Publications by authors named "Lars Nyberg"

293 Publications

Education and Income Show Heterogeneous Relationships to Lifespan Brain and Cognitive Differences Across European and US Cohorts.

Cereb Cortex 2021 Aug 31. Epub 2021 Aug 31.

Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin 14195, Germany.

Higher socio-economic status (SES) has been proposed to have facilitating and protective effects on brain and cognition. We ask whether relationships between SES, brain volumes and cognitive ability differ across cohorts, by age and national origin. European and US cohorts covering the lifespan were studied (4-97 years, N = 500 000; 54 000 w/brain imaging). There was substantial heterogeneity across cohorts for all associations. Education was positively related to intracranial (ICV) and total gray matter (GM) volume. Income was related to ICV, but not GM. We did not observe reliable differences in associations as a function of age. SES was more strongly related to brain and cognition in US than European cohorts. Sample representativity varies, and this study cannot identify mechanisms underlying differences in associations across cohorts. Differences in neuroanatomical volumes partially explained SES-cognition relationships. SES was more strongly related to ICV than to GM, implying that SES-cognition relations in adulthood are less likely grounded in neuroprotective effects on GM volume in aging. The relatively stronger SES-ICV associations rather are compatible with SES-brain volume relationships being established early in life, as ICV stabilizes in childhood. The findings underscore that SES has no uniform association with, or impact on, brain and cognition.
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http://dx.doi.org/10.1093/cercor/bhab248DOI Listing
August 2021

When functional blurring becomes deleterious: Reduced system segregation is associated with less white matter integrity and cognitive decline in aging.

Neuroimage 2021 Nov 3;242:118449. Epub 2021 Aug 3.

Department of Integrative Medical Biology, Umeå University, Umeå, Sweden; Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden; Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, Umeå, Sweden; Aging Research Center (ARC), Karolinska Institutet and Stockholm University, Stockholm, Sweden.

Healthy aging is accompanied by progressive decline in cognitive performance and concomitant changes in brain structure and functional architecture. Age-accompanied alterations in brain function have been characterized on a network level as weaker functional connections within brain networks along with stronger interactions between networks. This phenomenon has been described as age-related differences in functional network segregation. It has been suggested that functional networks related to associative processes are particularly sensitive to age-related deterioration in segregation, possibly related to cognitive decline in aging. However, there have been only a few longitudinal studies with inconclusive results. Here, we used a large longitudinal sample of 284 participants between 25 to 80 years of age at baseline, with cognitive and neuroimaging data collected at up to three time points over a 10-year period. We investigated age-related changes in functional segregation among two large-scale systems comprising associative and sensorimotor-related resting-state networks. We found that functional segregation of associative systems declines in aging with exacerbated deterioration from the late fifties. Changes in associative segregation were positively associated with changes in global cognitive ability, suggesting that decreased segregation has negative consequences for domain-general cognitive functions. Age-related changes in system segregation were partly accounted for by changes in white matter integrity, but white matter integrity only weakly influenced the association between segregation and cognition. Together, these novel findings suggest a cascade where reduced white-matter integrity leads to less distinctive functional systems which in turn contributes to cognitive decline in aging.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118449DOI Listing
November 2021

The genetic organization of longitudinal subcortical volumetric change is stable throughout the lifespan.

Elife 2021 06 28;10. Epub 2021 Jun 28.

Center for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Oslo, Norway.

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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http://dx.doi.org/10.7554/eLife.66466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260220PMC
June 2021

Antiviral treatment associated with reduced risk of clinical Alzheimer's disease-A nested case-control study.

Alzheimers Dement (N Y) 2021 9;7(1):e12187. Epub 2021 Jun 9.

Department of Community Medicine and Rehabilitation Geriatric Medicine, Umeå University Umeå Sweden.

Introduction: In this nested case-control study, we investigated if antiviral treatment given prior to onset of Alzheimer's disease (AD) could influence incident AD.

Methods: From a large population-based cohort study in northern Sweden, 262 individuals that later developed AD were compared to a non-AD matched control group with respect to prescriptions of herpes antiviral treatment. All included subjects were herpes simplex virus 1 (HSV1) carriers and the matching criteria were age, sex, apolipoprotein E genotype (ε4 allele carriership), and study sample start year.

Results: Among those who developed AD, 6 prescriptions of antivirals were found, compared to 20 among matched controls. Adjusted for length of follow-up, a conditional logistic regression indicated a difference in the risk for AD development between groups (odds ratio for AD with an antiviral prescription 0.287, = .018).

