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BACKGROUND/AIMS: Screening instruments such as the Mini-Mental State Examination (MMSE) are useful for the early identification of Alzheimer's disease (AD). We tested whether macrostructural differences in brain volume are related to the MMSE. METHODS: The MMSE was related to cortical thickness and the volume of 19 brain structures in 96 patients with mild to moderate AD. In addition, the patients were compared to 93 healthy elderly controls. RESULTS: The MMSE was related to the volume of the total brain, cerebral cortex, accumbens, cerebral white matter, inferior lateral ventricles and hippocampus. Positive correlations with cortical thickness were found for 41% of the brain surface, and 58% of this area was significantly thinner in AD. CONCLUSION: The MMSE is sensitive to macrostructural brain atrophy in AD, but also to morphometric variation not specifically related to AD. [ABSTRACT FROM AUTHOR]

Background: Stimulant medication is commonly prescribed as treatment for attention-deficit/hyperactivity disorder (ADHD). While we previously found that short-term stimulant-treatment influences apparent cortical thickness development in an age-dependent manner, it remains unknown whether these effects persist throughout development into adulthood., Purpose: Investigate the long-term age-dependent effects of stimulant medication use on apparent cortical thickness development in adolescents and adults previously diagnosed with ADHD., Methods: This prospective study included the baseline and 4-year follow-up assessment of the "effects of Psychotropic drugs On the Developing brain-MPH" ("ePOD-MPH") project, conducted between June-1-2011 and December-28-2019. The analyses were pre-registered (https://doi.org/10.17605/OSF.IO/32BHF). T1-weighted MR scans were obtained from male adolescents and adults, and cortical thickness was estimated for predefined regions of interest (ROIs) using Freesurfer. We determined medication use and assessed symptoms of ADHD, anxiety, and depression at both time points. Linear mixed models were constructed to assess main effects and interactions of stimulant medication use, time, and age group on regional apparent cortical thickness., Results: A total of 32 male adolescents (aged mean ± SD, 11.2 ± 0.9 years at baseline) and 24 men (aged mean ± SD, 29.9 ± 5.0 years at baseline) were included that previously participated in the ePOD-MPH project. We found no evidence for long-term effects of stimulant medication use on ROI apparent cortical thickness. As expected, we did find age-by-time interaction effects in all ROIs (left prefrontal ROI: P=.002, right medial and posterior ROIs: P<.001), reflecting reductions in apparent cortical thickness in adolescents. Additionally, ADHD symptom severity (adolescents: P<.001, adults: P=.001) and anxiety symptoms (adolescents: P=0.03) were reduced, and more improvement of ADHD symptoms was associated with higher medication use in adults (P=0.001)., Conclusion: We found no evidence for long-term effects of stimulant-treatment for ADHD on apparent cortical thickness development in adolescents and adults. The identified age-dependent differences in apparent cortical thickness development are consistent with existing literature on typical cortical development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 van der Pal, Walhovd, Amlien, Guichelaar, Kaiser, Bottelier, Geurts, Reneman and Schrantee.)

Human fetal development has been associated with brain health at later stages. It is unknown whether growth in utero, as indexed by birth weight (BW), relates consistently to lifespan brain characteristics and changes, and to what extent these influences are of a genetic or environmental nature. Here we show remarkably stable and lifelong positive associations between BW and cortical surface area and volume across and within developmental, aging and lifespan longitudinal samples (N = 5794, 4-82 y of age, w/386 monozygotic twins, followed for up to 8.3 y w/12,088 brain MRIs). In contrast, no consistent effect of BW on brain changes was observed. Partly environmental effects were indicated by analysis of twin BW discordance. In conclusion, the influence of prenatal growth on cortical topography is stable and reliable through the lifespan. This early-life factor appears to influence the brain by association of brain reserve, rather than brain maintenance. Thus, fetal influences appear omnipresent in the spacetime of the human brain throughout the human lifespan. Optimizing fetal growth may increase brain reserve for life, also in aging., Competing Interests: KW, SK, IA, ØS, YW, AB, KO, JK, AM, FM, MH, AH, AF, DV No competing interests declared, (© 2023, Walhovd et al.)

Inflammatory responses to acute stimuli are proposed to regulate sleep, but the relationship between chronic inflammation and habitual sleep duration is elusive. Here, we study this relation using genetically predicted level of chronic inflammation, indexed by CRP and IL6 signaling, and self-reported sleep duration. By Mendelian randomization analysis, we show that elevated CRP level within <10 mg/L has a homeostatic effect that facilitates maintaining 7-8 h sleep duration per day - making short-sleepers sleep longer (p = 2.42 × 10 -2 ) and long-sleepers sleep shorter (1.87 × 10 -7 ); but it is not associated with the overall sleep duration (p = 0.17). This homeostatic effect replicated in an independent CRP dataset. We observed causal effects of the soluble interleukin 6 receptor and gp130 on overall sleep duration (p = 1.62 × 10 -8 , p = 2.61 × 10 -58 , respectively), but these effects disappeared when CRP effects were accounted for in the model. Using polygenic score analysis, we found that the homeostatic effect of CRP on sleep duration stems primarily from the genetic variants within the CRP gene region: when genetic variants outside of this region were used to predict CRP levels, the opposite direction of effect was observed. In conclusion, we show that elevated CRP level may causally facilitate maintaining an optimal sleep duration that is beneficial to health, thus updating our current knowledge of immune regulation on sleep., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

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., (© 2023. The Author(s).)

