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Publications
LCBC research contributes to human cognitive neuroscience nationally and internationally by publication of results in scientific journals either as open access or by depositions in preprint servers. LCBC also publishes its codes and methods, in accordance with FAIR principles.
R-packages of LCBC:
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Akimova, Evelina T.; Fauske, Agnes; Jørgensen, Ruth Eva; Havdahl, Alexandra; Corfield, Elizabeth Claire & Mills, Melinda C.
[Show all 7 contributors for this article]
(2026).
When children shape their families: Evocative effects analysis of 40,000 trios from the Norwegian Mother, Father and Child Cohort Study.
Proceedings of the National Academy of Sciences of the United States of America (PNAS).
ISSN 0027-8424.
123(30).
doi:
10.1073/pnas.2532642123.
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Krogsrud, Stine Kleppe; Nordeng, Hedvig Marie Egeland; Roe, James Michael; Torkildsen, Janne von Koss; Wood, Mollie Elizabeth & Ystrøm, Eivind
(2025).
Associations between prenatal paracetamol exposure and brain development from ages 4–16: A longitudinal MRI study.
Developmental Cognitive Neuroscience.
ISSN 1878-9293.
78.
doi:
10.1016/j.dcn.2025.101667.
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Research has raised concerns regarding the potential impact of prenatal paracetamol exposure on fetal neurodevelopment. This is the first longitudinal study to investigate whether such exposure is related to structural brain development and cognitive abilities during childhood and adolescence. The sample includes 447 children aged 4.1–16.2 years with 905 MRI scans. The study is based on The Norwegian Mother, Father and Child Study (MoBa), and uses data from the Medical Birth Registry of Norway. The exposure variable is mothers’ self-reported use of paracetamol from prenatal and postnatal questionnaires. Among 447 children (229 girls; mean age 8.38 years), 193 (43.2 %) were prenatally exposed. Days of exposure range from 1 to 128 (mean 8.2). Vertex-wise linear mixed effect models showed that exposed children (n = 193; 393 scans) had slightly smaller cortical surface area and volume in some regions compared to non-exposed children. These results were seemingly driven by long-term exposed children (≥14 days in utero; n = 35; 72 scans, and exposed in all three trimesters, n = 21; 44 scans). However, group differences in brain structure were small with largely overlapping distributions, and the observational design and risk of unmeasured confounding preclude causal inference. Thus, the clinical significance remains uncertain. For cognitive abilities, results were reassuring showing no significant effect of prenatal paracetamol exposure on working memory capacity or IQ scores.
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Roe, James Michael; Vidal-Piñeiro, Didac; Sørensen, Øystein; Grydeland, Håkon; Leonardsen, Esten Høyland & Iakunchykova, Olena
[Show all 35 contributors for this article]
(2024).
Brain change trajectories in healthy adults correlate with Alzheimer’s related genetic variation and memory decline across life.
Nature Communications.
15(1).
doi:
10.1038/s41467-024-53548-z.
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Throughout adulthood and ageing our brains undergo structural loss in an average pattern resembling faster atrophy in Alzheimer’s disease (AD). Using a longitudinal adult lifespan sample (aged 30-89; 2–7 timepoints) and four polygenic scores for AD, we show that change in AD-sensitive brain features correlates with genetic AD-risk and memory decline in healthy adults. We first show genetic risk links with more brain loss than expected for age in early Braak regions, and find this extends beyond APOE genotype. Next, we run machine learning on AD-control data from the Alzheimer’s Disease Neuroimaging Initiative using brain change trajectories conditioned on age, to identify AD-sensitive features and model their change in healthy adults. Genetic AD-risk linked with multivariate change across many AD-sensitive features, and we show most individuals over age ~50 are on an accelerated trajectory of brain loss in AD-sensitive regions. Finally, high genetic risk adults with elevated brain change showed more memory decline through adulthood, compared to high genetic risk adults with less brain change. Our findings suggest quantitative AD risk factors are detectable in healthy individuals, via a shared pattern of ageing- and AD-related neurodegeneration that occurs along a continuum and tracks memory decline through adulthood.
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Kransberg, Jonas; Sneve, Markus Handal; Falch, Emilie Sogn; Bråthen, Anne Cecilie Sjøli; Fjell, Anders Martin & Walhovd, Kristine B
(2024).
Failure to replicate detection of grid-cell like representations in human fMRI.
Alzheimer's & Dementia.
ISSN 1552-5260.
20,
p. e086080–e086080.
doi:
10.1002/alz.086080.
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Binnewies, Julia; Nawijn, Laura; Brandmaier, Andreas M.; Baaré, William F.C.; Boraxbekk, Carl-Johan & Demnitz, Naiara
[Show all 15 contributors for this article]
(2023).
Lifestyle-related risk factors and their cumulative associations with hippocampal and total grey matter volume across the adult lifespan: A pooled analysis in the European Lifebrain consortium.
Brain Research Bulletin.
ISSN 0361-9230.
200.
doi:
10.1016/j.brainresbull.2023.110692.
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Background Lifestyle-related risk factors, such as obesity, physical inactivity, short sleep, smoking and alcohol use, have been associated with low hippocampal and total grey matter volumes (GMV). However, these risk factors have mostly been assessed as separate factors, leaving it unknown if variance explained by these factors is overlapping or additive. We investigated associations of five lifestyle-related factors separately and cumulatively with hippocampal and total GMV, pooled across eight European cohorts. Methods We included 3838 participants aged 18–90 years from eight cohorts of the European Lifebrain consortium. Using individual person data, we performed cross-sectional meta-analyses on associations of presence of lifestyle-related risk factors separately (overweight/obesity, physical inactivity, short sleep, smoking, high alcohol use) as well as a cumulative unhealthy lifestyle score (counting the number of present lifestyle-related risk factors) with FreeSurfer-derived hippocampal volume and total GMV. Lifestyle-related risk factors were defined according to public health guidelines. Results High alcohol use was associated with lower hippocampal volume (r = −0.10, p = 0.021), and overweight/obesity with lower total GMV (r = −0.09, p = 0.001). Other lifestyle-related risk factors were not significantly associated with hippocampal volume or GMV. The cumulative unhealthy lifestyle score was negatively associated with total GMV (r = −0.08, p = 0.001), but not hippocampal volume (r = −0.01, p = 0.625). Conclusions This large pooled study confirmed the negative association of some lifestyle-related risk factors with hippocampal volume and GMV, although with small effect sizes. Lifestyle factors should not be seen in isolation as there is evidence that having multiple unhealthy lifestyle factors is associated with a linear reduction in overall brain volume.
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Iakunchykova, Olena; Schirmer, Henrik; Vangberg, Torgil Riise; Wang, Yunpeng; Benavente, Ernest D. & Es, René van
[Show all 12 contributors for this article]
(2023).
Machine-learning-derived heart and brain age are independently associated with cognition.
European Journal of Neurology.
ISSN 1351-5101.
30(9),
p. 2611–2619.
doi:
10.1111/ene.15902.
