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  • 1. Abelein, Axel
    et al.
    Ciofi-Baffoni, Simone
    Mörman, Cecilia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Karolinska Institutet, Sweden.
    Kumar, Rakesh
    Giachetti, Andrea
    Piccioli, Mario
    Biverstål, Henrik
    Molecular Structure of Cu(II)-Bound Amyloid-β Monomer Implicated in Inhibition of Peptide Self-Assembly in Alzheimer’s Disease2022Ingår i: JACS Au, E-ISSN 2691-3704, Vol. 2, nr 11, s. 2571-2584Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Metal ions, such as copper and zinc ions, have been shown to strongly modulate the self-assembly of the amyloid-β (Aβ) peptide into insoluble fibrils, and elevated concentrations of metal ions have been found in amyloid plaques of Alzheimer’s patients. Among the physiological transition metal ions, Cu(II) ions play an outstanding role since they can trigger production of neurotoxic reactive oxygen species. In contrast, structural insights into Cu(II) coordination of Aβ have been challenging due to the paramagnetic nature of Cu(II). Here, we employed specifically tailored paramagnetic NMR experiments to determine NMR structures of Cu(II) bound to monomeric Aβ. We found that monomeric Aβ binds Cu(II) in the N-terminus and combined with molecular dynamics simulations, we could identify two prevalent coordination modes of Cu(II). For these, we report here the NMR structures of the Cu(II)–bound Aβ complex, exhibiting heavy backbone RMSD values of 1.9 and 2.1 Å, respectively. Further, applying aggregation kinetics assays, we identified the specific effect of Cu(II) binding on the Aβ nucleation process. Our results show that Cu(II) efficiently retards Aβ fibrillization by predominately reducing the rate of fibril-end elongation at substoichiometric ratios. A detailed kinetic analysis suggests that this specific effect results in enhanced Aβ oligomer generation promoted by Cu(II). These results can quantitatively be understood by Cu(II) interaction with the Aβ monomer, forming an aggregation inert complex. In fact, this mechanism is strikingly similar to other transition metal ions, suggesting a common mechanism of action of retarding Aβ self-assembly, where the metal ion binding to monomeric Aβ is a key determinant. 

  • 2. Adams, Rick A.
    et al.
    Moutoussis, Michael
    Nour, Matthew M.
    Dahoun, Tarik
    Lewis, Declan
    Illingworth, Benjamin
    Veronese, Mattia
    Mathys, Christoph
    de Boer, Lieke
    Guitart-Masip, Marc
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Max Planck-UCL Centre for Computational Psychiatry and Ageing Research, UK.
    Friston, Karl J.
    Howes, Oliver D.
    Roiser, Jonathan P.
    Variability in Action Selection Relates to Striatal Dopamine 2/3 Receptor Availability in Humans: A PET Neuroimaging Study Using Reinforcement Learning and Active Inference Models2020Ingår i: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 30, nr 6, s. 3573-3589Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Choosing actions that result in advantageous outcomes is a fundamental function of nervous systems. All computational decision-making models contain a mechanism that controls the variability of (or confidence in) action selection, but its neural implementation is unclear-especially in humans. We investigated this mechanism using two influential decision-making frameworks: active inference (AI) and reinforcement learning (RL). In AI, the precision (inverse variance) of beliefs about policies controls action selection variability-similar to decision 'noise' parameters in RL-and is thought to be encoded by striatal dopamine signaling. We tested this hypothesis by administering a 'go/no-go' task to 75 healthy participants, and measuring striatal dopamine 2/3 receptor (D2/3R) availability in a subset (n = 25) using [C-11]-(+)-PHNO positron emission tomography. In behavioral model comparison, RL performed best across the whole group but AI performed best in participants performing above chance levels. Limbic striatal D2/3R availability had linear relationships with AI policy precision (P = 0.029) as well as with RL irreducible decision 'noise' (P = 0.020), and this relationship with D2/3R availability was confirmed with a 'decision stochasticity' factor that aggregated across both models (P = 0.0006). These findings are consistent with occupancy of inhibitory striatal D(2/3)Rs decreasing the variability of action selection in humans.

  • 3.
    Adlerz, Linda
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Processing of the amyloid precursor protein and its paralogues amyloid precursor-like proteins 1 and 22007Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

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  • 4.
    Adlerz, Linda
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi och neurotoxikologi.
    Beckman, Marie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi och neurotoxikologi.
    Holback, Sofia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi och neurotoxikologi.
    Tehranian, Roya
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi och neurotoxikologi.
    Cortés Toro, Veronica
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi och neurotoxikologi.
    Iverfeldt, Kerstin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi och neurotoxikologi.
    Accumulation of the amyloid precursor-like protein APLP2 and reduction of APLP1 in retinoic acid-differentiated human neuroblastoma cells upon curcumin-induced neurite retraction2003Ingår i: Brain Research. Molecular Brain Research, ISSN 0169-328X, E-ISSN 1872-6941, Vol. 119, nr 1, s. 62-72Artikel i tidskrift (Refereegranskat)
    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.

  • 5.
    Adlerz, Linda
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi och neurotoxikologi.
    Soomets, Ursel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi och neurotoxikologi. University of Tartu, Estonia.
    Holmlund, Linda
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi och neurotoxikologi.
    Virland, Saade
    Langel, Ülo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi och neurotoxikologi.
    Iverfeldt, Kerstin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi och neurotoxikologi.
    Down-regulation of amyloid precursor protein by peptide nucleic acid oligomer in cultured rat primary neurons and astrocytes2003Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 336, nr 1, s. 55-59Artikel i tidskrift (Refereegranskat)
    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.

  • 6.
    af Klinteberg, Britt
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om ojämlikhet i hälsa (CHESS). Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Biologisk psykologi. 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 levels2017Ingår i: Personality and Individual Differences, ISSN 0191-8869, E-ISSN 1873-3549, Vol. 118, s. 71-76Artikel i tidskrift (Refereegranskat)
    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.