Discussion: Antiviral treatment might possibly reduce the risk for later development of HSV1-associated AD.
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http://dx.doi.org/10.1002/trc2.12187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190532PMC
June 2021

Sex differences in dopamine integrity and brain structure among healthy older adults: Relationships to episodic memory.

Neurobiol Aging 2021 09 2;105:272-279. Epub 2021 May 2.

Aging Research Center, Karolinska Institute & Stockholm University, Stockholm, Sweden.

Normal brain aging is a multidimensional process that includes deterioration in various brain structures and functions, with large heterogeneity in patterns and rates of decline. Sex differences have been reported for various cognitive and brain parameters, but little is known in relation to neuromodulatory aspects of brain aging. We examined sex differences in dopamine D2-receptor (D2DR) availability in relation to episodic memory, but also, grey-matter volumes, white-matter lesions, and cerebral perfusion in healthy older adults (n = 181, age: 64-68 years) from the Cognition, Brain, and Aging study. Women had higher D2DR availability in midbrain and left caudate and putamen, as well as superior episodic memory performance. Controlling for left caudate D2DR availability attenuated sex differences in memory performance. In men, lower left caudate D2DR levels were associated with lower cortical perfusion and higher burden of white-matter lesions, as well as with episodic memory performance. However, sex was not a significant moderator of the reported links to D2DR levels. Our findings suggest that sex differences in multiple associations among DA receptor availability, vascular factors, and structural connectivity contribute to sex differences in episodic memory. Future longitudinal studies need to corroborate these patterns by lead-lag associations. This manuscript is part of the Special Issue entitled 'Cognitive Neuroscience of Healthy and Pathological Aging' edited by Drs. M. N. Rajah, S. Belleville, and R. Cabeza. This article is part of the Virtual Special Issue titled COGNITIVE NEUROSCIENCE OF HEALTHY AND PATHOLOGICAL AGING. The full issue can be found on ScienceDirect at https://www.sciencedirect.com/journal/neurobiology-of-aging/special-issue/105379XPWJP.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.022DOI Listing
September 2021

Self-Reported Sleep Relates to Microstructural Hippocampal Decline in β-Amyloid Positive Adults Beyond Genetic Risk.

Sleep 2021 Apr 27. Epub 2021 Apr 27.

Research Group for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, 0317 Oslo, Norway.

Study Objectives: A critical role linking sleep with memory decay and β-amyloid (Aβ) accumulation, two markers of Alzheimer's disease (AD) pathology, may be played by hippocampal integrity. We tested the hypotheses that worse self-reported sleep relates to decline in memory and intra-hippocampal microstructure, including in the presence of Aβ.

Methods: Two-hundred and forty-three cognitively healthy participants, aged 19-81 years, completed the Pittsburgh Sleep Quality Index once, and 2 diffusion tensor imaging sessions, on average 3 years apart, allowing measures of decline in intra-hippocampal microstructure as indexed by increased mean diffusivity. We measured memory decay at each imaging session using verbal delayed recall. One session of positron emission tomography, in 108 participants above 44 years of age, yielded 23 Aβ positive. Genotyping enabled control for APOE ε4 status, and polygenic scores for sleep and AD, respectively.

Results: Worse global sleep quality and sleep efficiency related to more rapid reduction of hippocampal microstructure over time. Focusing on efficiency (the percentage of time in bed at night spent asleep), the relation was stronger in presence of Aβ accumulation, and hippocampal integrity decline mediated the relation with memory decay. The results were not explained by genetic risk for sleep efficiency or AD.

Conclusions: Worse sleep efficiency related to decline in hippocampal microstructure, especially in the presence of Aβ accumulation, and Aβ might link poor sleep and memory decay. As genetic risk did not account for the associations, poor sleep efficiency might constitute a risk marker for AD, although the driving causal mechanisms remain unknown.
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http://dx.doi.org/10.1093/sleep/zsab110DOI Listing
April 2021

Educational attainment does not influence brain aging.