Many sleep less than recommended without experiencing daytime sleepiness. According to prevailing views, short sleep increases risk of lower brain health and cognitive function. Chronic mild sleep deprivation could cause undetected sleep debt, negatively affecting cognitive function and brain health. However, it is possible that some have less sleep need and are more resistant to negative effects of sleep loss. We investigated this using a cross-sectional and longitudinal sample of 47,029 participants of both sexes (20-89 years) from the Lifebrain consortium, Human Connectome project (HCP) and UK Biobank (UKB), with measures of self-reported sleep, including 51,295 MRIs of the brain and cognitive tests. A total of 740 participants who reported to sleep <6 h did not experience daytime sleepiness or sleep problems/disturbances interfering with falling or staying asleep. These short sleepers showed significantly larger regional brain volumes than both short sleepers with daytime sleepiness and sleep problems ( n = 1742) and participants sleeping the recommended 7-8 h ( n = 3886). However, both groups of short sleepers showed slightly lower general cognitive function (GCA), 0.16 and 0.19 SDs, respectively. Analyses using accelerometer-estimated sleep duration confirmed the findings, and the associations remained after controlling for body mass index, depression symptoms, income, and education. The results suggest that some people can cope with less sleep without obvious negative associations with brain morphometry and that sleepiness and sleep problems may be more related to brain structural differences than duration. However, the slightly lower performance on tests of general cognitive abilities warrants closer examination in natural settings. SIGNIFICANCE STATEMENT Short habitual sleep is prevalent, with unknown consequences for brain health and cognitive performance. Here, we show that daytime sleepiness and sleep problems are more strongly related to regional brain volumes than sleep duration. However, participants sleeping ≤6 h had slightly lower scores on tests of general cognitive function (GCA). This indicates that sleep need is individual and that sleep duration per se is very weakly if at all related brain health, while daytime sleepiness and sleep problems may show somewhat stronger associations. The association between habitual short sleep and lower scores on tests of general cognitive abilities must be further scrutinized in natural settings., (Copyright © 2023 the authors.)

Cortical asymmetry is a ubiquitous feature of brain organization that is subtly altered in some neurodevelopmental disorders, yet we lack knowledge of how its development proceeds across life in health. Achieving consensus on the precise cortical asymmetries in humans is necessary to uncover the developmental timing of asymmetry and the extent to which it arises through genetic and later influences in childhood. Here, we delineate population-level asymmetry in cortical thickness and surface area vertex-wise in seven datasets and chart asymmetry trajectories longitudinally across life (4-89 years; observations = 3937; 70% longitudinal). We find replicable asymmetry interrelationships, heritability maps, and test asymmetry associations in large-scale data. Cortical asymmetry was robust across datasets. Whereas areal asymmetry is predominantly stable across life, thickness asymmetry grows in childhood and peaks in early adulthood. Areal asymmetry is low-moderately heritable (max h 2 SNP ~19%) and correlates phenotypically and genetically in specific regions, indicating coordinated development of asymmetries partly through genes. In contrast, thickness asymmetry is globally interrelated across the cortex in a pattern suggesting highly left-lateralized individuals tend towards left-lateralization also in population-level right-asymmetric regions (and vice versa), and exhibits low or absent heritability. We find less areal asymmetry in the most consistently lateralized region in humans associates with subtly lower cognitive ability, and confirm small handedness and sex effects. Results suggest areal asymmetry is developmentally stable and arises early in life through genetic but mainly subject-specific stochastic effects, whereas childhood developmental growth shapes thickness asymmetry and may lead to directional variability of global thickness lateralization in the population., Competing Interests: JR, DV, IA, MP, MS, MT, PF, ZS, CF, EE, YW, KW, AF, RW No competing interests declared, (© 2023, Roe et al.)

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 cognitively healthy brain imaging cohorts (n = 3327, 7002 MRI scans, baseline age 20-88 years, followed-up for 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., (© 2022. The Author(s).)

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., (© The Author(s) 2021. Published by Oxford University Press.)