  • 7. Aguila, Julio
    et al.
    Cheng, Shangli
    Kee, Nigel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Karolinska Institutet, Sweden.
    Cao, Ming
    Wang, Menghan
    Deng, Qiaolin
    Hedlund, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Karolinska Institutet, Sweden.
    Spatial RNA Sequencing Identifies Robust Markers of Vulnerable and Resistant Human Midbrain Dopamine Neurons and Their Expression in Parkinson's Disease2021Ingår i: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 14, artikel-id 699562Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Defining transcriptional profiles of substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) dopamine neurons is critical to understanding their differential vulnerability in Parkinson's Disease (PD). Here, we determine transcriptomes of human SNc and VTA dopamine neurons using LCM-seq on a large sample cohort. We apply a bootstrapping strategy as sample input to DESeq2 and identify 33 stably differentially expressed genes (DEGs) between these two subpopulations. We also compute a minimal sample size for identification of stable DEGs, which highlights why previous reported profiles from small sample sizes display extensive variability. Network analysis reveal gene interactions unique to each subpopulation and highlight differences in regulation of mitochondrial stability, apoptosis, neuronal survival, cytoskeleton regulation, extracellular matrix modulation as well as synapse integrity, which could explain the relative resilience of VTA dopamine neurons. Analysis of PD tissues showed that while identified stable DEGs can distinguish the subpopulations also in disease, the SNc markers SLIT1 and ATP2A3 were down-regulated and thus appears to be biomarkers of disease. In summary, our study identifies human SNc and VTA marker profiles, which will be instrumental for studies aiming to modulate dopamine neuron resilience and to validate cell identity of stem cell-derived dopamine neurons.

  • 8. Albrecht, Daniel S.
    et al.
    Forsberg, Anton
    Sandstrom, Angelica
    Bergan, Courtney
    Kadetoff, Diana
    Protsenko, Ekaterina
    Lampa, Jon
    Lee, Yvonne C.
    Hoglund, Caroline Olgart
    Catana, Ciprian
    Cervenka, Simon
    Akeju, Oluwaseun
    Lekander, Mats
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Stressforskningsinstitutet. Karolinska Institutet, Sweden; Karolinska University Hospital, Sweden.
    Cohen, George
    Halldin, Christer
    Taylor, Norman
    Kim, Minhae
    Hooker, Jacob M.
    Edwards, Robert R.
    Napadow, Vitaly
    Kosek, Eva
    Loggia, Marco L.
    Brain glial activation in fibromyalgia - A multi-site positron emission tomography investigation2019Ingår i: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 75, s. 72-83Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [C-11]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [C-11]-L-deprenyl-D2 PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [C-11]PBR28 PET. 11 FM patients and 11 HC were scanned using [C-11]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (V-T) were computed from the [C-11]PBR28 data. [C-11]-L-deprenyl-D2 was quantified using lambda k(3). PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [C-11]PBR28 ITT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [C-11]-L-deprenyl-Ds signal, including those demonstrating elevated [C-11] PBR28 signal in patients (p's >= 0.53, uncorrected). The elevations in [C-11]PBR28 V-T and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [C-11] PBR28 SUVR in the anterior and posterior middle cingulate cortices (p's < 0.03). SUVR was not significantly associated with any other clinical variable. Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [C-11]PBR28 signal were not also accompanied by increased [C-11]-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [C-11]-L-deprenyl-D2 signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.

  • 9. Alier, Kwai
    et al.
    Chen, Yishen
    Eriksson Sollenberg, Ulla
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Langel, Ülo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Smith, Peter
    Selective stimulation of GalR1 and GalR2 in rat substantia gelatinosa reveals a cellular basis for the anti- and pro-nociceptive actions of galanin2008Ingår i: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 137, nr 1, s. 138-146Artikel i tidskrift (Refereegranskat)
    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.

  • 10.
    Alikhani, Nyosha
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Guo, Lan
    Yan, Shiqiang
    Du, Heng
    Pinho, Catarina Moreira
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Chen, John Xi
    Glaser, Elzbieta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Yan, Shirley ShiDu
    Decreased proteolytic activity of the mitochondrial amyloid-β degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria2011Ingår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 27, nr 1, s. 75-87Artikel i tidskrift (Refereegranskat)
    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.

  • 11. Aljeaidi, Muhamad S.
    et al.
    Tan, Edwin C. K.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Stressforskningsinstitutet. The University of Sydney, Australia; Monash University, Australia .
    The association between polypharmacy and cognitive ability in older adults: A national cohort study2022Ingår i: Research in Social and Administrative Pharmacy, ISSN 1551-7411, E-ISSN 1934-8150, Vol. 18, nr 3, s. 2505-2509Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Polypharmacy, the use of multiple medications by one individual, may be associated with adverse health outcomes including poor cognition. However, it remains unclear whether a longitudinal relationship exists.

    Objectives: To investigate the association between polypharmacy and 3-year cognitive ability in older adults.

    Methods: A longitudinal cohort study of older adults 65 years and older, residing in the community, who participated in waves 12 (2012), 13 (2013) and 16 (2016) of the Household Income and Labour Dynamics (HILDA) Survey was conducted. Polypharmacy was defined as the regular use of 5 or more prescription medications. Cognitive ability was assessed using backwards digit span test (BDS), 25-item version of the National Adult Reading Test (NART-25) and symbol-digit modalities test (SDM). Linear regression was used to test the longitudinal association between polypharmacy and cognitive test scores at 3 years. All analyses were adjusted for age, sex, education, comorbidities, socioeconomic and lifestyle factors, and baseline cognitive test scores.

    Results: A total of 2141 participants (mean age 72.9 years, 54.4% female) were included in the study sample. Polypharmacy was present in 27.3%. After adjusting for potential confounders, polypharmacy was negatively associated with cognitive ability at 3 years: BDS: −0.067 (95% CI = −0.353 to −0.051), NART-25: −0.071 (95% CI = −1.428 to −0.294), SDM: −0.073 (95% CI = −2.960 to −0.696).

    Conclusion: Polypharmacy was associated with poorer cognitive ability at 3 years, even after adjusting for comorbidities and other confounders. Future research should consider the long-term impact of polypharmacy on cognitive ability, and identify strategies to optimise medication use and cognition in older adults.

  • 12.
    Almkvist, Ove
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Biologisk psykologi. Karolinska Institutet, Sweden; Karolinska University Hospital, Sweden.
    Brüggen, Katharina
    Nordberg, Agneta
    Subcortical and Cortical Regions of Amyloid-β Pathology Measured by C-11-PiB PET Are Differentially Associated with Cognitive Functions and Stages of Disease in Memory Clinic Patients2021Ingår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 81, nr 4, s. 1613-1624Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The effect of regional brain amyloid-beta (A beta) pathology on specific cognitive functions is incompletely known.

