Article

Healthy minds 0-100 years: Optimising the use of European brain imaging cohorts (“Lifebrain”)

November 2017
European Psychiatry (in Press)(10)

DOI:10.1016/j.eurpsy.2017.10.005

License
CC BY 4.0

Authors:

Kristine Walhovd

Oslo University Hospital

Lars Nyberg

Umeå University

Show all 47 authorsHide

The main objective of "Lifebrain" is to identify the determinants of brain, cognitive and mental (BCM) health at different stages of life. By integrating, harmonising and enriching major European neuroimaging studies across the life span, we will merge fine-grained BCM health measures of more than 5,000 individuals. Longitudinal brain imaging, genetic and health data are available for a major part, as well as cognitive and mental health measures for the broader cohorts, exceeding 27,000 examinations in total. By linking these data to other databases and biobanks, including birth registries, national and regional archives, and by enriching them with a new online data collection and novel measures, we will address the risk factors and protective factors of BCM health. We will identify pathways through which risk and protective factors work and their moderators. Exploiting existing European infrastructures and initiatives, we hope to make major conceptual, methodological and analytical contributions towards large integrative cohorts and their efficient exploitation. We will thus provide novel information on BCM health maintenance, as well as the onset and course of BCM disorders. This will lay a foundation for earlier diagnosis of brain disorders, aberrant development and decline of BCM health, and translate into future preventive and therapeutic strategies. Aiming to improve clinical practice and public health we will work with stakeholders and health authorities, and thus provide the evidence base for prevention and intervention.

Stakeholder engagement in European brain research: Experiences of the Lifebrain consortium

Article

Full-text available

Mar 2023
HEALTH EXPECT

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.

Individual differences in brain aging: heterogeneity in cortico-hippocampal but not caudate atrophy rates

Article

Full-text available

Oct 2022

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.

Brain aging differs with cognitive ability regardless of education

Preprint

Full-text available

Feb 2022

Higher general cognitive ability (GCA) is associated with lower risk of neurodegenerative disorders, but neural mechanisms are unknown. GCA could be associated with more cortical tissue, from young age, i.e. brain reserve, or less cortical atrophy in adulthood, i.e. brain maintenance. Controlling for education, we investigated the relative association of GCA with reserve and maintenance of cortical volume, -area and -thickness through the adult lifespan, using multiple longitudinal brain imaging cohorts (n = 3327, 7002 MRI scans, baseline age 20-88 years, followed-up up to 11 years). There were widespread positive relationships between GCA and cortical characteristics (level-level associations). In select regions, higher baseline GCA was associated with less atrophy over time (level-change associations). Relationships remained when controlling for polygenic scores for both GCA and education. Our findings suggest that higher GCA is associated with cortical volumes by both brain reserve and -maintenance mechanisms through the adult lifespan.

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

Article

Full-text available

Aug 2021

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.

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

Article

Full-text available

Apr 2021

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.

Are People Ready for Personalized Brain Health? Perspectives of Research Participants in the Lifebrain Consortium

Article

Full-text available

Nov 2019
GERONTOLOGIST

Background and objectives: A healthy brain is central to physical and mental well-being. In this multi-site, qualitative study, we investigated views and attitudes of adult participants in brain research studies on the brain and personalized brain health as well as interest in maintaining a healthy brain. Design and methods: We conducted individual interviews with 44 adult participants in brain research cohorts of the Lifebrain consortium in Spain, Norway, Germany, and the United Kingdom. The interviews were audio recorded, transcribed, and coded using a cross-country codebook. The interview data were analyzed using qualitative content analysis. Results: Most participants did not focus on their own brain health and expressed uncertainty regarding how to maintain it. Those actively focusing on brain health often picked one specific strategy like diet or memory training. The participants were interested in taking brain health tests to learn about their individual risk of developing brain diseases, and were willing to take measures to maintain their brain health if personalized follow-up was provided and the measures had proven impact. The participants were interested in more information on brain health. No differences in responses were identified between age groups, sex, or countries. Discussion and implications: Concise, practical, personalized, and evidence-based information about the brain may promote brain health. Based on our findings, we have launched an ongoing global brain health survey to acquire more extensive, quantitative, and representative data on public perception of personalized brain health.

Genome-wide QTL mapping across three tissues highlights several Alzheimer's and Parkinson's disease loci potentially acting via DNA methylation

Preprint

Full-text available

Dec 2023

DNA methylation (DNAm) is an epigenetic mark with essential roles in disease development and predisposition. Here, we created genome-wide maps of methylation quantitative trait loci (meQTL) in three peripheral tissues and used Mendelian randomization (MR) analyses to assess the potential causal relationships between DNAm and risk for two common neurodegenerative disorders, i.e. Alzheimer's disease (AD) and Parkinson's disease (PD). Genome-wide single nucleotide polymorphism (SNP; ~5.5M sites) and DNAm (~850K CpG sites) data were generated from whole blood (n=1,058), buccal (n=1,527) and saliva (n=837) specimens. We identified between 11 and 15 million genome-wide significant (p<10-14) SNP-CpG associations in each tissue. Combining these meQTL GWAS results with recent AD/PD GWAS summary statistics by MR strongly suggests that the previously described associations between PSMC3, PICALM, and TSPAN14 and AD may be founded on differential DNAm in or near these genes. In addition, there is strong, albeit less unequivocal, support for causal links between DNAm at PRDM7 in AD as well as at KANSL1/MAPT in AD and PD. Our study adds valuable insights on AD/PD pathogenesis by combining two high-resolution "omics" domains, and the meQTL data shared along with this publication will allow like-minded analyses in other diseases.

No phenotypic or genotypic evidence for a link between sleep duration and brain atrophy

Article

Full-text available

Oct 2023
Nat. Hum. Behav.

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.

Brain health assessment. An exploratory review of tools related to its cognitive dimension

Article

Oct 2023

Background Brain health is an evolving concept and relates to physical and mental health, social well-being, productivity, creativity. Brain health has several dimensions (cognitive, motor, functional, social, and emotional), and should be recognized as one top global priorities of health policies. The purpose of this paper is to provide a summary of tools developed for assessing the cognitive dimension of brain health in the out-patient services. Methods A literature search on PubMed was performed (from inception to May 31, 2023). We identified cognitive tests, functional and psychological scales, and focused on screening tools specifically proposed to characterize cognition within the construct of brain health, comparing them with common global screening tests. Results Among 1947 records, we identified 17 cognitive screening tools used in the context of brain health assessment, of which four were ad hoc developed: Brain Health Assessment (BHA), Brain Health Test (BHT), Brain Health Test-7 (BHT-7), and The Cogniciti Brain Health Assessment. The four tests have administration time ranging from 4 to 30 min, and different administration methods (paper-and-pencil or tablet-based). All four tools assess memory and other cognitive domains. Specific cut-offs have been identified for BHT and BHT-7, while the other tools have automated scoring systems. All but one test also assess other dimensions. Compared to commonly used cognitive screening tests, the brain health tools are less widely used, translated, and validated. Conclusions The concept of brain health is new and requires further validation of tools for its assessment, especially for the cognition dimension.

Public perceptions of brain health: an international, online cross-sectional survey

Article

Full-text available

Apr 2022

Objectives To investigate public perspectives on brain health. Design Cross-sectional multilanguage online survey. Setting Lifebrain posted the survey on its website and social media and shared it with stakeholders. The survey was open from 4 June 2019 to 31 August 2020. Participants n=27 590 aged ≥18 years from 81 countries in five continents completed the survey. The respondents were predominantly women (71%), middle aged (41–60 years; 37%) or above (>60 years; 46%), highly educated (69%) and resided in Europe (98%). Main outcome measures Respondents’ views were assessed regarding factors that may influence brain health, life periods considered important to look after the brain and diseases and disorders associated with the brain. We run exploratory linear models at a 99% level of significance to assess correlates of the outcome variables, adjusting for likely confounders in a targeted fashion. Results Of all significant effects, the respondents recognised the impact of lifestyle factors on brain health but had relatively less awareness of the role socioeconomic factors might play. Most respondents rated all life periods as important for the brain (95%–96%), although the prenatal period was ranked significantly lower (84%). Equally, women and highly educated respondents more often rated factors and life periods to be important for brain health. Ninety-nine per cent of respondents associated Alzheimer’s disease and dementia with the brain. The respondents made a connection between mental health and the brain, and mental disorders such as schizophrenia and depression were significantly more often considered to be associated with the brain than neurological disorders such as stroke and Parkinson’s disease. Few respondents (<32%) associated cancer, hypertension, diabetes and arthritis with the brain. Conclusions Differences in perceptions of brain health were noted among specific segments of the population. Policies providing information about brain-friendly health behaviours and targeting people less likely to have relevant experience may be needed.

Chinese Color Nest Project : An accelerated longitudinal brain-mind cohort

Article

Full-text available

Dec 2021

The ongoing Chinese Color Nest Project (CCNP) was established to create normative charts for brain structure and function across the human lifespan, and link age-related changes in brain imaging measures to psychological assessments of behavior, cognition, and emotion using an accelerated longitudinal design. In the initial stage, CCNP aims to recruit 1520 healthy individuals (6–90 years), which comprises three phases: developing (devCCNP: 6–18 years, N = 480), maturing (matCCNP: 20–60 years, N = 560) and aging (ageCCNP: 60–84 years, N = 480). In this paper, we present an overview of the devCCNP, including study design, participants, data collection and preliminary findings. The devCCNP has acquired data with three repeated measurements from 2013 to 2017 in Southwest University, Chongqing, China (CCNP-SWU, N = 201). It has been accumulating baseline data since July 2018 and the second wave data since September 2020 in Chinese Academy of Sciences, Beijing, China (CCNP-CAS, N = 168). Each participant in devCCNP was followed up for 2.5 years at 1.25-year intervals. The devCCNP obtained longitudinal neuroimaging, biophysical, social, behavioral and cognitive data via MRI, parent- and self-reported questionnaires, behavioral assessments, and computer tasks. Additionally, data were collected on children’s learning, daily life and emotional states during the COVID-19 pandemic in 2020. We address data harmonization across the two sites and demonstrated its promise of characterizing the growth curves for the overall brain morphometry using multi-center longitudinal data. CCNP data will be shared via the National Science Data Bank and requests for further information on collaboration and data sharing are encouraged.