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Background and purpose - A heart age biomarker has been developed using deep neural networks applied to electrocardiograms. Whether this biomarker is associated with cognitive function was investigated.<p> <p>Methods - Using 12-lead electrocardiograms, heart age was estimated for a population-based sample (N = 7779, age 40–85 years, 45.3% men). Associations between heart delta age (HDA) and cognitive test scores were studied adjusted for cardiovascular risk factors. In addition, the relationship between HDA, brain delta age (BDA) and cognitive test scores was investigated in mediation analysis.<p> <p>Results - Significant associations between HDA and the Word test, Digit Symbol Coding Test and tapping test scores were found. HDA was correlated with BDA (Pearson's r = 0.12, p = 0.0001). Moreover, 13% (95% confidence interval 3–36) of the HDA effect on the tapping test score was mediated through BDA.<p> <p>Discussion - Heart delta age, representing the cumulative effects of life-long exposures, was associated with brain age. HDA was associated with cognitive function that was minimally explained through BDA.
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Korbmacher, Max; Wang, Mengyun; Eikeland, Rune; Buchert, Ralph; Andreassen, Ole & Espeseth, Thomas
[Show all 10 contributors for this article]
(2023).
Considerations on brain age predictions from repeatedly sampled data across time.
Brain and Behavior.
doi:
10.1002/brb3.3219.
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Introduction Brain age, the estimation of a person's age from magnetic resonance imaging (MRI) parameters, has been used as a general indicator of health. The marker requires however further validation for application in clinical contexts. Here, we show how brain age predictions perform for the same individual at various time points and validate our findings with age-matched healthy controls. Methods We used densely sampled T1-weighted MRI data from four individuals (from two densely sampled datasets) to observe how brain age corresponds to age and is influenced by acquisition and quality parameters. For validation, we used two cross-sectional datasets. Brain age was predicted by a pretrained deep learning model. Results We found small within-subject correlations between age and brain age. We also found evidence for the influence of field strength on brain age which replicated in the cross-sectional validation data and inconclusive effects of scan quality. Conclusion The absence of maturation effects for the age range in the presented sample, brain age model bias (including training age distribution and field strength), and model error are potential reasons for small relationships between age and brain age in densely sampled longitudinal data. Clinical applications of brain age models should consider of the possibility of apparent biases caused by variation in the data acquisition process.
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Leonardsen, Esten Høyland; Vidal-Piñeiro, Didac; Roe, James Michael; Frei, Oleksandr; Shadrin, Alexey & Iakunchykova, Olena
[Show all 14 contributors for this article]
(2023).
Genetic architecture of brain age and its casual relations with brain and mental disorders.
Molecular Psychiatry.
ISSN 1359-4184.
doi:
10.1038/s41380-023-02087-y.
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Abstract The difference between chronological age and the apparent age of the brain estimated from brain imaging data—the brain age gap (BAG)—is widely considered a general indicator of brain health. Converging evidence supports that BAG is sensitive to an array of genetic and nongenetic traits and diseases, yet few studies have examined the genetic architecture and its corresponding causal relationships with common brain disorders. Here, we estimate BAG using state-of-the-art neural networks trained on brain scans from 53,542 individuals (age range 3–95 years). A genome-wide association analysis across 28,104 individuals (40–84 years) from the UK Biobank revealed eight independent genomic regions significantly associated with BAG ( p < 5 × 10 −8 ) implicating neurological, metabolic, and immunological pathways – among which seven are novel. No significant genetic correlations or causal relationships with BAG were found for Parkinson’s disease, major depressive disorder, or schizophrenia, but two-sample Mendelian randomization indicated a causal influence of AD ( p = 7.9 × 10 −4 ) and bipolar disorder ( p = 1.35 × 10 −2 ) on BAG. These results emphasize the polygenic architecture of brain age and provide insights into the causal relationship between selected neurological and neuropsychiatric disorders and BAG.
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Aksnes, Mari; Capogna, Elettra; Vidal-Piñeiro, Didac; Chaudhry, Farrukh Abbas; Myrstad, Marius & Idland, Ane-Victoria
[Show all 13 contributors for this article]
(2023).
Matrix metalloproteinases are associated with brain atrophy in cognitively unimpaired individuals.
Neurobiology of Aging.
ISSN 0197-4580.
131,
p. 11–23.
doi:
10.1016/j.neurobiolaging.2023.05.012.
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Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been linked to age-related neurodegeneration and Alzheimer’s disease (AD), but their role in normal aging is poorly understood. We used linear mixed models to determine if baseline or rate of yearly change in cerebrospinal fluid (CSF) levels of MMP-2; MMP-3; MMP-10; TIMP-123 (composite of TIMP-1, TIMP-2, and TIMP-3); or TIMP-4 predicted changes in bilateral entorhinal cortex thickness, hippocampal volume, or lateral ventricle volume in cognitively unimpaired individuals. We also assessed effects on the CSF AD biomarkers amyloid-β42 and phosphorylated tau181. Low baseline levels of MMP-3 predicted larger ventricle volumes and more entorhinal cortex thinning. Increased CSF MMP-2 levels over time predicted more entorhinal thinning, hippocampal atrophy, and ventricular expansion, while increased TIMP-123 over time predicted ventricular expansion. No MMP/TIMPs predicted changes in CSF AD biomarkers. Notably, we show for the first time that longitudinal increases in MMP-2 and TIMP-123 levels may predict age-associated brain atrophy. In conclusion, MMPs and TIMPs may play a role in brain atrophy in cognitively unimpaired aging.
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Fjell, Anders Martin; Sørensen, Øystein; Wang, Yunpeng; Amlien, Inge; Baaré, William F. C. & Bartrés-Faz, David
[Show all 24 contributors for this article]
(2023).
No phenotypic or genotypic evidence for a link between sleep duration and brain atrophy.
Nature Human Behaviour.
7,
p. 2008–2022.
doi:
10.1038/s41562-023-01707-5.
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Abstract Short sleep is held to cause poorer brain health, but is short sleep associated with higher rates of brain structural decline? Analysing 8,153 longitudinal MRIs from 3,893 healthy adults, we found no evidence for an association between sleep duration and brain atrophy. In contrast, cross-sectional analyses (51,295 observations) showed inverse U-shaped relationships, where a duration of 6.5 (95% confidence interval, (5.7, 7.3)) hours was associated with the thickest cortex and largest volumes relative to intracranial volume. This fits converging evidence from research on mortality, health and cognition that points to roughly seven hours being associated with good health. Genome-wide association analyses suggested that genes associated with longer sleep for below-average sleepers were linked to shorter sleep for above-average sleepers. Mendelian randomization did not yield evidence for causal impacts of sleep on brain structure. The combined results challenge the notion that habitual short sleep causes brain atrophy, suggesting that normal brains promote adequate sleep duration—which is shorter than current recommendations.
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Ljøsne, Isabelle Sylvie Budin; Friedman, Barbara Bodorkos; Baaré, William F. C.; Bartrés-Faz, David; Carver, Rebecca Bruu & Drevon, Christian André
[Show all 17 contributors for this article]
(2023).
Stakeholder engagement in European brain research: Experiences of the Lifebrain consortium.
Health Expectations.
ISSN 1369-6513.
26(3),
p. 1318–1326.
doi:
10.1111/hex.13747.