The apolipoprotein E gene ε4 allele (APOE ε4) and higher circulating level of C-reactive protein (CRP) have been extensively investigated as risk factors for Alzheimer's disease (AD). Paradoxically, APOE ε4 has been associated with lower levels of blood CRP in middle-aged and older populations. However, few studies have investigated this intriguing relation and its impact on neurological markers for AD in younger ages, nor across the whole lifespan. Here, we examine associations of blood CRP levels, APOE ε4, and biomarkers for AD in a cognitively healthy lifespan cohort (N up to 749; 20-81 years of age) and replicate the findings in UK Biobank (N = 304 322; 37-72 years of age), the developmental ABCD study (N = 10 283; 9-11 years of age), and a middle-aged sample (N = 339; 40-65 years of age). Hippocampal volume, brain amyloid-β (Aβ) plaque levels, cerebrospinal fluid (CSF) levels of Aβ and tau species, and neurofilament protein light protein (NFL) were used as AD biomarkers in subsamples. In addition, we examined the genetic contribution to the variation of CRP levels over different CRP ranges using polygenic scores for CRP (PGS-CRP). Our results show APOE ε4 consistently associates with low blood CRP levels across all age groups (p < 0.05). Strikingly, both ε4 and PGS-CRP associated mainly with blood CRP levels within the low range (<5mg/L). We then show both APOE ε4 and high CRP levels associate with smaller hippocampus volumes across the lifespan (p < 0.025). APOE ε4 was associated with high Aβ plaque levels in the brain (FDR-corrected p = 8.69x10 -4 ), low levels of CSF Aβ42 (FDR-corrected p = 6.9x10 -2 ), and lower ratios of Aβ42 to Aβ40 (FDR-corrected p = 5.08x10 -5 ). Blood CRP levels were weakly correlated with higher ratio of CSF Aβ42 to Aβ40 (p = 0.03, FDR-corrected p = 0.4). APOE ε4 did not correlate with blood concentrations of another 9 inflammatory cytokines, and none of these cytokines correlated with AD biomarkers. CONCLUSION: The inverse correlation between APOEε 4 and blood CRP levels existed before any pathological AD biomarker was observed, and only in the low CRP level range. Thus, we suggest to investigate whether APOEε 4 can confer risk by being associated with a lower inflammatory response to daily exposures, possibly leading to greater accumulation of low-grade inflammatory stress throughout life. A lifespan perspective is needed to understand this relationship concerning risk of developing AD., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Brain age is a widely used index for quantifying individuals' brain health as deviation from a normative brain aging trajectory. Higher-than-expected brain age is thought partially to reflect above-average rate of brain aging. Here, we explicitly tested this assumption in two independent large test datasets (UK Biobank [main] and Lifebrain [replication]; longitudinal observations ≈ 2750 and 4200) by assessing the relationship between cross-sectional and longitudinal estimates of brain age. Brain age models were estimated in two different training datasets (n ≈ 38,000 [main] and 1800 individuals [replication]) based on brain structural features. The results showed no association between cross-sectional brain age and the rate of brain change measured longitudinally. Rather, brain age in adulthood was associated with the congenital factors of birth weight and polygenic scores of brain age, assumed to reflect a constant, lifelong influence on brain structure from early life. The results call for nuanced interpretations of cross-sectional indices of the aging brain and question their validity as markers of ongoing within-person changes of the aging brain. Longitudinal imaging data should be preferred whenever the goal is to understand individual change trajectories of brain and cognition in aging., Competing Interests: DV, YW, SK, IA, WB, DB, LB, AB, RK, SK, EL, FM, AM, LN, JR, BS, SS, ØS, SS, RW, AZ, EZ, KW, AF No competing interests declared, CD CAD: Is an employee of Vitas Ltd, (© 2021, Vidal-Pineiro et al.)

Working memory (WM) supports several higher-level cognitive abilities, yet we know less about factors associated with development and decline in WM compared to other cognitive processes. Here, we investigated lifespan changes in WM capacity and their structural brain correlates, using a longitudinal sample including 2358 magnetic resonance imaging (MRI) scans and WM scores from 1656 participants (4.4-86.4 years, mean follow-up interval 4.3 years). 8764 participants (9.0-10.9 years) with MRI, WM scores and genetic information from the Adolescent Brain Cognitive Development study were used for follow-up analyses. Results showed that both the information manipulation component and the storage component of WM improved during childhood and adolescence, but the age-decline could be fully explained by reductions in passive storage capacity alone. Greater WM function in development was related to apparent thinner cortex in both samples, also when general cognitive function was accounted for. The same WM-apparent thickness relationship was found for young adults. The WM-thickness relationships could not be explained by SNP-based co-heritability or by socioeconomic status. A larger sample with genetic information may be necessary to disentangle the true gene-environment effects. In conclusion, WM capacity changes greatly through life and has anatomically extended rather than function-specific structural cortical correlates., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Development and aging of the cerebral cortex show similar topographic organization and are governed by the same genes. It is unclear whether the same is true for subcortical regions, which follow fundamentally different ontogenetic and phylogenetic principles. We tested the hypothesis that genetically governed neurodevelopmental processes can be traced throughout life by assessing to which degree brain regions that develop together continue to change together through life. Analyzing over 6000 longitudinal MRIs of the brain, we used graph theory to identify five clusters of coordinated development, indexed as patterns of correlated volumetric change in brain structures. The clusters tended to follow placement along the cranial axis in embryonic brain development, suggesting continuity from prenatal stages, and correlated with cognition. Across independent longitudinal datasets, we demonstrated that developmental clusters were conserved through life. Twin-based genetic correlations revealed distinct sets of genes governing change in each cluster. Single-nucleotide polymorphisms-based analyses of 38,127 cross-sectional MRIs showed a similar pattern of genetic volume-volume correlations. In conclusion, coordination of subcortical change adheres to fundamental principles of lifespan continuity and genetic organization., Competing Interests: AF, HG, YW, IA, DB, AB, SD, JE, CF, AH, TK, RK, WK, SK, SK, UL, DM, AM, LN, MP, CS, ØS, RW, KW No competing interests declared, (© 2021, Fjell et al.)

