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Nyberg, L., Andersson, M., Lundquist, A., Salami, A. & Wåhlin, A. (2019). Frontal Contribution to Hippocampal Hyperactivity During Memory Encoding in Aging. Frontiers in Molecular Neuroscience, 12, Article ID 229.
Open this publication in new window or tab >>Frontal Contribution to Hippocampal Hyperactivity During Memory Encoding in Aging
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2019 (English)In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 12, article id 229Article in journal (Refereed) Published
Abstract [en]

Hippocampal hypo- as well as hyper-activation have been reported during memory encoding in older individuals. Prefrontal cortex (PFC) provides top-down state signals to the hippocampus that bias its computation during memory encoding and retrieval, and disturbed top-down signals could contribute to hippocampal hyper-activation. Here, we used >500 cross-sectional and longitudinal observations from a face-name encoding-retrieval fMRI task to examine hippocampal hypo-and hyper-activation in aging. Age-related anterior hippocampal hypo-activation was observed during memory encoding. Next, older individuals who longitudinally dropped-out were compared with those who remained in the study. Older dropouts had lower memory performance and higher dementia risk, and hyper-activated right anterior and posterior hippocampus during memory encoding. During encoding, the dropouts also activated right prefrontal regions that instead were active during retrieval in younger and older remainers. Moreover, the dropouts showed altered frontal-hippocampal functional connectivity, notably elevated right PFC to anterior hippocampus (aHC) connectivity during encoding. In the context of a general pattern of age-related anterior hippocampal hypo-activation during encoding, these findings support a top-down contribution to paradoxically high anterior hippocampal activity in older dropouts who were at elevated risk of pathology.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2019
Keywords
hippocampus, pattern completion bias, aging, episodic memory, cognitive control
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-164045 (URN)10.3389/fnmol.2019.00229 (DOI)000487635300001 ()
Available from: 2019-10-15 Created: 2019-10-15 Last updated: 2019-10-15Bibliographically approved
Kissel, T., van Schie, K., Hafkenscheid, L., Lundquist, A., Scherer, H. U., Kokkonen, H., . . . Rantapää-Dahlqvist, S. (2019). Rising ACPA igg variable domain glycosylation pre-disease associates with an increase in autoantibody levels and the development of rheumatoid arthritis. Paper presented at Annual European Congress of Rheumatology (EULAR), Madrid, Spain, June 12-15, 2019. Annals of the Rheumatic Diseases, 78, 249-250
Open this publication in new window or tab >>Rising ACPA igg variable domain glycosylation pre-disease associates with an increase in autoantibody levels and the development of rheumatoid arthritis
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2019 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, p. 249-250Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background: Anti-citrullinated protein antibodies (ACPA) are present in the majority of rheumatoid arthritis (RA) patients (60-70%) and play a pivotal role in disease development1. ACPA IgGs are unique in a way that they are abundantly N-glycosylated within their variable regions2. These variable domain (V-domain) glycans are found on over 90% of ACPAs present in sera from RA-patients3. To undergo N-linked glycosylation, a consensus sequence in the protein backbone is required (N-X-S/T, where X ≠ P)4. Recently, it was shown that the N-linked glycosylation sites in ACPA-IgG V-domains are introduced during somatic hypermutation and that the introduction of such sites likely conveys a selective advantage to ACPA expressing B-cells5. However, it is currently unknown, whether ACPA-expressing B-cells already introduced glycosylation-sites into their V-domains before disease onset or when ACPA-V-domain glycosylation occurs.

Objectives: Investigate the appearance of ACPA V-domain glycosylation in pre-symptomatic individuals and RA patients.

Methods In a case-control study, individuals (n=201) from the Medical Biobank, who were sampled before onset of symptoms (mean±SEM predating time; 5.8±0.3 years) (140 aCCP+ and 61 aCCP-), and after diagnosis of RA (n=99, 94 aCCP+ and 5 aCCP-) and randomly selected control samples (n=43, 3 aCCP+ and 40 aCCP-) were analyzed for their ACPA IgG V-domain glycosylation levels. ACPA IgGs were affinity purified, N-linked glycans released, and 2-AA labeled for further analysis using UHPLC6. Data calibration and integration was performed and a cut-off defined. Samples below the cut-off were determined as non-detectable and excluded from the analysis. The percentage V-domain glycosylation was calculated as described previously3. Statistical calculations were performed using SPSS.