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Introduction Stakeholder engagement remains scarce in basic brain research. However, it can greatly improve the relevance of investigations and accelerate the translation of study findings to policy. The Lifebrain consortium investigated risk and protective factors influencing brain health using cognition, lifestyle and imaging data from European cohorts. Stakeholder activities of Lifebrain—organized in a separate work package—included organizing stakeholder events, investigating public perceptions of brain health and dissemination. Here, we describe the experiences of researchers and stakeholders regarding stakeholder engagement in the Lifebrain project. Methods Stakeholder engagement in Lifebrain was evaluated through surveys among researchers and stakeholders and stakeholders' feedback at stakeholder events through evaluation forms. Survey data were analysed using a simple content analysis approach, and results from evaluation forms were summarized after reviewing the frequency of responses. Results Consortium researchers and stakeholders experienced the engagement activities as meaningful and relevant. Researchers highlighted that it made the research and research processes more visible and contributed to new networks, optimized data collection on brain health perceptions and the production of papers and provided insights into stakeholder views. Stakeholders found research activities conducted in the stakeholder engagement work package to be within their field of interest and research results relevant to their work. Researchers identified barriers to stakeholder engagement, including lack of time, difficulties in identifying relevant stakeholders, and challenges in communicating complex scientific issues in lay language and maintaining relationships with stakeholders over time. Stakeholders identified barriers such as lack of budget, limited resources in their organization, time constraints and insufficient communication between researchers and stakeholders. Conclusion Stakeholder engagement in basic brain research can greatly benefit researchers and stakeholders alike. Its success is conditional on dedicated human and financial resources, clear communication, transparent mutual expectations and clear roles and responsibilities. Public Contribution Patient organizations, research networks, policymakers and members of the general public were involved in engagement and research activities throughout the project duration.
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Neumann, Alexander; Ohlei, Olena; Küçükali, Fahri; Bos, Isabelle J.; Timsina, Jigyasha & Vos, Stephanie
[Show all 41 contributors for this article]
(2023).
Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning.
Genome Medicine.
15(1).
doi:
10.1186/s13073-023-01233-z.
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Background Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences. Methods We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects. Results Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. Conclusions These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.
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Ghannoum, Salim; Fantini, Damiano; Zahoor, Muhammad; Reiterer, Veronika; Phuyal, Santosh & Netto, Waldir Leoncio
[Show all 13 contributors for this article]
(2023).
A combined experimental-computational approach uncovers a role for the Golgi matrix protein Giantin in breast cancer progression.
PLoS Computational Biology.
ISSN 1553-734X.
19(4).
doi:
10.1371/journal.pcbi.1010995.
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Our understanding of how speed and persistence of cell migration affects the growth rate and size of tumors remains incomplete. To address this, we developed a mathematical model wherein cells migrate in two-dimensional space, divide, die or intravasate into the vasculature. Exploring a wide range of speed and persistence combinations, we find that tumor growth positively correlates with increasing speed and higher persistence. As a biologically relevant example, we focused on Golgi fragmentation, a phenomenon often linked to alterations of cell migration. Golgi fragmentation was induced by depletion of Giantin, a Golgi matrix protein, the downregulation of which correlates with poor patient survival. Applying the experimentally obtained migration and invasion traits of Giantin depleted breast cancer cells to our mathematical model, we predict that loss of Giantin increases the number of intravasating cells. This prediction was validated, by showing that circulating tumor cells express significantly less Giantin than primary tumor cells. Altogether, our computational model identifies cell migration traits that regulate tumor progression and uncovers a role of Giantin in breast cancer progression.
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Lilja-Lund, Otto; Maripuu, Martin; Kockum, Karin; Andersson, Johanna; Lindam, Anna & Nyberg, Lars Erik
[Show all 7 contributors for this article]
(2023).
Longitudinal neuropsychological trajectories in idiopathic normal pressure hydrocephalus: a population–based study.
BMC Geriatrics.
23(1).
doi:
10.1186/s12877-023-03747-y.
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Background Idiopathic normal pressure hydrocephalus (iNPH) is a progressive syndrome affecting gait, incontinence, and cognition in a significant number of older adults. Still, prospective studies on early development of symptoms are scarce. Aim To investigate how neuropsychological functions develop before and in already diagnosed iNPH over a two-year period in a population-based material. Method A sample of 104 participants (median [IQR] 75 [72–80] years old) from the general population underwent CT-imaging and clinical assessment at baseline and follow-up. We used the iNPH symptom scale covering four domains (Neuropsychology, Gait, Balance, Incontinence) and additional tests of executive functions. Morphological signs were rated with the iNPH Radscale. Non-parametric statistics with Bonferroni corrections and a significance-level of p < 0.05 were used. Results Median (IQR) time to follow-up was 25 (23–26) months. Effect size (ES) for individuals who developed iNPH (n = 8) showed a large (ES r = -0.55) decline in the Gait domain and on the Radscale (ES r = -0.60), with a medium deterioration in declarative memory (ES r = -0.37). Those having iNPH at baseline (n = 12) performed worse on one executive sub-function i.e., shifting (p = 0.045). Conclusion Besides deterioration in gait and radiology, our results suggest that a neuropsychological trajectory for those developing iNPH includes a reduction in declarative memory. Executive dysfunction was limited to those already having iNPH at baseline. These findings could suggest that memory impairments are included in the early development of iNPH.
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Capogna, Elettra; Watne, Leiv; Sørensen, Øystein; Guichelaar, Carlijn Jamila; Idland, Ane-Victoria & Halaas, Nathalie Bodd
[Show all 11 contributors for this article]
(2023).
Associations of neuroinflammatory IL-6 and IL-8 with brain atrophy, memory decline, and core AD biomarkers – in cognitively unimpaired older adults.
Brain, Behavior, and Immunity.
ISSN 0889-1591.
113,
p. 56–65.
doi:
10.1016/j.bbi.2023.06.027.
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Concentrations of pro-inflammatory cytokines –interleukin-6 (IL-6) and interleukin-8 (IL-8) – are increased with age and in Alzheimer’s disease (AD). It is not clear whether concentrations of IL-6 and IL-8 in the central nervous system predict later brain and cognitive changes over time nor whether this relationship is mediated by core AD biomarkers. Here, 219 cognitively healthy older adults (62–91 years), with baseline cerebrospinal fluid (CSF) measures of IL-6 and IL-8 were followed over time – up to 9 years – with assessments that included cognitive function, structural magnetic resonance imaging, and CSF measurements of phosphorylated tau (p-tau) and amyloid-β (Aβ-42) concentrations (for a subsample). Higher baseline CSF IL-8 was associated with better memory performance over time in the context of lower levels of CSF p-tau and p-tau/Aβ-42 ratio. Higher CSF IL-6 was related to less CSF p-tau changes over time. The results are in line with the hypothesis suggesting that an up-regulation of IL-6 and IL-8 in the brain may play a neuroprotective role in cognitively healthy older adults with lower load of AD pathology.
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Fjell, Anders Martin; Sørensen, Øystein; Wang, Yunpeng; Amlien, Inge; Baaré, William F C & Bartrés-Faz, David
[Show all 21 contributors for this article]
(2023).
Is Short Sleep Bad for the Brain? Brain Structure and Cognitive Function in Short Sleepers.
Journal of Neuroscience.
ISSN 0270-6474.
43(28),
p. 5241–5250.
doi:
10.1523/JNEUROSCI.2330-22.2023.