    Objective: The relationship between A beta and cognitive functions was investigated in this cross-sectional multicenter study of memory clinic patients.

    Methods: The participants were patients diagnosed with Alzheimer's disease (AD, n = 83), mild cognitive impairment (MCI, n = 60), and healthy controls (HC, n = 32), who had been scanned by C-11-PiB PET in 13 brain regions of both hemispheres and who had been assessed by cognitive tests covering seven domains.

    Results: Hierarchic multiple regression analyses were performed on each cognitive test as dependent variable, controlling for demographic characteristics and APOE status (block 1) and PiB measures in 13 brain regions (block 2) as independent variables. The model was highly significant for each cognitive test and most strongly for tests of episodic memory (learning and retention) versus PiB in putamen, visuospatially demanding tests (processing and retention) versus the occipital lobe, semantic fluency versus the parietal lobe, attention versus posterior gyrus cinguli, and executive function versus nucleus accumbens. In addition, education had a positively and APOE status a negatively significant effect on cognitive tests.

    Conclusion: Five subcortical and cortical regions with A beta pathology are differentially associated with cognitive functions and stages of disease in memory clinic patients.

  • 13.
    Almkvist, Ove
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Biologisk psykologi. Karolinska Institutet, Sweden; Karolinska University Hospital, Sweden.
    Graff, Caroline
    The APOE ε4 Allele Affects Cognitive Functions Differently in Carriers of APP Mutations Compared to Carriers of PSEN1 Mutations in Autosomal-Dominant Alzheimer’s Disease2021Ingår i: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 12, nr 12, artikel-id 1954Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mounting evidence shows that the APOE ε4 allele interferes with cognition in sporadic Alzheimer’s disease. Less is known about APOE in autosomal-dominant Alzheimer’s disease (adAD). The present study explored the effects on cognition associated with the gene–gene interactions between the APOE gene and the APP and PSEN1 genes in adAD. This study includes mutation carriers (MC) and non-carriers (NC) from adAD families with mutations in APP (n = 28 and n = 25; MC and NC, respectively) and PSEN1 (n = 12 and n = 15; MC and NC, respectively) that represent the complete spectrum of disease: AD dementia (n = 8) and mild cognitive impairment (MCI, n = 15 and presymptomatic AD, n = 17). NC represented unimpaired normal aging. There was no significant difference in the distribution of APOE ε4 (absence vs. presence) between the APP vs. PSEN1 adAD genes and mutation status (MC vs. NC). However, episodic memory was significantly affected by the interaction between APOE and the APP vs. PSEN1 genes in MC. This was explained by favorable performance in the absence of APOE ε4 in PSEN1 compared to APP MC. Similar trends were seen in other cognitive functions. No significant associations between APOE ε4 and cognitive performance were obtained in NC. In conclusion, cognitive effects of APOE–adAD gene interaction were differentiated between the PSEN1 and APP mutation carriers, indicating epistasis.

  • 14.
    Almkvist, Ove
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Biologisk psykologi. 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 Disease2017Ingår i: Journal of the International Neuropsychological Society, ISSN 1355-6177, E-ISSN 1469-7661, Vol. 23, nr 3, s. 195-203Artikel i tidskrift (Refereegranskat)
    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.

  • 15.
    Amelina, Hanna
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Holm, Tina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Langel, Ülo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Cristobal, Susana
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Delivering catalase to yeast peroxisomes using cell-penetrating peptidesIngår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658Artikel i tidskrift (Refereegranskat)
  • 16. Ammari, Rachida
    et al.
    Broberger, Christian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Karolinska Institutet, Sweden.
    Pre- and post-synaptic modulation by GABA(B) receptors of rat neuroendocrine dopamine neurones2020Ingår i: Journal of neuroendocrinology (Print), ISSN 0953-8194, E-ISSN 1365-2826, Vol. 32, nr 11, artikel-id e12881Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The secretion of prolactin from the pituitary is negatively controlled by tuberoinfundibular dopamine (TIDA) neurones. The electrical properties of TIDA cells have recently been identified as a modulatory target of neurotransmitters and hormones in the lactotrophic axis. The role of the GABA(B) receptor in this control has received little attention, yet is of particular interest because it may act as a TIDA neurone autoreceptor. Here, this issue was explored in a spontaneously active rat TIDA in vitro slice preparation using whole-cell recordings. Application of the GABA(B) receptor agonist, baclofen, dose-dependently slowed down or abolished the network oscillations typical of this preparation. Pharmacological manipulations identify the underlying mechanism as an outward current mediated by G-protein-coupled inwardly rectifying K+-like channels. In addition to this postsynaptic modulation, we describe a presynaptic modulation where GABA(B) receptors restrain the release of glutamate and GABA onto TIDA neurones. Our data identify both pre- and postsynaptic modulation of TIDA neurones by GABA(B) receptors that may play a role in the neuronal network control of pituitary prolactin secretion and lactation.

  • 17. Anderson, Maria E.
    et al.
    Runesson, Johan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Saar, Indrek
    Langel, Ülo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi. University of Tartu, Estonia.
    Robinson, John K.
    Galanin, through GalR1 but not GalR2 receptors, decreases motivation at times of high appetitive behavior2013Ingår i: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 239, s. 90-93Artikel i tidskrift (Refereegranskat)
    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.

  • 18. Andersson, Gerhard
    et al.
    Rozental, Alexander
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Klinisk psykologi. University College London, England.
    Shafran, Roz
    Carlbring, Per
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Klinisk psykologi. University College London, England.
    Long-term effects of internet-supported cognitive behaviour therapy2018Ingår i: Expert Review of Neurotherapeutics, ISSN 1473-7175, E-ISSN 1744-8360, Vol. 18, nr 1, s. 21-28Artikel, forskningsöversikt (Refereegranskat)
    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.

  • 19. Andersson, Linus
    et al.
    Sandberg, Petra
    Olofsson, Jonas K.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Perception och psykofysik.
    Nordin, Steven
    Effects of Task Demands on Olfactory, Auditory, and Visual Event-Related Potentials Suggest Similar Top-Down Modulation Across Senses2018Ingår i: Chemical Senses, ISSN 0379-864X, E-ISSN 1464-3553, Vol. 43, nr 2, s. 129-134Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A widely held view is that top-down modulation of sensory information relies on an amodal control network that acts through the thalamus to regulate incoming signals. Olfaction lacks a direct thalamic projection, which suggests that it may differ from other modalities in this regard. We investigated the late positive complex (LPC) amplitudes of event-related potentials (ERP) from 28 participants, elicited by intensity-matched olfactory, auditory and visual stimuli, during a condition of focused attention, a neutral condition, and a condition in which stimuli were to be actively ignored. Amplitudes were largest during the attend condition, lowest during the ignore condition, with the neutral condition in between. A Bayesian analysis resulted in strong evidence for similar effects of task across sensory modalities. We conclude that olfaction, despite its unique neural projections, does not differ from audition and vision in terms of task-dependent neural modulation of the LPC.