Proc Natl Acad Sci U S A 2021 May;118(18)

Center for Lifespan Changes in Brain and Cognition, University of Oslo, 0317 Oslo, Norway;

Education has been related to various advantageous lifetime outcomes. Here, using longitudinal structural MRI data (4,422 observations), we tested the influential hypothesis that higher education translates into slower rates of brain aging. Cross-sectionally, education was modestly associated with regional cortical volume. However, despite marked mean atrophy in the cortex and hippocampus, education did not influence rates of change. The results were replicated across two independent samples. Our findings challenge the view that higher education slows brain aging.
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http://dx.doi.org/10.1073/pnas.2101644118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106299PMC
May 2021

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Transl Psychiatry 2021 03 22;11(1):182. Epub 2021 Mar 22.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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http://dx.doi.org/10.1038/s41398-021-01213-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985307PMC
March 2021

Acute hyperglycaemia leads to altered frontal lobe brain activity and reduced working memory in type 2 diabetes.

PLoS One 2021 19;16(3):e0247753. Epub 2021 Mar 19.

Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden.

How acute hyperglycaemia affects memory functions and functional brain responses in individuals with and without type 2 diabetes is unclear. Our aim was to study the association between acute hyperglycaemia and working, semantic, and episodic memory in participants with type 2 diabetes compared to a sex- and age-matched control group. We also assessed the effect of hyperglycaemia on working memory-related brain activity. A total of 36 participants with type 2 diabetes and 34 controls (mean age, 66 years) underwent hyperglycaemic clamp or placebo clamp in a blinded and randomised order. Working, episodic, and semantic memory were tested. Overall, the control group had higher working memory (mean z-score 33.15 ± 0.45) than the group with type 2 diabetes (mean z-score 31.8 ± 0.44, p = 0.042) considering both the placebo and hyperglycaemic clamps. Acute hyperglycaemia did not influence episodic, semantic, or working memory performance in either group. Twenty-two of the participants (10 cases, 12 controls, mean age 69 years) were randomly invited to undergo the same clamp procedures to challenge working memory, using 1-, 2-, and 3-back, while monitoring brain activity by blood oxygen level-dependent functional magnetic resonance imaging (fMRI). The participants with type 2 diabetes had reduced working memory during the 1- and 2-back tests. fMRI during placebo clamp revealed increased BOLD signal in the left lateral frontal cortex and the anterior cingulate cortex as a function of working memory load in both groups (3>2>1). During hyperglycaemia, controls showed a similar load-dependent fMRI response, whereas the type 2 diabetes group showed decreased BOLD response from 2- to 3-back. These results suggest that impaired glucose metabolism in the brain affects working memory, possibly by reducing activity in important frontal brain areas in persons with type 2 diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247753PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978337PMC
September 2021

Multimodal Image Analysis of Apparent Brain Age Identifies Physical Fitness as Predictor of Brain Maintenance.

Cereb Cortex 2021 Jun;31(7):3393-3407

Umeå Center for Functional Brain Imaging (UFBI), Umeå University, S-901 87 Umeå, Sweden.

Maintaining a youthful brain structure and function throughout life may be the single most important determinant of successful cognitive aging. In this study, we addressed heterogeneity in brain aging by making image-based brain age predictions and relating the brain age prediction gap (BAPG) to cognitive change in aging. Structural, functional, and diffusion MRI scans from 351 participants were used to train and evaluate 5 single-modal and 4 multimodal prediction models, based on 7 regression methods. The models were compared on mean absolute error and whether they were related to physical fitness and cognitive ability, measured both currently and longitudinally, as well as study attrition and years of education. Multimodal prediction models performed at a similar level as single-modal models, and the choice of regression method did not significantly affect the results. Correlation with the BAPG was found for current physical fitness, current cognitive ability, and study attrition. Correlations were also found for retrospective physical fitness, measured 10 years prior to imaging, and slope for cognitive ability during a period of 15 years. The results suggest that maintaining a high physical fitness throughout life contributes to brain maintenance and preserved cognitive ability.
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http://dx.doi.org/10.1093/cercor/bhab019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196254PMC
June 2021

Distinct and Common Large-Scale Networks of the Hippocampal Long Axis in Older Age: Links to Episodic Memory and Dopamine D2 Receptor Availability.

Cereb Cortex 2021 Jun;31(7):3435-3450

Umeå Center for Functional Brain Imaging, Umeå University, S-90187 Umeå, Sweden.