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Many sleep less than recommended without experiencing daytime sleepiness. According to prevailing views, short sleep increases risk of lower brain health and cognitive function. Chronic mild sleep deprivation could cause undetected sleep debt, negatively affecting cognitive function and brain health. However, it is possible that some have less sleep need and are more resistant to negative effects of sleep loss. We investigated this using a cross-sectional and longitudinal sample of 47,029 participants of both sexes (20–89 years) from the Lifebrain consortium, Human Connectome project (HCP) and UK Biobank (UKB), with measures of self-reported sleep, including 51,295 MRIs of the brain and cognitive tests. A total of 740 participants who reported to sleep <6 h did not experience daytime sleepiness or sleep problems/disturbances interfering with falling or staying asleep. These short sleepers showed significantly larger regional brain volumes than both short sleepers with daytime sleepiness and sleep problems ( n = 1742) and participants sleeping the recommended 7–8 h ( n = 3886). However, both groups of short sleepers showed slightly lower general cognitive function (GCA), 0.16 and 0.19 SDs, respectively. Analyses using accelerometer-estimated sleep duration confirmed the findings, and the associations remained after controlling for body mass index, depression symptoms, income, and education. The results suggest that some people can cope with less sleep without obvious negative associations with brain morphometry and that sleepiness and sleep problems may be more related to brain structural differences than duration. However, the slightly lower performance on tests of general cognitive abilities warrants closer examination in natural settings. SIGNIFICANCE STATEMENT Short habitual sleep is prevalent, with unknown consequences for brain health and cognitive performance. Here, we show that daytime sleepiness and sleep problems are more strongly related to regional brain volumes than sleep duration. However, participants sleeping ≤6 h had slightly lower scores on tests of general cognitive function (GCA). This indicates that sleep need is individual and that sleep duration per se is very weakly if at all related brain health, while daytime sleepiness and sleep problems may show somewhat stronger associations. The association between habitual short sleep and lower scores on tests of general cognitive abilities must be further scrutinized in natural settings.
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Holm, Madelene Christin; Leonardsen, Esten Høyland; Beck, Dani; Dahl, Andreas; Kjelkenes, Rikka & Lange, Ann-Marie Glasø de
[Show all 7 contributors for this article]
(2023).
Linking brain maturation and puberty during early adolescence using longitudinal brain age prediction in the ABCD cohort.
Developmental Cognitive Neuroscience.
ISSN 1878-9293.
60.
doi:
10.1016/j.dcn.2023.101220.
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The temporal characteristics of adolescent neurodevelopment are shaped by a complex interplay of genetic, biological, and environmental factors. Using a large longitudinal dataset of children aged 9–13 from the Adolescent Brain Cognitive Development (ABCD) study we tested the associations between pubertal status and brain maturation. Brain maturation was assessed using brain age prediction based on convolutional neural networks and minimally processed T1-weighted structural MRI data. Brain age prediction provided highly accurate and reliable estimates of individual age, with an overall mean absolute error of 0.7 and 1.4 years at the two timepoints respectively, and an intraclass correlation of 0.65. Linear mixed effects (LME) models accounting for age and sex showed that on average, a one unit increase in pubertal maturational level was associated with a 2.22 months higher brain age across time points (β = 0.10, p < .001). Moreover, annualized change in pubertal development was weakly related to the rate of change in brain age (β = .047, p = 0.04). These results demonstrate a link between sexual development and brain maturation in early adolescence, and provides a basis for further investigations of the complex sociobiological impacts of puberty on life outcomes.
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Küçükali, Fahri; Neumann, Alexander; Dongen, Jasper Van; Pooter, Tim De; Joris, Geert & Rijk, Peter De
[Show all 40 contributors for this article]
(2022).
Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits.
Alzheimer's & Dementia.
ISSN 1552-5260.
doi:
10.1002/alz.12842.
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Introduction
Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes.
Methods
We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808).
Results
Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively.
Discussion
The identification of these novel gene–trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.
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Solvang, Stein-Erik Hafstad; Hodge, Allison; Watne, Leiv; Cabral-Marques, Otavio; Nordrehaug, Jan Erik & Giles, Graham G.
[Show all 16 contributors for this article]
(2022).
Kynurenine Pathway Metabolites in the Blood and Cerebrospinal Fluid Are Associated with Human Aging.
Oxidative Medicine and Cellular Longevity.
ISSN 1942-0900.
2022,
p. 1–15.
doi:
10.1155/2022/5019752.
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The kynurenine pathway is implicated in aging, longevity, and immune regulation, but longitudinal studies and assessment of the cerebrospinal fluid (CSF) are lacking. We investigated tryptophan (Trp) and downstream kynurenine metabolites and their associations with age and change over time in four cohorts using comprehensive, targeted metabolomics. The study included 1574 participants in two cohorts with repeated metabolite measurements (mean age at baseline and ), 3161 community-dwelling older adults (age range 71-74 years), and 109 CSF donors (mean age ). In the first two cohorts, age was associated with kynurenine (Kyn), quinolinic acid (QA), and the kynurenine to tryptophan ratio (KTR), and inversely with Trp. Consistent with these findings, Kyn, QA, and KTR increased over time, whereas Trp decreased. Similarly, QA and KTR were higher in community-dwelling older adults of age 74 compared to 71, whereas Trp was lower. Kyn and QA were more strongly correlated with age in the CSF compared to serum and increased in a subset of participants with repeated CSF sampling () over four years. We assessed associations with frailty and mortality in two cohorts. QA and KTR were most strongly associated with mortality and frailty. Our study provides robust evidence of changes in tryptophan and kynurenine metabolism with human aging and supports links with adverse health outcomes. Our results suggest that aging activates the inflammation and stress-driven kynurenine pathway systemically and in the brain, but we cannot determine whether this activation is harmful or adaptive. We identified a relatively stronger age-related increase of the potentially neurotoxic end-product QA in brain.
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Allesøe, Rosa Lundbye; Nudel, Ron; Thompson, Wesley K.; Wang, Yunpeng; Nordentoft, Merete & Børglum, Anders D
[Show all 10 contributors for this article]
(2022).
Deep learning-based integration of genetics with registry data for stratification of schizophrenia and depression.
Science Advances.
8(26).
doi:
10.1126/sciadv.abi7293.
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Currently, psychiatric diagnoses are, in contrast to most other medical fields, based on subjective symptoms and observable signs and call for new and improved diagnostics to provide the most optimal care. On the basis of a deep learning approach, we performed unsupervised patient stratification of 19,636 patients with depression [major depressive disorder (MDD)] and/or schizophrenia (SCZ) and 22,467 population controls from the iPSYCH2012 case cohort. We integrated data of disorder severity, history of mental disorders and disease comorbidities, genetics, and medical birth data. From this, we stratified the individuals in six and seven unique clusters for MDD and SCZ, respectively. When censoring data until diagnosis, we could predict MDD clusters with areas under the curve (AUCs) of 0.54 to 0.80 and SCZ clusters with AUCs of 0.71 to 0.86. Overall cases and controls could be predicted with an AUC of 0.81, illustrating the utility of data-driven subgrouping in psychiatry.
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Carver, Rebecca Bruu; Fredheim, Nanna Alida Grit; Mowinckel, Athanasia Monika; Ebmeier, Klaus P.; Friedman, Barbara Bodorkos & Rosness, Tor Atle
[Show all 20 contributors for this article]
(2022).
People's interest in brain health testing: Findings from an international, online cross-sectional survey.
Frontiers in Public Health.
10,
p. 1–19.
doi:
10.3389/fpubh.2022.998302.