  • 20.
    Andersson, Patrik
    et al.
    Stockholms universitet, Humanistiska fakulteten, Institutionen för lingvistik. University of Trento, Italy.
    Ragni, Flavio
    Lingnau, Angelika
    Visual imagery during real-time fMRI neurofeedback from occipital and superior parietal cortex2019Ingår i: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 200, s. 332-343Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Visual imagery has been suggested to recruit occipital cortex via feedback projections from fronto-parietal regions, suggesting that these feedback projections might be exploited to boost recruitment of occipital cortex by means of real-time neurofeedback. To WA this prediction, we instructed a group of healthy participants to perform peripheral visual imagery while they received real-time auditory feedback based on the BOLD signal from either early visual cortex or the medial superior parietal lobe. We examined the amplitude and temporal aspects of the BOLD response in the two regions. Moreover, we compared the impact of self-rated mental focus and vividness of visual imagery on the BOLD responses in these two areas. We found that both early visual cortex and the medial superior parietal cortex are susceptible to auditory neurofeedback within a single feedback session per region. However, the signal in parietal cortex was sustained for a longer time compared to the signal in occipital cortex. Moreover, the BOLD signal in the medial superior parietal lobe was more affected by focus and vividness of the visual imagery than early visual cortex. Our results thus demonstrate that (a) participants can learn to self-regulate the BOLD signal in early visual and parietal cortex within a single session, (b) that different nodes in the visual imagery network respond differently to neurofeedback, and that (c) responses in parietal, but not in occipital cortex are susceptible to self-rated vividness of mental imagery. Together, these results suggest that medial superior parietal cortex might be a suitable candidate to provide real-time feedback to patients suffering from visual field defects.

  • 21. Andin, Josefine
    et al.
    Holmer, Emil
    Schönström, Krister
    Stockholms universitet, Humanistiska fakulteten, Institutionen för lingvistik.
    Rudner, Mary
    Working Memory for Signs with Poor Visual Resolution: fMRI Evidence of Reorganization of Auditory Cortex in Deaf Signers2021Ingår i: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 31, nr 7, s. 3165-3176Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Stimulus degradation adds to working memory load during speech processing. We investigated whether this applies to sign processing and, if so, whether the mechanism implicates secondary auditory cortex. We conducted an fMRI experiment where 16 deaf early signers (DES) and 22 hearing non-signers performed a sign-based n-back task with three load levels and stimuli presented at high and low resolution. We found decreased behavioral performance with increasing load and decreasing visual resolution, but the neurobiological mechanisms involved differed between the two manipulations and did so for both groups. Importantly, while the load manipulation was, as predicted, accompanied by activation in the frontoparietal working memory network, the resolution manipulation resulted in temporal and occipital activation. Furthermore, we found evidence of cross-modal reorganization in the secondary auditory cortex: DES had stronger activation and stronger connectivity between this and several other regions. We conclude that load and stimulus resolution have different neural underpinnings in the visual–verbal domain, which has consequences for current working memory models, and that for DES the secondary auditory cortex is involved in the binding of representations when task demands are low.

  • 22.
    Araujo, Priscila
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen, Avdelningen för funktionell zoomorfologi. Universidade Federal de Minas Gerais, Brazil.
    de Araujo, Fernanda Figueiredo
    Vidal, Diogo Montes
    Mota, Theo
    Schlindwein, Clemens
    The role of visual and olfactory floral cues in twilight foraging by Ptiloglossa and Xylocopa bees2024Ingår i: Behavioral Ecology and Sociobiology, ISSN 0340-5443, E-ISSN 1432-0762, Vol. 78, nr 2, artikel-id 25Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Bees of Ptiloglossa and Xylocopa explore the chiropterophilous flowers of Pseudobombax longiflorum at twilight, but how the bees find the flowers in low light is unclear. In field experiments, we investigated if visual and olfactory floral cues are used by these bees to find P. longiflorum flowers, and which behaviors are triggered by these cues. While the crepuscular Ptiloglossa bees were more attracted to flowers with a combination of visual and olfactory cues than to isolated cues, the diurnal Xylocopa bees were equally attracted to the combination of visual and olfactory cues and to flowers with visual cues alone. Ptiloglossa bees visit the flowers under lower light intensity than Xylocopa bees. This indicates that the synergy between visual-olfactory cues facilitates flower detection in crepuscular bees. However, in higher light intensities, the large size of flowers with their broad spectrum reflectance may be enough to produce a reliable visual signal for the Xylocopa bees. Olfactory stimuli alone trigger only floral approaches in bees, while visual ones frequently trigger approaches followed by landings on flowers. This suggests that olfactory cues guide the bees to the flowers in twilight, but the presence of a visual cue is necessary to trigger landings and collection of floral resources.

  • 23. Arshamian, Artin
    et al.
    Gerkin, Richard C.
    Kruspe, Nicole
    Wnuk, Ewelina
    Floyd, Simeon
    O'Meara, Carolyn
    Garrido Rodriguez, Carolyn
    Lundström, Johan N.
    Stockholms universitet, Humanistiska fakulteten, Institutionen för lingvistik. Karolinska Institutet, Sweden; Monell Chemical Senses Center, USA; University of Pennsylvania, USA.
    Mainland, Joel D.
    Majid, Asifa
    The perception of odor pleasantness is shared across cultures2022Ingår i: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 32, nr 9, s. 2061-2066, e1-e3Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Humans share sensory systems with a common anatomical blueprint, but individual sensory experience nevertheless varies. In olfaction, it is not known to what degree sensory perception, particularly the perception of odor pleasantness, is founded on universal principles dictated by culture or merely a matter of personal taste. To address this, we asked 225 individuals from 9 diverse nonwestern cultures—hunter-gatherer to urban dwelling—to rank the monomolecular odorants from most to least pleasant. Contrary to expectations, culture explained only 6% of the variance in pleasantness rankings, whereas individual variability or personal taste explained 54%. Importantly, there was substantial global consistency, with molecular identity explaining 41% of the variance in odor pleasantness rankings. Critically, these universal rankings were predicted by the physicochemical properties of out-of-sample molecules and out-of-sample pleasantness ratings given by a tenth group of western urban participants. Taken together, this shows human olfactory perception is strongly constrained by universal principles.