Cohort profile: follow-up of a Berlin Aging Study II (BASE-II) subsample as part of the GendAge study

Article

Full-text available

Jun 2021

Purpose The study ‘Sex- and gender-sensitive prevention of cardiovascular and metabolic disease in older adults in Germany’, the GendAge study, focuses on major risk factors for cardiovascular and metabolic diseases and on the development of major outcomes from intermediate phenotypes in the context of sex and gender differences. It is based on a follow-up examination of a subsample (older group) of the Berlin Aging Study II (BASE-II). Participants The GendAge study assessments took place between 22 June 2018 and 10 March 2020. A total of 1100 participants (older BASE-II subsample, aged ≥65 years) with baseline data assessed at least by one of the BASE-II partner sites were investigated in the follow-up. These participants had a mean age of 75.6 years (SD ±3.8), with a mean follow-up at 7.4 years (SD ±1.5). Findings to date Data from different domains such as internal medicine, geriatrics, immunology and psychology were collected, with a focus on cardiometabolic diseases and in the context of sex and gender differences. Diabetes mellitus type 2 was reported by 15.6% and 8.6% of men and women, respectively. In contrast, this disease was diagnosed in 20.7% of men and 13.3% of women, indicating that a substantial proportion of almost 30% was unaware of the disease. Echocardiography revealed that left ventricular ejection fraction was higher in women than in men, in agreement with previous reports. Future plans A gender questionnaire assessing sociocultural aspects implemented as part of the follow-up described here will allow to calculate a gender score and its evaluation based on the newly collected data. At the same time, the other BASE-II research foci established over the past 10 years will be continued and strengthened by the BASE-II transition into a longitudinal study with follow-up data on the older subsample. Trial registration number DRKS00016157.

Longitudinal Developmental Trajectories Do Not Follow Cross-Sectional Age Associations in Hippocampal Subfield and Memory Development

Preprint

Full-text available

Jun 2021

Many cross-sectional findings suggest that volumes of specific hippocampal subfields increase in middle childhood and early adolescence. In contrast, a small number of available longitudinal studies observed decreased volumes in most subfields over this age range. Further, it remains unknown whether structural changes in development are associated with corresponding gains in children’s memory. Here we report cross-sectional age differences in children’s hippocampal subfield volumes together with longitudinal developmental trajectories and their relationships with memory performance. In two waves, 109 healthy participants aged 6 to 10 years (wave 1: M Age =7.25, wave 2: M Age =9.27) underwent high-resolution magnetic resonance imaging to assess hippocampal subfield volumes, and completed cognitive tasks assessing hippocampus dependent memory processes. We found that cross-sectional age-associations and longitudinal developmental trends in hippocampal subfield volumes were highly discrepant, both by subfields and in direction. Further, volumetric changes were largely unrelated to changes in memory, with the exception that increase in subiculum volume was associated with gains in spatial memory. Importantly, the observed longitudinal patterns of brain-cognition coupling could not be inferred from cross-sectional findings. We discuss potential sources of these discrepancies. This study underscores that children’s structural brain development and its relationship to cognition cannot be inferred from cross-sectional age comparisons. Highlights The subiculum undergoes volumetric increase between 6-10 years of age Change across two years in CA1-2 and DG-CA3 was not observed in this age window Change across two years did not reflect age differences spanning two years Cross-sectional and longitudinal slopes in stark contrast for hippocampal subfields Longitudinal brain-cognition coupling cannot be inferred from cross-sectional data

Educational attainment does not influence brain aging

Article

Full-text available

May 2021
P NATL ACAD SCI USA

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.

Constructing and optimizing 3D atlases from 2D data with application to the developing mouse brain

Article

Full-text available

Feb 2021
eLife

3D imaging data necessitate 3D reference atlases for accurate quantitative interpretation. Existing computational methods to generate 3D atlases from 2D-derived atlases result in extensive artifacts, while manual curation approaches are labor-intensive. We present a computational approach for 3D atlas construction that substantially reduces artifacts by identifying anatomical boundaries in the underlying imaging data and using these to guide 3D transformation. Anatomical boundaries also allow extension of atlases to complete edge regions. Applying these methods to the eight developmental stages in the Allen Developing Mouse Brain Atlas (ADMBA) led to more comprehensive and accurate atlases. We generated imaging data from fifteen whole mouse brains to validate atlas performance and observed qualitative and quantitative improvement (37% greater alignment between atlas and anatomical boundaries). We provide the pipeline as the MagellanMapper software and the eight 3D reconstructed ADMBA atlases. These resources facilitate whole-organ quantitative analysis between samples and across development.

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

Article

Full-text available

Feb 2021

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.

A recipe for accurate estimation of lifespan brain trajectories, distinguishing longitudinal and cohort effects

Article

Full-text available

Feb 2021

We address the problem of estimating how different parts of the brain develop and change throughout the lifespan, and how these trajectories are affected by genetic and environmental factors. Estimation of these lifespan trajectories is statistically challenging, since their shapes are typically highly nonlinear, and although true change can only be quantified by longitudinal examinations, as follow-up intervals in neuroimaging studies typically cover less than 10% of the lifespan, use of cross-sectional information is necessary. Linear mixed models (LMMs) and structural equation models (SEMs) commonly used in longitudinal analysis rely on assumptions which are typically not met with lifespan data, in particular when the data consist of observations combined from multiple studies. While LMMs require a priori specification of a polynomial functional form, SEMs do not easily handle data with unstructured time intervals between measurements. Generalized additive mixed models (GAMMs) offer an attractive alternative, and in this paper we propose various ways of formulating GAMMs for estimation of lifespan trajectories of 12 brain regions, using a large longitudinal dataset and realistic simulation experiments. We show that GAMMs are able to more accurately fit lifespan trajectories, distinguish longitudinal and cross-sectional effects, and estimate effects of genetic and environmental exposures. Finally, we discuss and contrast questions related to lifespan research which strictly require repeated measures data and questions which can be answered with a single measurement per participant, and in the latter case, which simplifying assumptions that need to be made. The examples are accompanied with R code, providing a tutorial for researchers interested in using GAMMs.

The Functional Foundations of Episodic Memory Remain Stable Throughout the Lifespan

Article

Full-text available

Nov 2020

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.

Effect of apolipoprotein E polymorphism on cognition and brain in the Cambridge Centre for Ageing and Neuroscience cohort

Article

Full-text available

Oct 2020

Polymorphisms in the apolipoprotein E (APOE) gene have been associated with individual differences in cognition, brain structure and brain function. For example, the ε4 allele has been associated with cognitive and brain impairment in old age and increased risk of dementia, while the ε2 allele has been claimed to be neuroprotective. According to the ‘antagonistic pleiotropy’ hypothesis, these polymorphisms have different effects across the lifespan, with ε4, for example, postulated to confer benefits on cognitive and brain functions earlier in life. In this stage 2 of the Registered Report – https://osf.io/bufc4 , we report the results from the cognitive and brain measures in the Cambridge Centre for Ageing and Neuroscience cohort ( www.cam-can.org ). We investigated the antagonistic pleiotropy hypothesis by testing for allele-by-age interactions in approximately 600 people across the adult lifespan (18–88 years), on six outcome variables related to cognition, brain structure and brain function (namely, fluid intelligence, verbal memory, hippocampal grey-matter volume, mean diffusion within white matter and resting-state connectivity measured by both functional magnetic resonance imaging and magnetoencephalography). We found no evidence to support the antagonistic pleiotropy hypothesis. Indeed, Bayes factors supported the null hypothesis in all cases, except for the (linear) interaction between age and possession of the ε4 allele on fluid intelligence, for which the evidence for faster decline in older ages was ambiguous. Overall, these pre-registered analyses question the antagonistic pleiotropy of APOE polymorphisms, at least in healthy adults.

Meta-analysis of generalized additive models in neuroimaging studies

Article

Full-text available

Oct 2020
NEUROIMAGE

Analyzing data from multiple neuroimaging studies has great potential in terms of increasing statistical power, enabling detection of effects of smaller magnitude than would be possible when analyzing each study separately and also allowing to systematically investigate between-study differences. Restrictions due to privacy or proprietary data as well as more practical concerns can make it hard to share neuroimaging datasets, such that analyzing all data in a common location might be impractical or impossible. Meta-analytic methods provide a way to overcome this issue, by combining aggregated quantities like model parameters or risk ratios. Most meta-analytic tools focus on parametric statistical models, and methods for meta-analyzing semi-parametric models like generalized additive models have not been well developed. Parametric models are often not appropriate in neuroimaging, where for instance age-brain relationships may take forms that are difficult to accurately describe using such models. In this paper we introduce meta-GAM, a method for meta-analysis of generalized additive models which does not require individual participant data, and hence is suitable for increasing statistical power while upholding privacy and other regulatory concerns. We extend previous works by enabling the analysis of multiple model terms as well as multivariate smooth functions. In addition, we show how meta-analytic p-values can be computed for smooth terms. The proposed methods are shown to perform well in simulation experiments, and are demonstrated in a real data analysis on hippocampal volume and self-reported sleep quality data from the Lifebrain consortium. We argue that application of meta-GAM is especially beneficial in lifespan neuroscience and imaging genetics. The methods are implemented in an accompanying R package metagam, which is also demonstrated.