The hippocampal longitudinal axis has been linked to dissociated functional networks relevant to episodic memory. However, the organization of axis-dependent networks and their relation to episodic memory in aging remains less explored. Moreover, age-related deterioration of the dopamine (DA) system, affecting memory and functional network properties, might constitute a source of reduced specificity of hippocampal networks in aging. Here, we characterized axis-dependent large-scale hippocampal resting-state networks, their relevance to episodic memory, and links to DA in older individuals (n = 170, 64-68 years). Partial least squares identified 2 dissociated networks differentially connected to the anterior and posterior hippocampus. These overlapped with anterior-temporal/posterior-medial networks in young adults, indicating preserved organization of axis-dependent connectivity in old age. However, axis-specific networks were overall unrelated to memory and hippocampal DA D2 receptor availability (D2DR) measured with [11C]-raclopride positron emission tomography. Further analyses identified a memory-related network modulated by hippocampal D2DR, equally connected to anterior-posterior regions. This network included medial frontal, posterior parietal, and striatal areas. The results add to the current understanding of large-scale hippocampal connectivity in aging, demonstrating axis-dependent connectivity with dissociated anterior and posterior networks, as well as a primary role in episodic memory of connectivity shared by regions along the hippocampalaxis.
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http://dx.doi.org/10.1093/cercor/bhab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196260PMC
June 2021

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years.

Hum Brain Mapp 2021 Feb 17. Epub 2021 Feb 17.

Laboratory of Psychiatric Neuroimaging, Departamento e Instituto de Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.
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http://dx.doi.org/10.1002/hbm.25364DOI Listing
February 2021

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years.

Hum Brain Mapp 2021 Feb 11. Epub 2021 Feb 11.

Department of Psychology, Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.
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http://dx.doi.org/10.1002/hbm.25320DOI Listing
February 2021

Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer's disease.

Nat Commun 2021 02 1;12(1):721. Epub 2021 Feb 1.

Center for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Oslo, Norway.

Aging and Alzheimer's disease (AD) are associated with progressive brain disorganization. Although structural asymmetry is an organizing feature of the cerebral cortex it is unknown whether continuous age- and AD-related cortical degradation alters cortical asymmetry. Here, in multiple longitudinal adult lifespan cohorts we show that higher-order cortical regions exhibiting pronounced asymmetry at age ~20 also show progressive asymmetry-loss across the adult lifespan. Hence, accelerated thinning of the (previously) thicker homotopic hemisphere is a feature of aging. This organizational principle showed high consistency across cohorts in the Lifebrain consortium, and both the topological patterns and temporal dynamics of asymmetry-loss were markedly similar across replicating samples. Asymmetry-change was further accelerated in AD. Results suggest a system-wide dedifferentiation of the adaptive asymmetric organization of heteromodal cortex in aging and AD.
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http://dx.doi.org/10.1038/s41467-021-21057-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851164PMC
February 2021

Hand grip strength is strongly associated with lower limb strength but only weakly with postural control in community-dwelling older adults.

Arch Gerontol Geriatr 2021 May-Jun;94:104345. Epub 2021 Jan 16.

Department of Health Sciences, Division of Health, Medicine and Rehabilitation, Luleå University of Technology, Laboratorievägen 14, 971 87 Luleå, Sweden.

Background: Hand grip strength is frequently used as a measurement of muscle strength, especially among older adults. Muscle strength is only one of the many components in postural control and it is currently unclear to what extent hand grip strength is associated with postural control. The aim was to analyze the association between hand grip strength and lower limb muscle strength, and postural control among older adults.

Methods: Forty-five community-dwelling individuals over 70 years of age provided isometric hand grip strength and lower limb strength (including hip extension and abduction, knee flexion and extension, and ankle dorsiflexion and plantarflexion), as well as postural control measurements. In the latter, center of pressure excursions were recorded for quiet stance and limits of stability tests on a force plate. Orthogonal projection of latent structures regression models were used to analyze associations between hand grip strength and lower limb strength as well as postural control, respectively.

Results: Lower limb strength explained 74.4% of the variance in hand grip strength. All lower limb muscle groups were significantly associated with hand grip strength. In a corresponding model, postural control measured with center of pressure excursions explained 20.7% of the variance in a statistically significant, albeit weak, model.

Conclusions: These results support that hand grip strength is a valid method to estimate lower limb strength among older adults on a group level. However, strength measurements seem insufficient as a substitute for measuring postural control, and therefore specific balance tests are necessary.
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http://dx.doi.org/10.1016/j.archger.2021.104345DOI Listing
May 2021

Ancient Mnemonic in New Format-Episodic Memory Training With the Method of Loci in a Smart Phone Application.