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., (© The Author(s) 2020. Published by Oxford University Press.)

We examined whether sleep quality and quantity are associated with cortical and memory changes in cognitively healthy participants across the adult lifespan. Associations between self-reported sleep parameters (Pittsburgh Sleep Quality Index, PSQI) and longitudinal cortical change were tested using five samples from the Lifebrain consortium (n = 2205, 4363 MRIs, 18-92 years). In additional analyses, we tested coherence with cell-specific gene expression maps from the Allen Human Brain Atlas, and relations to changes in memory performance. "PSQI # 1 Subjective sleep quality" and "PSQI #5 Sleep disturbances" were related to thinning of the right lateral temporal cortex, with lower quality and more disturbances being associated with faster thinning. The association with "PSQI #5 Sleep disturbances" emerged after 60 years, especially in regions with high expression of genes related to oligodendrocytes and S1 pyramidal neurons. None of the sleep scales were related to a longitudinal change in episodic memory function, suggesting that sleep-related cortical changes were independent of cognitive decline. The relationship to cortical brain change suggests that self-reported sleep parameters are relevant in lifespan studies, but small effect sizes indicate that self-reported sleep is not a good biomarker of general cortical degeneration in healthy older adults., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

There is evidence for a hippocampal long axis anterior-posterior (AP) differentiation in memory processing, which may have implications for the changes in episodic memory performance seen across development and aging. The hippocampus shows substantial structural changes with age, but the lifespan trajectories of hippocampal sub-regions along the AP axis are not established. The aim of the present study was to test whether the micro- and macro-structural age-trajectories of the anterior (aHC) and posterior (pHC) hippocampus are different. In a single-center longitudinal study, 1,790 cognitively healthy participants, 4.1-93.4 years of age, underwent a total of 3,367 MRI examinations and 3,033 memory tests sessions over 1-6 time points, spanning an interval up to 11.1 years. T1-weighted scans were used to estimate the volume of aHC and pHC (macrostructure), and diffusion tensor imaging to measure mean diffusion (MD, microstructure) within each region. We found that the macro- and microstructural lifespan-trajectories of aHC and pHC were clearly distinguishable, with partly common and partly unique variance shared with age. aHC showed a protracted period of microstructural development, while pHC microstructural development as indexed by MD was more or less completed in early childhood. In contrast, pHC showed larger unique aging-related changes. An aHC-pHC difference was also observed for volume, with pHC changing relatively more with higher age. All regions showed age-dependent relationships with episodic memory. aHC micro- and macrostructure was significantly related to verbal memory independently of age, but the relationships were still strongest among the older participants. We suggest that memory processes supported by each sub-region improve or decline in concert with volumetric and microstructural changes in the same age-period. Future research should disentangle the lifespan relationship between changes in these structural properties and different memory processes, encoding versus retrieval in particular, as well as other cognitive functions depending on the hippocampal long-axis specialization., (© 2020 The Authors. Hippocampus published by Wiley Periodicals, Inc.)

Functional magnetic resonance imaging (fMRI) is a standard tool to investigate the neural correlates of cognition. fMRI noninvasively measures brain activity, allowing identification of patterns evoked by tasks performed during scanning. Despite the long history of this technique, the idiosyncrasies of each dataset have led to the use of ad-hoc preprocessing protocols customized for nearly every different study. This approach is time consuming, error prone and unsuitable for combining datasets from many sources. Here we showcase fMRIPrep (http://fmriprep.org), a robust tool to prepare human fMRI data for statistical analysis. This software instrument addresses the reproducibility concerns of the established protocols for fMRI preprocessing. By leveraging the Brain Imaging Data Structure to standardize both the input datasets (MRI data as stored by the scanner) and the outputs (data ready for modeling and analysis), fMRIPrep is capable of preprocessing a diversity of datasets without manual intervention. In support of the growing popularity of fMRIPrep, this protocol describes how to integrate the tool in a task-based fMRI investigation workflow.

