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  • 1.
    Adlerz, Linda
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Processing of the amyloid precursor protein and its paralogues amyloid precursor-like proteins 1 and 22007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Alzheimer’s disease (AD) is a neurodegenerative disorder which is histopathologically characterised by amyloid plaques and neurofibrillary tangles. Amyloid plaques consist of the amyloid β-peptide (Aβ) that can form aggregates in the brain. Aβ is generated from the amyloid precursor protein (APP) through proteolytic cleavage. APP belongs to a conserved protein family that also includes the two paralogues, APP-like proteins 1 and 2 (APLP1 and APLP2). Despite the immense amount of research on APP, motivated by its implication in AD, the function of this protein family has not yet been determined. In this thesis, we have studied the expression and proteolytic processing of the APP protein family. Our results are consistent with previous findings that suggest a role for APP during neuronal development. Treatment of cells with retinoic acid (RA) resulted in increased synthesis. In addition, we observed that RA treatment shifted the processing of APP from the amyloidogenic to the non-amyloidogenic pathway. The proteins in the APP family have been hard to distinguish both with respect to function and proteolytic processing. However, for development of new drugs with APP processing enzymes as targets this is of great importance. Our studies suggest similarities, but also differences in the mechanism regulating the processing of the different paralogues. We found that brain-derived neurotrophic factor (BDNF) had different impact on the members of the APP family. Most interestingly, we also found that the mechanism behind the increased processing in response to IGF-1 was not identical between the homologous proteins. In summary, our results indicate that in terms of regulation APLP1 and APLP2 differ more from each other than from APP. Our studies open up the possibility of finding means to selectively block Aβ production without interfering with the processing and function of the paralogous proteins.

  • 2.
    Adlerz, Linda
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Beckman, Marie
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Holback, Sofia
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Tehranian, Roya
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Cortés Toro, Veronica
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Accumulation of the amyloid precursor-like protein APLP2 and reduction of APLP1 in retinoic acid-differentiated human neuroblastoma cells upon curcumin-induced neurite retraction2003In: Brain Research. Molecular Brain Research, ISSN 0169-328X, E-ISSN 1872-6941, Vol. 119, no 1, p. 62-72Article in journal (Refereed)
    Abstract [en]

    Amyloid precursor protein (APP) belongs to a conserved gene family, also including the amyloid precursor-like proteins, APLP1 and APLP2. The function of these three proteins is not yet fully understood. One of the proposed roles of APP is to promote neurite outgrowth. The aim of this study was to investigate the regulation of the expression levels of APP family members during neurite outgrowth. We observed that retinoic acid (RA)-induced neuronal differentiation of human SH-SY5Y cells resulted in increased expression of APP, APLP1 and APLP2. We also examined the effect of the NFκB, AP-1 and c-Jun N-terminal kinase inhibitor curcumin (diferuloylmethane) on the RA-induced expression levels of these proteins. We found that treatment with curcumin counteracted the RA-induced mRNA expression of all APP family members. In addition, we observed that curcumin treatment resulted in neurite retraction without any effect on cell viability. Surprisingly, curcumin had differential effects on the APLP protein levels in RA-differentiated cells. RA-induced APLP1 protein expression was blocked by curcumin, while the APLP2 protein levels were further increased. APP protein levels were not affected by curcumin treatment. We propose that the sustained levels of APP and the elevated levels of APLP2, in spite of the reduced mRNA expression, are due to altered proteolytic processing of these proteins. Furthermore, our results suggest that APLP1 does not undergo the same type of regulated processing as APP and APLP2.

  • 3.
    Adlerz, Linda
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Soomets, Ursel
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology. University of Tartu, Estonia.
    Holmlund, Linda
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Virland, Saade
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Down-regulation of amyloid precursor protein by peptide nucleic acid oligomer in cultured rat primary neurons and astrocytes2003In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 336, no 1, p. 55-59Article in journal (Refereed)
    Abstract [en]

    The amyloid precursor protein (APP) and its proteolytic cleavage products, the amyloid P peptides, have been implicated as a cause of Alzheimer's disease. Peptide nucleic acids (PNA), the DNA mimics, have been shown to block the expression of specific proteins at both transcriptional and translational levels. Generally, the cellular uptake of PNA is low. However, recent studies have indicated that the effect of unmodified antisense PNA uptake is more pronounced in nervous tissue. In this study we have shown that biotinylated PNA directed to the initiator codon region of the APP mRNA (-4 - +11) was taken up into the cytoplasm of primary rat cerebellar granule cells and cortical astrocytes, using fluorescence and confocal microscopy studies. Uptake of PNA was faster in neurons than in astrocytes. Western blotting analysis showed that APP was strongly down-regulated in both neurons and astrocytes. Thus, unmodified PNA can be used for studies on the function of APP in neurons and astrocytes.

  • 4.
    af Klinteberg, Britt
    et al.
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS). Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden.
    Johansson, Sven-Erik
    Levander, Maria
    Alm, Per Olof
    Oreland, Lars
    Smoking habits – Associations with personality/behavior, platelet monoamine oxidase activity and plasma thyroid hormone levels2017In: Personality and Individual Differences, ISSN 0191-8869, E-ISSN 1873-3549, Vol. 118, p. 71-76Article in journal (Refereed)
    Abstract [en]

    The objective was to outline results from our scientific studies on the associations among childhood behavior, adult personality, and biochemical factors in smoking habits. The studies consisted of: (1) follow-up of young criminals and controls, subdivided into risk for antisocial behavior groups, based on childhood rating levels of a projective test; and adult smoking habit groups; and (2) a large group of young adults examined on the same inventories. Personality in terms of KSP and EPQ-I scale scores, controlled for intelligence, indicated that the high and very high risk groups displayed significantly higher self-rated impulsiveness, anxiety, and nonconformity, as compared to the low risk group. Further, the very high risk group subjects, found to be overrepresented among subjects with heavy smoking habits, displayed lower mean platelet MAO-B activity and higher thyroid hormone levels than the low risk group. Thus, the higher the childhood risk for antisocial behavior, the clearer the adult personality pattern making subjects more disposed for smoking appeared; and the higher smoking habits, the stronger the relationships with biochemical measures. Results are discussed in terms of possible underlying mechanisms influencing personality and smoking habits.

  • 5.
    Akerstedt, Torbjörn
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Hallvig, David
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Anund, Anna
    Fors, Carina
    Schwarz, Johanna F A
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Having to stop driving at night because of dangerous sleepiness - awareness, physiology and behaviour2013In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 22, no 4, p. 380-388Article in journal (Refereed)
    Abstract [en]

    A large number of accidents are due to the driver falling asleep at the wheel, but details of this link have not been studied on a real road. The purpose of the present study was to describe the development of sleepiness indicators, leading to the drive being terminated prematurely by the onboard expert driving instructor because of imminent danger. Eighteen individuals participated during a day drive and a night drive on a motorway (both 90 min). Eight drivers terminated (N) prematurely (after 43 min) because of sleep-related imminent danger [according to the driving instructor or their own judgement (two cases)]. The results showed very high sleepiness ratings (8.5 units on the Karolinska Sleepiness Scale) immediately before termination (<7 at a similar time interval for those 10 who completed the drive). Group N also showed significantly higher levels of sleep intrusions on the electroencephalography/electro-oculography (EEG/EOG) than those who completed the drive (group C). The sleep intrusions were increased in group N during the first 40 min of the night drive. During the day drive, sleep intrusions were increased significantly in group N. The night drive showed significant increases of all sleepiness indicators compared to the day drive, but also reduced speed and driving to the left in the lane. It was concluded that 44% of drivers during late-night driving became dangerously sleepy, and that this group showed higher perceived sleepiness and more sleep intrusions in the EEG/EOG.

  • 6. Alier, Kwai
    et al.
    Chen, Yishen
    Eriksson Sollenberg, Ulla
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Smith, Peter
    Selective stimulation of GalR1 and GalR2 in rat substantia gelatinosa reveals a cellular basis for the anti- and pro-nociceptive actions of galanin2008In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 137, no 1, p. 138-146Article in journal (Refereed)
    Abstract [en]

    Galanin modulates spinal nociceptive processing by interacting with two receptors, GalR1 and GalR2. The underlying neurophysiological mechanisms were examined by whole-cell recording from identified neurons in the substantia gelatinosa of young adult rats. GalR1 was activated with a 'cocktail' containing the GalR1/2 agonist, AR-M 961 (0.5 mu M), in the presence of the GalR2 antagonist, M871 (1.0-2.5 mu M). GalR2 was activated with the selective agonist, AR-M 1896 (0.5-1.0 mu M). Application of the 'GalR1 agonist cocktail' often activated an inwardly-rectifying conductance in delay firing (excitatory) and tonically firing (inhibitory) neurons. This conductance was not activated by AR-M 1896 which instead decreased or increased an outwardly-rectifying conductance at voltages positive to -70 rnV. Despite this variability in its actions on current-voltage relationships, AR-M 1896 very consistently decreased membrane excitability, as measured by cumulative action potential latency in response to a depolarizing current ramp. This strong GalR2-mediated effect was seen in neurons where membrane conductance was decreased, and where membrane excitability might be predicted to increase. GalR2 was also located presynaptically, as AR-M 1896 increased the interevent interval of spontaneous EPSCs in both delay and tonic cells. By contrast, the 'GalR1 agonist cocktail' had little effect on spontaneous EPSCs, suggesting that presynaptic terminals do not express GalR1. These diverse actions of GalR1 and GalR2 activation on both inhibitory and excitatory neurons are discussed in relation to the known spinal antinociceptive and pro-nociceptive actions of galanin, to the possible association of GalR1 with the inhibitory G-protein, G(i/o) and to report that GalR2 activation suppresses Ca(2+) channel currents.