J Gerontol B Psychol Sci Soc Sci 2021 03;76(4):681-691

Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Sweden.

Objectives: Episodic memory is age-sensitive but can be strengthened by targeted training interventions. The method of loci (MoL) is a classic mnemonic which if successfully implemented greatly improves memory performance. We developed and investigated the effects of a MoL training program implemented in a smart phone application (app) with the aim of studying usage of the application, training effect and its modifiability by age, predictors for MoL proficiency, transfer effects to a face-name memory task, and perceived benefit in everyday memory.

Method: A total of 359 adults participated. Instruction and training of the MoL, transfer test (face-name paired associates cued recall task), and surveys were performed in an in-house developed app.

Results: The app interested people across the adult life span. Older adults practiced the most, whereas younger and young-old participants showed the highest level of MoL proficiency. Level of proficiency was modulated by amount of practice, but in the oldest participants this effect was less pronounced. Greater self-rated health was associated with higher level of proficiency. No transfer effect was observed. Among those who answered the survey, about half expressed that MoL training had benefitted memory in their everyday life.

Discussion: App-based memory training in the MoL can be delivered successfully via an app across the adult life span. Level of performance reached in training is variable but generally high, and mainly influenced by amount of training and age of the participants. Our data suggest plasticity across the life span, but to a lesser degree for adults between 70 and 90 years.
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http://dx.doi.org/10.1093/geronb/gbaa216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955968PMC
March 2021

Cerebral arterial pulsatility is linked to hippocampal microvascular function and episodic memory in healthy older adults.

J Cereb Blood Flow Metab 2021 07 14;41(7):1778-1790. Epub 2021 Jan 14.

Department of Radiation Sciences, Umeå University, Umeå, Sweden.

Microvascular damage in the hippocampus is emerging as a central cause of cognitive decline and dementia in aging. This could be a consequence of age-related decreases in vascular elasticity, exposing hippocampal capillaries to excessive cardiac-related pulsatile flow that disrupts the blood-brain barrier and the neurovascular unit. Previous studies have found altered intracranial hemodynamics in cognitive impairment and dementia, as well as negative associations between pulsatility and hippocampal volume. However, evidence linking features of the cerebral arterial flow waveform to hippocampal function is lacking. We used a high-resolution 4D flow MRI approach to estimate global representations of the time-resolved flow waveform in distal cortical arteries and in proximal arteries feeding the brain in healthy older adults. Waveform-based clustering revealed a group of individuals featuring steep systolic onset and high amplitude that had poorer hippocampus-sensitive episodic memory (p = 0.003), lower whole-brain perfusion (p = 0.001), and weaker microvascular low-frequency oscillations in the hippocampus (p = 0.035) and parahippocampal gyrus (p = 0.005), potentially indicating compromised neurovascular unit integrity. Our findings suggest that aberrant hemodynamic forces contribute to cerebral microvascular and hippocampal dysfunction in aging.
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http://dx.doi.org/10.1177/0271678X20980652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217890PMC
July 2021

Role of dopamine and gray matter density in aging effects and individual differences of functional connectomes.

Brain Struct Funct 2021 Apr 9;226(3):743-758. Epub 2021 Jan 9.

Aging Research Center, Karolinska Institutet, Stockholm, Sweden.

With increasing age, functional connectomes become dissimilar across normal individuals, reflecting heterogenous aging effects on functional connectivity (FC). We investigated the distribution of these effects across the connectome and their relationship with age-related differences in dopamine (DA) D1 receptor availability and gray matter density (GMD). With this aim, we determined aging effects on mean and interindividual variance of FC using fMRI in 30 younger and 30 older healthy subjects and mapped the contribution of each connection to the patterns of age-related similarity loss. Aging effects on mean FC accounted mainly for the dissimilarity between connectomes of younger and older adults, and were related, across brain regions, to aging effects on DA D1 receptor availability. Aging effects on the variance of FC indicated a global increase in variance with advancing age, explained connectome dissimilarity among older subjects and were related to aging effects on variance of GMD. The relationship between aging and the similarity of connectomes can thus be partly explained by age differences in DA modulation and gray matter structure.
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http://dx.doi.org/10.1007/s00429-020-02205-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981334PMC
April 2021

Neural correlates of reward processing: Functional dissociation of two components within the ventral striatum.

Brain Behav 2021 02 9;11(2):e01987. Epub 2020 Dec 9.

Department of Radiation Sciences, Umeå Center for Functional Brain Imaging, Umeå University, Umeå, Sweden.