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 21,390 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., (© Sleep Research Society 2019. Published by Oxford University Press [on behalf of the Sleep Research Society].)

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Change in hippocampal function is a major factor in life span development and decline of episodic memory. Evidence indicates a long-axis specialization where anterior hippocampus is more engaged during encoding than during retrieval, and posterior more engaged during retrieval than during encoding. We tested the life span trajectory of hippocampal long-axis episodic memory-related activity and functional connectivity (FC) in 496 participants (6.8-80.8 years) encoding and retrieving associative memories. We found evidence for a long-axis encoding-retrieval specialization that declined linearly during development and aging, eventually vanishing in the older adults. This was mainly driven by age effects on retrieval, which was associated with gradually lower activity from childhood to adulthood, followed by positive age relationships until 70 years. This pattern of age effects characterized task engagement regardless of memory success or failure. Especially for retrieval, children engaged posterior hippocampus more than anterior, while anterior was relatively more activated already in teenagers. Significant intrahippocampal connectivity was found during task, which declined with age. The results suggest that hippocampal long-axis differentiation and communication during episodic memory tasks develop rapidly during childhood, are different in older compared with younger adults, and that the age effects are related to task engagement, not the successful retrieval of episodic memories specifically., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Variations in levels of processing affect memory encoding and subsequent retrieval performance, but it is unknown how processing depth affects communication patterns within the network of interconnected brain regions involved in episodic memory encoding. In 113 healthy adults scanned with functional MRI, we used graph theory to calculate centrality indices representing the brain regions' relative importance in the memory network. We tested how communication patterns in 42 brain regions involved in episodic memory encoding changed as a function of processing depth, and how these changes were related to episodic memory ability. Centrality changes in right middle frontal gyrus, right inferior parietal lobule and left superior frontal gyrus were positively related to semantic elaboration during encoding. In the same regions, centrality during successful episodic memory encoding was related to performance on the episodic memory task, indicating that these centrality changes reflect processes that support memory encoding through deep elaborative processing. Similar analyses were performed for congruent trials, i.e. events that fit into existing knowledge structures, but no relationship between centrality changes and congruity were found. The results demonstrate that while elaboration and congruity have similar beneficial effects on source memory performance, the cortical signatures of these processes are probably not identical.

The formation of episodic memories is associated with deactivation during encoding and activation during retrieval in the posteromedial cortex (PMC). We hypothesized that the encoding/retrieval (E/R) flip is a critical component of episodic memory across the lifespan because structural and metabolic changes in the PMC coincide with the fine tuning of the episodic memory system in development and the reductions of memory performance in aging. The aims of the present study were, first, to describe lifespan trajectories of PMC encoding and retrieval activity in 270 human participants (167 females) from 6 to 80 years of age. Our second goal was to construct a model for episodic memory development in which contributions from brain activity, cortical thickness (CT), and structural connectivity are accounted for. We found that modulation of neural activity in response to memory encoding and retrieval demands was not fully developed until adolescence and decreased from adulthood through old age. The magnitude of the E/R flip was related to source memory and 55% of the age-related variance in source memory performance during childhood and adolescence could be accounted for by the E/R flip, CT, and mean diffusivity together. However, only CT and the E/R flip provided unique contributions with which to explain memory performance. The results suggest that neural dynamics in the PMC is related to the development of episodic memory during childhood and adolescence. The similar trajectories of the E/R flip and episodic memory emergence and decline through development and aging further suggests that a lifelong relationship exists. SIGNIFICANCE STATEMENT Modulation of neural activity in the posteromedial cortex (PMC) in response to memory encoding/retrieval (E/R) demands (E/R flip) does not reach its peak until adolescence and decreases from adulthood through old age. The magnitude of the E/R flip is related to source memory and 55% of the age-related variance in source memory performance during childhood and adolescence can be accounted for by the E/R flip and brain structure together. The results suggest that neural dynamics in the PMC is related to the development of episodic memory function during childhood and adolescence and the similar trajectories of the E/R flip and episodic memory performance through development and aging suggests that a lifelong relationship exists., (Copyright © 2018 the authors 0270-6474/18/388666-14$15.00/0.)

At a large scale, the human brain is organized into modules of interconnected regions, some of which play opposing roles in supporting cognition. In particular, the Default-Mode Network (DMN) has been linked to operations on internal representations, while task-positive networks are recruited during interactions with the external world. Here, we test the hypothesis that the generation of durable long-term memories depends on optimal recruitment of such antagonistic large-scale networks. As long-term memory consolidation is a process ongoing for days and weeks after an experience, we propose that individuals characterized by strong decoupling of the DMN and task-positive networks at rest operate in a mode beneficial for the long-term stabilization of episodic memories. To capture network connectivity unaffected by transient task demands and representative of brain behavior outside an experimental setting, 87 participants were scanned during rest before performing an associative encoding task. To link individual resting-state functional connectivity patterns to time-dependent memory consolidation processes, participants were given an unannounced memory test, either after a brief interval or after a retention period of ~6 weeks. We found that participants with a resting state characterized by high synchronicity in a DMN-centered network system and low synchronicity between task-positive networks showed superior recollection weeks after encoding. These relationships were not observed for information probed only hours after encoding. Furthermore, the two network systems were found to be anticorrelated. Our results suggest that this memory-relevant antagonism between DMN and task-positive networks is maintained through complex regulatory interactions between the systems., (Copyright © 2017. Published by Elsevier Inc.)