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Brain health entails mental wellbeing and cognitive health in the absence of brain disorders. The past decade has seen an explosion of tests, cognitive and biological, to predict various brain conditions, such as Alzheimer's Disease. In line with these current developments, we investigated people's willingness and reasons to—or not to—take a hypothetical brain health test to learn about risk of developing a brain disease, in a cross-sectional multilanguage online survey. The survey was part of the Global Brain Health Survey, open to the public from 4th June 2019 to 31st August 2020. Respondents were largely recruited via European brain councils and research organizations. 27,590 people responded aged 18 years or older and were predominantly women (71%), middle-aged or older (>40 years; 83%), and highly educated (69%). Responses were analyzed to explore the relationship between demographic variables and responses. Results: We found high public interest in brain health testing: over 91% would definitely or probably take a brain health test and 86% would do so even if it gave information about a disease that cannot be treated or prevented. The main reason for taking a test was the ability to respond if one was found to be at risk of brain disease, such as changing lifestyle, seeking counseling or starting treatment. Higher interest in brain health testing was found in men, respondents with lower education levels and those with poor self-reported cognitive health. Conclusion: High public interest in brain health and brain health testing in certain segments of society, coupled with an increase of commercial tests entering the market, is likely to put pressure on public health systems to inform the public about brain health testing in years to come.
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Nyberg, Lars Erik; Andersson, Micael; Lundquist, Anders; Baaré, William F C; Bartrés-Faz, David & Bertram, Lars
[Show all 29 contributors for this article]
(2022).
Individual differences in brain aging: heterogeneity in cortico-hippocampal but not caudate atrophy rates.
Cerebral Cortex.
ISSN 1047-3211.
33(9),
p. 5075–5081.
doi:
10.1093/cercor/bhac400.
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Abstract It is well documented that some brain regions, such as association cortices, caudate, and hippocampus, are particularly prone to age-related atrophy, but it has been hypothesized that there are individual differences in atrophy profiles. Here, we document heterogeneity in regional-atrophy patterns using latent-profile analysis of 1,482 longitudinal magnetic resonance imaging observations. The results supported a 2-group solution reflecting differences in atrophy rates in cortical regions and hippocampus along with comparable caudate atrophy. The higher-atrophy group had the most marked atrophy in hippocampus and also lower episodic memory, and their normal caudate atrophy rate was accompanied by larger baseline volumes. Our findings support and refine models of heterogeneity in brain aging and suggest distinct mechanisms of atrophy in striatal versus hippocampal-cortical systems.
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Lilja-Lund, Otto; Nyberg, Lars Erik; Maripuu, Martin & Laurell, Katarina
(2022).
Dual-Task Performance in Older Adults With and Without Idiopathic Normal Pressure Hydrocephalus.
Frontiers in Aging Neuroscience.
14.
doi:
10.3389/fnagi.2022.904194.
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Voldsbekk, Irene; Bjørnerud, Atle; Groote, Inge Rasmus; Zak, Nathalia; Roelfs, Daniël & Maximov, Ivan
[Show all 18 contributors for this article]
(2022).
Evidence for widespread alterations in cortical microstructure after 32 h of sleep deprivation.
Translational Psychiatry.
12(161).
doi:
10.1038/s41398-022-01909-x.
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Cortical microstructure is influenced by circadian rhythm and sleep deprivation, yet the precise underpinnings of these effects remain unclear. The ratio between T1-weighted and T2-weighted magnetic resonance images (T1w/T2w ratio) has been linked to myelin levels and dendrite density and may offer novel insight into the intracortical microstructure of the sleep deprived brain. Here, we examined intracortical T1w/T2w ratio in 41 healthy young adults (26 women) before and after 32 h of either sleep deprivation (n = 18) or a normal sleep-wake cycle (n = 23). Linear models revealed significant group differences in T1w/T2w ratio change after 32 h in four clusters, including bilateral effects in the insular, cingulate, and superior temporal cortices, comprising regions involved in attentional, auditory and pain processing. Across clusters, the sleep deprived group showed an increased T1w/T2w ratio, while the normal sleep-wake group exhibited a reduced ratio. These changes were not explained by in-scanner head movement, and 95% of the effects across clusters remained significant after adjusting for cortical thickness and hydration. Compared with a normal sleep-wake cycle, 32 h of sleep deprivation yields intracortical T1w/T2w ratio increases. While the intracortical changes detected by this study could reflect alterations in myelin or dendritic density, or both, histological analyses are needed to clarify the precise underlying cortical processes.
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Sommerer, Yasmine; Ohlei, Olena; Dobricic, Valerija; Oakley, Derek H.; Wesse, Tanja & Sabet, Sanaz Sedghpour
[Show all 11 contributors for this article]
(2022).
A correlation map of genome-wide DNA methylation patterns between paired human brain and buccal samples.
Clinical Epigenetics.
14(1).
doi:
10.1186/s13148-022-01357-w.
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Epigenome-wide association studies (EWAS) assessing the link between DNA methylation (DNAm) and phenotypes related to structural brain measures, cognitive function, and neurodegenerative diseases are becoming increasingly more popular. Due to the inaccessibility of brain tissue in humans, several studies use peripheral tissues such as blood, buccal swabs, and saliva as surrogates. To aid the functional interpretation of EWAS findings in such settings, there is a need to assess the correlation of DNAm variability across tissues in the same individuals. In this study, we performed a correlation analysis between DNAm data of a total of n = 120 matched post-mortem buccal and prefrontal cortex samples. We identified nearly 25,000 (3% of approximately 730,000) cytosine-phosphate-guanine (CpG) sites showing significant (false discovery rate q < 0.05) correlations between buccal and PFC samples. Correlated CpG sites showed a preponderance to being located in promoter regions and showed a significant enrichment of being determined by genetic factors, i.e. methylation quantitative trait loci (mQTL), based on buccal and dorsolateral prefrontal cortex mQTL databases. Our novel buccal–brain DNAm correlation map will provide a valuable resource for future EWAS using buccal samples for studying DNAm effects on phenotypes relating to the brain. All correlation results are made freely available to the public online.
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Bråthen, Anne Cecilie Sjøli; Sørensen, Øystein; Lange, Ann-Marie Glasø de; Mowinckel, Athanasia Monika; Fjell, Anders Martin & Walhovd, Kristine B
(2022).
Cognitive and hippocampal changes weeks and years after memory training.
Scientific Reports.
12(1).
doi:
10.1038/s41598-022-11636-4.
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Cheng, Weiqiu; Meer, Dennis van der; Parker, Nadine; Hindley, Guy Frederick Lanyon; O'Connell, Kevin Sean & Wang, Yunpeng
[Show all 20 contributors for this article]
(2022).
Shared genetic architecture between schizophrenia and subcortical brain volumes implicates early neurodevelopmental processes and brain development in childhood.
Molecular Psychiatry.
ISSN 1359-4184.
doi:
10.1038/s41380-022-01751-z.
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Patients with schizophrenia have consistently shown brain volumetric abnormalities, implicating both etiological and pathological processes. However, the genetic relationship between schizophrenia and brain volumetric abnormalities remains poorly understood. Here, we applied novel statistical genetic approaches (MiXeR and conjunctional false discovery rate analysis) to investigate genetic overlap with mixed effect directions using independent genome-wide association studies of schizophrenia (n = 130,644) and brain volumetric phenotypes, including subcortical brain and intracranial volumes (n = 33,735). We found brain volumetric phenotypes share substantial genetic variants (74–96%) with schizophrenia, and observed 107 distinct shared loci with sign consistency in independent samples. Genes mapped by shared loci revealed (1) significant enrichment in neurodevelopmental biological processes, (2) three co-expression clusters with peak expression at the prenatal stage, and (3) genetically imputed thalamic expression of CRHR1 and ARL17A was associated with the thalamic volume as early as in childhood. Together, our findings provide evidence of shared genetic architecture between schizophrenia and brain volumetric phenotypes and suggest that altered early neurodevelopmental processes and brain development in childhood may be involved in schizophrenia development.