  • 7.
    Alikhani, Nyosha
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Guo, Lan
    Yan, Shiqiang
    Du, Heng
    Pinho, Catarina Moreira
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Chen, John Xi
    Glaser, Elzbieta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Yan, Shirley ShiDu
    Decreased proteolytic activity of the mitochondrial amyloid-β degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria2011In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 27, no 1, p. 75-87Article in journal (Refereed)
    Abstract [en]

    Accumulation of amyloid-β peptide (Aβ), the neurotoxic peptide implicated in the pathogenesis of Alzheimer's disease (AD), has been shown in brain mitochondria of AD patients and of AD transgenic mouse models. The presence of Aβ in mitochondria leads to free radical generation and neuronal stress. Recently, we identified the presequence protease, PreP, localized in the mitochondrial matrix in mammalian mitochondria as the novel mitochondrial Aβ-degrading enzyme. In the present study, we examined PreP activity in the mitochondrial matrix of the human brain's temporal lobe, an area of the brain highly susceptible to Aβ accumulation and reactive oxygen species (ROS) production. We found significantly lower hPreP activity in AD brains compared with non-AD age-matched controls. By contrast, in the cerebellum, a brain region typically spared from Aβ accumulation, there was no significant difference in hPreP activity when comparing AD samples to non-AD controls. We also found significantly reduced PreP activity in the mitochondrial matrix of AD transgenic mouse brains (Tg mAβPP and Tg mAβPP/ABAD) when compared to non-transgenic aged-matched mice. Furthermore, mitochondrial fractions isolated from AD brains and Tg mAβPP mice had higher levels of 4-hydroxynonenal, an oxidative product, as compared with those from non-AD and nonTg mice. Accordingly, activity of cytochrome c oxidase was significantly reduced in the AD mitochondria. These findings suggest that decreased PreP proteolytic activity, possibly due to enhanced ROS production, contributes to Aβ accumulation in mitochondria leading to the mitochondrial toxicity and neuronal death that is exacerbated in AD. Clearance of mitochondrial Aβ by PreP may thus be of importance in the pathology of AD.

  • 8.
    Almkvist, Ove
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden; Karolinska University Hospital at Huddinge, Sweden.
    Rodriguez-Vieitez, Elena
    Thordardottir, Steinunn
    Amberla, Kaarina
    Axelman, Karin
    Basun, Hans
    Kinhult-Ståhlbom, Anne
    Lilius, Lena
    Remes, Anne
    Wahlund, Lars-Olof
    Viitanen, Matti
    Lannfelt, Lars
    Graff, Caroline
    Predicting Cognitive Decline across Four Decades in Mutation Carriers and Non-carriers in Autosomal-Dominant Alzheimer's Disease2017In: Journal of the International Neuropsychological Society, ISSN 1355-6177, E-ISSN 1469-7661, Vol. 23, no 3, p. 195-203Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of this study was to investigate cognitive performance including preclinical and clinical disease course in carriers and non-carriers of autosomal-dominant Alzheimer's disease (adAD) in relation to multiple predictors, that is, linear and non-linear estimates of years to expected clinical onset of disease, years of education and age. Methods: Participants from five families with early-onset autosomal-dominant mutations (Swedish and Arctic APP, PSEN1 M146V, H163Y, and I143T) included 35 carriers (28 without dementia and 7 with) and 44 non-carriers. All participants underwent a comprehensive clinical evaluation, including neuropsychological assessment at the Memory Clinic, Karolinska University Hospital at Huddinge, Stockholm, Sweden. The time span of disease course covered four decades of the preclinical and clinical stages of dementia. Neuropsychological tests were used to assess premorbid and current global cognition, verbal and visuospatial functions, short-term and episodic memory, attention, and executive function. Results: In carriers, the time-related curvilinear trajectory of cognitive function across disease stages was best fitted to a formulae with three predictors: years to expected clinical onset (linear and curvilinear components), and years of education. In non-carriers, the change was minimal and best predicted by two predictors: education and age. The trajectories for carriers and non-carriers began to diverge approximately 10 years before the expected clinical onset in episodic memory, executive function, and visuospatial function. Conclusions: The curvilinear trajectory of cognitive functions across disease stages was mimicked by three predictors in carriers. In episodic memory, executive and visuospatial functions, the point of diverging trajectories occurred approximately 10 years ahead of the clinical onset compared to non-carriers.

  • 9.
    Amelina, Hanna
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Holm, Tina
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Cristobal, Susana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Delivering catalase to yeast peroxisomes using cell-penetrating peptidesIn: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658Article in journal (Refereed)
  • 10. Anderson, Maria E.
    et al.
    Runesson, Johan
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Saar, Indrek
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Robinson, John K.
    Galanin, through GalR1 but not GalR2 receptors, decreases motivation at times of high appetitive behavior2013In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 239, p. 90-93Article in journal (Refereed)
    Abstract [en]

    Galanin is a 29/30-amino acid long neuropeptide that has been implicated in many physiological and behavioral functions. Previous research has shown that i.c.v. administration of galanin strongly stimulates food intake in sated rats when food is freely available, but fails to stimulate this consumption when an operant response requirement is present. Using fixed ratio (FR) schedules, we sought to further clarify galanin's role in motivated behavior by administering galanin i.c.v. to rats working on fixed ratio schedules requiring either a low work condition (FR1) or higher work conditions (FR > 1) to obtain a 0.2% saccharin reward. Rats in the FR > 1 group were assigned to either an FR3, FR5 or FR7 schedule of reinforcement. The rate of reinforcement decreased for only the FR > 1 group as compared to saline controls. Furthermore, injections of GalR1 receptor agonist M617 led to a similar, marginally significant decrease in the number of reinforcers received in the FR > 1 condition, but a decrease was not seen after injections of GalR2 receptor agonist M1153. Taken together, these results show that galanin may be playing a role in decreasing motivation at times of high appetitive behavior, and that this effect is likely mediated by the GalR1 receptor.

  • 11. Andersson, Gerhard
    et al.
    Rozental, Alexander
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Clinical psychology. University College London, England.
    Shafran, Roz
    Carlbring, Per
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Clinical psychology. University College London, England.
    Long-term effects of internet-supported cognitive behaviour therapy2018In: Expert Review of Neurotherapeutics, ISSN 1473-7175, E-ISSN 1744-8360, Vol. 18, no 1, p. 21-28Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Internet-supported and therapist-guided cognitive behaviour therapy (ICBT) is effective for a range of problems in the short run, but less is known about the long-term effects with follow-ups of two years or longer.

    Areas covered: This paper reviews studies in which the long-term effects of guided ICBT were investigated. Following literature searches in PubMed and other sources meta-analytic statistics were calculated for 14 studies involving a total of 902 participants, and an average follow-up period of three years. Studies were from Sweden (n = 11) or the Netherlands (n = 3). Long-term outcome studies were found for panic disorder, social anxiety disorder, generalized anxiety disorder, depression, mixed anxiety and depression, obsessive-compulsive disorder, pathological gambling, stress and chronic fatigue. The duration of the treatments was usually short (8–15 weeks). The pre-to follow-up effect size was Hedge’s g = 1.52, but with a significant heterogeneity. The average symptom improvement across studies was 50%. Treatment seeking in the follow-up period was not documented and few studies mentioned negative effects.

    Expert commentary: While effects may be overestimated, it is likely that therapist-supported ICBT can have enduring effects. Long-term follow-up data should be collected for more conditions and new technologies like smartphone-delivered treatments.

  • 12.
    Aslam, Muhammad
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    The fruit fly Drosophila melanogaster GSTE6 and E7; characterization, immobilization and transgenic overexpression2014Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Glutathione transferases (GSTs) are multifunctional enzymes that are universally distributed in most eukaryotes and prokaryotes. They play a pivotal role in the metabolism and detoxication of numerous endogenous and exogenous electrophiles by conjugating them with ubiquitous tripeptide glutathione. In this study we have immobilized two heterologously expressed and purified Epsilon-class enzymes, GSTE6 and GSTE7, from of Drosophila melanogaster on nanoporous alumina membranes. The membranes were derivatized with 3-aminopropyl-triethoxysilane and the amino groups were activated with carbonyldiimidazole to allow coupling of the enzymes. Kinetic analyses of the immobilized enzymes were carried out in a circulating flow system using CDNB (1-chloro-2,4-dinitrobenzene) as substrate, followed by specificity screening with alternative substrates. A good correlation was observed between the substrate screening data for immobilized enzyme and corresponding data for the enzymes in solution. The stability of the immobilized enzymes was virtually identical to that for the enzymes in solution and no leakage of enzyme from the matrix could be observed.

    Additionally, we have investigated the catalytic activities of GSTE7 with organic isothiocyanates (ITCs). These reactive compounds are strong electrophilic molecules produced in plants by the hydrolysis of glucosinolates and exert toxicity in biological tissues.  Our in vitro studies, showed high catalytic activity of GSTE7 towards ITCs. We have then explored the in vivo effect of phenethyl isothiocyanate (PEITC) and allyl isothiocyanate (AITC) in transgenic fruit flies overexpressing GSTE7. A concentration of 0.25 mM PEITC in standard fly food was shown to be toxic to flies and significantly shortened the lifespan. We noticed that overexpression of GSTE7 could protect females from the initial acute toxic effects, but had no positive effect on long term exposure. The effect on males seems to be the opposite to that of females, where a higher mortality was seen in fly males overexpressing GST E7 after one week of exposure.  On the other hand 1mM concentration of AITC showed no toxic effects, but dramatically reduced the oviposition activity of wild-type flies in comparison to the transgenic flies.

  • 13.
    Aslam, Muhammad
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Dahlberg, Olle
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mannervik, Bengt
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Mannervik, Mattias
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Transgenic Overexpression of Glutathione Transferase E7 in Drosophila Attenuates Toxicity of Organic Isothiocyanates Affecting Survival and OvipositionManuscript (preprint) (Other academic)
    Abstract [en]

    Organic isothiocyanates (ITCs) are allelochemicals produced by plants in order to combat insects and other herbivores. The compounds are toxic electrophiles that can be inactivated and conjugated with intracellular glutathione in reactions catalyzed by glutathione transferases (GSTs). The Drosophila melanogaster GSTE7 was heterologously expressed in Escherichia coli and purified for functional studies. The enzyme showed high catalytic activity with various isothiocyanates including phenethyl isothiocyanate (PEITC) and allyl isothiocyanate (AITC), which in millimolar dietary concentrations conferred toxicity to adult D. melanogaster leading to death or a shortened life-span of the flies. In situ hybridization revealed a maternal contribution of GSTE7 transcripts to embryos, and strongest zygotic expression in the digestive tract.  Transgenesis involving the GSTE7 gene controlled by an actin promoter produced viable flies expressing the GSTE7 transcript ubiquitously. Transgenic females show a significant extension in life-span when subjected to the same PEITC treatment as the wild-type flies. By contrast, transgenic male flies showed no significant effect in the first few days, and subsequently showed a somewhat lower survival rate. At 1 mM AITC concentration, no toxicity was noted. However, the oviposition activity was dramatically enhanced from a very low level in wild-type flies reared in the presence of 1 mM AITC to values an order of magnitude higher for the transgenic flies. The results demonstrate a clear protective effect of GSTE7 against exposure to ITC allelochemicals which can affect both life-span and fecundity of female flies.