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. Hum Brain Mapp 38:561-573, 2017. © 2016 Wiley Periodicals, Inc., Competing Interests: The authors declare no competing financial interests., (© 2016 Wiley Periodicals, Inc.)

Neurodevelopmental origins of functional variation in older age are increasingly being acknowledged, but identification of how early factors impact human brain and cognition throughout life has remained challenging. Much focus has been on age-specific mechanisms affecting neural foundations of cognition and their change. In contrast to this approach, we tested whether cerebral correlates of general cognitive ability (GCA) in development could be extended to the rest of the lifespan, and whether early factors traceable to prenatal stages, such as birth weight and parental education, may exert continuous influences. We measured the area of the cerebral cortex in a longitudinal sample of 974 individuals aged 4-88 y (1,633 observations). An extensive cortical region was identified wherein area related positively to GCA in development. By tracking area of the cortical region identified in the child sample throughout the lifespan, we showed that the cortical change trajectories of higher and lower GCA groups were parallel through life, suggesting continued influences of early life factors. Birth weight and parental education obtained from the Norwegian Mother-Child Cohort study were identified as such early factors of possible life-long influence. Support for a genetic component was obtained in a separate twin sample (Vietnam Era Twin Study of Aging), but birth weight in the child sample had an effect on cortical area also when controlling for possible genetic differences in terms of parental height. Our results provide novel evidence for stability in brain-cognition relationships throughout life, and indicate that early life factors impact brain and cognition for the entire life course., Competing Interests: A.M.D. is a founder and holds equity in CorTechs Laboratories and also serves on its Scientific Advisory Board. The terms of this arrangement have been reviewed and approved by the University of California at San Diego, in accordance with its conflict of interest policies.

The human cerebral cortex undergoes a protracted, regionally heterogeneous development well into young adulthood. Cortical areas that expand the most during human development correspond to those that differ most markedly when the brains of macaque monkeys and humans are compared. However, it remains unclear to what extent this relationship derives from allometric scaling laws that apply to primate brains in general, or represents unique evolutionary adaptations. Furthermore, it is unknown whether the relationship only applies to surface area (SA), or also holds for cortical thickness (CT). In 331 participants aged 4 to 30, we calculated age functions of SA and CT, and examined the correspondence of human cortical development with macaque to human expansion, and with expansion across nonhuman primates. CT followed a linear negative age function from 4 to 30 years, while SA showed positive age functions until 12 years with little further development. Differential cortical expansion across primates was related to regional maturation of SA and CT, with age trajectories differing between high- and low-expanding cortical regions. This relationship adhered to allometric scaling laws rather than representing uniquely macaque-human differences: regional correspondence with human development was as large for expansion across nonhuman primates as between humans and macaque., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