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Vetter, Valentin Max; Sommerer, Yasmine; Kalies, Christian Humberto; Spira, Dominik; Bertram, Lars & Demuth, Ilja
(2022).
Vitamin D supplementation is associated with slower epigenetic aging.
GeroScience.
ISSN 2509-2715.
44(3),
p. 1847–1859.
doi:
10.1007/s11357-022-00581-9.
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Vidal-Piñeiro, Didac; Sørensen, Øystein; Blennow, Kaj; Capogna, Elettra; Halaas, Nathalie Bodd & Idland, Ane-Victoria
[Show all 12 contributors for this article]
(2022).
Relationship between cerebrospinal fluid neurodegeneration biomarkers and temporal brain atrophy in cognitively healthy older adults.
Neurobiology of Aging.
ISSN 0197-4580.
116,
p. 80–91.
doi:
10.1016/j.neurobiolaging.2022.04.010.
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It is unclear whether cerebrospinal fluid (CSF) biomarkers of neurodegeneration predict brain atrophy in cognitively healthy older adults, whether these associations can be explained by phosphorylated tau181 (p-tau) and the 42 amino acid form of amyloid-β (Aβ42) biomarkers, and which neural substrates may drive these associations. We addressed these questions in 2 samples of cognitively healthy older adults who underwent longitudinal structural MRI up to 7 years and had baseline CSF levels of heart-type fatty-acid binding protein (FABP3)=, total-tau, neurogranin, and neurofilament light (NFL) (n = 189, scans = 721). The results showed that NFL, total-tau, and FABP3 predicted entorhinal thinning and hippocampal atrophy. Brain atrophy was not moderated by Aβ42 and the associations between NFL and FABP3 with brain atrophy were independent of p-tau. The spatial pattern of cortical atrophy associated with the biomarkers overlapped with neurogenetic profiles associated with expression in the axonal (total-tau, NFL) and dendritic (neurogranin) components. CSF biomarkers of neurodegeneration are useful for predicting specific features of brain atrophy in older adults, independently of amyloid and tau pathology biomarkers.
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Solé-Padullés, Cristina; Macià, Dídac; Andersson, Micael; Stiernstedt, Mikael; Pudas, Sara & Düzel, Sandra
[Show all 19 contributors for this article]
(2022).
No Association Between Loneliness, Episodic Memory and Hippocampal Volume Change in Young and Healthy Older Adults: A Longitudinal European Multicenter Study.
Frontiers in Aging Neuroscience.
14.
doi:
10.3389/fnagi.2022.795764.
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Background Loneliness is most prevalent during adolescence and late life and has been associated with mental health disorders as well as with cognitive decline during aging. Associations between longitudinal measures of loneliness and verbal episodic memory and brain structure should thus be investigated. Methods We sought to determine associations between loneliness and verbal episodic memory as well as loneliness and hippocampal volume trajectories across three longitudinal cohorts within the Lifebrain Consortium, including children, adolescents ( N = 69, age range 10–15 at baseline examination) and older adults ( N = 1468 over 60). We also explored putative loneliness correlates of cortical thinning across the entire cortical mantle. Results Loneliness was associated with worsening of verbal episodic memory in one cohort of older adults. Specifically, reporting medium to high levels of loneliness over time was related to significantly increased memory loss at follow-up examinations. The significance of the loneliness-memory change association was lost when eight participants were excluded after having developed dementia in any of the subsequent follow-up assessments. No significant structural brain correlates of loneliness were found, neither hippocampal volume change nor cortical thinning. Conclusion In the present longitudinal European multicenter study, the association between loneliness and episodic memory was mainly driven by individuals exhibiting progressive cognitive decline, which reinforces previous findings associating loneliness with cognitive impairment and dementia.
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Hu, Maolin; Zong, Xiaofen; Sweeney, John A.; Bishop, Jeffrey R; Liao, Yanhui & Giase, Gina
[Show all 15 contributors for this article]
(2022).
Risperidone-induced changes in DNA methylation in peripheral blood from first-episode schizophrenia patients parallel changes in neuroimaging and cognitive phenotypes.
Psychiatry Research.
ISSN 0165-1781.
317.
doi:
10.1016/j.psychres.2022.114789.
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Background
Second generation antipsychotics such as risperidone are first-line pharmacotherapy treatment choices for schizophrenia. However, our ability to reliably predict and monitor treatment reaction is impeded by the lack of relevant biomarkers. As a biomarker for the susceptibility of schizophrenia and clozapine treatment response, DNA methylation (DNAm) has been studied, but the impact of antipsychotics on DNAm has not been explored in drug-naïve patients.
Objective
The aim of the present study was to examine changes of DNAm after short-term antipsychotic therapy in first-episode drug-naïve schizophrenia (FES) to identify the beneficial and adverse effect of risperidone on DNAm and their relation to treatment outcome.
Methods
Thirty-eight never treated schizophrenia patients and 38 demographically matched individuals (healthy controls) were assessed at baseline and at 8-week follow-up with symptom ratings, and cognitive and functional imaging procedures, at which time a blood draw for DNAm studies was performed. During the 8-week period, patients received treatment with risperidone monotherapy. An independent data set was used as replication.
Results
We identified brain related pathways enriched in 4,888 FES-associated CpG sites relative to controls. Risperidone administration in patients altered DNAm in 5,979 CpG sites relative to baseline. Significant group differences in DNAm at follow-up were seen in FES patients at 6,760 CpG sites versus healthy controls. Through comparison of effect size, we found 87.54% out of the risperidone-associated changes in DNAm showed possible beneficial effect, while only 12.46% showed potential adverse effect. There were 580 DNAm sites in which changes shifted methylation levels to be indistinguishable from controls after risperidone treatment. The DNAm changes of some sites that normalized after treatment were correlated with treatment-related changes in symptom severity, spontaneous neurophysiological activity, and cognition. We replicated our results in an independent data set.
Conclusion
The normalizing effect of risperidone monotherapy on gene DNAm, and its correlation with clinically relevant phenotypes, indicates that risperidone therapy is associated with DNAm changes that are related to changes in brain physiology, cognition and symptom severity.
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Krantz, Mette Falkenberg; Ellersgaard, Ditte; Andersen, Klaus Kaae; Hemager, Nicoline; Christiani, Camilla & Spang, Katrine Søborg
[Show all 23 contributors for this article]
(2022).
Accumulation of Disadvantages Across Multiple Domains Amongst Subgroups of Children of Parents with Schizophrenia or Bipolar Disorder: Clustering Data from the Danish High Risk and Resilience Study VIA 7.
Schizophrenia Bulletin Open.
3(1).
doi:
10.1093/schizbullopen/sgac010.