  • 14. Athanasiu, Lavinia
    et al.
    Giddaluru, Sudheer
    Fernandes, Carla
    Christoforou, Andrea
    Reinvang, Ivar
    Lundervold, Astri J.
    Nilsson, Lars-Göran
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Umeå University, Sweden.
    Kauppi, Karolina
    Adolfsson, Rolf
    Eriksson, Elias
    Sundet, Kjetil
    Djurovic, Srdjan
    Espeseth, Thomas
    Nyberg, Lars
    Steen, Vidar M.
    Andreassen, Ole A.
    Le Hellard, Stephanie
    A genetic association study of CSMD1 and CSMD2 with cognitive function2017In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 61, p. 209-216Article in journal (Refereed)
    Abstract [en]

    The complement cascade plays a role in synaptic pruning and synaptic plasticity, which seem to be involved in cognitive functions and psychiatric disorders. Genetic variants in the closely related CSMD1 and CSMD2 genes, which are implicated in complement regulation, are associated with schizophrenia. Since patients with schizophrenia often show cognitive impairments, we tested whether variants in CSMD1 and CSMD2 are also associated with cognitive functions per se. We took a discovery-replication approach, using well-characterized Scandinavian cohorts. A total of 1637 SNPs in CSMD1 and 206 SNPs in CSMD2 were tested for association with cognitive functions in the NCNG sample (Norwegian Cognitive NeuroGenetics; n = 670). Replication testing of SNPs with p-value < 0.001 (7 in CSMD1 and 3 in CSMD2) was carried out in the TOP sample (Thematically Organized Psychosis; n =1025) and the BETULA sample (Betula Longitudinal Study on aging, memory and dementia; n = 1742). Finally, we conducted a meta-analysis of these SNPs using all three samples. The previously identified schizophrenia marker in CSMD1 (SNP rs10503253) was also included. The strongest association was observed between the CSMDI SNP rs2740931 and performance in immediate episodic memory (p-value = 5 Chi 10(-6), minor allele A, MAF 0.48-0.49, negative direction of effect). This association reached the study-wide significance level (p <= 1.2 Chi 10(-5)). SNP rs10503253 was not significantly associated with cognitive functions in our samples. In conclusion, we studied n = 3437 individuals and found evidence that a variant in CSMD1 is associated with cognitive function. Additional studies of larger samples with cognitive phenotypes will be needed to further clarify the role of CSMD1 in cognitive phenotypes in health and disease.

  • 15.
    Attoff, Kristina
    Stockholm University, Faculty of Science, Department of Neurochemistry. Stockholm University.
    In vitro developmental neurotoxicity of acrylamide2016Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    The number of children with neurodevelopmental disorders is increasing worldwide which makes it a public concern. Exposure to environmental chemicals has been reported as a source of developmental neurotoxicity. There is also an increase in the number of chemicals reaching the global market each year and currently there are thousands of substances that have not yet been tested for developmental neurotoxicity. The current developmental neurotoxicity testing guidelines are time consuming, expensive, require a lot of animals and have relatively low sensitivity understanding for the mechanisms of toxicology. The field of developmental neurotoxicity testing is in need of a paradigm shift to the use of alternative in vitro methods capable of testing and screening large number of substances. The next generation developmental neurotoxicity testing will consist of both in silico and in vitro testing that has to be used in a combined fashion so that it will generate a more rapid and efficient toxicity testing. The methods need to be standardized between laboratories so that reproducible data can be obtained. Simple endpoints will simply not be enough for in vitro developmental neurotoxicity testing models. Rather, a battery of more refined endpoints that pinpoints the specific toxicity of a compound, discriminate between different neural subpopulations and different stages of neural differentiation is crucial for success. The use of mRNA biomarkers could be a good example of such an endpoint, and have been suggested to be valuable in detecting developmental neurotoxicity. This thesis will give a broad overview of different alternative in vitro models for developmental neurotoxicity. Developmental neurotoxicity of acrylamide was investigated by using selected cell models and endpoints. Acrylamide is a well-known neurotoxic compound and most people get exposed to the compound by food consumption and from environmental pollutants. Since acrylamide crosses the placenta barrier, the fetus is also being exposed and the risk for adverse effects in the developing nervous system is overwhelming. The neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5Y were used to study proliferation and differentiation as indicators for developmental neurotoxicity. The reduced neurite outgrowth in the SH-SY5Y cell model occurred at up to seven orders of magnitude lower than what have been previously shown for different neural cell systems. Acrylamide also affected the differentiation process in both neurons and glia cells in the C17.2 cell line. We show that acrylamide attenuated neural differentiation at seven orders of magnitude lower concentrations than the estimated plasma concentration of free acrylamide in the fetus. The fact that low concentrations seem to delay the differentiation process in both cell lines, raises cause for an alarm for developmental neurotoxicity induced by acrylamide.  

  • 16. Aufschnaiter, Andreas
    et al.
    Habernig, Lukas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Kohler, Verena
    Diessl, Jutta
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Carmona-Gutierrez, Didac
    Eisenberg, Tobias
    Keller, Walter
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    The Coordinated Action of Calcineurin and Cathepsin D Protects Against alpha-Synuclein Toxicity2017In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 10, article id 207Article in journal (Refereed)
    Abstract [en]

    The degeneration of dopaminergic neurons during Parkinson's disease (PD) is intimately linked to malfunction of alpha-synuclein (alpha Syn), the main component of the proteinaceous intracellular inclusions characteristic for this pathology. The cytotoxicity of alpha Syn has been attributed to disturbances in several biological processes conserved from yeast to humans, including Ca2+ homeostasis, general lysosomal function and autophagy. However, the precise sequence of events that eventually results in cell death remains unclear. Here, we establish a connection between the major lysosomal protease cathepsin D (CatD) and the Ca2+/calmodulin-dependent phosphatase calcineurin. In a yeast model for PD, high levels of human alpha Syn triggered cytosolic acidification and reduced vacuolar hydrolytic capacity, finally leading to cell death. This could be counteracted by overexpression of yeast CatD (Pep4), which re-installed pH homeostasis and vacuolar proteolytic function, decreased alpha Syn oligomers and aggregates, and provided cytoprotection. Interestingly, these beneficial effects of Pep4 were independent of autophagy. Instead, they required functional calcineurin signaling, since deletion of calcineurin strongly reduced both the proteolytic activity of endogenous Pep4 and the cytoprotective capacity of overexpressed Pep4. Calcineurin contributed to proper endosomal targeting of Pep4 to the vacuole and the recycling of the Pep4 sorting receptor Pep1 from prevacuolar compartments back to the trans-Golgi network. Altogether, we demonstrate that stimulation of this novel calcineurin-Pep4 axis reduces alpha Syn cytotoxicity.

  • 17.
    Axelsson, John
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Sundelin, Tina
    Olsson, Mats J.
    Sorjonen, Kimmo
    Axelsson, Charlotte
    Lasselin, Julie
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; Universitätsklinikum Essen, Germany.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Identification of acutely sick people and facial cues of sickness2018In: Proceedings of the Royal Society of London. Biological Sciences, ISSN 0962-8452, E-ISSN 1471-2954, Vol. 285, no 1870, article id 20172430Article in journal (Refereed)
    Abstract [en]

    Detection and avoidance of sick individuals have been proposed as essential components in a behavioural defence against disease, limiting the risk of contamination. However, almost no knowledge exists on whether humans can detect sick individuals, and if so by what cues. Here, we demonstrate that untrained people can identify sick individuals above chance level by looking at facial photos taken 2 h after injection with a bacterial stimulus inducing an immune response (2.0 ng kg-1 lipopolysaccharide) or placebo, the global sensitivity index being d' = 0.405. Signal detection analysis (receiver operating characteristic curve area) showed an area of 0.62 (95% confidence intervals 0.60-0.63). Acutely sick people were rated by naive observers as having paler lips and skin, a more swollen face, droopier corners of the mouth, more hanging eyelids, redder eyes, and less glossy and patchy skin, as well as appearing more tired. Our findings suggest that facial cues associated with the skin, mouth and eyes can aid in the detection of acutely sick and potentially contagious people.

  • 18.
    Axelsson, John
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institute, Sweden.
    Vyazovskiy, Vladyslav V.
    Banking Sleep and Biological Sleep Need2015In: Sleep, ISSN 0161-8105, E-ISSN 1550-9109, Vol. 38, no 12, p. 1843-1845Article in journal (Refereed)
  • 19.
    Axelsson, Viktoria
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Evaluation of neurotoxic properties of gliotoxin2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The occurrence of mould in food and animal feed is a severe problem due to the secondary metabolites, called mycotoxins, which can possess toxic activity. Aspergillus fumigatus is a common fungus found in improperly stored animal feed and the abundance of spores of the fungus is frequently spread into the air. Gliotoxin has been identified as one of the most toxic second metabolites produced by A. fumigatus. Although A. fumigatus is known to produce mycotoxins that induce neurological syndromes, the neurotoxic properties of gliotoxin have not previously been studied. In this thesis a neurotoxic activity of gliotoxin was demonstrated by using differentiated human neuroblastoma SH-SY5Y cells as a surrogate for the nervous system. The major findings were as follows:

    i. Gliotoxin is highly toxic to SH-SY5Y cells and there is a correlation between the toxicity and the cellular redox status.

    ii. Gliotoxin reduces the number of neurites, but does not affect the cell bodies morphologically, at non-cytotoxic concentrations. This indicates that the toxin may induce peripheral axonopathy in vivo.

    iii. The intracellular free Ca2+ concentration is increased after exposure to gliotoxin, an effect that is the most ubiquitous feature of neuronal cell death. Simultaneously, calpains and caspases, proteases known to be involved in neuronal death and axonal degeneration, are activated.

    iv. The observed irreversible neurite degenerative effects of gliotoxin are mainly dependent on caspase activation, whereas calpains are involved in the gliotoxin-induced cytotoxicity.

    v. Gliotoxin induces a decreased rate of protein synthesis at non-cytotoxic concentration, which may contribute to the degeneration of neurites.

    vi. We did also succeed in developing an in vitro method for determination of toxic activity in animal feed. This study was done in collaboration with National Veterinary Institute (SVA) in Uppsala, and the method is today established and in use at Department of Animal Feed, SVA.

