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Johansson, Jarkko
Publications (7 of 7) Show all publications
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
Johansson, J., Hirvonen, J., Lovro, Z., Ekblad, L., Kaasinen, V., Rajasilta, O., . . . Scheinin, M. (2019). Intranasal naloxone rapidly occupies brain mu-opioid receptors in human subjects. Neuropsychopharmacology, 44(9), 1667-1673
Open this publication in new window or tab >>Intranasal naloxone rapidly occupies brain mu-opioid receptors in human subjects
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2019 (English)In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 44, no 9, p. 1667-1673Article in journal (Refereed) Published
Abstract [en]

Nasal spray formulations of naloxone, a mu-opioid receptor (MOR) antagonist, are currently used for the treatment of opioid overdose. They may have additional therapeutic utility also in the absence of opioid agonist drugs, but the onset and duration of action at brain MORs have been inadequately characterized to allow such projections. This study provides initial characterization of brain MOR availability at high temporal resolution following intranasal (IN) naloxone administration to healthy volunteers in the absence of a competing opioid agonist. Fourteen participants were scanned twice using positron emission tomography (PET) and [11C]carfentanil, a selective MOR agonist radioligand. Concentrations of naloxone in plasma and MOR availability (relative to placebo) were monitored from 0 to 60 min and at 300–360 min post naloxone. Naloxone plasma concentrations peaked at ~20 min post naloxone, associated with slightly delayed development of brain MOR occupancy (half of peak occupancy reached at ~10 min). Estimated peak occupancies were 67 and 85% following 2 and 4 mg IN doses, respectively. The estimated half-life of occupancy disappearance was ~100 min. The rapid onset of brain MOR occupancy by IN naloxone, evidenced by the rapid onset of its action in opioid overdose victims, was directly documented in humans for the first time. The employed high temporal-resolution PET method establishes a model that can be used to predict brain MOR occupancy from plasma naloxone concentrations. IN naloxone may have therapeutic utility in various addictions where brain opioid receptors are implicated, such as gambling disorder and alcohol use disorder.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:umu:diva-161884 (URN)10.1038/s41386-019-0368-x (DOI)000475474900020 ()30867551 (PubMedID)2-s2.0-85063377936 (Scopus ID)
Available from: 2019-08-08 Created: 2019-08-08 Last updated: 2019-08-08Bibliographically approved
Papenberg, G., Jonasson, L. S., Karalija, N., Johansson, J., Koehncke, Y., Salami, A., . . . Backman, L. (2019). Mapping the landscape of human dopamine D2/3 receptors with [11C]raclopride. Brain Structure and Function, 224(8), 2871-2882
Open this publication in new window or tab >>Mapping the landscape of human dopamine D2/3 receptors with [11C]raclopride
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2019 (English)In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 224, no 8, p. 2871-2882Article in journal (Refereed) Published
Abstract [en]

The dopamine D2/3 system is fundamental for sensory, motor, emotional, and cognitive aspects of behavior. Small-scale human histopathological and animal studies show high density of D2/3 dopamine receptors (D2/3DR) in striatum, but also demonstrate the existence of such receptors across cortical and limbic regions. Assessment of D2/3DR BPND in the extrastriatal regions with [C-11]raclopride has long been considered unreliable due to the relatively low density of D2/3DR outside the striatum. We describe the distribution and interregional links of D2/3DR availability measured with PET and [C-11]raclopride across the human brain in a large sample (N = 176; age range 64-68 years). Structural equation modeling revealed that D2/3DR availability can be organized according to anatomical (nigrostriatal, mesolimbic, mesocortical) and functional (limbic, associative, sensorimotor) dopamine pathways. D2/3DR availability in corticolimbic functional subdivisions showed differential associations to corresponding striatal subdivisions, extending animal and pharmacological work. Our findings provide evidence on the dimensionality and organization of [C-11]raclopride D2/3DR availability in the living human brain that conforms to known dopaminergic pathways.