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Objective
Children with familial high-risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) are frequently affected in a range of domains known to be precursors of severe mental illness. No previous studies have gathered known precursors to examine whether they distribute evenly across familial high risk (FHR) children or if they cluster among a smaller group. Since such examination holds the potential to identify high and low risk of severe mental illness groups, we aimed to cluster FHR and control children affected to various degrees.
Method
In The Danish High Risk and Resilience Study VIA 7, a clinical cohort study, 514 7-year-old children with FHR-SZ or FHR-BP and matched controls were assessed in domains of motor function, neurocognition, emotional control, behavior, social cognition, self-perception, language, psychotic experiences, and psychopathology, and grouped using cluster analysis. Associations between clusters and parents' level of education, functioning, caregiver status, child's level of stimulation and support in the home, and polygenic risk scores were examined.
Results
A total of four groups including one of broadly affected children were identified. The broadly affected group was represented 4–5-fold (18.1%) amongst FHR-SZ children and 2–3-fold (10.2%) amongst FHR-BP children, compared to controls (4.1%) (P
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Wesenhagen, Kirsten E.J.; Gobom, Johan; Bos, Isabelle; Vos, Stephanie J.B.; Martinez-Lage, Pablo & Popp, Julius
[Show all 25 contributors for this article]
(2022).
Effects of age, amyloid, sex, and APOE ε4 on the CSF proteome in normal cognition.
Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring.
14(1).
doi:
10.1002/dad2.12286.
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Vetter, Valentin M.; Kalies, Christian H.; Sommerer, Yasmine; Spira, Dominik; Drewelies, Johanna & Regitz-Zagrosek, Vera
[Show all 9 contributors for this article]
(2022).
Relationship Between 5 Epigenetic Clocks, Telomere Length, and Functional Capacity Assessed in Older Adults: Cross-Sectional and Longitudinal Analyses.
The journals of gerontology. Series A, Biological sciences and medical sciences.
ISSN 1079-5006.
77(9),
p. 1724–1733.
doi:
10.1093/gerona/glab381.
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Vidal-Piñeiro, Didac; Wang, Yunpeng; Krogsrud, Stine Kleppe; Amlien, Inge; Baaré, William FC & Bartres-Faz, David
[Show all 31 contributors for this article]
(2021).
Individual variations in ‘brain age’ relate to early-life factors more than to longitudinal brain change.
eLIFE.
10.
doi:
10.7554/eLife.69995.
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Brain age is a widely used index for quantifying individuals’ brain health as deviation from a normative brain aging trajectory. Higher-than-expected brain age is thought partially to reflect above-average rate of brain aging. Here, we explicitly tested this assumption in two independent large test datasets (UK Biobank [main] and Lifebrain [replication]; longitudinal observations ≈ 2750 and 4200) by assessing the relationship between cross-sectional and longitudinal estimates of brain age. Brain age models were estimated in two different training datasets (n ≈ 38,000 [main] and 1800 individuals [replication]) based on brain structural features. The results showed no association between cross-sectional brain age and the rate of brain change measured longitudinally. Rather, brain age in adulthood was associated with the congenital factors of birth weight and polygenic scores of brain age, assumed to reflect a constant, lifelong influence on brain structure from early life. The results call for nuanced interpretations of cross-sectional indices of the aging brain and question their validity as markers of ongoing within-person changes of the aging brain. Longitudinal imaging data should be preferred whenever the goal is to understand individual change trajectories of brain and cognition in aging.
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Sha, Zhiqiang; Pepe, Antonietta; Schijven, Dick; Carrion-Castillo, Amaia; Roe, James Michael & Westerhausen, Rene
[Show all 10 contributors for this article]
(2021).
Handedness and its genetic influences are associated with structural asymmetries of the cerebral cortex in 31,864 individuals.
Proceedings of the National Academy of Sciences of the United States of America (PNAS).
ISSN 0027-8424.
118(47),
p. 1–9.
doi:
10.1073/pnas.2113095118.
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Roughly 10% of the human population is left-handed, and this rate is increased in some brain-related disorders. The neuroanatomical correlates of hand preference have remained equivocal. We resampled structural brain image data from 28,802 right-handers and 3,062 left-handers (UK Biobank population dataset) to a symmetrical surface template, and mapped asymmetries for each of 8,681 vertices across the cerebral cortex in each individual. Left-handers compared to right-handers showed average differences of surface area asymmetry within the fusiform cortex, the anterior insula, the anterior middle cingulate cortex, and the precentral cortex. Meta-analyzed functional imaging data implicated these regions in executive functions and language. Polygenic disposition to left-handedness was associated with two of these regional asymmetries, and 18 loci previously linked with left-handedness by genome-wide screening showed associations with one or more of these asymmetries. Implicated genes included six encoding microtubule-related proteins: TUBB , TUBA1B , TUBB3 , TUBB4A , MAP2 , and NME7 —mutations in the latter can cause left to right reversal of the visceral organs. There were also two cortical regions where average thickness asymmetry was altered in left-handedness: on the postcentral gyrus and the inferior occipital cortex, functionally annotated with hand sensorimotor and visual roles. These cortical thickness asymmetries were not heritable. Heritable surface area asymmetries of language-related regions may link the etiologies of hand preference and language, whereas nonheritable asymmetries of sensorimotor cortex may manifest as consequences of hand preference.
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Uddin, Md Jamal; Ekstrøm, Claus Thorn; Hemager, Nicoline; Christiani, Camilla A J; Gregersen, Maja & Ellersgaard, Ditte Vestbjerg
[Show all 23 contributors for this article]
(2021).
Is the Association Between Parents’ Mental Illness and Child Psychopathology Mediated via Home Environment and Caregiver’s Psychosocial Functioning? A Mediation Analysis of the Danish High Risk and Resilience Study—VIA7, a Population-Based Cohort Study.
Schizophrenia Bulletin Open.
2(1).
doi:
10.1093/schizbullopen/sgab024.
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Wang, Yunpeng; Grydeland, Håkon; Roe, James Michael; Pan, Mengyu; Magnussen, Fredrik & Amlien, Inge
[Show all 17 contributors for this article]
(2021).
Associations of circulating C-reactive proteins, APOE ε4, and brain markers for Alzheimer’s disease in healthy samples across the lifespan.
Brain, Behavior, and Immunity.
ISSN 0889-1591.
100.
doi:
10.1016/j.bbi.2021.12.008.
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The apolipoprotein E gene ε4 allele (APOE ε4) and higher circulating level of C-reactive protein (CRP) have been extensively investigated as risk factors for Alzheimer’s disease (AD). Paradoxically, APOE ε4 has been associated with lower levels of blood CRP in middle-aged and older populations. However, few studies have investigated this intriguing relation and its impact on neurological markers for AD in younger ages, nor across the whole lifespan. Here, we examine associations of blood CRP levels, APOE ε4, and biomarkers for AD in a cognitively healthy lifespan cohort (N up to 749; 20–81 years of age) and replicate the findings in UK Biobank (N = 304 322; 37–72 years of age), the developmental ABCD study (N = 10 283; 9–11 years of age), and a middle-aged sample (N = 339; 40–65 years of age). Hippocampal volume, brain amyloid-β (Aβ) plaque levels, cerebrospinal fluid (CSF) levels of Aβ and tau species, and neurofilament protein light protein (NFL) were used as AD biomarkers in subsamples. In addition, we examined the genetic contribution to the variation of CRP levels over different CRP ranges using polygenic scores for CRP (PGS-CRP). Our results show APOE ε4 consistently associates with low blood CRP levels across all age groups (p < 0.05). Strikingly, both ε4 and PGS-CRP associated mainly with blood CRP levels within the low range (<5mg/L). We then show both APOE ε4 and high CRP levels associate with smaller hippocampus volumes across the lifespan (p < 0.025). APOE ε4 was associated with high Aβ plaque levels in the brain (FDR-corrected p = 8.69x10-4), low levels of CSF Aβ42 (FDR-corrected p = 6.9x10-2), and lower ratios of Aβ42 to Aβ40 (FDR-corrected p = 5.08x10-5). Blood CRP levels were weakly correlated with higher ratio of CSF Aβ42 to Aβ40 (p = 0.03, FDR-corrected p = 0.4). APOE ε4 did not correlate with blood concentrations of another 9 inflammatory cytokines, and none of these cytokines correlated with AD biomarkers.