  • 24.
    Arshamian, Artin
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Perception och psykofysik. Karolinska Institutet, Sweden; Donders Institute for Brain, Cognition, and Behavior, The Netherlands; Radboud University, The Netherlands.
    Iravani, Behzad
    Majid, Asifa
    Lundström, Johan N.
    Respiration Modulates Olfactory Memory Consolidation in Humans2018Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 38, nr 48, s. 10286-10294Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In mammals respiratory-locked hippocampal rhythms are implicated in the scaffolding and transfer of information between sensory and memory networks. These oscillations are entrained by nasal respiration and driven by the olfactory bulb. They then travel to the piriform cortex where they propagate further downstream to the hippocampus and modulate neural processes critical for memory formation. In humans, bypassing nasal airflow through mouth-breathing abolishes these rhythms and impacts encoding as well as recognition processes thereby reducing memory performance. It has been hypothesized that similar behavior should be observed for the consolidation process, the stage between encoding and recognition, were memory is reactivated and strengthened. However, direct evidence for such an effect is lacking in human and nonhuman animals. Here we tested this hypothesis by examining the effect of respiration on consolidation of episodic odor memory. In two separate sessions, female and male participants encoded odors followed by a 1 h awake resting consolidation phase where they either breathed solely through their nose or mouth. Immediately after the consolidation phase, memory for odors was tested. Recognition memory significantly increased during nasal respiration compared with mouth respiration during consolidation. These results provide the first evidence that respiration directly impacts consolidation of episodic events, and lends further support to the notion that core cognitive functions are modulated by the respiratory cycle.

  • 25. Arya, Ashwani
    et al.
    Chahal, Rubal
    Rao, Rekha
    Rahman, Md. Habibur
    Kaushik, Deepak
    Akhtar, Muhammad Furqan
    Saleem, Ammara
    Khalifa, Shaden A. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    El-Seedi, Hesham R.
    Kamel, Mohamed
    Albadrani, Ghadeer M.
    Abdel-Daim, Mohamed M.
    Mittal, Vineet
    Acetylcholinesterase Inhibitory Potential of Various Sesquiterpene Analogues for Alzheimer's Disease Therapy2021Ingår i: Biomolecules, E-ISSN 2218-273X, Vol. 11, nr 3, artikel-id 350Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Alzheimer’s disease (AD) is a gradually growing irreversible illness of the brain that almost affects every fifth person (aged > 80 years) in the world. World Health Organization (WHO) also revealed that the prevalence of this disease will enhance (upto double) significantly upto 2030. The poor cholinergic transmission at the synapse is considered to be one of the main reasons behind the progression and occurrence of this disorder. Natural inhibitors of acetylcholine (ACh) such as galanthamine and rivastigmine are used commercially in the treatmentof AD. The biomolecules such assesquiterpenes, possess a great structural diversity and are responsible for a plethora of pharmacological properties. The potential of various sesquiterpenes as anticholinesterase has been reviewed in this article. For this purpose, the various databases, mainly PubMed, Scopus, and Web of Science were investigatedwith different keywords such as “sesquiterpenes+acetylcholinesterase” and “sesquiterpenes+cholinesterase+inhibitors” in the surveyed time frame (2010–2020). A vast literature was evident in the last decade, which affirms the potential of various sesquiterpenes in the improvement of cholinergic transmission by inhibiting the AChE. After data analysis, it was found that 12 compounds out of a total of 58 sesquiterpenes were reported to possess IC50 < 9 μM and can be considered as potential candidates for the improvement of learning and memory. Sesquiterpene is an important category of terpenoids, found to possess a large spectrum of biological activities. The outcome of the review clearly states that sesquiterpenes (such as amberboin, lipidiol, etc.) from herbs could offer fresh, functional compounds for possible prevention and treatment of AD.

  • 26.
    Aslam, Muhammad
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    The fruit fly Drosophila melanogaster GSTE6 and E7; characterization, immobilization and transgenic overexpression2014Licentiatavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

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    Omslagsframsida
  • 27.
    Aslam, Muhammad
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Dahlberg, Olle
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Mannervik, Bengt
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Mannervik, Mattias
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Transgenic Overexpression of Glutathione Transferase E7 in Drosophila Attenuates Toxicity of Organic Isothiocyanates Affecting Survival and OvipositionManuskript (preprint) (Övrigt vetenskapligt)
    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.

  • 28. Asperholm, Martin
    et al.
    Nagar, Sanket
    Dekhtyar, Serhiy
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Herlitz, Agneta
    The magnitude of sex differences in verbal episodic memory increases with social progress: Data from 54 countries across 40 years2019Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 14, nr 4, artikel-id e0214945Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sex differences in episodic memory have been reported. We investigate (1) the existence of sex differences in verbal and other episodic memory tasks in 54 countries, and (2) the association between the time-and country-specific social progress indicators (a) female to male ratio in education and labor force participation, (b) population education and employment, and (c) GDP per capita, and magnitude of sex differences in verbal episodic memory tasks. Data were retrieved from 612 studies, published 1973-2013. Results showed that females outperformed (Cohen's d > 0) males in verbal (42 out of 45 countries) and other (28 out of 45 countries) episodic memory tasks. Although all three social progress indicators were, separately, positively associated with the female advantage in verbal episodic memory performance, only population education and employment remained significant when considering the social indicators together. Results suggest that women's verbal episodic memory performance benefits more than men's from education and employment.

  • 29. Athanasiu, Lavinia
    et al.
    Giddaluru, Sudheer
    Fernandes, Carla
    Christoforou, Andrea
    Reinvang, Ivar
    Lundervold, Astri J.
    Nilsson, Lars-Göran
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m 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 function2017Ingår i: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 61, s. 209-216Artikel i tidskrift (Refereegranskat)
    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.

  • 30.
    Attoff, Kristina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    In vitro developmental neurotoxicity of acrylamide2016Licentiatavhandling, sammanläggning (Övrigt vetenskapligt)
    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.  

