 1500 mL. Extensive amounts of blood foam were visual in the air traps. Although the manufacturer recommended extension of priming volume up to 3000 mL, this did not eliminate the foam. Microbubble measurement during HD revealed the air to derive from the dialyzers. When changing to PF210H dialyzers (Baxter) and using a priming volume of 1500 mL, the foam was significantly less (P<0.01). The extent of foam correlated with the size of the FX-dialyzer surface (P=0.002). The auto-priming program was updated to version 8.21 by the manufacturer and the extent of foam in the air trap using FX dialyzers was now reduced and there was no longer a difference between FX and PF dialyzers, although less foam was still visible in the venous air trap during several dialyses. In conclusion, this study urgently calls attention to blood foam development in the venous air trap when using Artis devices and priming software 8.15 in combination with Fresenius dialyzers. Updated auto-priming software (version 8.21) of Artis should be requested to reduce the extent of foam for the Fresenius dialyzers. Other interactions may also be present. We recommend further studies to clarify these problems. Meanwhile caution is warranted for the combined use of dialysis devices and dialyzers with incompatible automatic priming.

Keywords
dialysis, priming, foam, bubbles, air, blood
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-149031 (URN)10.1111/aor.13070 (DOI)000433563800012 ()29542180 (PubMedID)2-s2.0-85047846399 (Scopus ID)
Available from: 2018-06-14 Created: 2018-06-14 Last updated: 2019-05-20Bibliographically approved
Sandgren, K., Jonsson, J., Nyholm, T., Strandberg, S., Ögren, M., Axelsson, J., . . . Windmark, A. (2018). Histology correlation of in vivo [68Ga]PSMA-PET/MRI data of the prostate. Paper presented at 37th Meeting of the European-Society-for-Radiotherapy-and-Oncology (ESTRO), APR 20-24, 2018, Barcelona, SPAIN. Radiotherapy and Oncology, 127, S541-S541
Open this publication in new window or tab >>Histology correlation of in vivo [68Ga]PSMA-PET/MRI data of the prostate
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2018 (English)In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 127, p. S541-S541Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Elsevier, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-150494 (URN)10.1016/S0167-8140(18)31288-X (DOI)000437723402226 ()
Conference
37th Meeting of the European-Society-for-Radiotherapy-and-Oncology (ESTRO), APR 20-24, 2018, Barcelona, SPAIN
Available from: 2018-11-01 Created: 2018-11-01 Last updated: 2018-11-01Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3731-3612

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