The Global Brain Health Survey: Development of a Multi-Language Survey of Public Views on Brain Health

Article

Full-text available

Aug 2020

Background: Brain health is a multi-faceted concept used to describe brain physiology, cognitive function, mental health and well-being. Diseases of the brain account for one third of the global burden of disease and are becoming more prevalent as populations age. Diet, social interaction as well as physical and cognitive activity are lifestyle factors that can potentially influence facets of brain health. Yet, there is limited knowledge about the population's awareness of brain health and willingness to change lifestyle to maintain a healthy brain. This paper introduces the Global Brain Health Survey protocol, designed to assess people's perceptions of brain health and factors influencing brain health. Methods: The Global Brain Health Survey is an anonymous online questionnaire available in 14 languages to anyone above the age of 18 years. Questions focus on (1) willingness and motivation to maintain or improve brain health, (2) interest in learning more about individual brain health using standardized tests, and (3) interest in receiving individualized support to take care of own brain health. The survey questions were developed based on results from a qualitative interview study investigating brain health perceptions among participants in brain research studies. The survey includes 28 questions and takes 15–20 min to complete. Participants provide electronically informed consent prior to participation. The current survey wave was launched on June 4, 2019 and will close on August 31, 2020. We will provide descriptive statistics of samples distributions including analyses of differences as a function of age, gender, education, country of residence, and we will examine associations between items. The European Union funded Lifebrain project leads the survey in collaboration with national brain councils in Norway, Germany, and Belgium, Brain Foundations in the Netherlands and Sweden, the National University of Ostroh Academy and the Women's Brain Project. Discussion: Results from this survey will provide new insights in peoples' views on brain health, in particular, the extent to which the adoption of positive behaviors can be encouraged. The results will contribute to the development of policy recommendations for supporting population brain health, including measures tailored to individual needs, knowledge, motivations and life situations.

SEM-Tree hybrid models in the preferences analysis of the members of Polish households

Article

Full-text available

Aug 2020

The purpose of the paper is to identify the dimensions of the strategy of resources allocation of Polish households members and test the hypothesis concerning risky shift effect in the relationship between strategy of family decision making and trade-off in family scarce resources allocation. These dimensions were identified on the basis of nationwide empirical data gathered on a representative sample of 1020 respondents nested in 410 households. SEM-Tree hybrid models are used in the analysis of the results, which combine the confirmatory structural equation models with exploratory and predictive classification and regression trees. This allows to apply structural modeling for the study of heterogeneous populations and to assess the hierarchical impact of exogenous predictors on the identification of segments with separate and unique model structural parameters. The approach combines the advantages of a model approach (at the stage of constructing hypotheses on structural relationships and specifications of measurement models) and exploration-based data (at the stage of recursive division of the sample).

A Recipe for Accurate Estimation of Lifespan Brain Trajectories, Distinguishing Longitudinal and Cohort Effects

Preprint

Jul 2020

We address the problem of estimating how different parts of the brain develop and change throughout the lifespan, and how these trajectories are affected by genetic and environmental factors. Estimation of these lifespan trajectories is statistically challenging, since their shapes are typically highly nonlinear, and although true change can only be quantified by longitudinal examinations, as follow-up intervals in neuroimaging studies typically cover less than 10 % of the lifespan, use of cross-sectional information is necessary. Linear mixed models (LMMs) and structural equation models (SEMs) commonly used in longitudinal analysis rely on assumptions which are typically not met with lifespan data, in particular when the data consist of observations combined from multiple studies. Generalized additive mixed models (GAMMs) offer an attractive alternative to LMMs and SEMs. In this paper, we propose various ways of formulating GAMMs for accurate estimation of lifespan trajectories of 12 brain regions, using a large longitudinal dataset and realistic simulation experiments. We show that GAMMs are able to accurately fit lifespan trajectories, distinguish longitudinal and cross-sectional effects, and estimate effects of genetic and environmental exposures. Finally, we discuss and contrast questions related to lifespan research which strictly require longitudinal data and questions which can be answered with purely cross-sectional data, and in the latter case, which simplifying assumptions that need to be made. The examples are accompanied with R code, providing a tutorial for researchers interested in using GAMMs.

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

Preprint

Full-text available

Jun 2020

Normal aging and Alzheimer’s Disease (AD) are accompanied by large-scale alterations in brain organization that undermine brain function. Although hemispheric asymmetry is a global organizing feature of cortex thought to promote brain efficiency, current descriptions of cortical thinning in aging and AD have largely overlooked cortical asymmetry. Consequently, the foundational question of whether and where the cerebral hemispheres change at different rates in aging and AD remains open. First, applying vertex-wise data-driven clustering in a longitudinal discovery sample (aged 20-89; 2577 observations; 1851 longitudinal) we identified cortical regions exhibiting similar age-trajectories of asymmetry across the adult lifespan. Next, we sought replication in 4 independent longitudinal aging cohorts. We show that higher-order regions of cortex that exhibit pronounced asymmetry at age ~20 also show asymmetry change in aging. Results revealed that both leftward and rightward asymmetry is progressively lost on a similar time-scale across adult life. Hence, faster thinning of the (previously) thicker homotopic hemisphere is a feature of aging. This simple organizational principle showed high consistency across multiple aging cohorts in the Lifebrain consortium, and both the topological patterns and temporal dynamics of asymmetry-loss were markedly similar across replicating samples. Finally, we show that regions exhibiting gradual asymmetry-loss over healthy adult life exhibit faster asymmetry-change in AD. Overall, our results suggest a system-wide breakdown in the adaptive asymmetric organization of cortex across adult life which is further accelerated in AD, and may implicate thickness asymmetry as a viable marker for declining hemispheric specialization in aging and AD. Significance The brain becomes progressively disorganized with age, and brain alterations accelerated in Alzheimer’s disease may occur gradually over the lifespan. Although hemispheric asymmetry aids efficient network organization, efforts to identify structural markers of age-related decline have largely overlooked cortical asymmetry. Here we show the hemisphere that is thicker when younger, thins faster. This leads to progressive system-wide loss of regional thickness asymmetry across life. In multiple aging cohorts, asymmetry-loss showed high reproducibility topologically across cortex and similar timing-of-change in aging. Asymmetry-change was further accelerated in AD. Our findings uncover a new principle of brain aging – thicker homotopic cortex thins faster – and suggest we may have unveiled a structural marker for a widely-hypothesized decline in hemispheric specialization in aging and AD.

Sleep Efficiency Relates to Hippocampal Integrity Decline in β-Amyloid Positive Adults

Preprint

Full-text available

Apr 2020

Objective: To test the hypothesis that worse self-reported sleep relates to reduced hippocampal integrity as indexed by increased intra-hippocampal water diffusion, and that this relationship is stronger in the presence of β-amyloid (Aβ) accumulation, a marker of Alzheimer's disease (AD) pathology. Methods: Two-hundred and fifty-one participants, aged 19-81 years, completed the Pittsburgh Sleep Quality Index, and 2 diffusion tensor imaging sessions, on average 3 years apart, allowing estimates of decline in hippocampal microstructural integrity as indexed by increased mean diffusivity (MD). We used the delayed recall from the California Verbal Learning Test to measure memory change. 18F-Flutemetamol PET, in 108 participants above 44 years of age, yielded 23 Aβ positive cases. 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, this relationship was stronger in presence of cortical Aβ accumulation. Sleep efficiency also related to memory decline 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, and poor self-reported sleep efficiency might constitute a risk factor for AD, although the causal mechanisms driving the of observed associations are unknown.

Meta-Analysis of Generalized Additive Models in Neuroimaging Studies

Preprint

Feb 2020

The functional foundations of episodic memory remain stable throughout the lifespan

Preprint

Full-text available

Jan 2020

It is suggested that the functional mechanisms behind specific forms of cognition, particularly episodic memory, may be dynamic over the lifespan and that cognitive preservation or decay in older age thus relies on age-specific mechanisms such as compensatory processes. Here instead, we tested whether the functional foundations of successful episodic memory encoding adhere to a principle of lifespan continuity, shaped by developmental, structural and evolutionary influences. We identified the generic lifespan patterns of memory encoding function across the brain (n = 540; age range = 6 – 82 years). The lifespan trajectories of brain activity were organized in a topologically meaningful manner and aligned to fundamental aspects of brain organization, such as large-scale connectivity hierarchies and evolutionary cortical expansion gradients. None of the normative trajectories of encoding function was solely determined by late-life patterns of activity, but rather showed continuities across development and adulthood. Inter-individual differences in activity in age-sensitive regions were predicted by general cognitive abilities and variation in grey matter structure, which are core variables of cognitive and structural change throughout the lifespan. Altogether, the results provide evidence for the lifelong continuity of the functional foundations of episodic memory which are bounded by both brain architecture and core mechanisms of cognitive and structural change over life. 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. Significance statement It is suggested that cognitive function in older age largely relies on late-life specific mechanisms such as compensatory processes. In contrast, here we tested whether and to what degree brain activity during episodic memory encoding adheres to fundamental principles of life-long brain organization and continuity. The results revealed that generic lifespan trajectories of memory encoding function were not specific to late-life. Instead, the age-trajectories showed a continuity through life, were related to fundamental features of brain structure and cognition and to functional and evolutionary hierarchies. We argue that rather than focusing on older-age specific mechanisms, a framework that takes lifespan mechanisms of cognition and brain anatomy into account is necessary to understand episodic memory vulnerability in older age.

Self-reported sleep relates to hippocampal atrophy across the adult lifespan – results from the Lifebrain consortium

Article

Full-text available

Nov 2019

Objectives Poor sleep is associated with multiple age-related neurodegenerative and neuropsychiatric conditions. The hippocampus plays a special role in sleep and sleep-dependent cognition, and accelerated hippocampal atrophy is typically seen with higher age. Hence, it is critical to establish how the relationship between sleep and hippocampal volume loss unfolds across the adult lifespan. Methods Self-reported sleep measures and MRI-derived hippocampal volumes were obtained from 3105 cognitively normal participants (18-90 years) from major European brain studies in the Lifebrain consortium. Hippocampal volume change was estimated from 5116 MRIs from 1299 participants for whom longitudinal MRIs were available, followed up to 11 years with a mean interval of 3.3 years. Cross-sectional analyses were repeated in a sample of 21390 participants from the UK Biobank. Results No cross-sectional sleep – hippocampal volume relationships were found. However, worse sleep quality, efficiency, problems, and daytime tiredness were related to greater hippocampal volume loss over time, with high scorers showing 0.22% greater annual loss than low scorers. The relationship between sleep and hippocampal atrophy did not vary across age. Simulations showed that the observed longitudinal effects were too small to be detected as age-interactions in the cross-sectional analyses. Conclusions Worse self-reported sleep is associated with higher rates of hippocampal volume decline across the adult lifespan. This suggests that sleep is relevant to understand individual differences in hippocampal atrophy, but limited effect sizes call for cautious interpretation.