Introduction: Rewarding and punishing stimuli elicit BOLD responses in the affective division of the striatum. The responses typically traverse from the affective to the associative division of the striatum, suggesting an involvement of associative processes during the modulation of stimuli valance. In this study, we hypothesized that fMRI responses to rewards versus punishments in a guessing card game can be disassociated into two functional component processes that reflect the convergence of limbic and associative functional networks in the ventral striatum.

Methods: We used fMRI data of 175 (92 female) subjects from the human connectome project´s gambling task, working memory task, and resting-state scans. A reward > punish contrast identified a ventral striatum cluster from which voxelwise GLM parameter estimates were entered into a k-means clustering algorithm. The k-means analysis supported separating the cluster into two spatially distinct components. These components were used as seeds to investigate their functional connectivity profile. GLM parameter estimates were extracted and compared from the task contrasts reward > punish and 2-back > 0-back from two ROIs in the ventral striatum and one ROI in hippocampus.

Results: The analyses converged to show that a superior striatal component, coupled with the ventral attention and frontal control networks, was responsive to both a modulation of cognitive control in working memory and to rewards, whereas the most inferior part of the ventral striatum, coupled with the limbic and default mode networks including the hippocampus, was selectively responsive to rewards.

Conclusion: We show that the fMRI response to rewards in the ventral striatum reflects a mixture of component processes of reward. An inferior ventral striatal component and hippocampus are part of an intrinsically coupled network that responds to reward-based processing during gambling. The more superior ventral striatal component is intrinsically coupled to networks involved with executive functioning and responded to both reward and cognitive control demands.
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http://dx.doi.org/10.1002/brb3.1987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882172PMC
February 2021

The Functional Foundations of Episodic Memory Remain Stable Throughout the Lifespan.

Cereb Cortex 2021 03;31(4):2098-2110

Department of Psychology, Centre for Lifespan Changes in Brain and Cognition, University of Oslo, Oslo 0317, Norway.

It has been suggested that specific forms of cognition in older age rely largely on late-life specific mechanisms. Here instead, we tested using task-fMRI (n = 540, age 6-82 years) whether the functional foundations of successful episodic memory encoding adhere to a principle of lifespan continuity, shaped by developmental, structural, and evolutionary influences. We clustered regions of the cerebral cortex according to the shape of the lifespan trajectory of memory activity in each region so that regions showing the same pattern were clustered together. The results revealed that lifespan trajectories of memory encoding function showed a continuity through life but no evidence of age-specific mechanisms such as compensatory patterns. Encoding activity was related to general cognitive abilities and variations of grey matter as captured by a multi-modal independent component analysis, variables reflecting core aspects of cognitive and structural change throughout the lifespan. Furthermore, memory encoding activity aligned to fundamental aspects of brain organization, such as large-scale connectivity and evolutionary cortical expansion gradients. Altogether, we provide novel support for a perspective on memory aging in which maintenance and decay of episodic memory in older age needs to be understood from a comprehensive life-long perspective rather than as a late-life phenomenon only.
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http://dx.doi.org/10.1093/cercor/bhaa348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945016PMC
March 2021

Poor Self-Reported Sleep is Related to Regional Cortical Thinning in Aging but not Memory Decline-Results From the Lifebrain Consortium.

Cereb Cortex 2021 03;31(4):1953-1969

Center for Lifespan Changes in Brain and Cognition, University of Oslo, 0315 Oslo, Norway.

We examined whether sleep quality and quantity are associated with cortical and memory changes in cognitively healthy participants across the adult lifespan. Associations between self-reported sleep parameters (Pittsburgh Sleep Quality Index, PSQI) and longitudinal cortical change were tested using five samples from the Lifebrain consortium (n = 2205, 4363 MRIs, 18-92 years). In additional analyses, we tested coherence with cell-specific gene expression maps from the Allen Human Brain Atlas, and relations to changes in memory performance. "PSQI # 1 Subjective sleep quality" and "PSQI #5 Sleep disturbances" were related to thinning of the right lateral temporal cortex, with lower quality and more disturbances being associated with faster thinning. The association with "PSQI #5 Sleep disturbances" emerged after 60 years, especially in regions with high expression of genes related to oligodendrocytes and S1 pyramidal neurons. None of the sleep scales were related to a longitudinal change in episodic memory function, suggesting that sleep-related cortical changes were independent of cognitive decline. The relationship to cortical brain change suggests that self-reported sleep parameters are relevant in lifespan studies, but small effect sizes indicate that self-reported sleep is not a good biomarker of general cortical degeneration in healthy older adults.
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http://dx.doi.org/10.1093/cercor/bhaa332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945023PMC
March 2021

Frequency domain shows: Fall-related concerns and sensorimotor decline explain inability to adjust postural control strategy in older adults.