Results: Our data indicated that ACPA IgG V-domain glycans are already present years before symptom onset, in pre-symptomatic individuals who subsequently will develop RA. Analysis of matched pairs showed a significant increase of ACPA V-domain glycosylation in RA patients compared to individuals pre-disease (p<0.001). The results showed that ACPA N-glycosylation was correlated with anti-CCP concentrations pre-disease (rs =0.504, p<0.001), while no such association can be found after RA onset. Further, V-domain glycosylation levels increase closer to symptom onset.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-161721 (URN)10.1136/annrheumdis-2019-eular.5341 (DOI)000472207100546 ()
Conference
Annual European Congress of Rheumatology (EULAR), Madrid, Spain, June 12-15, 2019
Note

 Supplement: 2

Meeting Abstract: OP0333

Available from: 2019-07-26 Created: 2019-07-26 Last updated: 2019-07-26Bibliographically approved
Davies, G., Lam, M., Harris, S. E., Trampush, J. W., Luciano, M., Hill, W. D., . . . Deary, I. J. (2018). Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Nature Communications, 9, Article ID 2098.
Open this publication in new window or tab >>Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 2098Article in journal (Refereed) Published
Abstract [en]

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 x 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-149020 (URN)10.1038/s41467-018-04362-x (DOI)000433297900009 ()29844566 (PubMedID)2-s2.0-85048027481 (Scopus ID)
Note

Errata: Davies, G., Lam, M., Harris, S. E., Trampush, J. W., Luciano, M., Hill, W. D., … Deary, I. J. (2019). Author correction to Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. [Nature Communications (2018), 9, Article number 2098]. Nature Communications, 10, Article number: 2068. DOI: 10.1038/s41467-019-10160-w

Available from: 2018-06-15 Created: 2018-06-15 Last updated: 2019-05-21Bibliographically approved
Jonasson, L., Nyberg, L., Kramer, A., Lundquist, A., Riklund, K. & Boraxbekk, C.-J. (2017). Aerobic Exercise Intervention, CognitivePerformance, and Brain Structure: results from the Physical Influences on Brain in Aging (PHIBRA) Study. Frontiers in Aging Neuroscience, 8, 1-15, Article ID 336.
Open this publication in new window or tab >>Aerobic Exercise Intervention, CognitivePerformance, and Brain Structure: results from the Physical Influences on Brain in Aging (PHIBRA) Study
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2017 (English)In: Frontiers in Aging Neuroscience, ISSN 1663-4365, E-ISSN 1663-4365, Vol. 8, p. 1-15, article id 336Article in journal (Refereed) Published
Abstract [en]

Studies have shown that aerobic exercise has the potential to improve cognition and reduce brain atrophy in older adults. However, the literature is equivocal with regards to the specificity or generality of these effects. To this end, we report results on cognitive function and brain structure from a 6-month training intervention with 60 sedentary adults (64–78 years) randomized to either aerobic training or stretching and toning control training. Cognitive functions were assessed with a neuropsychological test battery in which cognitive constructs were measured using several different tests. Freesurfer was used to estimate cortical thickness in frontal regions and hippocampus volume. Results showed that aerobic exercisers, compared to controls, exhibited a broad, rather than specific, improvement in cognition as indexed by a higher “Cognitive score,” a composite including episodic memory, processing speed, updating, and executive function tasks (p = 0.01). There were no group differences in cortical thickness, but additional analyses revealed that aerobic fitness at baseline was specifically related to larger thickness in dorsolateral prefrontal cortex (dlPFC), and hippocampus volume was positively associated with increased aerobic fitness over time. Moreover, “Cognitive score” was related to dlPFC thickness at baseline, but changes in “Cognitive score” and dlPFC thickness were associated over time in the aerobic group only. However, aerobic fitness did not predict dlPFC change, despite the improvement in “Cognitive score” in aerobic exercisers. Our interpretation of these observations is that potential exercise-induced changes in thickness are slow, and may be undetectable within 6-months, in contrast to change in hippocampus volume which in fact was predicted by the change in aerobic fitness. To conclude, our results add to a growing literature suggesting that aerobic exercise has a broad influence on cognitive functioning, which may aid in explaining why studies focusing on a narrower range of functions have sometimes reported mixed results.

Keywords
aerobic exercise, cognition, executive function, plasticity, hippocampus, prefrontal cortex, freesurfer, transfer
National Category
Neurosciences Sport and Fitness Sciences Psychology (excluding Applied Psychology)
Identifiers
urn:nbn:se:umu:diva-130526 (URN)10.3389/fnagi.2016.00336 (DOI)000392049000001 ()
Funder
Swedish Research Council, 2012- 00530
Available from: 2017-01-22 Created: 2017-01-22 Last updated: 2018-06-09Bibliographically approved
Gorbach, T., Pudas, S., Lundquist, A., Orädd, G., Josefsson, M., Salami, A., . . . Nyberg, L. (2017). Longitudinal association between hippocampus atrophy and episodic-memory decline. Neurobiology of Aging, 51, 167-176
Open this publication in new window or tab >>Longitudinal association between hippocampus atrophy and episodic-memory decline
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2017 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 51, p. 167-176Article in journal (Refereed) Published
Abstract [en]