  • 31. Aufschnaiter, Andreas
    et al.
    Habernig, Lukas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of Graz, Austria.
    Kohler, Verena
    Diessl, Jutta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Carmona-Gutierrez, Didac
    Eisenberg, Tobias
    Keller, Walter
    Büttner, Sabrina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of Graz, Austria.
    The Coordinated Action of Calcineurin and Cathepsin D Protects Against alpha-Synuclein Toxicity2017Ingår i: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 10, artikel-id 207Artikel i tidskrift (Refereegranskat)
    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.

  • 32. Aufschnaiter, Andreas
    et al.
    Kohler, Verena
    Walter, Corvin
    Tosal-Castano, Sergi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Habernig, Lukas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wolinski, Heimo
    Keller, Walter
    Vögtle, F-Nora
    Büttner, Sabrina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of Graz, Austria.
    The Enzymatic Core of the Parkinson's Disease-Associated Protein LRRK2 Impairs Mitochondria Biogenesis in Aging Yeast2018Ingår i: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 11, artikel-id 205Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mitochondrial dysfunction is a prominent trait of cellular decline during aging and intimately linked to neuronal degeneration during Parkinson's disease (PD). Various proteins associated with PD have been shown to differentially impact mitochondrial dynamics, quality control and function, including the leucine-rich repeat kinase 2 (LRRK2). Here, we demonstrate that high levels of the enzymatic core of human LRRK2, harboring GTPase as well as kinase activity, decreases mitochondrial mass via an impairment of mitochondria! biogenesis in aging yeast. We link mitochondrial depletion to a global downregulation of mitochondria-related gene transcripts and show that this catalytic core of LRRK2 localizes to mitochondria and selectively compromises respiratory chain complex IV formation. With progressing cellular age, this culminates in dissipation of mitochondrial transmembrane potential, decreased respiratory capacity, ATP depletion and generation of reactive oxygen species. Ultimately, the collapse of the mitochondrial network results in cell death. A point mutation in LRRK2 that increases the intrinsic GTPase activity diminishes mitochondrial impairment and consequently provides cytoprotection. In sum, we report that a downregulation of mitochondrial biogenesis rather than excessive degradation of mitochondria underlies the reduction of mitochondrial abundance induced by the enzymatic core of LRRK2 in aging yeast cells. Thus, our data provide a novel perspective for deciphering the causative mechanisms of LRRK2-associated PD pathology.

  • 33.
    Avelar-Pereira, Bárbara
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Umeå University, Sweden.
    Bäckman, Lars
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Wåhlin, Anders
    Nyberg, Lars
    Salami, Alireza
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Umeå University, Sweden.
    Increased functional homotopy of the prefrontal cortex is associated with corpus callosum degeneration and working memory decline2020Ingår i: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 96, s. 68-78Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Functional homotopy reflects the link between spontaneous activity in a voxel and its counterpart in the opposite hemisphere. Alterations in homotopic functional connectivity (FC) are seen in normal aging, with highest and lowest homotopy being present in sensory-motor and higher-order regions, respectively. Homotopic FC relates to underlying structural connections, but its neurobiological underpinnings remain unclear. The genu of the corpus callosum joins symmetrical parts of the prefrontal cortex (PFC) and is susceptible to age-related degeneration, suggesting that PFC homotopic connectivity is linked to changes in white-matter integrity. We investigated homotopic connectivity changes and whether these were associated with white-matter integrity in 338 individuals. In addition, we examined whether PFC homotopic FC was related to changes in the genu over 10 years and working memory over 5 years. There were increases and decreases in functional homotopy, with the former being prevalent in subcortical and frontal regions. Increased PFC homotopic FC was partially driven by structural degeneration and negatively associated with working memory, suggesting that it reflects detrimental age-related changes.

  • 34.
    Axelsson, John
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Stressforskningsinstitutet. Karolinska Institutet, Sweden.
    Sundelin, Tina
    Olsson, Mats J.
    Sorjonen, Kimmo
    Axelsson, Charlotte
    Lasselin, Julie
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Stressforskningsinstitutet. Karolinska Institutet, Sweden; Universitätsklinikum Essen, Germany.
    Lekander, Mats
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Stressforskningsinstitutet. Karolinska Institutet, Sweden.
    Identification of acutely sick people and facial cues of sickness2018Ingår i: Proceedings of the Royal Society of London. Biological Sciences, ISSN 0962-8452, E-ISSN 1471-2954, Vol. 285, nr 1870, artikel-id 20172430Artikel i tidskrift (Refereegranskat)
    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.

  • 35.
    Axelsson, John
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Stressforskningsinstitutet. Karolinska Institute, Sweden.
    Vyazovskiy, Vladyslav V.
    Banking Sleep and Biological Sleep Need2015Ingår i: Sleep, ISSN 0161-8105, E-ISSN 1550-9109, Vol. 38, nr 12, s. 1843-1845Artikel i tidskrift (Övrigt vetenskapligt)
  • 36.
    Axelsson, Viktoria
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Evaluation of neurotoxic properties of gliotoxin2006Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

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  • 37.
    Balter, Leonie J. T.
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Stressforskningsinstitutet. Karolinska Institutet, Sweden.
    Axelsson, John
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Stressforskningsinstitutet. Karolinska Institutet, Sweden.
    Sleep and subjective age: protect your sleep if you want to feel young2024Ingår i: Proceedings of the Royal Society of London. Biological Sciences, ISSN 0962-8452, E-ISSN 1471-2954, Vol. 291, nr 2019, artikel-id 20240171Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The current studies examined the impact of insufficient sleep and sleepiness on the subjective experience of age. Study 1, a cross-sectional study of 429 participants (282 females (66%), 144 males, 3 other gender; age range 18-70), showed that for each additional day of insufficient sleep in the last 30 days, subjective age increased by 0.23 years. Study 2, an experimental crossover sleep restriction study (n = 186; 102 females (55%), 84 males; age range 18-46), showed that two nights of sleep restriction (4 h in bed per night) made people feel 4.44 years older compared to sleep saturation (9 h in bed per night). Additionally, moving from feeling extremely alert (Karolinska Sleepiness Scale (KSS) score of 1) to feeling extremely sleepy (KSS score of 9) was associated with feeling 10 years older in both studies. These findings provide compelling support for insufficient sleep and sleepiness to exert a substantial influence on how old we feel, and that safeguarding sleep is probably a key factor in feeling young.