PLoS One 2020 20;15(11):e0242608. Epub 2020 Nov 20.

Department of Health Sciences, Luleå University of Technology, Luleå, Sweden.

Human postural control is a complex system and changes as we age. Frequency based analyses have been argued to be useful to identify altered postural control strategies in balance tasks. The aim of this study was to explore the frequency domain of the quiet stance centre of pressure of older adults with various degrees of fall-related concerns and sensorimotor functioning. We included 45 community dwelling older adults and used a force plate to register 30 seconds of quiet stance with eyes open and closed respectively. We also measured sensory and motor functions, as well as fall-related concerns and morale. We analysed the centre of pressure power spectrum density and extracted the frequency of 4 of its features for each participant. Orthogonal projection of latent structures-discriminant analysis revealed two groups for each quiet stance trial. Group 1 of each trial showed less sensory and motor decline, low/no fall-related concerns and higher frequencies. Group 2 showed more decline, higher fall-related concerns and lower frequencies. During the closed eyes trial, group 1 and group 2 shifted their features to higher frequencies, but only group 1 did so in any significant way. Higher fall-related concerns, sensory and motor decline, and explorative balancing strategies are highly correlated. The control system of individuals experiencing this seems to be highly dependent on vision. Higher fall-related concerns, and sensory and motor decline are also correlated with the inability to adjust to faster, more reactive balancing strategies, when vision is not available.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242608PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678972PMC
January 2021

Wide temporal horns are associated with cognitive dysfunction, as well as impaired gait and incontinence.

Sci Rep 2020 10 23;10(1):18203. Epub 2020 Oct 23.

Department of Neuroscience, Uppsala University, Uppsala, Sweden.

The association between morphology of the brain and symptoms of suspected idiopathic normal pressure hydrocephalus (iNPH) is largely unknown. We investigated how ventricular expansion (width of the temporal horns [TH], callosal angle [CA], and Evans' index [EI]) related to symptom severity in suspected iNPH. Participants (n = 168; 74.9 years ± SD 6.7; 55% females) from the general population underwent neurological examination, computed tomography, and neuropsychological testing. Multiple linear regression analysis revealed that wide TH was independently associated with all examined iNPH symptoms (p < 0.01) except for fine-motor performance, whereas a narrow CA only was associated to specific motor and cognitive functions (p < 0.05). TH and EI correlated significantly with incontinence (r 0.17 and r 0.16; p < 0.05). In conclusion, wide TH was significantly associated with most iNPH-symptoms. This finding potentially reflects the complex nature of the hippocampus, however further studies are needed to demonstrate functional connectivity.
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http://dx.doi.org/10.1038/s41598-020-75381-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584644PMC
October 2020

Retrieval practice facilitates learning by strengthening processing in both the anterior and posterior hippocampus.

Brain Behav 2021 01 22;11(1):e01909. Epub 2020 Oct 22.

Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umea, Sweden.

Introduction And Methods: A large number of behavioral studies show that retrieval practice is a powerful way of strengthening learning of new information. Repeated retrieval might support long-term retention in a quantitative sense by inducing stronger episodic representations or in a qualitative sense by contributing to the formation of more gist-like representations. Here we used fMRI to examine the brain bases related to the learning effects following retrieval practice and provide imaging support for both views by showing increased activation of anterior and posterior hippocampus regions during a delayed memory test.

Results: Brain activity in the posterior hippocampus increased linearly as a function of number of successful retrievals during initial learning, whereas anterior hippocampus activity was restricted to items retrieved many but not few times during the learning phase.

Conclusion: Taken together, these findings indicate that retrieval practice strengthens subsequent retention via "dual action" in the anterior and posterior hippocampus, possibly reflecting coding of individual experiences as well as integration and generalization across multiple experiences. Our findings are of educational significance by providing insight into the brain bases of a learning method of applied relevance.
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http://dx.doi.org/10.1002/brb3.1909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821628PMC
January 2021

Greater male than female variability in regional brain structure across the lifespan.