  • 20.
    Becker, Nina
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Max Planck Institute for Human Development, Germany.
    Kalpouzos, Grégoria
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Persson, Jonas
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Laukka, Erika J.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Brehmer, Yvonne
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Max Planck Institute for Human Development, Germany.
    Differential Effects of Encoding Instructions on Brain Activity Patterns of Item and Associative Memory2017In: Journal of cognitive neuroscience, ISSN 0898-929X, E-ISSN 1530-8898, Vol. 29, no 3, p. 545-559Article in journal (Refereed)
    Abstract [en]

    Evidence from neuroimaging studies suggests a critical role of hippocampus and inferior frontal gyrus (IFG) in associative relative to item encoding. Here, we investigated similarities and differences in functional brain correlates for associative and item memory as a function of encoding instruction. Participants received either incidental (animacy judgments) or intentional encoding instructions while fMRI was employed during the encoding of associations and items. In a subsequent recognition task, memory performance of participants receiving intentional encoding instructions was higher compared with those receiving incidental encoding instructions. Furthermore, participants remembered more items than associations, regardless of encoding instruction. Greater brain activation in the left anterior hippocampus was observed for intentionally compared with incidentally encoded associations, although activity in this region was not modulated by the type of instruction for encoded items. Furthermore, greater activity in the left anterior hippocampus and left IFG was observed during intentional associative compared with item encoding. The same regions were related to subsequent memory of intentionally encoded associations and were thus task relevant. Similarly, connectivity of the anterior hippocampus to the right superior temporal lobe and IFG was uniquely linked to subsequent memory of intentionally encoded associations. Our study demonstrates the differential involvement of anterior hippocampus in intentional relative to incidental associative encoding. This finding likely reflects that the intent to remember triggers a specific binding process accomplished by this region.

  • 21.
    Becker, Nina
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Max Planck Institute for Human Development, Germany.
    Laukka, Erika J.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Kalpouzos, Gregoria
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Naveh-Benjamin, Moshe
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Brehmer, Yvonne
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Max Planck Institute for Human Development, Germany.
    Structural brain correlates of associative memory in older adults2015In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 118, p. 146-153Article in journal (Refereed)
    Abstract [en]

    Associative memory involves binding two or more items into a coherent memory episode. Relative to memory for single items, associative memory declines greatly in aging. However, older individuals vary substantially in their ability to memorize associative information. Although functional studies link associative memory to the medial temporal lobe (MTL) and prefrontal cortex (PFC), little is known about how volumetric differences in MTL and PFC might contribute to individual differences in associative memory. We investigated regional gray-matter volumes related to individual differences in associative memory in a sample of healthy older adults (n = 54; age = 60 years). To differentiate item from associative memory, participants intentionally learned face-scene picture pairs before performing a recognition task that included single faces, scenes, and face-scene pairs. Gray-matter volumes were analyzed using voxel-based morphometry region-of-interest (ROI) analyses. To examine volumetric differences specifically for associative memory, item memory was controlled for in the analyses. Behavioral results revealed large variability in associative memory that mainly originated from differences in false-alarm rates. Moreover, associative memory was independent of individuals' ability to remember single items. Older adults with better associative memory showed larger gray-matter volumes primarily in regions of the left and right lateral PFC. These findings provide evidence for the importance of PFC in intentional learning of associations, likely because of its involvement in organizational and strategic processes that distinguish older adults with good from those with poor associative memory.

  • 22.
    Beckman, Marie
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Temporal events in neuronal differentiation and cell death: expression and processing of the Alzheimer's amyloid precursor protein family and a protein at the nuclear pore2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The present study had two major objectives: 1) to elucidate the involvement of Alzheimer’s amyloid precursor protein (APP) family in neuronal differentiation, and the effect of the Alzheimer’s disease (AD)-linked mutation APPV642I on signal transduction; 2) to investigate the fate of the nuclear pore complex protein POM121 during apoptosis and to examine the possibility of using green fluorescent protein (GFP)-labelled POM121 as a non-invasive sensor of apoptosis in living (non-fixed) cells.

    APP is the parent protein of the b-amyloid peptide, which is the major peptide constituent in the “senile plaques” of AD. APP and the homologous amyloid precursor-like proteins, APLP1 and APLP2, are members of the APP family. We compared the temporal expression patterns of these proteins during retinoic acid (RA)-induced neuronal differentiation of human neuroblastoma cells. To this end, we established a quantitative non-radioactive Northern blot assay for APLP1, APLP2 and APP. We found that the transcripts of all three APP family members were increased in response to RA. This occurred simultaneously with progressive neurite outgrowth and increased expression of neuronal markers. In addition, we observed that the increase in APLP2 mRNA was similar to that of APP mRNA, whereas the increase in APLP1 mRNA was significantly higher. The elevated mRNA levels also resulted in an in-creased protein expression of APLP1, APLP2 and the neuronal APP695 isoform. Studies using curcumin (diferuloylmethane), an inhibitor of the transcription factors NFkB/AP-1, and the mitogen-activated protein kinase (MAPK) JNK (c-Jun N-terminal kinase), revealed a diffe-rential regulation of APLP1 and APLP2. Curcumin suppressed the RA-induced mRNA expression of the APP family, in particular that of APLP1. On the protein level, curcumin also reduced the expression of APLP1. In contrast, curcumin induced an accumulation of APLP2, which we propose is due to inhibition of its proteolytic processing. Furthermore, curcumin induced neurite retraction in RA-differentiated cells without affecting their viability. Our results suggest that NFkB/AP-1 signal transduction pathways mediate a co-ordinated regula-tion of the mRNA expression of the APP family and that APLP1 processing is not regulated by the same mechanisms as the processing of APLP2 and APP. Our results are in agreement with important functions for APLP1, APLP2 and APP within the period of neurite extension and synaptic maturation, and a proposed role for these proteins in neuronal differentiation and synaptic plasticity.

    Using a doxycycline-controlled gene expression system (Tet-On), we investigated the effect of wild-type APP695 and the pathogenic familial AD-linked APPV642I mutant on signal transduction. Overexpression was induced at different levels in rat pheochromocytoma (PC12) Tet-On cells. We observed a nerve growth factor-dependent increase in the levels of phosphorylated extracellular regulated kinases 1 and 2 in response to expression of mutant APP. Our results support that increased signalling via MAPKs may have a role in the development of AD. In addition, we found that the inducing agent doxycycline in itself affected cell signalling and protected against oxidative stress. This information is critical for evaluation of the effects of transgene expression using Tet systems.

    Finally, we showed that POM121 is cleaved by a caspase-3-dependent mechanism at aspartate 531 during apoptosis. Characterising the degradation of POM121-GFP in relation to other apoptotic events, revealed that it can be applied as an early non-invasive sensor of nuc-lear apoptosis in living cells using fluorescence microscopy or fluorimetric analysis.

  • 23.
    Beckman, Marie
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Kihlmark, Madeleine
    Södertörn University, Stockholm, Sweden.
    Hallberg, Einar
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Nucleus and Nuclear Envelope: Methods for Preparation2010Book (Other academic)
    Abstract [en]

    The cell nucleus of eukaryotic organisms contains the genome surrounded by a nuclear envelope consisting of a double-lipid membrane with embedded nuclear pores and an underlying nuclear lamina. The uniformity in size and density makes it possible to isolate pure intact nuclei at high yields from tissue homogenates by centrifugation through a sucrose cushion. Nuclear envelopes can be prepared from isolated nuclei by enzymatic degradation of their nucleic acid content. The resulting nuclear envelope preparations contain structurally well-conserved inner and outer nuclear membranes with attached ribosomes, nuclear pore complexes and nuclear lamina. Reliable methods for preparation of nuclei and nuclear envelopes play an important role in the successful identification of components that are located in nuclei and in nuclear subcompartments.

  • 24. Bell, Thomas J.
    et al.
    Eiríksdóttir, Emelía
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Eberwine, James
    PAIR technology: exon-specific RNA binding protein isolation in live cells2011In: Cell-penetrating peptides: Methods and Protocols / [ed] Ülo Langel, New York: Humana Press, 2011, p. 473-486Chapter in book (Refereed)
    Abstract [en]

    RNA-binding proteins (RBPs) are fundamental regulatory proteins for all forms of transcriptional and posttranscriptional control of gene expression. However, isolating RBPs is technically challenging for investigators. Currently, the most widely used techniques to isolate RBPs are in vitro biochemical approaches. Although these approaches have been useful, they have several limitations. One key limitation to using in vitro biochemical approaches is that RBP–RNA interactions are isolated under nonbiological conditions. Here we review a novel experimental approach to identify RBPs called peptide nucleic acid (PNA)-assisted identification of RBPs (PAIR) technology (Zielinski et al., Proc Natl Acad Sci USA 103:1557–1562, 2006). This technology has two significant advantages over traditional approaches. (1) It overcomes the in vitro limitation of biochemical approaches by allowing investigators to isolate RBP–RNA interactions under in vivo conditions. (2) This technology is highly mRNA specific; it isolates RBPs in an exon-specific manner. By selectively targeting alternatively spliced exons with PAIR technology, investigators can isolate splice variant-specific and mRNA region-specific (5-UTR and 3-UTR) RBP complexes for any mRNA of interest.