  • 38.
    Balter, Leonie J. T.
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Stressforskningsinstitutet. Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Biologisk psykologi. Karolinska Institutet, Sweden.
    Li, Xueqi
    Schwieler, Lilly
    Erhardt, Sophie
    Axelsson, John
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Stressforskningsinstitutet. Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Biologisk psykologi. Karolinska Institutet, Sweden.
    Olsson, Mats J.
    Lasselin, Julie
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Stressforskningsinstitutet. Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Biologisk psykologi. Karolinska Institutet, Sweden.
    Lekander, Mats
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Stressforskningsinstitutet. Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen, Biologisk psykologi. Karolinska Institutet, Sweden.
    Lipopolysaccharide-induced changes in the kynurenine pathway and symptoms of sickness behavior in humans2023Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 153, artikel-id 106110Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Metabolites of the kynurenine pathway are hypothesized to be implicated in inflammation-associated depression, but there is a lack of experimental studies in humans assessing the kinetics of kynurenine metabolites in relation to experimentally-induced sickness. The aim of the present study was to assess changes in the kynurenine pathway and to explore its relation to symptoms of sickness behavior during an acute experimental immune challenge.

    This double-blind placebo-controlled randomized cross-over study included 22 healthy human participants (n = 21 both sessions, Mage = 23.4, SD = 3.6, nine women) who received an intravenous injection of 2.0 ng/kg lipopolysaccharide (LPS) and saline (placebo) on two different occasions in a randomized order. Blood samples (0 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 7 h post-injection) were analyzed for kynurenine metabolites and inflammatory cytokines. The intensity of symptoms of sickness behavior was assessed using the 10-item Sickness Questionnaire at 0 h, 1.5 h, 3 h, 5 h, and 7 h post-injection.

    LPS induced significantly lower concentrations of plasma tryptophan (at 2 h, 4 h, 5 h, and 7 h post-injection), kynurenine (at 2 h, 3 h, 4 h, and 5 h post-injection), nicotinamide (at 4 h, 5 h, and 7 h post-injection), and higher levels for quinolinic acid at 5 h post-injection as compared to placebo. LPS did not affect kynurenic acid, 3-hydroxykynurenine, and picolinic acid. The development of the sickness symptoms was largely similar across items, with the highest levels around 1.5–3 h post-injection. Changes in plasma levels of kynurenine metabolites seem to coincide rather than precede or follow changes in subjective sickness. Exploratory analyses indicate that higher Sickness Questionnaire total scores at 1.5–5 h post-injection were correlated with lower kynurenic acid and nicotinamide levels.

    These results lend further support for LPS-induced changes in the kynurenine pathway, but may not, as interpreted from blood levels, causally link to LPS-induced acute symptoms of sickness behavior. Future research may consider a larger sample to further scrutinize the role of the kynurenine pathway in the sickness response.

  • 39. Barbera, Mariagnese
    et al.
    Mangialasche, Francesca
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Jongstra, Susan
    Guillemont, Juliette
    Ngandu, Tiia
    Beishuizen, Cathrien
    Coley, Nicola
    Brayne, Carol
    Andrieu, Sandrine
    Richard, Edo
    Soininen, Hilkka
    Kivipelto, Miia
    Designing an Internet-Based Multidomain Intervention for the Prevention of Cardiovascular Disease and Cognitive Impairment in Older Adults: The HATICE Trial2018Ingår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 62, nr 2, s. 649-663Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Many dementia and cardiovascular disease (CVD) cases in older adults are attributable to modifiable vascular and lifestyle-related risk factors, providing opportunities for prevention. In the Healthy Aging Through Internet Counselling in the Elderly (HATICE) randomized controlled trial, an internet-based multidomain intervention is being tested to improve the cardiovascular risk (CVR) profile of older adults. Objective: To design a multidomain intervention to improve CVR, based on the guidelines for CVR management, and administered through a coach-supported, interactive, platform to over 2500 community-dwellers aged 65+ in three European countries. Methods: A comparative analysis of national and European guidelines for primary and secondary CVD prevention was performed. Results were used to define the content of the intervention. Results: The intervention design focused on promoting awareness and self-management of hypertension, dyslipidemia, diabetes mellitus, and overweight, and supporting smoking cessation, physical activity, and healthy diet. Overall, available guidelines lacked specific recommendations for CVR management in older adults. The comparative analysis of the guidelines showed general consistency for lifestyle-related recommendations. Key differences, identified mostly in methods used to assess the overall CVR, did not hamper the intervention design. Minor country-specific adaptations were implemented to maximize the intervention feasibility in each country. Conclusion: Despite differences inCVRmanagement within the countries considered, itwas possible to design and implement the HATICE multidomain intervention. The study can help define preventative strategies for dementia and CVD that are applicable internationally.

  • 40. Barde, Swapnali
    et al.
    Aguila, Julio
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Karolinska Institutet, Sweden.
    Zhong, Wen
    Solarz, Anna
    Mei, Irene
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Prud'homme, Josee
    Palkovits, Miklos
    Turecki, Gustavo
    Mulder, Jan
    Uhlén, Mathias
    Nagy, Corina
    Mechawar, Naguib
    Hedlund, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Karolinska Institutet, Sweden.
    Hökfelt, Tomas
    Substance P, NPY, CCK and their receptors in five brain regions in major depressive disorder with transcriptomic analysis of locus coeruleus neurons2024Ingår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 78, s. 54-63Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems are involved in mood regulation. The aim of this study is two-fold: (i) to monitor, with qPCR, transcript levels of the substance P/tachykinin (TAC), NPY and CCK systems in bulk samples from control and suicide subjects, targeting five postmortem brain regions including locus coeruleus (LC); and (ii) to analyse expression of neuropeptide family transcripts in LC neurons of ‘normal’ postmortem brains by using laser capture microdissection with Smart-Seq2 RNA sequencing. qPCR revealed distinct regional expression patterns in male and female controls with higher levels for the TAC system in the dorsal raphe nucleus and LC, versus higher transcripts levels of the NPY and CCK systems in prefrontal cortex. In suicide patients, TAC, TAC receptors and a few NPY family transcript levels were increased mainly in prefrontal cortex and LC. The second study on ‘normal’ noradrenergic LC neurons revealed expression of transcripts for GAL, NPY, TAC1, CCK, and TACR1 and many other peptides (e.g. Cerebellin4 and CARTPT) and receptors (e.g. Adcyap1R1 and GPR173). These data and our previous results on suicide brains indicates that the tachykinin and galanin systems may be valid targets for developing antidepressant medicines. Moreover, the perturbation of neuropeptide systems in MDD patients, and the detection of further neuropeptide and receptor transcripts in LC, shed new light on signalling in noradrenergic LC neurons and on mechanisms possibly associated with mood disorders.