Hum Brain Mapp 2020 Oct 12. Epub 2020 Oct 12.

FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.
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http://dx.doi.org/10.1002/hbm.25204DOI Listing
October 2020

Longitudinal association between hippocampus atrophy and episodic-memory decline in non-demented ε4 carriers.

Alzheimers Dement (Amst) 2020 28;12(1):e12110. Epub 2020 Sep 28.

Department of Integrative Medical Biology Umeå University Umeå Sweden.

Introduction: The apolipoprotein E () ε4 allele is the main genetic risk factor for Alzheimer's disease (AD), accelerated cognitive aging, and hippocampal atrophy, but its influence on the association between hippocampus atrophy and episodic-memory decline in non-demented individuals remains unclear.

Methods: We analyzed longitudinal (two to six observations) magnetic resonance imaging (MRI)-derived hippocampal volumes and episodic memory from 748 individuals (55 to 90 years at baseline, 50% female) from the European consortium.

Results: The change-change association for hippocampal volume and memory was significant only in ε4 carriers (N = 173, r = 0.21, = .007; non-carriers: N = 467, r = 0.073, = .117). The linear relationship was significantly steeper for the carriers [t(629) = 2.4, = .013]. A similar trend toward a stronger change-change relation for carriers was seen in a subsample with more than two assessments.

Discussion: These findings provide evidence for a difference in hippocampus-memory association between ε4 carriers and non-carriers, thus highlighting how genetic factors modulate the translation of the AD-related pathophysiological cascade into cognitive deficits.
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http://dx.doi.org/10.1002/dad2.12110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521596PMC
September 2020

Biological and environmental predictors of heterogeneity in neurocognitive ageing: Evidence from Betula and other longitudinal studies.

Ageing Res Rev 2020 12 28;64:101184. Epub 2020 Sep 28.

Department of Clinical Sciences, Umeå University, S-90187 Umeå, Sweden.

Individual differences in cognitive performance increase with advancing age, reflecting marked cognitive changes in some individuals along with little or no change in others. Genetic and lifestyle factors are assumed to influence cognitive performance in ageing by affecting the magnitude and extent of age-related brain changes (i.e., brain maintenance or atrophy), as well as the ability to recruit compensatory processes. The purpose of this review is to present findings from the Betula study and other longitudinal studies, with a focus on clarifying the role of key biological and environmental factors assumed to underlie individual differences in brain and cognitive ageing. We discuss the vital importance of sampling, analytic methods, consideration of non-ignorable dropout, and related issues for valid conclusions on factors that influence healthy neurocognitive ageing.
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http://dx.doi.org/10.1016/j.arr.2020.101184DOI Listing
December 2020

Increased functional homotopy of the prefrontal cortex is associated with corpus callosum degeneration and working memory decline.

Neurobiol Aging 2020 12 25;96:68-78. Epub 2020 Aug 25.

Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden; Umeå Center for Functional Brain Imaging, Umeå University, Umeå, Sweden; Department of Radiation Sciences, Umeå University, Umeå, Sweden; Department of Integrative Medical Biology, Umeå University, Umeå, Sweden; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.

Functional homotopy reflects the link between spontaneous activity in a voxel and its counterpart in the opposite hemisphere. Alterations in homotopic functional connectivity (FC) are seen in normal aging, with highest and lowest homotopy being present in sensory-motor and higher-order regions, respectively. Homotopic FC relates to underlying structural connections, but its neurobiological underpinnings remain unclear. The genu of the corpus callosum joins symmetrical parts of the prefrontal cortex (PFC) and is susceptible to age-related degeneration, suggesting that PFC homotopic connectivity is linked to changes in white-matter integrity. We investigated homotopic connectivity changes and whether these were associated with white-matter integrity in 338 individuals. In addition, we examined whether PFC homotopic FC was related to changes in the genu over 10 years and working memory over 5 years. There were increases and decreases in functional homotopy, with the former being prevalent in subcortical and frontal regions. Increased PFC homotopic FC was partially driven by structural degeneration and negatively associated with working memory, suggesting that it reflects detrimental age-related changes.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.08.008DOI Listing
December 2020

The genetic architecture of human brainstem structures and their involvement in common brain disorders.

Nat Commun 2020 08 11;11(1):4016. Epub 2020 Aug 11.

Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.

Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson's disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.
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http://dx.doi.org/10.1038/s41467-020-17376-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7421944PMC
August 2020
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