  • 25.
    Bellander, Martin
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Berggren, Rasmus
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Mårtensson, Johan
    Brehmer, Yvonne
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Max Planck Institute for Human Development, Germany.
    Wenger, Elisabeth
    Li, Tie-Qiang
    Bodammer, Nils C.
    Shing, Yee-Lee
    Werkle-Bergner, Markus
    Lövdén, Martin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Behavioral correlates of changes in hippocampal gray matter structure during acquisition of foreign vocabulary2016In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 131, p. 205-213Article in journal (Refereed)
    Abstract [en]

    Experience can affect human gray matter volume. The behavioral correlates of individual differences in such brain changes are not well understood. In a group of Swedish individuals studying Italian as a foreign language, we investigated associations among time spent studying, acquired vocabulary, baseline performance on memory tasks, and gray matter changes. As a way of studying episodic memory training, the language learning focused on acquiring foreign vocabulary and lasted for 10 weeks. T-1-weighted structural magnetic resonance imaging and cognitive testing were performed before and after the studies. Learning behavior was monitored via participants' use of a smartphone application dedicated to the study of vocabulary. A whole-brain analysis showed larger changes in gray matter structure of the right hippocampus in the experimental group (N = 33) compared to an active control group (N = 23). A first path analyses revealed that time spent studying rather than acquired knowledge significantly predicted change in gray matter structure. However, this association was not significant when adding performance on baseline memory measures into the model, instead only the participants' performance on a short-term memory task with highly similar distractors predicted the change. This measure may tap similar individual difference factors as those involved in gray matter plasticity of the hippocampus.

  • 26. Bergendal, G.
    et al.
    Martola, J.
    Stawiarz, L.
    Kristoffersen-Wiberg, M.
    Fredrikson, S.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Callosal atrophy in multiple sclerosis is related to cognitive speed2013In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 127, no 4, p. 281-289Article in journal (Refereed)
    Abstract [en]

    Bergendal G, Martola J, Stawiarz L, Kristoffersen-Wiberg M, Fredrikson S, Almkvist O. Callosal atrophy in multiple sclerosis is related to cognitive speed. Acta Neurol Scand: 2013: 127: 281-289. (C) 2012 John Wiley & Sons A/S. Background Long-term changes regarding corpus callosum area (CCA) and information processing speed in cognitive and sensory-motor tasks have rarely been studied in multiple sclerosis (MS). Objective and methods Information processing speed in cognitive (Symbol Digit Modalities Test, SDMT), sensory (visual and auditory reaction time) and motor (finger-tapping speed, FT; right and left hand) tasks as well as auditory inter-hemispheric transfer (verbal dichotic listening, VDL) was related to CCA, measured by MRI at baseline and at follow-up after nine years in 22 patients with MS. Possible confounding by demographic (age, gender and education), clinical (symptom onset, duration, severity of disease) and relative brain volume (RBV) as well as T2 lesion load was taken into account. Results The smaller the CCA at baseline, the slower was SDMT performance at baseline. In a similar way, CCA at follow-up was associated with poor SDMT result at follow-up. Furthermore, the higher the annual rate of change in CCA, the poorer was performance in VDL on the left ear and the more pronounced was the right ear advantage. A positive relationship between performance in VDL right ear and annual rate of change in RBV was also seen. Sensory-motor tests were not significantly associated with CCA. T2 lesion load at baseline was associated with FT performance at baseline. Demographic, clinical and radiological (RBV and T2 lesion load) characteristics did not confound the significant relation between CCA and SDMT. Conclusions CCA unlike RBV and T2 lesion load was associated with SDMT, which indicated a marked cognitive rather than perceptual-motor component.

  • 27.
    Berglund, Birgitta
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Writings in remembrance of Professor Trygg Engen2012In: Olfactory Cognition: From Perception and Memory to Environmental Odours and Neuroscience / [ed] Gesualdo M. Zucco, Rachel S. Herz, and Benoist Schaal, Amsterdam, Philadelphia: John Benjamins Publishing Company, 2012, p. 295-312Chapter in book (Refereed)
  • 28.
    Berglund, Birgitta
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Höglund, Anders
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Is there a measurement system for odour quality?2012In: Olfactory Cognition: From Perception and Memory to Environmental Odours and Neuroscience, John Benjamins Publishing Company, 2012, p. 3-21Chapter in book (Refereed)
    Abstract [en]

    Although humans can discriminate a huge number of odours, the mechanisms behind the perception of odours are not well understood. The theory of the present essay and our experiments were developed with the view that odours are homogeneous perceptions (as opposed to visual objects that are heterogeneous percepts). Other typical examples of homogeneous perceptions are colours and some emotional states. Thus, through perceptual learning, which is a prerequisite for perceiving, we become aware of and may recognise odours in the environment. Typically, odours are detected at very low concentrations as compared to chemical instruments, the electronic nose inclusive. Four principles of investigating the human world of odour qualities are discussed: (i) classification and sorting according to odour-quality resemblance, (ii) using names and verbal attributes for odour sources, (iii) using odour qualities for a representative set of reference odorants, and (iv) measuring odour quality by similarity scaling of pairs of odorous stimuli. Although a huge number of odours can be discriminated, the quality of odour mixtures is intermediary among the odour qualities of their components. This applies to single chemical compounds or mixtures thereof and for very broadband mixtures like indoor air. Our perceptual world simply consists of a massive amount of odour qualities potentially attributable to sources in the environment. Their organisation is, however, still a mystery.

  • 29.
    Berntzon, Lotta
    et al.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Ronnevi, L. O.
    Bergman, Birgitta
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Eriksson, Johan
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    DETECTION OF BMAA IN THE HUMAN CENTRAL NERVOUS SYSTEM2015In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 292, p. 137-147Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is an extremely devastating neurodegenerative disease with an obscure etiology. The amino acid beta-N-methyl-L-alanine (BMAA) produced by globally widespread phytoplankton has been implicated in the etiology of human motor neuron diseases. BMAA was recently proven to be present in Baltic Sea food webs, ranging from plankton to larger Baltic Sea organisms, some serving as important food items (fish) for humans. To test whether exposure to BMAA in a Baltic Sea setting is reflected in humans, blood and cerebrospinal fluid (CSF) from individuals suffering from ALS were analyzed, together with sex- and age-matched individuals not inflicted with ALS. Ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and multiple reaction monitoring (MRM), in conjunction with diagnostic transitions revealed BMAA in three (12%) of the totally 25 Swedish individuals tested, with no preference for those suffering from ALS. The three BMAA-positive samples were all retrieved from the CSF, while BMAA was not detected in the blood. The data show that BMAA, potentially originating from Baltic Sea phytoplankton, may reach the human central nervous system, but does not lend support to the notion that BMAA is resident specifically in ALS-patients. However, while dietary exposure to BMAA may be intermittent and, if so, difficult to detect, our data provide the first demonstration of BMAA in the central nervous system of human individuals ante mortem quantified with UHPLC-MS/MS, and therefore calls for extended research efforts.

  • 30.
    Berthet, Pierre
    et al.
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Royal Institute of Technology, Sweden.
    Hellgren-Kotaleski, Jeanette
    Lansner, Anders
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Royal Institute of Technology, Sweden.
    Action selection performance of a reconfigurable basal ganglia inspired model with Hebbian-Bayesian Go- NoGo connectivity2012In: Frontiers in Behavioral Neuroscience, ISSN 1662-5153, E-ISSN 1662-5153, Vol. 6, article id 65Article in journal (Refereed)
    Abstract [en]

    Several studies have shown a strong involvement of the basal ganglia (BG) in action selection and dopamine dependent learning. The dopaminergic signal to striatum, the input stage of the BG, has been commonly described as coding a reward prediction error (RPE), i.e., the difference between the predicted and actual reward. The RPE has been hypothesized to be critical in the modulation of the synaptic plasticity in cortico-striatal synapses in the direct and indirect pathway. We developed an abstract computational model of the BG, with a dual pathway structure functionally corresponding to the direct and indirect pathways, and compared its behavior to biological data as well as other reinforcement learning models. The computations in our model are inspired by Bayesian inference, and the synaptic plasticity changes depend on a three factor Hebbian-Bayesian learning rule based on co-activation of pre- and post-synaptic units and on the value of the RPE. The model builds on a modified Actor-Critic architecture and implements the direct (Go) and the indirect(NoGo) pathway, as well as the reward prediction (RP) system, acting in a complementary fashion. We investigated the performance of the model system when different configurations of the Go, NoGo, and RP system were utilized, e.g., using only the Go, NoGo, or RP system, or combinations of those. Learning performance was investigated in several types of learning paradigms, such as learning-relearning, successive learning, stochastic learning, reversal learning and a two-choice task. The RPE and the activity of the model during learning were similar to monkey electrophysiological and behavioral data. Our results, however, show that there is not a unique best way to configure this BG model to handle well all the learning paradigms tested. We thus suggest that an agent might dynamically configure its action selection mode, possibly depending on task characteristics and also on how much time is available.

  • 31.
    Berthet, Pierre
    et al.
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Karolinska Institute, Sweden.
    Lindahl, Mikael
    Tully, Philip J.
    Hellgren-Kotaleski, Jeanette
    Lansner, Anders
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Karolinska Institute, Sweden.
    Functional Relevance of Different Basal Ganglia Pathways Investigated in a Spiking Model with Reward Dependent Plasticity2016In: Frontiers in Neural Circuits, ISSN 1662-5110, E-ISSN 1662-5110, Vol. 10, article id 53Article in journal (Refereed)
    Abstract [en]

    The brain enables animals to behaviorally adapt in order to survive in a complex and dynamic environment, but how reward-oriented behaviors are achieved and computed by its underlying neural circuitry is an open question. To address this concern, we have developed a spiking model of the basal ganglia (BG) that learns to dis-inhibit the action leading to a reward despite ongoing changes in the reward schedule. The architecture of the network features the two pathways commonly described in BG, the direct (denoted D1) and the indirect (denoted D2) pathway, as well as a loop involving striatum and the dopaminergic system. The activity of these dopaminergic neurons conveys the reward prediction error (RPE), which determines the magnitude of synaptic plasticity within the different pathways. All plastic connections implement a versatile four-factor learning rule derived from Bayesian inference that depends upon pre- and post-synaptic activity, receptor type, and dopamine level. Synaptic weight updates occur in the D1 or D2 pathways depending on the sign of the RPE, and an efference copy informs upstream nuclei about the action selected. We demonstrate successful performance of the system in a multiple-choice learning task with a transiently changing reward schedule. We simulate lesioning of the various pathways and show that a condition without the D2 pathway fares worse than one without D1. Additionally, we simulate the degeneration observed in Parkinson's disease (PD) by decreasing the number of dopaminergic neurons during learning. The results suggest that the D1 pathway impairment in PD might have been overlooked. Furthermore, an analysis of the alterations in the synaptic weights shows that using the absolute reward value instead of the RPE leads to a larger change in D1.