There is marked variability in both onset and rate of episodic-memory decline in aging. Structural magnetic resonance imaging studies have revealed that the extent of age-related brain changes varies markedly across individuals. Past studies of whether regional atrophy accounts for episodic-memory decline in aging have yielded inconclusive findings. Here we related 15-year changes in episodic memory to 4-year changes in cortical and subcortical gray matter volume and in white-matter connectivity and lesions. In addition, changes in word fluency, fluid IQ (Block Design), and processing speed were estimated and related to structural brain changes. Significant negative change over time was observed for all cognitive and brain measures. A robust brain-cognition change-change association was observed for episodic-memory decline and atrophy in the hippocampus. This association was significant for older (65-80 years) but not middle-aged (55-60 years) participants and not sensitive to the assumption of ignorable attrition. Thus, these longitudinal findings highlight medial-temporal lobe system integrity as particularly crucial for maintaining episodic-memory functioning in older age. 

Keywords
Aging, cognitive decline, episodic memory, hippocampus, longitudinal changes, non-ignorable attrition
National Category
Probability Theory and Statistics Neurosciences
Identifiers
urn:nbn:se:umu:diva-128725 (URN)10.1016/j.neurobiolaging.2016.12.002 (DOI)000397168600018 ()28089351 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationRagnar Söderbergs stiftelse
Available from: 2016-12-15 Created: 2016-12-13 Last updated: 2019-01-25Bibliographically approved
Hagg, S., Zhan, Y., Karlsson, R., Gerritsen, L., Ploner, A., van der Lee, S. J., . . . Pedersen, N. L. (2017). Short telomere length is associated with impaired cognitive performance in European ancestry cohorts. Translational Psychiatry, 7, Article ID e1100.
Open this publication in new window or tab >>Short telomere length is associated with impaired cognitive performance in European ancestry cohorts
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2017 (English)In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 7, article id e1100Article in journal (Refereed) Published
Abstract [en]

The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N = 17 052; mean age = 59.2 +/- 8.8 years) provided results for associations between qPCR-measuredTL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (beta = 0.051 per s. d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P = 0.0002), and MMSE (beta = 0.025; 95% CI: 0.002, 0.047; P = 0.03), and faster STROOP (beta = -0.053; 95% CI: -0.087, -0.018; P = 0.003). Effects for DSST were stronger in APOE epsilon 4 non-carriers (beta = 0.081; 95% CI: 0.045, 0.117; P = 1.0 x 10(-5)), whereas carriers performed better in STROOP (beta = -0.074; 95% CI: -0.140, -0.009; P = 0.03). Causal associations were found for STROOP only (beta = -0.598 per s. d.-increase of TL; 95% CI: -1.125, -0.072; P = 0.026), with a larger effect in epsilon 4-carriers (beta = -0.699; 95% CI: -1.330, -0.069; P = 0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE epsilon 4-carriers might be at differential risk.

National Category
Psychology (excluding Applied Psychology)
Identifiers
urn:nbn:se:umu:diva-136343 (URN)10.1038/tp.2017.73 (DOI)000402330500008 ()28418400 (PubMedID)
Available from: 2017-06-16 Created: 2017-06-16 Last updated: 2019-05-09Bibliographically approved
Nyberg, L., Pudas, S. & Lundquist, A. (2017). Structural and functional imaging of aging: longitudinal sudies (2ed.). In: Roberto Cabeza, Lars Nyberg, and Denise C. Park (Ed.), Cognitive neuroscience of aging: linking cognitive and cerebral aging (pp. 155-182). New York: Oxford University Press
Open this publication in new window or tab >>Structural and functional imaging of aging: longitudinal sudies
2017 (English)In: Cognitive neuroscience of aging: linking cognitive and cerebral aging / [ed] Roberto Cabeza, Lars Nyberg, and Denise C. Park, New York: Oxford University Press, 2017, 2, p. 155-182Chapter in book (Refereed)
Abstract [en]

This chapter on longitudinal structural and functional brain imaging examines points of convergence and divergence in findings from neuroimaging studies using cross-sectional versus longitudinal designs. Representative longitudinal age gradients are identified. It presents key methodological issues in longitudinal imaging, including test-retest effects, the influence of attrition, and different kinds of missing data. Various ways of handling data missingness in statistical analyses are also discussed.