Keywords
[C-11]raclopride, Dopamine D2, 3 receptors, Inter-individual differences, Structural-equation deling, COBRA study
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-165669 (URN)10.1007/s00429-019-01938-1 (DOI)000489147300018 ()31444615 (PubMedID)
Available from: 2019-12-06 Created: 2019-12-06 Last updated: 2019-12-06Bibliographically approved
Toppala, S., Ekblad, L. L., Lötjönen, J., Helin, S., Hurme, S., Johansson, J., . . . Rinne, J. O. (2019). Midlife Insulin Resistance as a Predictor for Late-Life Cognitive Function and Cerebrovascular Lesions. Journal of Alzheimer's Disease, 72(1), 215-228
Open this publication in new window or tab >>Midlife Insulin Resistance as a Predictor for Late-Life Cognitive Function and Cerebrovascular Lesions
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2019 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 72, no 1, p. 215-228Article in journal (Refereed) Published
Abstract [en]

Background: Type 2 diabetes (T2DM) increases the risk for Alzheimer’s disease (AD) but not for AD neuropathology. The association between T2DM and AD is assumed to be mediated through vascular mechanisms. However, insulin resistance (IR), the hallmark of T2DM, has been shown to associate with AD neuropathology and cognitive decline.

Objective: To evaluate if midlife IR predicts late-life cognitive performance and cerebrovascular lesions (white matter hyperintensities and total vascular burden), and whether cerebrovascular lesions and brain amyloid load are associated with cognitive functioning.

Methods: This exposure-to-control follow-up study examined 60 volunteers without dementia (mean age 70.9 years) with neurocognitive testing, brain 3T-MRI and amyloid-PET imaging. The volunteers were recruited from the Finnish Health 2000 survey (n = 6062) to attend follow-up examinations in 2014–2016 according to their insulin sensitivity in 2000 and their APOE genotype. The exposure group (n = 30) had IR in 2000 and the 30 controls had normal insulin sensitivity. There were 15 APOE ɛ4 carriers per group. Statistical analyses were performed with multivariable linear models.

Results: At follow-up the IR+group performed worse on executive functions (p = 0.02) and processing speed (p = 0.007) than the IR- group. The groups did not differ in cerebrovascular lesions. No associations were found between cerebrovascular lesions and neurocognitive test scores. Brain amyloid deposition associated with slower processing speed.

Conclusion: Midlife IR predicted poorer executive functions and slower processing speed, but not cerebrovascular lesions. Brain amyloid deposition was associated with slower processing speed. The association between midlife IR and late-life cognition might not be mediated through cerebrovascular lesions measured here.

Place, publisher, year, edition, pages
IOS Press, 2019
Keywords
Alzheimer's disease, amyloid, APOE, C-11-PIB, cerebrovascular lesions, cognition, follow-up study, insulin resistance, magnetic resonance imaging, PET scan
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:umu:diva-166832 (URN)10.3233/JAD-190691 (DOI)000500780700018 ()31561373 (PubMedID)
Available from: 2020-01-03 Created: 2020-01-03 Last updated: 2020-01-03Bibliographically approved
Laaksonen, L., Kallioinen, M., Löngsjö, J., Laitio, T., Scheinin, A., Scheinin, J., . . . Scheinin, H. (2018). Comparative effects of dexmedetomidine, propofol, sevoflurane, and S-ketamine on regional cerebral glucose metabolism in humans: a positron emission tomography study. British Journal of Anaesthesia, 121(1), 281-290
Open this publication in new window or tab >>Comparative effects of dexmedetomidine, propofol, sevoflurane, and S-ketamine on regional cerebral glucose metabolism in humans: a positron emission tomography study
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2018 (English)In: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 121, no 1, p. 281-290Article in journal (Refereed) Published
Abstract [en]

Introduction: The highly selective α2-agonist dexmedetomidine has become a popular sedative for neurointensive care patients. However, earlier studies have raised concern that dexmedetomidine might reduce cerebral blood flow without a concomitant decrease in metabolism. Here, we compared the effects of dexmedetomidine on the regional cerebral metabolic rate of glucose (CMRglu) with three commonly used anaesthetic drugs at equi-sedative doses.