  • 32. Besga, A.
    et al.
    Cedazo-Minguez, A.
    Kåreholt, I.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Solomon, A.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Björkhem, I.
    Winblad, B.
    Leoni, V.
    Hooshmand, B.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Spulber, G.
    Gonzalez-Pinto, A.
    Kivipelto, M.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wahlund, L. O.
    Differences in brain cholesterol metabolism and insulin in two subgroups of patients with different CSF biomarkers but similar white matter lesions suggest different pathogenic mechanisms2012In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 510, no 2, p. 121-126Article in journal (Refereed)
    Abstract [en]

    Investigate possible associations of white matter hyperintensities (WMHs) with the metabolism of cholesterol and insulin in two subgroups of patients with memory complaints and different CSF A beta 42 and CSF tau levels. 59 patients from the memory clinic at Karolinska Hospital were included. Degree of WMHs was rated using the ARWMC scale and the following biomarkers were measured in CSF and plasma: insulin, cholesterol, lanosterol, lathosterol, and oxidized cholesterol metabolites. The WMHs in CSF control-like group correlated with increased brain cholesterol synthesis and reduced efflux of oxysterols and insulin in CSF. In the CSF AD-like group, the WMHs correlated with increased peripheral cholesterol metabolism. Despite having similar appearance on FLAIR images, the pathogenic mechanisms of WMHS are likely to be different in the two groups investigated.

  • 33.
    Birse, Ryan Tyge
    Stockholm University, Faculty of Science, Department of Zoology.
    Tachykinin-related peptide signaling and its role in metabolic stress in Drosophila2006Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Tachykinins (TKs) constitute a highly conserved family of multifunctional neuropeptides that are known to be involved in a multitude of functions in mammals. Peptides that are presumed ancestrally related to tachykinins, so called Tachykinin-related peptides (TKRP) have been identified in invertebrates.

    Little is known about the in vivo actions of TKRPs in invertebrates. Therefore, we decided to study the TKRP signaling in the Drosophila melanogaster. Drosophila has been shown to have a tachykinin system with multiple peptides encoded on a single gene (Tk) and two G-protein coupled receptors (GPCRs), designated DTKR and NKD. The two GPCRs were further characterized in this thesis with native DTKs.

    We raised several antibodies for immunocytochemical detection of DTKR and NKD to investigate the distribution of the two receptors. We found that the two GPCRs are differentially distributed and when combined cover all regions of the DTK distribution.

    To analyze receptor function in vivo we used the GAL4-UAS system to over express DTKR and NKD with different cell specific GAL4 drivers, likely to shed light on metabolic stress responses. We also tested the effect of a DTK RNA interference (Tk-KO) transgene, in, which levels of DTK transcript was decreased by up to 95%. These flies were tested for different parameters like trehalose and lipid levels, longevity, and locomotor activity levels at starvation. We found that the Tk-KO flies displayed a prolonged lifespan and no detectable decrease trehalose. We also showed that over expression of the two GPCRs elicits different responses depending on the cell type they are expressed in. Over expression of NKD in AKH producing cells is likely to cause a release of adipokinetic hormone (AKH) while DTKR appears to have an inhibitory action on release of Drosophila insulin-like peptides (DILPs) when expressed on DILP2 producing cells.

    It has been previously shown in the locust that TKRPs are released into the haemolymph from the midgut upon starvation. We therefore used Gal4s specifically directed to the two different cells types (principal and stellate cells) of the Malpighian tubules to drive DTKR and NKD. Only when expressing the DTKR receptor in the principal cells did we see an altered phenotype during nutritional and desiccative stress. We found that over expression of DTKR produced an abbreviated lifespan. We also tested the Tk-KO flies and found that they exhibited under desiccative stress. Finally, we expressed a DTKR-RNAi construct in the both Malpighian tubules cells type and found that in both cell types the receptor knockdown produced an extended lifespan compared to controls. These data suggests that since only substances in the circulation can activate receptors on the Malpighian tubules DTKs are likely to be released into the circulation upon starvation. In summary our data indicate that DTKs and the two GPCRs are involved in signalling during metabolic stress.

  • 34. Boraxbekk, C. J.
    et al.
    Hagkvist, Filip
    Lindner, Philip
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Clinical psychology. Umeå University, Sweden; Karolinska Institutet, Sweden.
    Motor and mental training in older people: Transfer, interference, and associated functional neural responses2016In: Neuropsychologia, ISSN 0028-3932, E-ISSN 1873-3514, Vol. 89, p. 371-377Article in journal (Refereed)
    Abstract [en]

    Learning new motor skills may become more difficult with advanced age. In the present study, we randomized 56 older individuals, including 30 women (mean age 70.6 years), to 6 weeks of motor training, mental (motor imagery) training, or a combination of motor and mental training of a finger tapping sequence. Performance improvements and post-training functional magnetic resonance imaging (fMRI) were used to investigate performance gains and associated underlying neural processes. Motor only training and a combination of motor and mental training improved performance in the trained task more than mental-only training. The fMRI data showed that motor training was associated with a representation in the premotor cortex and mental training with a representation in the secondary visual cortex. Combining motor and mental training resulted in both premotor and visual cortex representations. During fMRI scanning, reduced performance was observed in the combined motor and mental training group, possibly indicating interference between the two training methods. We concluded that motor and motor imagery training in older individuals is associated with different functional brain responses. Furthermore, adding mental training to motor training did not result in additional performance gains compared to motor-only training and combining training methods may result in interference between representations, reducing performance.

  • 35. Boraxbekk, Carl-Johan
    et al.
    Lundquist, Anders
    Nordin, Annelie
    Nyberg, Lars
    Nilsson, Lars-Göran
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Adolfsson, Rolf
    Free Recall Episodic Memory Performance Predicts Dementia Ten Years prior to Clinical Diagnosis: Findings from the Betula Longitudinal Study2015In: Dementia and geriatric cognitive disorders extra, E-ISSN 1664-5464, Vol. 5, no 2, p. 191-202Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Early dementia diagnosis is a considerable challenge. The present study examined the predictive value of cognitive performance for a future clinical diagnosis of late-onset Alzheimer's disease or vascular dementia in a random population sample. Methods: Cognitive performance was retrospectively compared between three groups of participants from the Betula longitudinal cohort. Group 1 developed dementia 11-22 years after baseline testing (n = 111) and group 2 after 1-10 years (n = 280); group 3 showed no deterioration towards dementia during the study period (n = 2,855). Multinomial logistic regression analysis was used to investigate the predictive value of tests reflecting episodic memory performance, semantic memory performance, visuospatial ability, and prospective memory performance. Results: Age-and education-corrected performance on two free recall episodic memory tests significantly predicted dementia 10 years prior to clinical diagnosis. Free recall performance also predicted dementia 11-22 years prior to diagnosis when controlling for education, but not when age was added to the model. Conclusion: The present results support the suggestion that two free recall-based tests of episodic memory function may be useful for detecting individuals at risk of developing dementia 10 years prior to clinical diagnosis.

  • 36. Bosnes, O.
    et al.
    Dahl, O. -P.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden.
    Including a subject-paced trial may make the PASAT more acceptable for MS patients2015In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 132, no 4, p. 219-225Article in journal (Refereed)
    Abstract [en]

    The Paced Auditory Serial Addition Test (PASAT) is regularly used in the evaluation of cognition in multiple sclerosis (MS). However, the test may impose frustration, distress, and anxiety in patients, which may result in refusal to participate by many patients. ObjectivesIn this study, a subject- and experimenter-paced PASAT was compared and analyzed, with regard to independent measures of cognitive functions, as well as disability, fatigue, depression, and anxiety. MethodsA population-based sample of patients with MS (n=34; mean age 47.28.6) was examined with the PASAT, including a subject-paced condition, in addition to the standard experimenter-paced conditions using three levels of interstimuli intervals (ISI: 3.0, 2.5, and 2.0s). A comprehensive set of neuropsychological tests, measures of disease severity, fatigue, anxiety, and depression were studied as potentially associated factors. ResultsSubject- and experimenter-paced PASAT performance correlated significantly and the subject-paced administration correlated even higher with measures of information processing speed, executive function, attention, and working memory than standard experimenter-paced administration of PASAT. DiscussionThe associations between PASAT performance and measures of fatigue, anxiety, and depression were not significant. ConclusionThe results indicate that the altered PASAT procedure measures the same cognitive functions in MS as the standard procedure. At the same time, the altered procedure may make the PASAT more user-friendly for patients with MS.

  • 37.
    Brehmer, Yvonne
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Rieckmann, Anna
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Bellander, Martin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Westerberg, Helena
    Fischer, Håkan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Neural correlates of training-related working-memory gains in old age2011In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 58, no 4, p. 1110-1120Article in journal (Refereed)
    Abstract [en]

    Working memory (WM) functioning declines in old age. Due to its impact on many higher-order cognitive functions, investigating whether training can modify WM performance has recently been of great interest. We examined the relationship between behavioral performance and neural activity following five weeks of intensive WM training in 23 healthy older adults (M = 63.7 years). 12 participants received adaptive training (i.e. individually adjusted task difficulty to bring individuals to their performance maximum), whereas the others served as active controls (i.e. fixed low-level practice). Brain activity was measured before and after training, using fMRI, while subjects performed a WM task under two difficulty conditions. Although there were no training-related changes in WM during scanning, neocortical brain activity decreased post training and these decreases were larger in the adaptive training group than in the controls under high WM load. This pattern suggests intervention-related increases in neural efficiency. Further, there were disproportionate gains in the adaptive training group in trained as well as in non-trained (i.e. attention, episodic memory) tasks assessed outside the scanner, indicating the efficacy of the training regimen. Critically, the degree of training-related changes in brain activity (i.e. neocortical decreases and subcortical increases) was related to the maximum gain score achieved during the intervention period. This relationship suggests that the decreased activity, but also specific activity increases, observed were functionally relevant.