Cohort Harmonization and Integrative Analysis From a Biomedical Engineering Perspective

Article

Jul 2018

In this review the critical parts and milestones for data harmonization, from the biomedical engineering perspective, are outlined. The need for data sharing between heterogeneous sources pave the way for cohort harmonization; thus, fostering data integration and interdisciplinary research. Unmet needs in chronic as well as in other diseases, can be addressed based on the integration of patient health records and the sharing of information of the clinical picture and outcome. The stratification of patients, the determination of various clinical and outcome features and the identification of novel biomarkers for the different phenotypes of the disease characterize the impact of cohort harmonization in patient-centered clinical research and in precision medicine. Subsequently, the establishment of matching techniques and ontologies for the creation of data schemas are also presented. The exploitation of web technologies and data-collection tools support the opportunities to achieve new levels of integration and interoperability. Ethical and legal issues which arise when sharing and harmonizing individual-level data are discussed in order to evaluate the harmonization potential. Use cases that shape and test the harmonization approach are explicitly analyzed along with their significant results on their research objectives. Finally, future trends and directions are discussed and critically reviewed towards a roadmap in cohort harmonization for clinical medicine.

No moderating influence of education on the association between changes in hippocampus volume and memory performance in aging

Article

Full-text available

Jun 2023

Contemporary accounts of factors that may modify the risk for age-related neurocognitive disorders highlight education and its contribution to a cognitive reserve. By this view, individuals with higher educational attainment should show weaker associations between changes in brain and cognition than individuals with lower educational attainment. We tested this prediction in longitudinal data on hippocampus volume and episodic memory from 708 middle-aged and older individuals using local structural equation modeling. This technique does not require categorization of years of education and does not constrain the shape of relationships, thereby maximizing the chances of revealing an effect of education on the hippocampus-memory association. The results showed that the data were plausible under the assumption that there was no influence of education on the association between change in episodic memory and change in hippocampus volume. Restricting the sample to individuals with elevated genetic risk for dementia (APOE ε4 carriers) did not change these results. We conclude that the influence of education on changes in episodic memory and hippocampus volume is inconsistent with predictions by the cognitive reserve theory.

Is short sleep bad for the brain? Brain structure and cognitive function in short sleepers

Preprint

Full-text available

Dec 2022

Many sleep less than recommended without experiencing daytime tiredness. 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 question using a combined cross-sectional and longitudinal sample of 47,029 participants (age 20-89 years) with measures of self-reported sleep, including 51,295 MRIs of the brain and cognitive tests. 701 participants who reported to sleep < 6 hours did not experience daytime tiredness or sleep problems. These short sleepers showed significantly larger regional brain volumes than both short sleepers with daytime tiredness and sleep problems (n = 1619) and participants sleeping the recommended 7-8 hours (n = 3754). However, both groups of short sleepers showed slightly lower general cognitive function, 0.16 and 0.19 standard deviations, respectively. Analyses using acelerometer-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 consequences for brain morphometry, in line with a view on sleep need as individualized. Tiredness and sleep problems seem to be more relevant for brain structural differences than sleep duration per se. However, the slightly lower performance on tests of general cognitive function warrants closer examination by experimental designs in natural settings. Significance statement Short habitual sleep is prevalent, with unknown consequences for brain health and cognitive performance. Here we show that daytime tiredness and sleep problems are more important variables for regional brain volumes than sleep duration. However, participants sleeping < 6 hours had slightly lower scores on tests of general cognitive function. This indicates that sleep need is individual, and that sleep duration per se may be a less relevant variable for brain health than daytime tiredness and sleep problems. The association between habitual short sleep and lower scores on tests of general cogntitive function must be further scrutinized in natural settings.

Using large, publicly available datasets to study adolescent development: Opportunities and challenges

Article

Full-text available

Oct 2021

Adolescence is a period of rapid change, with cognitive, mental wellbeing, environmental biological factors interacting to shape lifelong outcomes. Large, longitudinal phenotypically rich datasets available for reuse (secondary data) have revolutionized the way we study adolescence, allowing the field to examine these unfolding processes across hundreds or even thousands of individuals. Here, we outline the opportunities and challenges associated with such secondary datasets, provide an overview of particularly valuable resources available to the field, and recommend best practices to improve the rigour and transparency of analyses conducted on large, secondary datasets.

Longitudinal association between hippocampus atrophy and episodic‐memory decline in non‐demented APOE ε4 carriers

Article

Full-text available

Sep 2020

Introduction: The apolipoprotein E (APOE) 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 Lifebrain consortium. Results: The change-change association for hippocampal volume and memory was significant only in ε4 carriers (N = 173, r = 0.21, P = .007; non-carriers: N = 467, r = 0.073, P = .117). The linear relationship was significantly steeper for the carriers [t(629) = 2.4, P = .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.

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

Article

Full-text available

Nov 2020

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 aging by affecting the Journal Pre-proof 3 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 aging. 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 aging.

Delirium

Chapter

Jul 2019

A concise and up-to-date text on the mental health of older people, this second edition is fully updated to reflect changes in technology, competency-based training, guidelines, law and treatments. Each chapter sits alone as an informative, readable and helpful resource for a range of health care professionals. Together the chapters form an essential text that contributes to the rising standards in old age psychiatry. With practical guidelines on clinical management, this edition also includes new sections on topics such as palliative care and migrant health, all written by a global authorship, considering international perspectives. Targeted at qualified and trainee consultant psychiatrists, this text is also useful to other doctors, medical students and healthcare professionals who work with older people.

Seminars in Old Age PsychiatrySend content to

Article

Jun 2019

Imaging

Chapter

Jul 2019

Generalizing age effects on brain structure and cognition: A two‐study comparison approach

Article

Full-text available

Jan 2019
HUM BRAIN MAPP

Normal aging is accompanied by an interindividually variable decline in cognitive abilities and brain structure. This variability, in combination with methodical differences and differences in sample characteristics across studies, pose a major challenge for generalizability of results from different studies. Therefore, the current study aimed at cross‐validating age‐related differences in cognitive abilities and brain structure (measured using cortical thickness [CT]) in two large independent samples, each consisting of 228 healthy older adults aged between 65 and 85 years: the Longitudinal Healthy Aging Brain (LHAB) database (University of Zurich, Switzerland) and the 1000BRAINS (Research Centre Jülich, Germany). Participants from LHAB showed significantly higher education, physical well‐being, and cognitive abilities (processing speed, concept shifting, reasoning, semantic verbal fluency, and vocabulary). In contrast, CT values were larger for participants of 1000BRAINS. Though, both samples showed highly similar age‐related differences in both, cognitive abilities and CT. These effects were in accordance with functional aging theories, for example, posterior to anterior shift in aging as was shown for the default mode network. Thus, the current two‐study approach provides evidence that independently on heterogeneous metrics of brain structure or cognition across studies, age‐related effects on cognitive ability and brain structure can be generalized over different samples, assuming the same methodology is used.

Successful Memory Aging

Article

Jan 2019

For more than 50 years, psychologists, gerontologists, and, more recently, neuroscientists have considered the possibility of successful aging. How to define successful aging remains debated, but well-preserved age-sensitive cognitive functions, like episodic memory, is an often-suggested criterion. Evidence for successful memory aging comes from cross-sectional and longitudinal studies showing that some older individuals display high and stable levels of performance. Successful memory aging may be accomplished via multiple paths. One path is through brain maintenance, or relative lack of age-related brain pathology. Through another path, successful memory aging can be accomplished despite brain pathology by means of efficient compensatory and strategic processes. Genetic, epigenetic, and lifestyle factors influence memory aging via both paths. Some of these factors can be promoted throughout the life course, which, at the individual as well as the societal level, can positively impact successful memory aging. Expected final online publication date for the Annual Review of Psychology Volume 70 is January 4, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Associations between self‐reported sleep quality and white matter in community‐dwelling older adults: A prospective cohort study

Article

Full-text available

Jul 2017
HUM BRAIN MAPP

Both sleep disturbances and decline in white matter microstructure are commonly observed in ageing populations, as well as in age-related psychiatric and neurological illnesses. A relationship between sleep and white matter microstructure may underlie such relationships, but few imaging studies have directly examined this hypothesis. In a study of 448 community-dwelling members of the Whitehall II Imaging Sub-Study aged between 60 and 82 years (90 female, mean age 69.2 ± 5.1 years), we used the magnetic resonance imaging technique diffusion tensor imaging to examine the relationship between self-reported sleep quality and white matter microstructure. Poor sleep quality at the time of the diffusion tensor imaging scan was associated with reduced global fractional anisotropy and increased global axial diffusivity and radial diffusivity values, with small effect sizes. Voxel-wise analysis showed that widespread frontal-subcortical tracts, encompassing regions previously reported as altered in insomnia, were affected. Radial diffusivity findings remained significant after additional correction for demographics, general cognition, health, and lifestyle measures. No significant differences in general cognitive function, executive function, memory, or processing speed were detected between good and poor sleep quality groups. The number of times participants reported poor sleep quality over five time-points spanning a 16-year period was not associated with white matter measures. In conclusion, these data demonstrate that current sleep quality is linked to white matter microstructure. Small effect sizes may limit the extent to which poor sleep is a promising modifiable factor that may maintain, or even improve, white matter microstructure in ageing. Hum Brain Mapp, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Physical activity, cognitive decline, and risk of dementia: 28 year follow-up of Whitehall II cohort study