Place, publisher, year, edition, pages
New York: Oxford University Press, 2017 Edition: 2
Keywords
Longitudinal design, cross-sectional study, attrition, test-retest reliability, data missingness
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-131280 (URN)10.1093/acprof:oso/9780199372935.003.0007 (DOI)9780199372935 (ISBN)
Available from: 2017-02-10 Created: 2017-02-10 Last updated: 2018-06-09Bibliographically approved
Karlsson, M., Lundquist, A. & Lundin, M. (2017). Student active learning online and in the classroom by combining the best of Flipped Classroom and MOOCs when teaching statistics. In: Royal Statistical Society 2017 International Conference, Glasgow, 4-7 september 2017: . Paper presented at Royal Statistical Society 2017 International Conference.
Open this publication in new window or tab >>Student active learning online and in the classroom by combining the best of Flipped Classroom and MOOCs when teaching statistics
2017 (English)In: Royal Statistical Society 2017 International Conference, Glasgow, 4-7 september 2017, 2017Conference paper, Oral presentation with published abstract (Other academic)
National Category
Probability Theory and Statistics Didactics
Identifiers
urn:nbn:se:umu:diva-140579 (URN)
Conference
Royal Statistical Society 2017 International Conference
Available from: 2017-10-13 Created: 2017-10-13 Last updated: 2018-06-09
Karlsson, M., Lundquist, A. & Lundin, M. (2017). Student active learning online and in the classroom by combining the best ofFlipped Classroom and MOOCs. In: Universitetspedagogiska konferensen 2017.: Undervisning i praktiken – föreläsning, flexibelt eller mitt emellan?. Paper presented at Universitetspedagogiska konferensen 2017, Umeå, 24-25 oktober, 2017. (pp. 37-37).
Open this publication in new window or tab >>Student active learning online and in the classroom by combining the best ofFlipped Classroom and MOOCs
2017 (English)In: Universitetspedagogiska konferensen 2017.: Undervisning i praktiken – föreläsning, flexibelt eller mitt emellan?, 2017, p. 37-37Conference paper, Oral presentation with published abstract (Other academic)
National Category
Probability Theory and Statistics Didactics
Identifiers
urn:nbn:se:umu:diva-141381 (URN)
Conference
Universitetspedagogiska konferensen 2017, Umeå, 24-25 oktober, 2017.
Available from: 2017-10-31 Created: 2017-10-31 Last updated: 2018-06-09
Giddaluru, S., Espeseth, T., Salami, A., Westlye, L. T., Lundquist, A., Christoforou, A., . . . Nyberg, L. (2016). Genetics of structural connectivity and information processing in the brain. Brain Structure and Function, 221(9), 4643-4661
Open this publication in new window or tab >>Genetics of structural connectivity and information processing in the brain
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2016 (English)In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 221, no 9, p. 4643-4661Article in journal (Refereed) Published
Abstract [en]

Understanding the genetic factors underlying brain structural connectivity is a major challenge in imaging genetics. Here, we present results from genome-wide association studies (GWASs) of whole-brain white matter (WM) fractional anisotropy (FA), an index of microstructural coherence measured using diffusion tensor imaging. Data from independent GWASs of 355 Swedish and 250 Norwegian healthy adults were integrated by meta-analysis to enhance power. Complementary GWASs on behavioral data reflecting processing speed, which is related to microstructural properties of WM pathways, were performed and integrated with WM FA results via multimodal analysis to identify shared genetic associations. One locus on chromosome 17 (rs145994492) showed genome-wide significant association with WM FA (meta P value = 1.87 × 10(-08)). Suggestive associations (Meta P value <1 × 10(-06)) were observed for 12 loci, including one containing ZFPM2 (lowest meta P value = 7.44 × 10(-08)). This locus was also implicated in multimodal analysis of WM FA and processing speed (lowest Fisher P value = 8.56 × 10(-07)). ZFPM2 is relevant in specification of corticothalamic neurons during brain development. Analysis of SNPs associated with processing speed revealed association with a locus that included SSPO (lowest meta P value = 4.37 × 10(-08)), which has been linked to commissural axon growth. An intergenic SNP (rs183854424) 14 kb downstream of CSMD1, which is implicated in schizophrenia, showed suggestive evidence of association in the WM FA meta-analysis (meta P value = 1.43 × 10(-07)) and the multimodal analysis (Fisher P value = 1 × 10(-07)). These findings provide novel data on the genetics of WM pathways and processing speed, and highlight a role of ZFPM2 and CSMD1 in information processing in the brain.

Keywords
Imaging genetics, DTI, GWAS, Processing speed, Fractional anisotropy, Cognition
National Category
Neurosciences Medical Genetics
Identifiers
urn:nbn:se:umu:diva-117931 (URN)10.1007/s00429-016-1194-0 (DOI)000387657200023 ()26852023 (PubMedID)
Available from: 2016-03-07 Created: 2016-03-07 Last updated: 2018-06-07Bibliographically approved
Projects
Methods for non-ignorable missingness in longitudinal brain imaging studies. [P16-0628:1_RJ]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-1524-0851

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