  • 38.
    Brehmer, Yvonne
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Max Planck Institute for Human Development, Germany.
    Shing, Yee Lee
    Heekeren, Hauke R.
    Lindenberger, Ulman
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Training-induced changes in subsequent-memory effects: No major differences among children, younger adults, and older adults2016In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 131, p. 214-225Article in journal (Refereed)
    Abstract [en]

    The neural correlates of encoding mode, or the state of forming new memory episodes, have been found to change with age and mnemonic training. However, it is unclear whether neural correlates of encoding success, termed subsequent-memory (SM) effects, also differ by age and mnemonic skill. In a multi-session training study, we investigated whether SM effects are altered by instruction and training in a mnemonic skill, and whether such alterations differ among children, younger adults, and older adults. Before and after strategy training, fMRI data were collected while participants were memorizing word pairs. In all age groups, participants receiving training showed greater performance gains than control group participants. Analysis of task-relevant regions showed training-induced reductions in SM effects in left frontal regions. Reductions in SM effects largely generalized across age and primarily reflected greater training-induced activation increases for omissions than for remembered items, indicating that training resulted in more consistent use of the mnemonic strategy. The present results reveal no major age differences in SM effects in children, younger adults, and older adults.

  • 39. Breidbach, O
    et al.
    Dircksen, Heinrich
    Institute of Zoophysiology, University of Bonn, Germany.
    Wegerhoff, R
    Common general morphological pattern of peptidergic neurons in the arachnid brain: crustacean cardioactive peptide-immunoreactive neurons in the protocerebrum of seven arachnid species.1995In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 279, no 1, p. 183-197Article in journal (Refereed)
    Abstract [en]

    A polyclonal antiserum raised against crustacean cardioactive peptide labels 14 clusters of immunoreactive neurons in the protocerebrum of the spiders Tegenaria atrica and Nephila clavipes, and the harvestman (opilionid) Rilaena triangularis. In all species, these clusters possess the same number of neurons, and share similar structural and topological characteristics. Two sets of bilateral symmetrical neurons associated with the optic lobes and the arachnid "central body" were analysed in detail, comparing the harvestman R. triangularis and the spiders Brachypelma albopilosa (Theraphosidae), Cupiennius salei (Lycosidae), Tegenaria atrica (Agelenidae), Meta segmentata (Metidae) and Nephila clavipes (Araneidae). Sixteen neurons have been identified that display markedly similar axonal pathways and arborization patterns in all species. These neurons are considered homologues in the opilionid and the araneid brains. We presume that these putative phylogenetically persisting neurons represent part of the general morphological pattern of the arachnid brain.

  • 40. Broda, Anja
    et al.
    Bieber, Anja
    Meyer, Gabriele
    Hopper, Louise
    Joyce, Rachael
    Irving, Kate
    Zanetti, Orazio
    Portolani, Elisa
    Kerpershoek, Liselot
    Verhey, Frans
    de Vugt, Marjolein
    Wolfs, Claire
    Eriksen, Siren
    Rosvik, Janne
    Marques, Maria J.
    Goncalves-Pereira, Manuel
    Sjölund, Britt-Marie
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University of Gävle, Sweden.
    Woods, Bob
    Jelley, Hannah
    Orrell, Martin
    Stephan, Astrid
    Perspectives of policy and political decision makers on access to formal dementia care: expert interviews in eight European countries2017In: BMC Health Services Research, ISSN 1472-6963, E-ISSN 1472-6963, Vol. 17, article id 518Article in journal (Refereed)
    Abstract [en]

    Background: As part of the ActifCare (ACcess to Timely Formal Care) project, we conducted expert interviews in eight European countries with policy and political decision makers, or representatives of relevant institutions, to determine their perspectives on access to formal care for people with dementia and their carers. Methods: Each ActifCare country (Germany, Ireland, Italy, The Netherlands, Norway, Portugal, Sweden, United Kingdom) conducted semi-structured interviews with 4-7 experts (total N = 38). The interview guide addressed the topics Complexity and Continuity of Care, Formal Services, and Public Awareness. Country-specific analysis of interview transcripts used an inductive qualitative content analysis. Cross-national synthesis focused on similarities in themes across the ActifCare countries. Results: The analysis revealed ten common themes and two additional sub-themes across countries. Among others, the experts highlighted the need for a coordinating role and the necessity of information to address issues of complexity and continuity of care, demanded person-centred, tailored, and multidisciplinary formal services, and referred to education, mass media and campaigns as means to raise public awareness. Conclusions: Policy and political decision makers appear well acquainted with current discussions among both researchers and practitioners of possible approaches to improve access to dementia care. Experts described pragmatic, realistic strategies to influence dementia care. Suggested innovations concerned how to achieve improved dementia care, rather than transforming the nature of the services provided. Knowledge gained in these expert interviews may be useful to national decision makers when they consider reshaping the organisation of dementia care, and may thus help to develop best-practice strategies and recommendations.

  • 41. Brose, Annette
    et al.
    Schmiedek, Florian
    Lövdén, Martin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Lindenberger, Ulman
    Normal aging dampens the link between intrusive thoughts and negative affect in reaction to daily stressors2011In: Psychology and aging, ISSN 0882-7974, Vol. 26, no 2, p. 488-502Article in journal (Refereed)
    Abstract [en]

    We charted daily variations in intrusive thoughts to gain access to adult age differences in affective reactivity to daily stressors. On 100 days, 101 younger and 103 older adults reported stressors, intrusive thoughts, and negative affect. Although increments in intrusive thoughts were similar in both age groups on days with stressors, older adults' negative affect increased less than younger adults' on such days. In addition, (a) levels of intrusive thoughts and negative affect across study time were positively associated; (b) days with increased thoughts were days with increased negative affect; and (c) experiencing above-average intrusive thoughts about stressors strengthened affective reactions to stress. Relative to younger adults, all three associations were reduced in older adults. We tentatively conclude that normal aging dampens the stress-induced link between intrusive thoughts and affect. This dampening may contribute to preserved affective well-being and reduced affective reactivity to daily stress in old age.

  • 42. Burzynska, Agnieszka Z.
    et al.
    Garrett, Douglas D.
    Preuschhof, Claudia
    Nagel, Irene E.
    Li, Shu-Chen
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Heekeren, Hauke R.
    Lindenberger, Ulman
    A Scaffold for Efficiency in the Human Brain2013In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, no 43, p. 17150-17159Article in journal (Refereed)
    Abstract [en]

    The comprehensive relations between healthy adult human brain white matter(WM) microstructure and gray matter (GM) function, and their joint relations to cognitive performance, remain poorly understood. We investigated these associations in 27 younger and 28 older healthy adults by linking diffusion tensor imaging (DTI) with functional magnetic resonance imaging (fMRI) data collected during an n-back working memory task. We present a novel application of multivariate Partial Least Squares (PLS) analysis that permitted the simultaneous modeling of relations between WM integrity values from all major WM tracts and patterns of condition-related BOLD signal across all GM regions. Our results indicate that greater microstructural integrity of the major WM tracts was negatively related to condition-related blood oxygenation level-dependent (BOLD) signal in task-positive GM regions. This negative relationship suggests that better quality of structural connections allows for more efficient use of task-related GM processing resources. Individuals with more intact WM further showed greater BOLD signal increases in typical task-negative regions during fixation, and notably exhibited a balanced magnitude of BOLD response across task-positive and-negative states. Structure-function relations also predicted task performance, including accuracy and speed of responding. Finally, structure-function behavior relations reflected individual differences over and above chronological age. Our findings provide evidence for the role of WM microstructure as a scaffold for the context-relevant utilization of GM regions.

  • 43.
    Bäckman, Lars
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Nyberg, Lars
    Dopamine and training-related working-memory improvement2013In: Neuroscience and Biobehavioral Reviews, ISSN 0149-7634, E-ISSN 1873-7528, Vol. 37, no 9, p. 2209-2219Article, review/survey (Refereed)
    Abstract [en]

    Converging evidence indicates that the neurotransmitter dopamine (DA) is implicated in working-memory (WM) functioning and that WM is trainable. We review recent work suggesting that DA is critically involved in the ability to benefit from WM interventions. Functional MRI studies reveal increased striatal BOLD activity following certain forms of WM interventions, such as updating training. Increased striatal BOLD activity has also been linked to transfer of learning to non-trained WM tasks, suggesting a neural signature of transfer. The striatal BOLD signal is partly determined by DA activity. Consistent with this assertion, PET research demonstrates increased striatal DA release during updating of information in WM after training. Genetic studies indicate larger increases in WM performance post training for those who carry advantageous alleles of DA-relevant genes. These patterns of results corroborate the role of DA in WM improvement. Future research avenues include: (a) neuromodulatory correlates of transfer; (b) the potential of WM training to enhance DA release in older adults; (c) comparisons among different WM processes (i.e., updating, switching, inhibition) regarding regional patterns of training-related DA release; and (d) gene–gene interactions in relation to training-related WM gains.

  • 44.
    Bäckman, Lars
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Waris, Otto
    Johansson, Jarkko
    Andersson, Micael
    Rinne, Juha O.
    Alakurtti, Kati
    Soveri, Anna
    Laine, Matti
    Nyberg, Lars
    Increased dopamine release after working-memory updating training: Neurochemical correlates of transfer2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 7160Article in journal (Refereed)
    Abstract [en]

    Previous work demonstrates that working-memory (WM) updating training results in improved performance on a letter-memory criterion task, transfers to an untrained n-back task, and increases striatal dopamine (DA) activity during the criterion task. Here, we sought to replicate and extend these findings by also examining neurochemical correlates of transfer. Four positron emission tomography (PET) scans using the radioligand raclopride were performed. Two of these assessed DAD2 binding (letter memory; n-back) before 5 weeks of updating training, and the same two scans were performed post training. Key findings were (a) pronounced training-related behavioral gains in the lettermemory criterion task, (b) altered striatal DAD2 binding potential after training during letter-memory performance, suggesting training-induced increases in DA release, and (c) increased striatal DA activity also during the n-back transfer task after the intervention, but no concomitant behavioral transfer. The fact that the training-related DA alterations during the transfer task were not accompanied by behavioral transfer suggests that increased DA release may be a necessary, but not sufficient, condition for behavioral transfer to occur.

  • 45. Campanella, Fabio
    et al.
    Palese, Alvisa
    Del Missier, Fabio
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Cognitive psychology. University of Trieste, Italy.
    Moreale, Renzo
    Ius, Tamara
    Shallice, Tim
    Fabbro, Franco
    Skrap, Miran
    Long-Term Cognitive Functioning and Psychological Well-Being in Surgically Treated Patients with Low-Grade Glioma2017In: World Neurosurgery, ISSN 1878-8750, E-ISSN 1878-8769, Vol. 103, p. 799-808.e9Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this work is to provide an in-depth investigation of the impact of low-grade gliomas (LGG) and their surgery on patients' cognitive and emotional functioning and well-being, carried out via a comprehensive and multiple-measure psychological and neuropsychological assessment.