Article

Full-text available

Jun 2017

Objective To test the hypotheses that physical activity in midlife is not associated with a reduced risk of dementia and that the preclinical phase of dementia is characterised by a decline in physical activity. Design Prospective cohort study with a mean follow-up of 27 years. Setting Civil service departments in London (Whitehall II study). Participants 10 308 participants aged 35-55 years at study inception (1985-88). Exposures included time spent in mild, moderate to vigorous, and total physical activity assessed seven times between 1985 and 2013 and categorised as “recommended” if duration of moderate to vigorous physical activity was 2.5 hours/week or more. Main outcome measures A battery of cognitive tests was administered up to four times from 1997 to 2013, and incident dementia cases (n=329) were identified through linkage to hospital, mental health services, and mortality registers until 2015. Results Mixed effects models showed no association between physical activity and subsequent 15 year cognitive decline. Similarly, Cox regression showed no association between physical activity and risk of dementia over an average 27 year follow-up (hazard ratio in the “recommended” physical activity category 1.00, 95% confidence interval 0.80 to 1.24). For trajectories of hours/week of total, mild, and moderate to vigorous physical activity in people with dementia compared with those without dementia (all others), no differences were observed between 28 and 10 years before diagnosis of dementia. However, physical activity in people with dementia began to decline up to nine years before diagnosis (difference in moderate to vigorous physical activity −0.39 hours/week; P=0.05), and the difference became more pronounced (−1.03 hours/week; P=0.005) at diagnosis. Conclusion This study found no evidence of a neuroprotective effect of physical activity. Previous findings showing a lower risk of dementia in physically active people may be attributable to reverse causation—that is, due to a decline in physical activity levels in the preclinical phase of dementia.

Symptoms of depression in a large healthy population cohort are related to subjective memory complaints and memory performance in negative contexts

Article

Full-text available

Jun 2017

Background Decades of research have investigated the impact of clinical depression on memory, which has revealed biases and in some cases impairments. However, little is understood about the effects of subclinical symptoms of depression on memory performance in the general population. Methods Here we report the effects of symptoms of depression on memory problems in a large population-derived cohort ( N = 2544), 87% of whom reported at least one symptom of depression. Specifically, we investigate the impact of depressive symptoms on subjective memory complaints, objective memory performance on a standard neuropsychological task and, in a subsample ( n = 288), objective memory in affective contexts. Results There was a dissociation between subjective and objective memory performance, with depressive symptoms showing a robust relationship with self-reports of memory complaints, even after adjusting for age, sex, general cognitive ability and symptoms of anxiety, but not with performance on the standardised measure of verbal memory. Contrary to our expectations, hippocampal volume (assessed in a subsample, n = 592) did not account for significant variance in subjective memory, objective memory or depressive symptoms. Nonetheless, depressive symptoms were related to poorer memory for pictures presented in negative contexts, even after adjusting for memory for pictures in neutral contexts. Conclusions Thus the symptoms of depression, associated with subjective memory complaints, appear better assessed by memory performance in affective contexts, rather than standardised memory measures. We discuss the implications of these findings for understanding the impact of depressive symptoms on memory functioning in the general population.

Theory-Guided Exploration With Structural Equation Model Forests

Article

Full-text available

Dec 2016

Structural equation model (SEM) trees, a combination of SEMs and decision trees, have been proposed as a data-analytic tool for theory-guided exploration of empirical data. With respect to a hypothesized model of multivariate outcomes, such trees recursively find subgroups with similar patterns of observed data. SEM trees allow for the automatic selection of variables that predict differences across individuals in specific theoretical models, for instance, differences in latent factor profiles or developmental trajectories. However, SEM trees are unstable when small variations in the data can result in different trees. As a remedy, SEM forests, which are ensembles of SEM trees based on resamplings of the original dataset, provide increased stability. Because large forests are less suitable for visual inspection and interpretation, aggregate measures provide researchers with hints on how to improve their models: (a) variable importance is based on random permutations of the out-of-bag (OOB) samples of the individual trees and quantifies, for each variable, the average reduction of uncertainty about the model-predicted distribution; and (b) case proximity enables researchers to perform clustering and outlier detection. We provide an overview of SEM forests and illustrate their utility in the context of cross-sectional factor models of intelligence and episodic memory. We discuss benefits and limitations, and provide advice on how and when to use SEM trees and forests in future research.

How Common are WM Deficits in Children with Difficulties in Reading and Mathematics?

Article

Full-text available

Sep 2016

The extent to which deficits in working memory (WM) are characteristic of children with reading and mathematics difficulties was investigated in a large sample aged 5–15 years reported to have problems in attention, learning and memory. WM performance was highly correlated with reading and mathematics scores. Although deficits in individual tests of short-term memory (STM) and WM occurred in less than half of the children with detected learning difficulties, three-quarters of the children with low reading and mathematics scores obtained one or more WM scores in the deficit range. These findings are consistent with proposals that WM or the broader cognitive dimensions it taps impede school-based learning, and point to the importance of managing WM loads in the classroom.

Effect of intellectual enrichment on AD biomarker trajectories: Longitudinal imaging study

Article

Full-text available

Feb 2016

Objective: To investigate the effect of age, sex, APOE4 genotype, and lifestyle enrichment (education/occupation, midlife cognitive activity, and midlife physical activity) on Alzheimer disease (AD) biomarker trajectories using longitudinal imaging data (brain β-amyloid load via Pittsburgh compound B PET and neurodegeneration via (18)fluorodeoxyglucose (FDG) PET and structural MRI) in an elderly population without dementia. Methods: In the population-based longitudinal Mayo Clinic Study of Aging, we studied 393 participants without dementia (340 clinically normal, 53 mild cognitive impairment; 70 years and older) who had cognitive and physical activity measures and at least 2 visits with imaging biomarkers. We dichotomized participants into high (≥14 years) and low (<14 years) education levels using the median. For the entire cohort and the 2 education strata, we built linear mixed models to investigate the effect of the predictors on each of the biomarker outcomes. Results: Age was associated with amyloid and neurodegeneration trajectories; APOE4 status appears to influence only the amyloid and FDG trajectories but not hippocampal volume trajectory. In the high-education stratum, high midlife cognitive activity was associated with lower amyloid deposition in APOE4 carriers. APOE4 status was associated with lower FDG uptake in the entire cohort and in participants with lower education but not the high-education cohort. Conclusions: There were minimal effects of lifestyle enrichment on AD biomarker trajectories (specifically rates). Lifetime intellectual enrichment (high education, high midlife cognitive activity) is associated with lower amyloid in APOE4 carriers. High education is protective from the APOE4 effect on FDG metabolism. Differing education levels may explain the conflicting results seen in the literature.

Cohort Differences in Psychosocial Function over 20 Years: Current Older Adults Feel Less Lonely and Less Dependent on External Circumstances

Article

Full-text available

Jan 2016
GERONTOLOGY

Background: Lifespan psychological and life course sociological perspectives indicate that individual development is shaped by social and historical circumstances. Increases in fluid cognitive performance over the last century are well documented and researchers have begun examining historical trends in personality and subjective well-being in old age. Relatively less is known about secular changes in other key components of psychosocial function among older adults. Objective: In the present study, we examined cohort differences in key components of psychosocial function, including subjective age, control beliefs, and perceived social integration, as indicated by loneliness and availability of very close others. Methods: We compared data obtained 20 years apart in the Berlin Aging Study (in 1990-1993) and the Berlin Aging Study II (in 2013-2014) and identified case-matched cohort groups based on age, gender, cohort-normed education, and marital or partner status (n = 153 in each cohort, mean age = 75 years). In follow-up analyses, we controlled for having lived in former East versus West Germany, physical diseases, cohort-normed household income, cognitive performance, and the presence of a religious affiliation. Results: Consistently across analyses, we found that, relative to the earlier-born BASE cohort (year of birth: mean = 1916; SD = 3.38 years; range = 1901-1922), participants in the BASE-II sample (year of birth: mean = 1939; SD = 3.22 years; range = 1925-1949) reported lower levels of external control beliefs (d = -1.01) and loneliness (d = -0.63). Cohorts did not differ in subjective age, availability of very close others, and internal control beliefs. Conclusion: Taken together, our findings suggest that some aspects of psychosocial function of older adults have improved across the two recent decades. We discuss the possible role of sociocultural factors that might have led to the observed set of cohort differences.

Vitamin D supplementation to prevent depression and poor physical function in older adults: Study protocol of the D-Vitaal study, a randomized placebo-controlled clinical trial

Article

Full-text available

Dec 2015
BMC Geriatr

Background: Depressive symptoms and decreased physical functioning are interrelated conditions and common in older persons, causing significant individual and societal burden. Evidence suggests that vitamin D supplementation may be beneficial for both mental and physical functioning. However, previous randomized controlled trials have yielded inconsistent results and often had suboptimal designs. This study examines the effect of vitamin D supplementation on both depressive symptoms and physical functioning in a high-risk population of older persons with low vitamin D status. Methods/design: The D-Vitaal study is a randomized, double-blind, placebo-controlled trial investigating the effects of a daily dose of 1200 IU vitamin D3 versus placebo for one year on depressive symptoms and physical functioning (primary outcomes) in older adults. Participants (N = 155, age 60-80 years) were recruited from the general population. Eligibility criteria included the presence of depressive symptoms, ≥1 functional limitation and serum 25-hydroxyvitamin D levels between 15 and 50/70 nmol/L (depending on season). Secondary outcomes include incidence of major depressive disorder, anxiety symptoms, health-related quality of life, cognitive function and cost-effectiveness of the intervention. Discussion: With this study, we aim to elucidate the effects of vitamin D supplementation on depressive symptoms and physical functioning in older persons who are at high risk of developing more substantial mental and physical problems. If effective, vitamin D supplementation can be a preventive intervention strategy that is easy to implement in the primary care setting. Trial registration: Netherlands Trial Register NTR3845 . Registered 6 February 2013.