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Fjell, Anders Martin; Grydeland, Håkon; Wang, Yunpeng; Amlien, Inge; Bartrés-Faz, David & Brandmaier, Andreas M.
[Show all 24 contributors for this article]
(2021).
The genetic organization of longitudinal subcortical volumetric change is stable throughout the lifespan running title: Genetics of subcortical lifespan change.
eLIFE.
10,
p. 1–22.
doi:
10.7554/eLife.66466.
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Development and aging of the cerebral cortex show similar topographic organization and are governed by the same genes. It is unclear whether the same is true for subcortical regions, which follow fundamentally different ontogenetic and phylogenetic principles. We tested the hypothesis that genetically governed neurodevelopmental processes can be traced throughout life by assessing to which degree brain regions that develop together continue to change together through life. Analyzing over 6000 longitudinal MRIs of the brain, we used graph theory to identify five clusters of coordinated development, indexed as patterns of correlated volumetric change in brain structures. The clusters tended to follow placement along the cranial axis in embryonic brain development, suggesting continuity from prenatal stages, and correlated with cognition. Across independent longitudinal datasets, we demonstrated that developmental clusters were conserved through life. Twin-based genetic correlations revealed distinct sets of genes governing change in each cluster. Single-nucleotide polymorphisms-based analyses of 38,127 cross-sectional MRIs showed a similar pattern of genetic volume–volume correlations. In conclusion, coordination of subcortical change adheres to fundamental principles of lifespan continuity and genetic organization.
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Grydeland, Håkon; Sederevicius, Donatas; Wang, Yunpeng; Bartres-Faz, David; Bertram, Lars & Dobricic, Valerija
[Show all 16 contributors for this article]
(2021).
Self-Reported Sleep Relates to Microstructural Hippocampal Decline in β-Amyloid Positive Adults Beyond Genetic Risk.
Sleep.
ISSN 0161-8105.
44(11).
doi:
10.1093/sleep/zsab110.
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Background To test the hypothesis that worse self-reported sleep relates to memory decay and reduced hippocampal integrity as indexed by increased intra-hippocampal water diffusion, and that the relations are stronger in the presence of β-amyloid (Aβ) accumulation, a marker of Alzheimer’s disease (AD) pathology.
Methods Two-hundred and forty-three cognitively healthy participants, aged 19-81 years, completed the Pittsburgh Sleep Quality Index, and 2 diffusion tensor imaging sessions, on average 3 years apart, allowing measures of decline in hippocampal microstructural integrity as indexed by increased mean diffusivity. We measured memory decay using delayed recall from the California Verbal Learning Test. 18F-Flutemetamol positron emission tomography, in 108 participants above 44 years of age, yielded 23 Aβ positive. Genotyping enabled controlling for APOE ε4 status, and polygenic scores for sleep efficiency and AD.
Results Worse global sleep quality and sleep efficiency related to more rapid reduction in hippocampal microstructural integrity over time. Focusing on sleep efficiency, the relation was stronger in presence of Aβ accumulation. Sleep efficiency related to memory decay indirectly via hippocampal integrity decline. The results were not explained by genetic risk for sleep efficiency and AD.
Conclusions Poor self-reported sleep efficiency related to decline in hippocampal integrity, especially in the presence of Aβ accumulation. Poor sleep and hippocampal microstructural decline may partly explain memory decline in older adults with Aβ pathology. The relationships were not explained by genetic risk. Poor self-reported sleep efficiency might constitute a risk factor for AD, although the causal mechanisms driving the of observed associations remain unknown.
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Maihofer, Adam X.; Choi, Karmel W.; Coleman, Jonathan R.I.; Daskalakis, Nikolaos P.; Denckla, Christy A. & Ketema, Elizabeth
[Show all 181 contributors for this article]
(2021).
Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information.
Biological Psychiatry.
ISSN 0006-3223.
p. 1–11.
doi:
10.1016/j.biopsych.2021.09.020.
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Background Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.
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Irene, Bergstrøm Ida; Roe, James Michael & Asgeir, Kobro-Flatmoen
(2025).
Hukommelsen ryker med alderen, men det går utfor lenge før du blir gammel.
[Internet].
forskning.no.
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Strømstad, Marie Lorentsen; Fjell, Anders Martin; Walhovd, Kristine B; Vidal-Piñeiro, Didac & Sørensen, Øystein
(2024).
Longitudinal association between structural brain change and episodic memory change.
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Garrido, Pablo F.; Bråthen, Anne Cecilie Sjøli; Falch, Emilie Sogn; Kransberg, Jonas; Sørensen, Øystein & Walhovd, Kristine B
(2024).
A novel analysis approach to Mirror Tracing Task performance to detect fine-grained age-related differences.
Alzheimer's & Dementia.
ISSN 1552-5260.
20,
p. e092273–e092273.
doi:
10.1002/alz.092273.
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Fjell, Anders Martin
(2024).
Hukommelse, falske minner, déjà vu og hjernetrim.
[Internet].
Ganske aktuelt med Kenneth Bergh" podcast.
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Fjell, Anders Martin & Walhovd, Kristine B
(2024).
Imaging the timing of influences on brain and cognition across the lifespan.
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Fjell, Anders Martin
(2023).
Not getting enough sleep may be less harmful to the brain than some have feared.
[Internet].
The New Scientist.
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Fjell, Anders Martin
(2023).
Tett på Kristine Beate Walhovd og Anders Fjell: Forsker på hjernen vår for å forstå hvorfor vi utvikler oss så forskjellig.
[Internet].
UiO Podcast.
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Fjell, Anders Martin
(2022).
In search of factors influencing or not influencing brain and cognition - Results from the Lifebrain 2020 project and beyond.
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Visser, Pieter Jelle; Reus, Lianne M.; Gobom, Johan; Jansen, Iris; Dicks, Ellen & Lee, Sven J. van der
[Show all 28 contributors for this article]
(2022).
Correction: Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer’s disease (Molecular Neurodegeneration, (2022), 17, 1, (27), 10.1186/s13024-022-00521-3).
Molecular Neurodegeneration.
17(1).
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10.1186/s13024-022-00540-0.
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Vidal-Piñeiro, Didac
(2022).
Individual variations in Brain age: capturing ongoing brain change or reflecting early-life differences?
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Vidal-Piñeiro, Didac
(2022).
Individual variations in brain age: capturing ongoing brain change or reflecting early-life differences?
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Published Dec. 18, 2023 10:26 AM
- Last modified Jan. 29, 2024 11:00 AM