  • 41.
    Bartfai, Tamas
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. University of Pennsylvania, USA.
    Lees, Graham
    Alzheimer Drug Trials: Combination of Safe and Efficacious Biologicals to Break the Amyloidosis-Neuroinflammation Vicious Cycle2020Ingår i: ASN Neuro, E-ISSN 1759-0914, Vol. 12, artikel-id 1759091420918557Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Late-onset Alzheimer's disease (LOAD) is a long-enduring neurodegenerative disease that progresses for decades before the symptoms of cognitive decline and loss of executive function are measurable. Amyloid deposits among other pathological changes, tau hyperphosphorylation, synapse loss, microglia and astroglia activation, and hippocampal atrophy are among the pathological hallmarks of the disease. These are present in the brain before memory complaints are reported and an AD diagnosis is made. The attempt to postpone or prevent the disease is becoming a more and more plausible goal because new early electrophysiological, cognitive, blood-based, and imaging-based diagnostics are being brought forward at the same time as the first anti-amyloid antibody is about to be approved. In view of known contributions of neuroinflammation to the pathology of LOAD, we should not focus solely on anti-amyloid therapies and ignore the interactive neuroinflammatory component of AD. Our belief is that it would be more rewarding to start clinical trials using combination therapies that are based on approved, safe, and efficacious anti-neuroinflammatory agents such as anti-interleukin-1 signaling agents in combination with the anti-amyloid antibodies that have been shown to be safe in multiyear trials. The proposal is that we should administer these two classes of safe biologicals to symptom-free individuals in midlife who are identified as having a high-risk-for-Alzheimer's-disease using precision medicine.

  • 42.
    Becker, Nina
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Max Planck Institute for Human Development, Germany.
    Kalpouzos, Grégoria
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Persson, Jonas
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Laukka, Erika J.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Brehmer, Yvonne
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Max Planck Institute for Human Development, Germany.
    Differential Effects of Encoding Instructions on Brain Activity Patterns of Item and Associative Memory2017Ingår i: Journal of cognitive neuroscience, ISSN 0898-929X, E-ISSN 1530-8898, Vol. 29, nr 3, s. 545-559Artikel i tidskrift (Refereegranskat)
    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.

  • 43.
    Becker, Nina
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Max Planck Institute for Human Development, Germany; Karolinska Institute, Sweden.
    Kalpouzos, Grégoria
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Salami, Alireza
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Umeå University, Sweden.
    Laukka, Erika J.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Brehmer, Yvonne
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Max Planck Institute for Human Development, Sweden; Tilburg University, The Netherlands.
    Structure-function associations of successful associative encoding2019Ingår i: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 201, artikel-id 116020Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Functional magnetic resonance imaging (MRI) studies have demonstrated a critical role of hippocampus and inferior frontal gyrus (IFG) in associative memory. Similarly, evidence from structural MRI studies suggests a relationship between gray-matter volume in these regions and associative memory. However, how brain volume and activity relate to each other during associative-memory formation remains unclear. Here, we used joint independent component analysis (jICA) to examine how gray-matter volume and brain activity would be associated during associative encoding, especially in medial-temporal lobe (MTL) and IFG. T1-weighted images were collected from 27 young adults, and functional MRI was employed during intentional encoding of object pairs. A subsequent recognition task tested participants' memory performance. Unimodal analyses using voxel-based morphometry revealed that participants with better associative memory showed larger gray-matter volume in left anterior hippocampus. Results from the jICA revealed one component that comprised a covariance pattern between gray-matter volume in anterior and posterior MTL and encoding-related activity in IFG. Our findings suggest that gray matter within the MTL modulates distally distinct parts of the associative encoding circuit, and extend previous studies that demonstrated MTL-IFG functional connectivity during associative memory tasks.

  • 44.
    Becker, Nina
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Max Planck Institute for Human Development, Germany.
    Laukka, Erika J.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Kalpouzos, Gregoria
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Naveh-Benjamin, Moshe
    Bäckman, Lars
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Brehmer, Yvonne
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Max Planck Institute for Human Development, Germany.
    Structural brain correlates of associative memory in older adults2015Ingår i: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 118, s. 146-153Artikel i tidskrift (Refereegranskat)
    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.

  • 45.
    Beckman, Marie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    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 pore2003Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

  • 46.
    Beckman, Marie
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Kihlmark, Madeleine
    Södertörn University, Stockholm, Sweden.
    Hallberg, Einar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Nucleus and Nuclear Envelope: Methods for Preparation2010Bok (Övrigt vetenskapligt)
    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.

  • 47. Bell, Thomas J.
    et al.
    Eiríksdóttir, Emelía
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Langel, Ülo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Eberwine, James
    PAIR technology: exon-specific RNA binding protein isolation in live cells2011Ingår i: Cell-penetrating peptides: Methods and Protocols / [ed] Ülo Langel, New York: Humana Press, 2011, s. 473-486Kapitel i bok, del av antologi (Refereegranskat)
    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.

  • 48.
    Bellander, Martin
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Berggren, Rasmus
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Mårtensson, Johan
    Brehmer, Yvonne
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Max Planck Institute for Human Development, Germany.
    Wenger, Elisabeth
    Li, Tie-Qiang
    Bodammer, Nils C.
    Shing, Yee-Lee
    Werkle-Bergner, Markus
    Lövdén, Martin
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Behavioral correlates of changes in hippocampal gray matter structure during acquisition of foreign vocabulary2016Ingår i: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 131, s. 205-213Artikel i tidskrift (Refereegranskat)
    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.

  • 49. Bergendal, G.
    et al.
    Martola, J.
    Stawiarz, L.
    Kristoffersen-Wiberg, M.
    Fredrikson, S.
    Almkvist, Ove
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen.
    Callosal atrophy in multiple sclerosis is related to cognitive speed2013Ingår i: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 127, nr 4, s. 281-289Artikel i tidskrift (Refereegranskat)
    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.

  • 50.
    Berglund, Birgitta
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen.
    Writings in remembrance of Professor Trygg Engen2012Ingår i: 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, s. 295-312Kapitel i bok, del av antologi (Refereegranskat)
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