Interaction between years of education and APOE 4 status on frontal and temporal metabolism

Article

Full-text available

Sep 2015
NEUROLOGY

Objective: To examine interactions between years of education and APOE ε4 status on gray matter volume and metabolism in cognitively healthy participants. Methods: Seventy-two healthy participants (28 APOE ε4 carriers and 44 noncarriers; from 23 to 84 years of age) with FDG-PET and structural MRI were included. A subgroup also underwent florbetapir-PET. We tested the interaction effect between years of education and APOE ε4 status (carrier vs noncarrier) on FDG-PET and structural MRI within the whole brain (voxel-wise) adjusting for age and sex. Computed florbetapir standardized uptake value ratios were used for complementary analyses. Results: We found an interaction between years of education and APOE ε4 status on frontotemporal FDG-PET metabolism, such that higher education was positively related to frontotemporal metabolism only in APOE ε4 carriers. Complementary analyses revealed that (1) this interaction was independent from amyloid load; (2) increased metabolism in APOE ε4 carriers in this region correlated with episodic memory performances; (3) lower educated APOE ε4 carriers showed decreased metabolism relative to noncarriers in medial temporal and prefrontal areas, while higher educated carriers were comparable to noncarriers in these areas and showed increased metabolism in the middle temporal lobe. Conclusions: Our results showed that education may counteract the effects of APOE ε4 on metabolism independently of amyloid deposition. Higher metabolism in higher (compared to lower) educated APOE ε4 carriers was found in regions that sustain episodic memory. Overall, our results point to education as a protective factor that may help to postpone cognitive changes in APOE ε4 carriers.

The Cambridge Centre for Ageing and Neuroscience (Cam-CAN) data repository: Structural and functional MRI, MEG, and cognitive data from a cross-sectional adult lifespan sample

Article

Full-text available

Sep 2015
NEUROIMAGE

This paper describes the data repository for the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) initial study cohort. The Cam-CAN Stage 2 repository contains multi-modal (MRI, MEG, and cognitive-behavioural) data from a large (approximately N=700), cross-sectional adult lifespan (18-87years old) population-based sample. The study is designed to characterise age-related changes in cognition and brain structure and function, and to uncover the neurocognitive mechanisms that support healthy cognitive ageing. The database contains raw and preprocessed structural MRI, functional MRI (active tasks and resting state), and MEG data (active tasks and resting state), as well as derived scores from cognitive behavioural experiments spanning five broad domains (attention, emotion, action, language, and memory), and demographic and neuropsychological data. The dataset thus provides a depth of neurocognitive phenotyping that is currently unparalleled, enabling integrative analyses of age-related changes in brain structure, brain function, and cognition, and providing a testbed for novel analyses of multi-modal neuroimaging data.

Is It Important to Consider Sex and Gender in Neurocognitive Studies?

Article

Full-text available

Jun 2015

Adrianna Mendreka

PERSONALITY AND DEPRESSIVE SYMPTOMS: INDIVIDUAL PARTICIPANT META-ANALYSIS OF 10 COHORT STUDIES: Research Article: Personality and Depression

Article

Full-text available

May 2015
DEPRESS ANXIETY

Personality is suggested to be a major risk factor for depression but large-scale individual participant meta-analyses on this topic are lacking. Data from 10 prospective community cohort studies with 117,899 participants (mean age 49.0 years; 54.7% women) were pooled for individual participant meta-analysis to determine the association between personality traits of the five-factor model and risk of depressive symptoms. In cross-sectional analysis, low extraversion (pooled standardized regression coefficient (B) = -.08; 95% confidence interval = -0.11, -0.04), high neuroticism (B = .39; 0.32, 0.45), and low conscientiousness (B = -.09; -0.10, -0.06) were associated with depressive symptoms. Similar associations were observed in longitudinal analyses adjusted for baseline depressive symptoms (n = 56,735; mean follow-up of 5.0 years): low extraversion (B = -.03; -0.05, -0.01), high neuroticism (B = .12; 0.10, 0.13), and low conscientiousness (B = -.04; -0.06, -0.02) were associated with an increased risk of depressive symptoms at follow-up. In turn, depressive symptoms were associated with personality change in extraversion (B = -.07; 95% CI = -0.12, -0.02), neuroticism (B = .23; 0.09, 0.36), agreeableness (B = -.09; -0.15, -0.04), conscientiousness (B = -.14; -0.21, -0.07), and openness to experience (B = -.04; -0.08, 0.00). Personality traits are prospectively associated with the development of depressive symptoms. Depressive symptoms, in turn, are associated with changes in personality that may be temporary or persistent. © 2015 Wiley Periodicals, Inc.

LIFESPAN: A tool for the computer-aided design of longitudinal studies

Article

Full-text available

Mar 2015

Researchers planning a longitudinal study typically search, more or less informally, a multivariate space of possible study designs that include dimensions such as the hypothesized true variance in change, indicator reliability, the number and spacing of measurement occasions, total study time, and sample size. The main search goal is to select a research design that best addresses the guiding questions and hypotheses of the planned study while heeding applicable external conditions and constraints, including time, money, feasibility, and ethical considerations. Because longitudinal study selection ultimately requires optimization under constraints, it is amenable to the general operating principles of optimization in computer-aided design. Based on power equivalence theory (MacCallum et al., 2010; von Oertzen, 2010), we propose a computational framework to promote more systematic searches within the study design space. Starting with an initial design, the proposed framework generates a set of alternative models with equal statistical power to detect hypothesized effects, and delineates trade-off relations among relevant parameters, such as total study time and the number of measurement occasions. We present LIFESPAN (Longitudinal Interactive Front End Study Planner), which implements this framework. LIFESPAN boosts the efficiency, breadth, and precision of the search for optimal longitudinal designs. Its initial version, which is freely available at http://www.brandmaier.de/lifespan, is geared toward the power to detect variance in change as specified in a linear latent growth curve model.

Common genetic variants influence human subcortical brain structures

Article

Full-text available

Jan 2015

The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

COBRA: A prospective multimodal imaging study of dopamine, brain structure and function, and cognition

Article

Full-text available

Sep 2014
BRAIN RES

Cognitive decline is a characteristic feature of normal human aging. Previous work has demonstrated marked interindividual variability in onset and rate of decline. Such variability has been linked to factors such as maintenance of functional and structural brain integrity, genetics, and lifestyle. Still, few, if any, studies have combined a longitudinal design with repeated multimodal imaging and a comprehensive assessment of cognition as well as genetic and lifestyle factors. The present paper introduces the Cognition, Brain, and Aging (COBRA) study, in which cognitive performance and brain structure and function are measured in a cohort of 181 older adults aged 64 to 68 years at baseline. Participants will be followed longitudinally over a 10-year period, resulting in a total of three equally spaced measurement occasions. The measurement protocol at each occasion comprises a comprehensive set of behavioral and imaging measures. Cognitive performance is evaluated via computerized testing of working memory, episodic memory, perceptual speed, motor speed, implicit sequence learning, and vocabulary. Brain imaging is performed using positron emission tomography with [(11)C]-raclopride to assess dopamine D2/D3 receptor availability. Structural magnetic resonance imaging (MRI) is used for assessment of white and grey matter integrity and cerebrovascular perfusion, and functional MRI maps brain activation during rest and active task conditions. Lifestyle descriptives are collected, and blood samples are obtained and stored for future evaluation. Here, we present selected results from the baseline assessment along with a discussion of sample characteristics and methodological considerations that determined the design of the study.

Study protocol: The Whitehall II imaging sub-study

Article

Full-text available

May 2014
BMC PSYCHIATRY

Background: The Whitehall II (WHII) study of British civil servants provides a unique source of longitudinal data to investigate key factors hypothesized to affect brain health and cognitive ageing. This paper introduces the multi-modal magnetic resonance imaging (MRI) protocol and cognitive assessment designed to investigate brain health in a random sample of 800 members of the WHII study. Methods/design: A total of 6035 civil servants participated in the WHII Phase 11 clinical examination in 2012-2013. A random sample of these participants was included in a sub-study comprising an MRI brain scan, a detailed clinical and cognitive assessment, and collection of blood and buccal mucosal samples for the characterisation of immune function and associated measures. Data collection for this sub-study started in 2012 and will be completed by 2016. The participants, for whom social and health records have been collected since 1985, were between 60-85 years of age at the time the MRI study started. Here, we describe the pre-specified clinical and cognitive assessment protocols, the state-of-the-art MRI sequences and latest pipelines for analyses of this sub-study. Discussion: The integration of cutting-edge MRI techniques, clinical and cognitive tests in combination with retrospective data on social, behavioural and biological variables during the preceding 25 years from a well-established longitudinal epidemiological study (WHII cohort) will provide a unique opportunity to examine brain structure and function in relation to age-related diseases and the modifiable and non-modifiable factors affecting resilience against and vulnerability to adverse brain changes.

The changing face of cognitive gender differences in Europe

Article

Full-text available

Jul 2014

Significance Results showing that gender differences in mathematics and science are smaller in countries with higher gender equality have led researchers to conclude that cognitive gender differences are decreasing as a function of increased gender equality. Instead, we find that improved living conditions and less gender-restricted educational opportunities are associated with increased gender differences favoring women in some cognitive functions and decreases or elimination of gender differences in other cognitive abilities. Our results suggest that these changes take place as a result of women gaining more than men from societal improvements over time, thereby increasing their general cognitive ability more than men.

Dietary patterns and cognitive decline in an Australian study of ageing

Article

Full-text available

Jul 2014
MOL PSYCHIATR

The aim of this paper was to investigate the association of three well-recognised dietary patterns with cognitive change over a 3-year period. Five hundred and twenty-seven healthy participants from the Australian Imaging, Biomarkers and Lifestyle study of ageing completed the Cancer Council of Victoria food frequency questionnaire at baseline and underwent a comprehensive neuropsychological assessment at baseline, 18 and 36 months follow-up. Individual neuropsychological test scores were used to construct composite scores for six cognitive domains and a global cognitive score. Based on self-reported consumption, scores for three dietary patterns, (1) Australian-style Mediterranean diet (AusMeDi), (2) western diet and (3) prudent diet were generated for each individual. Linear mixed model analyses were conducted to examine the relationship between diet scores and cognitive change in each cognitive domain and for the global score. Higher baseline adherence to the AusMeDi was associated with better performance in the executive function cognitive domain after 36 months in apolipoprotein E (APOE) ɛ4 allele carriers (P<0.01). Higher baseline western diet adherence was associated with greater cognitive decline after 36 months in the visuospatial cognitive domain in APOE ɛ4 allele non-carriers (P<0.01). All other results were not significant. Our findings in this well-characterised Australian cohort indicate that adherence to a healthy diet is important to reduce risk for cognitive decline, with the converse being true for the western diet. Executive function and visuospatial functioning appear to be particularly susceptible to the influence of diet.Molecular Psychiatry advance online publication, 29 July 2014; doi:10.1038/mp.2014.79.