A major task of contemporary cognitive neuroscience of aging is to explain why episodic memory declines. Change in resting-state functional connectivity (rsFC) could be a mechanism accounting for reduced function. We addressed this through 3 studies. In study 1, 119 healthy participants (20-83 years) were followed for 3.5 years with verbal recall testing and magnetic resonance imaging. Independent of atrophy, recall change was related to change in rsFC in anatomically widespread areas. Striking age-effects were observed in that a positive relationship between rsFC and memory characterized older participants while a negative relationship was seen among the younger and middle-aged. This suggests that cognitive consequences of rsFC change are not stable across age. In study 2 and 3, the age-dependent differences in rsFC-memory relationship were replicated by use of a simulation model (study 2) and by a cross-sectional experimental recognition memory task (study 3). In conclusion, memory changes were related to altered rsFC in an age-dependent manner, and future research needs to detail the mechanisms behind age-varying relationships., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is regarded a human-specific condition, and it has been suggested that brain regions highly expanded in humans compared with other primates are selectively targeted. We calculated shared and unique variance in the distribution of AD atrophy accounted for by cortical expansion between macaque and human, affiliation to the default mode network (DMN), ontogenetic development and normal aging. Cortical expansion was moderately related to atrophy, but a critical discrepancy was seen in the medial temporo-parietal episodic memory network. Identification of "hotspots" and "coldspots" of expansion across several primate species did not yield compelling evidence for the hypothesis that highly expanded regions are specifically targeted. Controlling for distribution of atrophy in aging substantially attenuated the expansion-AD relationship. A path model showed that all variables explained unique variance in AD atrophy but were generally mediated through aging. This supports a systems-vulnerability model, where critical networks are subject to various negative impacts, aging in particular, rather than being selectively targeted in AD. An alternative approach is suggested, focused on the interplay of the phylogenetically old and preserved medial temporal lobe areas with more highly expanded association cortices governed by different principles of plasticity and stability., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Advances in the treatment of acute lymphoblastic leukemia (ALL) have led to great improvements in survival rates and outcomes, but there is concern about cognitive late effects. We aimed to determine whether ALL survivors have smaller cortical surface area and/or thickness, and test whether this is related to disease and treatment variables and self-reported executive functioning in everyday life., Procedure: Magnetic resonance imaging (MRI) scans from 130 adult long-term survivors of childhood ALL (age: 18-46 years; age at diagnosis: 0-16 years; years since diagnosis: 7-40) and 130 healthy controls were assessed to estimate and compare regional cortical surface area and thickness. Information on disease and treatment factors were obtained from patients' records, and executive functioning in survivors was measured using a validated questionnaire (BRIEF-A)., Results: Smaller cortical surface area was observed in several regions in both cerebral hemispheres in ALL survivors. In these regions, mean surface area was 4.1-5.5% smaller in ALL survivors compared to healthy controls. In contrast, only one region showed lower cortical thickness in ALL survivors. There were no significant associations between cortical surface area/thickness in these regions and disease or treatment variables. In ALL survivors, smaller surface area in prefrontal regions, encompassing parts of the superior frontal gyri and the left anterior cingulate cortex, was associated with problems in executive functioning, specifically with emotional control and self-monitoring., Conclusions: ALL survivors had smaller surface area in several cortical regions and smaller surface area in prefrontal regions was associated with reported problems in executive functioning., (© 2015 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.)

We continuously encounter and process novel events in the surrounding world, but only some episodes will leave detailed memory traces that can be recollected after weeks and months. Here, our aim was to monitor brain activity during encoding of events that eventually transforms into long-term stable memories. Previous functional magnetic resonance imaging (fMRI) studies have shown that the degree of activation of different brain regions during encoding is predictive of later recollection success. However, most of these studies tested participants' memories the same day as encoding occurred, whereas several lines of research suggest that extended post-encoding processing is of crucial importance for long-term consolidation. Using fMRI, we tested whether the same encoding mechanisms are predictive of recollection success after hours as after a retention interval of several weeks. Seventy-eight participants were scanned during an associative encoding task and given a source memory test the same day or after ∼6 weeks. We found a strong link between regional activity levels during encoding and recollection success over short time intervals. However, results further showed that durable source memories, i.e., events recollected after several weeks, were not simply the events associated with the highest activity levels at encoding. Rather, strong levels of connectivity between the right hippocampus and perceptual areas, as well as with parts of the self-referential default-mode network, seemed instrumental in establishing durable source memories. Thus, we argue that an initial intensity-based encoding is necessary for short-term encoding of events, whereas additional processes involving hippocampal-cortical communication aid transformation into stable long-term memories., (Copyright © 2015 the authors 0270-6474/15/355202-11$15.00/0.)

Background: Extrauterine growth restriction is common among very low birth weight infants (VLBW, BW <1,500 g). Optimal postnatal nutrient supply is essential to limit growth restriction and ensure adequate growth and neurodevelopment., Objectives: We compared an enhanced postnatal nutrient supply to a standard supply and evaluated the effects on growth velocity, head circumference growth and cerebral maturation - the latter by magnetic resonance diffusion tensor imaging (DTI). We hypothesized increased growth velocity, head circumference growth and decreased mean diffusivity (MD) in cerebral white matter (WM) areas, suggesting improved cerebral maturation among infants on the enhanced nutrient supply., Methods: In this randomized controlled trial, infants on the enhanced nutrient supply received increased amounts of energy, protein, fat, essential fatty acids and vitamin A until discharge. DTI was performed close to term equivalent age. Outcomes were growth velocity, head circumference growth and WM mean diffusivity., Results: Among the 50 included infants, 14 in the intervention group and 11 controls underwent a successful DTI. Infants on the enhanced diet achieved improved growth velocity (16.5 vs. 13.8 g/kg/day, p = 0.01) and increased head circumference (Δz score: 0.24 vs. -0.12, p = 0.15). A significantly lower MD was seen in a large WM area such as the superior longitudinal fasciculi (1.19 × 10(-3) vs. 1.24 × 10(-3) mm(2)/s, p = 0.04, adjusted for age when scanned)., Conclusions: Enhanced nutrient supply to VLBW infants is associated with improved growth velocity, increased head circumference growth and decreased regional WM mean diffusivity, suggesting improved maturation of cerebral connective tracts., (© 2014 S. Karger AG, Basel.)