Methods: One hundred and sixty healthy male subjects were randomised to EC50 for verbal command of dexmedetomidine (1.5 ng ml-1; n=40), propofol (1.7 μg ml-1; n=40), sevoflurane (0.9% end-tidal; n=40) or S-ketamine (0.75 μg ml−1; n=20) or placebo (n=20). Anaesthetics were administered using target-controlled infusion or vapouriser with end-tidal monitoring. 18F-labelled fluorodeoxyglucose was administered 20 min after commencement of anaesthetic administration, and high-resolution positron emission tomography with arterial blood activity samples was used to quantify absolute CMRglu for whole brain and 15 brain regions.

Results: At the time of [F18]fluorodeoxyglucose injection, 55% of dexmedetomidine, 45% of propofol, 85% of sevoflurane, 45% of S-ketamine, and 0% of placebo subjects were unresponsive. Whole brain CMRglu was 63%, 71%, 71%, and 96% of placebo in the dexmedetomidine, propofol, sevoflurane, and S-ketamine groups, respectively (P<0.001 between the groups). The lowest CMRglu was observed in nearly all brain regions with dexmedetomidine (P<0.05 compared with all other groups). With S-ketamine, CMRglu did not differ from placebo.

Conclusions: At equi-sedative doses in humans, potency in reducing CMRglu was dexmedetomidine>propofol>ketamine=placebo. These findings alleviate concerns for dexmedetomidine-induced vasoconstriction and cerebral ischaemia.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
cerebral blood flow, cerebral metabolism, positron emission tomography, sedation, target-controlled infusion
National Category
Anesthesiology and Intensive Care Other Medical Sciences not elsewhere specified
Identifiers
urn:nbn:se:umu:diva-150371 (URN)10.1016/j.bja.2018.04.008 (DOI)000439025500072 ()29935583 (PubMedID)2-s2.0-85046622088 (Scopus ID)
Available from: 2018-08-10 Created: 2018-08-10 Last updated: 2018-08-10Bibliographically approved
Ekblad, L. L., Johansson, J., Helin, S., Viitanen, M., Laine, H., Puukka, P., . . . Rinne, J. O. (2018). Midlife insulin resistance, APOE genotype, and late-life brain amyloid accumulation. Neurology, 90(13), e1150-e1157
Open this publication in new window or tab >>Midlife insulin resistance, APOE genotype, and late-life brain amyloid accumulation
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2018 (English)In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 90, no 13, p. e1150-e1157Article in journal (Refereed) Published
Abstract [en]

Objective To examine whether midlife insulin resistance is an independent risk factor for brain amyloid accumulation in vivo after 15 years, and whether this risk is modulated by APOE epsilon 4 genotype. Methods This observational study examined 60 elderly volunteers without dementia (mean age at baseline 55.4 and at follow-up 70.9 years, 55.5% women) from the Finnish population-based, nationwide Health2000 study with [C-11]Pittsburgh compound B-PET imaging in 2014-2016. The participants were recruited according to their homeostatic model assessment of insulin resistance (HOMA-IR) values in the year 2000, and their APOE epsilon 4 genotype. The exposure group (IR+, n = 30) consisted of individuals with HOMA-IR > 2.17 at baseline (highest tertile of the Health2000 study population), and the control group (IR-, n = 30) consisted of individuals with HOMA-IR < 1.25 at baseline (lowest tertile). The groups were enriched for APOE epsilon 4 carriers, resulting in 50% (n = 15) APOE epsilon 4 carriers in both groups. Analyses were performed with multivariate logistic and linear regression. Results An amyloid-positive PET scan was found in 33.3% of the IR-group and 60.0% of the IR+ group (odds ratio 3.0, 95% confidence interval 1.1-8.9, p = 0.04). The increased risk was seen in carriers and noncarriers of APOE epsilon 4 genotype. Higher midlife, but not late-life continuous HOMA-IR was associated with a greater brain amyloid burden at follow-up after multivariate adjustments for other cognitive and metabolic risk factors (ss = 0.11, 95% confidence interval 0.002-0.22, p = 0.04). Conclusions These results indicate that midlife insulin resistance is an independent risk factor for brain amyloid accumulation in elderly individuals without dementia.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2018
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-150496 (URN)10.1212/WNL.0000000000005214 (DOI)000439102000008 ()29476033 (PubMedID)
Available from: 2018-08-13 Created: 2018-08-13 Last updated: 2018-08-13Bibliographically approved
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