The Val/Met Polymorphism of the Brain-Derived Neurotrophic Factor (BDNF) Gene Predicts Decline in Perceptual Speed in Older Adults

Article

Full-text available

Mar 2014

The brain-derived neurotrophic factor (BDNF) promotes activity-dependent synaptic plasticity, and contributes to learning and memory. We investigated whether a common Val66Met missense polymorphism (rs6265) of the BDNF gene is associated with individual differences in cognitive decline (marked by perceptual speed) in old age. A total of 376 participants of the Berlin Aging Study, with a mean age of 83.9 years at first occasion, were assessed longitudinally up to 11 times across more than 13 years on the Digit-Letter task. Met carriers (n = 123, 34%) showed steeper linear decline than Val homozygotes (n = 239, 66%); the corresponding contrast explained 2.20% of the variance in change in the entire sample, and 3.41% after excluding individuals at risk for dementia. These effects were not moderated by sex or socioeconomic status. Results are consistent with the hypothesis that normal aging magnifies the effects of common genetic variation on cognitive functioning. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

Interaction between stress and the BDNF Val66Met polymorphism in depression: A systematic review and meta-analysis

Article

Full-text available

Jan 2014
BMC MED

Major depression is a disabling psychiatric illness with complex origins. Life stress (childhood adversity and recent stressful events) is a robust risk factor for depression. The relationship between life stress and Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene has received much attention. The aim of the present work was to review and conduct a meta-analysis on the results from published studies examining this interaction. A literature search was conducted using PsychINFO and PubMed databases until 22 November 2013. A total of 22 studies with a pooled total of 14,233 participants met the inclusion criteria, the results of which were combined and a meta-analysis performed using the Liptak-Stouffer z-score method. The results suggest that the Met allele of BDNF Val66Met significantly moderates the relationship between life stress and depression (P = 0.03). When the studies were stratified by type of environmental stressor, the evidence was stronger for an interaction with stressful life events (P = 0.01) and weaker for interaction of BDNF Val66Met with childhood adversity (P = 0.051). The interaction between BDNF and life stress in depression is stronger for stressful life events rather than childhood adversity. Methodological limitations of existing studies include poor measurement of life stress.

Sex differences in the structural connectome of the human brain

Article

Full-text available

Dec 2013
P NATL ACAD SCI USA

Significance Sex differences are of high scientific and societal interest because of their prominence in behavior of humans and nonhuman species. This work is highly significant because it studies a very large population of 949 youths (8–22 y, 428 males and 521 females) using the diffusion-based structural connectome of the brain, identifying novel sex differences. The results establish that male brains are optimized for intrahemispheric and female brains for interhemispheric communication. The developmental trajectories of males and females separate at a young age, demonstrating wide differences during adolescence and adulthood. The observations suggest that male brains are structured to facilitate connectivity between perception and coordinated action, whereas female brains are designed to facilitate communication between analytical and intuitive processing modes.

Data harmonization and federated analysis of population-based studies: The BioSHaRE project

Article

Full-text available

Nov 2013

Individual-level data pooling of large population-based studies across research centres in international research projects faces many hurdles. The BioSHaRE (Biobank Standardisation and Harmonisation for Research Excellence in the European Union) project aims to address these issues by building a collaborative group of investigators and developing tools for data harmonization, database integration and federated data analyses. Eight population-based studies in six European countries were recruited to participate in the BioSHaRE project. Through workshops, teleconferences and electronic communications, participating investigators identified a set of 96 variables targeted for harmonization to answer research questions of interest. Using each study's questionnaires, standard operating procedures, and data dictionaries, harmonization potential was assessed. Whenever harmonization was deemed possible, processing algorithms were developed and implemented in an open-source software infrastructure to transform study-specific data into the target (i.e. harmonized) format. Harmonized datasets located on server in each research centres across Europe were interconnected through a federated database system to perform statistical analysis. Retrospective harmonization led to the generation of common format variables for 73% of matches considered (96 targeted variables across 8 studies). Authenticated investigators can now perform complex statistical analyses of harmonized datasets stored on distributed servers without actually sharing individual-level data using the DataSHIELD method. New Internet-based networking technologies and database management systems are providing the means to support collaborative, multi-center research in an efficient and secure manner. The results from this pilot project show that, given a strong collaborative relationship between participating studies, it is possible to seamlessly co-analyse internationally harmonized research databases while allowing each study to retain full control over individual-level data. We encourage additional collaborative research networks in epidemiology, public health, and the social sciences to make use of the open source tools presented herein.

Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment

Article

Full-text available

May 2013
P NATL ACAD SCI USA

Is it possible to prevent atrophy of key brain regions related to cognitive decline and Alzheimer's disease (AD)? One approach is to modify nongenetic risk factors, for instance by lowering elevated plasma homocysteine using B vitamins. In an initial, randomized controlled study on elderly subjects with increased dementia risk (mild cognitive impairment according to 2004 Petersen criteria), we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 y. Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment. We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine (above the median, 11 µmol/L) and that, in these participants, a causal Bayesian network analysis indicates the following chain of events: B vitamins lower homocysteine, which directly leads to a decrease in GM atrophy, thereby slowing cognitive decline. Our results show that B-vitamin supplementation can slow the atrophy of specific brain regions that are a key component of the AD process and that are associated with cognitive decline. Further B-vitamin supplementation trials focusing on elderly subjets with high homocysteine levels are warranted to see if progression to dementia can be prevented.

Brain Characteristics of Individuals Resisting Age-Related Cognitive Decline over Two Decades

Article

Full-text available

May 2013
J NEUROSCI

Some elderly appear to resist age-related decline in cognitive functions, but the neural correlates of successful cognitive aging are not well known. Here, older human participants from a longitudinal study were classified as successful or average relative to the mean attrition-corrected cognitive development across 15-20 years in a population-based sample (n = 1561). Fifty-one successful elderly and 51 age-matched average elderly (mean age: 68.8 years) underwent functional magnetic resonance imaging while performing an episodic memory face-name paired-associates task. Successful older participants had higher BOLD signal during encoding than average participants, notably in the bilateral PFC and the left hippocampus (HC). The HC activation of the average, but not the successful, older group was lower than that of a young reference group (n = 45, mean age: 35.3 years). HC activation was correlated with task performance, thus likely contributing to the superior memory performance of successful older participants. The frontal BOLD response pattern might reflect individual differences present from young age. Additional analyses confirmed that both the initial cognitive level and the slope of cognitive change across the longitudinal measurement period contributed to the observed group differences in BOLD signal. Further, the differences between the older groups could not be accounted for by differences in brain structure. The current results suggest that one mechanism behind successful cognitive aging might be preservation of HC function combined with a high frontal responsivity. These findings highlight sources for heterogeneity in cognitive aging and may hold useful information for cognitive intervention studies.

Distinct resting-state functional connections associated with episodic and visuospatial memory in older adults

Article

Jul 2017

Episodic and spatial memory are commonly impaired in ageing and Alzheimer's disease. Volumetric and task-based functional magnetic resonance imaging (fMRI) studies suggest a preferential involvement of the medial temporal lobe (MTL), particularly the hippocampus, in episodic and spatial memory processing. The present study examined how these two memory types were related in terms of their associated resting-state functional architecture. 3T multiband resting state fMRI scans from 497 participants (60–82 years old) of the cross-sectional Whitehall II Imaging sub-study were analysed using an unbiased, data-driven network-modelling technique (FSLNets). Factor analysis was performed on the cognitive battery; the Hopkins Verbal Learning test and Rey-Osterreith Complex Figure test factors were used to assess verbal and visuospatial memory respectively. We present a map of the macroscopic functional connectome for the Whitehall II Imaging sub-study, comprising 58 functionally distinct nodes clustered into five major resting-state networks. Within this map we identified distinct functional connections associated with verbal and visuospatial memory. Functional anticorrelation between the hippocampal formation and the frontal pole was significantly associated with better verbal memory in an age-dependent manner. In contrast, hippocampus–motor and parietal–motor functional connections were associated with visuospatial memory independently of age. These relationships were not driven by grey matter volume and were unique to the respective memory domain. Our findings provide new insights into current models of brain-behaviour interactions, and suggest that while both episodic and visuospatial memory engage MTL nodes of the default mode network, the two memory domains differ in terms of the associated functional connections between the MTL and other resting-state brain networks.

Dementia prevention, intervention, and care

Article

Jul 2017
LANCET

Acting now on dementia prevention, intervention, and care will vastly improve living and dying for individuals with dementia and their families, and in doing so, will transform the future for society. Dementia is the greatest global challenge for health and social care in the 21st century. It occurs mainly in people older than 65 years, so increases in numbers and costs are driven, worldwide, by increased longevity resulting from the welcome reduction in people dying prematurely. The Lancet Commission on Dementia Prevention, Intervention, and Care met to consolidate the huge strides that have been made and the emerging knowledge as to what we should do to prevent and manage dementia. Globally, about 47 million people were living with dementia in 2015, and this number is projected to triple by 2050. Dementia affects the individuals with the condition, who gradually lose their abilities, as well as their relatives and other supporters, who have to cope with seeing a family member or friend become ill and decline, while responding to their needs, such as increasing dependency and changes in behaviour. Additionally, it affects the wider society because people with dementia also require health and social care. The 2015 global cost of dementia was estimated to be US$818 billion, and this figure will continue to increase as the number of people with dementia rises. Nearly 85% of costs are related to family and social, rather than medical, care. It might be that new medical care in the future, including public health measures, could replace and possibly reduce some of this cost.