    Patients and Methods: Fifty surgically treated patients with LGG were evaluated 40 months after surgery on their functioning over 6 different cognitive domains, 3 core affective/emotional aspects, and 3 different psychological well-being measures to obtain a clearer picture of the long-term impact of illness and surgery on their psychological and relational world. Close relatives were also involved to obtain an independent measure of the psychological dimensions investigated.

    Results: Cognitive status was satisfactory, with only mild short-term memory difficulties. The affective and well-being profile was characterized by mild signs of depression, good satisfaction with life and psychological well-being, and good personality development, with patients perceiving themselves as stronger and better persons after illness. However, patients showed higher emotional reactivity, and psychological well-being measures were negatively affected by epileptic burden. Well-being was related to positive affective/emotional functioning and unrelated to cognitive functioning. Good agreement between patients and relatives was found.

    Conclusions: In the long-term, patients operated on for LGG showed good cognitive functioning, with no significant long-term cognitive sequelae for the extensive surgical approach. Psychologically, patients appear to experience a deep psychological change and maturation, closely resembling that of so-called posttraumatic growth, which, to our knowledge, is for the first time described and quantified in patients with LGG.

  • 46. Capuron, Lucile
    et al.
    Lasselin, Julie
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Institute of MedicalKarolinska Institutet, Sweden; Psychology and Behavioral Immunobiology, Germany.
    Castanon, Nathalie
    Role of Adiposity-Driven Inflammation in Depressive Morbidity2017In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 42, no 1, p. 115-128Article, review/survey (Refereed)
    Abstract [en]

    Depression and metabolic disorders, including overweight and obesity, appear tightly interrelated. The prevalence of these conditions is concurrently growing worldwide, and both depression and overweight/obesity represent substantial risk factors for multiple medical complications. Moreover, there is now multiple evidence for a bidirectional relationship between depression and increased adiposity, with overweight/obesity being associated with an increased prevalence of depression, and in turn, depression augmenting the risk of weight gain and obesity. Although the reasons for this intricate link between depression and increased adiposity remain unclear, converging clinical and preclinical evidence points to a critical role for inflammatory processes and related alterations of brain functions. In support of this notion, increased adiposity leads to a chronic low-grade activation of inflammatory processes, which have been shown elsewhere to have a potent role in the pathophysiology of depression. It is therefore highly possible that adiposity-driven inflammation contributes to the development of depressive disorders and their growing prevalence worldwide. This review will present recent evidence in support of this hypothesis and will discuss the underlying mechanisms and potential therapeutic targets. Altogether, findings presented here should help to better understand the mechanisms linking adiposity to depression and facilitate the identification of new preventive and/or therapeutic strategies.

  • 47.
    Caracciolo, Barbara
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Gatz, Margaret
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Marengoni, Alessandra
    Pedersen, Nancy L.
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Relationship of Subjective Cognitive Impairment and Cognitive Impairment No Dementia to Chronic Disease and Multimorbidity in a Nation-Wide Twin Study2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 36, no 2, p. 275-284Article in journal (Refereed)
    Abstract [en]

    We investigated the relation of subjective cognitive impairment (SCI) and cognitive impairment no dementia (CIND) to common chronic diseases of the elderly and multimorbidity, and assessed the contribution of genetic background and shared familial environment to these associations. Subjects were 11,379 dementia-free twin individuals aged >= 65 from the Swedish Twin Registry. SCI was defined as subjective complaint of cognitive change without objective cognitive impairment and CIND was defined according to current criteria. In unmatched, fully-adjusted regression models, mental, musculoskeletal, respiratory, and urological diseases were all significantly associated with increased odds ratios (ORs) of SCI and CIND. Circulatory and gastrointestinal diseases were related to SCI only, while endocrine diseases were associated with CIND. The adjusted ORs of multimorbidity were 2.1 [95% confidence intervals (95% CI): 1.8-2.3] for SCI and 1.5 for CIND (95% CI: 1.3-1.8). A dose-dependent relationship was observed between number of chronic diseases and ORs for SCI but not for CIND. In co-twin control analyses, the chronic diseases-SCI association was largely unchanged. On the other hand, the chronic diseases-CIND association was no longer statistically significant, except for cancer, where an increased OR was observed. In conclusion, chronic morbidity is associated with both SCI and CIND but disease profiles do not always overlap between the two cognitive syndromes. The association is stronger when diseases co-occur, especially for SCI. Genetic and early-life environmental factors may partially explain the association of CIND but not that of SCI with chronic diseases.

  • 48. Cavallin, Lena
    et al.
    Bronge, Lena
    Zhang, Yi
    Oksengård, Anne-Rita
    Wahlund, Lars-Olof
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Axelsson, Rimma
    Comparison between visual assessment of MTA and hippocampal volumes in an elderly, non-demented population2012In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 53, no 5, p. 573-579Article in journal (Refereed)
    Abstract [en]

    Background It is important to have a replicable easy method for monitoring atrophy progression in Alzheimer's disease. Volumetric methods for calculating hippocampal volume are time-consuming and commonly used in research. Visual assessments of medial temporal lobe atrophy (vaMTA) is a rapid method for clinical use. This method has not been tested in a large non-demented population in comparison with volumetry mesurements. Since hippocampal volume decreases with time even in normal aging there is also a need to study the normal age differences of medial temporal lobe atrophy.                     

    Purpose To compare visual assessment of medial temporal lobe atrophy (vaMTA) with hippocampal volume in a healthy, non-demented elderly population. To describe normal ageing using vaMTA.                     

    Material and Methods Non-demented individuals aged 60, 66, 72, 78, 81, 84, and ≥87 years old were recruited from the Swedish National study on Ageing and Care in Kungsholmen (SNAC-K), Sweden. Standard magnetic resonance imaging (MRI) scans, vaMTA, and calculations of hippocampal volumes were performed in 544 subjects.                     

    Results Significant correlation (rs = −0.32, P < 0.001, sin; and rs = −0.26, P < 0.001, dx) was found between hippocampal volume measurements and vaMTA. In normal ageing, almost 95% of ≤66-year-olds had a medial temporal lobe atrophy (MTA) score ≤1, with possible scores ranging from 0 to 4. Subjects aged 72, 78, and 81 years scored ≤2, while the two oldest age groups had scores ≤3.                     

    Conclusion There was a highly significant correlation between volumetric measurements of the hippocampus and MTA scoring. In normal ageing, there is increasing MTA score. For non-demented elderly individuals ≤70 years, an MTA score of 0–1 may be considered normal, compared with MTA ≤2 for 70–80-years and MTA 3 for >80-year-old individuals.

  • 49. Cermakova, Pavla
    et al.
    Fereshtehnejad, Seyed-Mohammad
    Johnell, Kristina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Winblad, Bengt
    Eriksdotter, Maria
    Religa, Dorota
    Cardiovascular medication burden in dementia disorders: a nationwide study of 19,743 dementia patients in the Swedish Dementia Registry2014In: Alzheimer's research & therapy, ISSN 1758-9193, Vol. 6, no 3, p. 34-Article in journal (Refereed)
    Abstract [en]

    Introduction: Administration of several cardiovascular drugs has an effect on dementia. We aimed to investigate whether there are differences in the use of cardiovascular medication between different dementia disorders. Methods: We obtained information about dementia patients from the Swedish Dementia Registry. Patients were diagnosed with one of these dementia disorders: Alzheimer's disease (n = 8,139), mixed dementia (n = 5,203), vascular dementia (n = 4,982), Lewy body dementia (n = 605), frontotemporal dementia (n = 409) and Parkinson's disease dementia (n = 405). Multivariate logistic regression analysis was performed to investigate the association between use of cardiovascular medication and dementia disorders, after adjustment for age, gender, living alone, cognitive status and total number of drugs (a proxy for overall co-morbidity). Results: Seventy percent of all the dementia patients used cardiovascular medication. Use of cardiovascular drugs is common in patients with vascular and mixed dementia. Male gender, higher age, slightly better cognitive status and living with another person was associated with use of cardiovascular medication. Conclusions: Cardiovascular medication is used extensively across dementia disorders and particularly in vascular and mixed dementia. Future research should investigate the tolerability and effectiveness of these drugs in the different dementia disorders.

  • 50. Cermakova, Pavla
    et al.
    Johnell, Kristina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fastbom, Johan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Garcia-Ptacek, Sara
    Lund, Lars H.
    Winblad, Bengt
    Eriksdotter, Maria
    Religa, Dorota
    Cardiovascular Diseases in similar to 30,000 Patients in the Swedish Dementia Registry2015In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 48, no 4, p. 949-958Article in journal (Refereed)
    Abstract [en]

    Background: Cardiovascular diseases are leading causes of death and patients with dementia are often affected by them. Objective: Investigate associations of cardiovascular diseases with different dementia disorders and determine their impact on mortality. Methods: This study included 29,630 patients from the Swedish Dementia Registry (mean age 79 years, 59% women) diagnosed with Alzheimer's disease (AD), mixed dementia, vascular dementia, dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), frontotemporal dementia (FTD), or unspecified dementia. Records of cardiovascular diseases come from the Swedish National Patient Register. Multinomial logistic regression and cox proportional hazard models were applied. Results: Compared to AD, we found a higher burden of all cardiovascular diseases in mixed and vascular dementia. Cerebrovascular diseases were more associated with DLB than with AD. Diabetes mellitus was less associated with PDD and DLB than with AD. Ischemic heart disease was less associated with PDD and FTD than AD. All cardiovascular diseases predicted death in patients with AD, mixed, and vascular dementia. Only ischemic heart disease significantly predicted death in DLB patients (HR = 1.72; 95% CI = 1.16-2.55). In PDD patients, heart failure and diabetes mellitus were associated with a higher risk of death (HR = 3.06; 95% CI = 1.74-5.41 and HR = 3.44; 95% CI = 1.31-9.03). In FTD patients, ischemic heart disease and atrial fibrillation or flutter significantly predicted death (HR = 2.11; 95% CI = 1.08-4.14 and HR= 3.15; 95% CI = 1.60-6.22, respectively). Conclusion: Our study highlights differences in the occurrence and prognostic significance of cardiovascular diseases in several dementia disorders. This has implications for the care and treatment of the different dementia disorders.

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