Longitudinal associations of multiple physical symptoms with recurrence of depressive and anxiety disorders

Article

Jun 2017
J PSYCHOSOM RES

Longitudinal associations of multiple physical symptoms with recurrence of depressive and anxiety disorders

Article

Apr 2017

Objective: To examine longitudinal associations of multiple physical symptoms with recurrence of depressive and anxiety disorders. Methods: Follow-up data of 584 participants with remitted depressive or anxiety disorders were used from the Netherlands Study of Depressive and Anxiety disorders. Multiple physical symptoms were measured at baseline (T1) and two-year follow-up (T2) by the Four-Dimensional Symptom Questionnaire (4DSQ) somatization subscale. Recurrence of depressive and anxiety disorders was assessed at two-year (T2) and four-year (T4) follow-up with the Composite International Diagnostic Interview. Logistic Generalized Estimating Equations were used to examine associations of multiple physical symptoms with recurrence of depressive and anxiety disorders. Depressive (IDS-SR) and anxiety symptoms (BAI), and other relevant covariates were taken into account. Results: Multiple physical symptoms were significantly associated with recurrence of depression (OR=1.04, 95%CI=1.00-1.08), anxiety (OR=1.07, 95%CI=1.03-1.12), and depressive or anxiety disorders (OR=1.06, 95%CI=1.02-1.10), on average over time. Odds ratios did not change substantially when the IDS-SR mood-cognition and BAI subjective scale were included as covariates. Conclusion: The presence of multiple physical symptoms was positively related to recurrence of depressive and anxiety disorders, independent of depressive and anxiety symptoms. Knowledge of risk factors for recurrence of depressive and anxiety disorders, such as the presence of multiple physical symptoms, could provide possibilities for better targeting interventions to prevent recurrence.

Relationship between structural and functional connectivity change across the adult lifespan: A longitudinal investigation

Article

Sep 2016

Extensive efforts are devoted to understand the functional (FC) and structural connections (SC) of the brain. FC is usually measured by functional magnetic resonance imaging (fMRI), and conceptualized as degree of synchronicity in brain activity between different regions. SC is typically indexed by measures of white matter (WM) properties, for example, by diffusion weighted imaging (DWI). FC and SC are intrinsically related, in that coordination of activity across regions ultimately depends on fast and efficient transfer of information made possible by structural connections. Convergence between FC and SC has been shown for specific networks, especially the default mode network (DMN). However, it is not known to what degree FC is constrained by major WM tracts and whether FC and SC change together over time. Here, 120 participants (20-85 years) were tested at two time points, separated by 3.3 years. Resting-state fMRI was used to measure FC, and DWI to measure WM microstructure as an index of SC. TRACULA, part of FreeSurfer, was used for automated tractography of 18 major WM tracts. Cortical regions with tight structural couplings defined by tractography were only weakly related at the functional level. Certain regions of the DMN showed a modest relationship between change in FC and SC, but for the most part, the two measures changed independently. The main conclusions are that anatomical alignment of SC and FC seems restricted to specific networks and tracts, and that changes in SC and FC are not necessarily strongly correlated.

The rs9939609 Gene Variant in FTO Modified the Metabolic Response of Weight Loss After a 3-Month Intervention With a Hypocaloric Diet

Article

Jan 2013

Background Common polymorphisms in the fat mass and obesity associated gene (FTO) have been linked to obesity in some populations. Nevertheless, the role of FTO variants on body weight response after dietary intervention remains equivocal. Objective We decided to analyze the effects of the rs9939609 FTO gene polymorphism on body weight changes and metabolic parameters after 3 months of a hypocaloric diet. Design Before and after 3 months on a low-fat hypocaloric diet, a white population of 106 subjects with obesity was analyzed. Results Of the study subjects, 35 (33%) had the genotype TT and 71 (67%) had the next genotypes; TA (46 study subjects, 43.4%) or AA (25 study subjects, 23.6%). After dietary treatment and in TT group, weight, waist circumference, total cholesterol, LDL-cholesterol, insulin, and homeostasis model assessment decreases were less than subjects carrying the A allele [−3.1 (3.6) vs −2.4 (4.1) kg: P < 0.05], waist circumference [−5.4 (6.4) vs −2.6 (4.8) cm; P < 0.05], total cholesterol [−12.3 (35.3) vs −6.4 (4.7) mg/dL; P < 0.05], LDL-cholesterol [−22.3 (30.5) vs −10.7 (30.5) mg/dL; P < 0.05], insulin [−1.89 (5.5) vs +0.94 (8.2) mUI/L; P < 0.05], and homeostasis model assessment [−0.46 (1.11) vs −0.01 (2.4); P < 0.05]. Conclusions Our study confirmed a higher weight loss in A carriers of FTO rs9939609 polymorphism than in TT genotype study subjects.

Age, APOE and sex: Triad of risk of Alzheimer's disease

Article

Mar 2016

Age, apolipoprotein E ε4 (APOE) and chromosomal sex are well-established risk factors for late-onset Alzheimer’s disease (LOAD; AD). Over 60% of persons with AD harbor at least one APOE-ε4 allele. The sex-based prevalence of AD is well documented with over 60% of persons with AD being female. Evidence indicates that the APOE-ε4 risk for AD is greater in women than men, which is particularly evident in heterozygous women carrying one APOE-ε4 allele. Paradoxically, men homozygous for APOE-ε4 are reported to be at greater risk for mild cognitive impairment and AD. Herein, we discuss the complex interplay between the three greatest risk factors for Alzheimer’s disease, age, APOE-ε4 genotype and female sex. We propose that the convergence of these three risk factors, and specifically the bioenergetic aging perimenopause to menopause transition unique to the female, creates a risk profile for AD unique to the female. Further, we discuss the unique risk of the APOE4 positive male which appears to emerge early in the aging process. Evidence for impact of the triad of AD risk factors is most evident in the temporal trajectory of AD progression and burden of pathology in relation to APOE genotype, age and sex. Collectively, the data indicate complex interactions between age, APOE genotype and gender that belies a one size fits all approach and argues for a precision medicine approach that integrates across the three main risk factors for Alzheimer’s disease.

Relationships between sleep quality and brain volume, metabolism and amyloid deposition in late adulthood

Article

Feb 2016

Joint reconstruction of white-matter pathways from longitudinal diffusion MRI data with anatomical priors

Article

Dec 2015
NEUROIMAGE

We consider the problem of reconstructing white-matter pathways in a longitudinal study, where diffusion-weighted and T1-weighted MR images have been acquired at multiple time points for the same subject. We propose a method for joint reconstruction of a subject's pathways at all time points given the subject's entire set of longitudinal data. We apply a method for unbiased within-subject registration to generate a within-subject template from the T1-weighted images of the subject at all time points. We follow a global probabilistic tractography approach, where the unknown pathway is represented in the space of this within-subject template and propagated to the native space of the diffusion-weighted images at all time points to compute its posterior probability given the images. This ensures spatial correspondence of the reconstructed pathway among time points, which in turn allows longitudinal changes in diffusion measures to be estimated consistently along the pathway. We evaluate thereliability of the proposed method on data from healthy controls scanned twice within a month, where no changes in white-matter microstructure are expected between scans. We evaluate the sensitivity of the method on data from Huntington's disease patients scanned repeatedly over the course of several months, where changes are expected between scans. We show that reconstructing white-matter pathways jointly using the data from all time points leads to improved reliability and sensitivity, when compared to reconstructing the pathways at each time point independently.

Sex beyond the genitalia: The human brain mosaic

Article

Nov 2015

Significance Sex/gender differences in the brain are of high social interest because their presence is typically assumed to prove that humans belong to two distinct categories not only in terms of their genitalia, and thus justify differential treatment of males and females. Here we show that, although there are sex/gender differences in brain and behavior, humans and human brains are comprised of unique “mosaics” of features, some more common in females compared with males, some more common in males compared with females, and some common in both females and males. Our results demonstrate that regardless of the cause of observed sex/gender differences in brain and behavior (nature or nurture), human brains cannot be categorized into two distinct classes: male brain/female brain.

Sex differences in neurodevelopmental and neurodegenerative disorders: Focus on microglial function and neuroinflammation during development

Article

Oct 2015

Sex differences and stress across the lifespan

Article

Sep 2015

Sex differences in stress responses can be found at all stages of life and are related to both the organizational and activational effects of gonadal hormones and to genes on the sex chromosomes. As stress dysregulation is the most common feature across neuropsychiatric diseases, sex differences in how these pathways develop and mature may predict sex-specific periods of vulnerability to disruption and increased disease risk or resilience across the lifespan. The aging brain is also at risk to the effects of stress, where the rapid decline of gonadal hormones in women combined with cellular aging processes promote sex biases in stress dysregulation. In this Review, we discuss potential underlying mechanisms driving sex differences in stress responses and their relevance to disease. Although stress is involved in a much broader range of diseases than neuropsychiatric ones, we highlight here this area and its examples across the lifespan.

Article

Jul 2015

Heritability studies document substantial genetic influences on cognitive performance and decline in old age. Increasing evidence shows that effects of genetic variations on cognition, brain structure, and brain function become stronger as people age. Disproportionate impairments are typically observed for older individuals carrying disadvantageous genotypes of different candidate genes. These data support the resource-modulation hypothesis, which states that genetic effects are magnified in persons with constrained neural resources, such as older adults. However, given that findings are not unequivocal, we discuss the need to address several factors that may resolve inconsistencies in the extant literature (gene-gene and gene-environment interactions, study populations, gene-environment correlations, and epigenetic mechanisms). Copyright © 2015 Elsevier Ltd. All rights reserved.

Biological Factors

Healthy minds 0-100 years: Optimising the use of European brain imaging cohorts (“Lifebrain”)

Abstract

No full-text available