Alzheimer's disease (AD) has traditionally been regarded as a disease of the gray matter (GM). However, the advent of diffusion tensor imaging (DTI) has contributed to new knowledge about how changes in white matter (WM) microstructure in vivo may be directly related to the pathophysiology of AD. It is now evident that WM is heavily affected in AD, even at early stages. Still, our knowledge about WM degeneration in AD is poor compared to what we know about GM atrophy. For instance, it has not been clear if WM can be directly affected in AD independently of GM degeneration, or whether WM changes mainly represent secondary effects of GM atrophy, e.g. through Wallerian degeneration. In this paper, we review recent studies using DTI to study WM alterations in AD. These studies suggest that microstructural WM affection at pre-AD stages cannot completely be accounted for by concomitant GM atrophy. Further, recent research has demonstrated relationships between increased cerebrospinal fluid levels of Tau proteins and changes in WM microstructure indexed by DTI, which could indicate that WM degeneration in pre-AD stages is related to ongoing axonal damage. We conclude that DTI is a promising biomarker for AD, with the potential also to identify subgroups of patients with especially high degree of WM affection, thereby contributing to more differentiated pre-AD diagnoses. However, more research and validation studies are needed before it is realistic to use this information in clinical practice with individual patients., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)

Purpose: To compare regional brain volumes in adult long-term survivors of childhood acute lymphoblastic leukemia (ALL) and healthy controls., Patients and Methods: We investigated 130 survivors of childhood ALL diagnosed between 1970 and 2002 with magnetic resonance imaging (MRI) and neuropsychological testing at a median of 22.5 years after diagnosis. Morphometric analyses including whole-brain segmentation were performed using a validated automated procedure; 130 healthy adults served as controls., Results: Compared with healthy controls, ALL survivors showed significantly smaller volumes of cortical gray matter, cerebral white matter, amygdala, caudate, hippocampus, thalamus, and estimated intracranial volume. Effect sizes ranged from small to medium. The strongest effect was found for the caudate, which on average was 5.2% smaller in ALL survivors. Caudate volumes were also smaller when controlling for intracranial volume, suggesting a specific effect. Neither age at diagnosis nor treatment variables such as radiation therapy or drug dose had a major impact on neuroanatomic volumes. Neuropsychological assessment revealed reduced processing speed, executive function, and verbal learning/memory in survivors compared with controls but no difference in estimated general intellectual ability. In ALL survivors, but not in controls, neuropsychological test results correlated with volumes of cortical gray matter, caudate, and thalamus as well as intracranial volume., Conclusion: Structural MRI of long-term survivors of childhood ALL demonstrated smaller volumes of multiple brain structures compared with healthy controls. Because of possible selection biases, these results must be interpreted with caution. Future studies are required to clarify the significance of these findings and the neurobiologic mechanisms involved.

Purpose: To evaluate the relationship between (a) pathologic levels of cerebrospinal fluid (CSF) total tau as an index of the intensity of ongoing neuronal degeneration and (b) longitudinal changes in white matter (WM) integrity in patients with mild cognitive impairment (MCI)., Materials and Methods: Participants gave written informed consent, and the Norwegian committee for medical research ethics approved the study. Thirty patients with MCI and nonpathologic CSF total tau levels, nine patients with MCI and pathologic CSF total tau levels, and 16 age-matched healthy control subjects underwent diffusion-tensor imaging at baseline and after a mean follow-up of 2.6 years ± 0.54 (standard deviation), with range of 1.58-3.98 years. The effect of diagnosis (MCI vs no MCI) at baseline and CSF tau levels at fractional anisotropy (FA), mean diffusivity, radial diffusivity (D(R)), and axial diffusivity were tested with tract-based spatial statistics. Differences in WM integrity at baseline and follow-up and change over time were compared among patients with pathologic CSF total tau levels (MCI high tau), patients with normal CSF total tau levels (MCI low tau), and healthy control subjects. Linear mixed-model between-group within-subject analyses were conducted to examine differences in rate of change over time in FA and D(R)., Results: Longitudinal analysis of regional WM change revealed significant decrease in FA (P = .038) and increase in D(R) (P = .018) in the MCI high-tau group relative to control subjects. For D(R), the changes were regionally specific to the right cingulum and the right superior and inferior longitudinal fasciculi., Conclusion: Reduction in WM integrity was greater in patients with MCI who had the most intense neuronal degeneration as indexed by using CSF total tau, suggesting that these patients might represent a subgroup of MCI with more intense WM degeneration who are possibly at greater risk of developing Alzheimer disease., (RSNA, 2012)

When people make mistakes in speeded cognitive tasks, their response time on the next trial will typically be slower. This is referred to as post-error slowing (PES), and is important for optimization of performance, but its exact function remains to be decided. However, although PES is relatively stable over time, we have almost no knowledge about how PES is affected by structural brain characteristics. The aim of this study was to test to what extent white matter (WM) macro- and microstructure can account for individual differences in PES. PES was calculated for 255 healthy participants who performed a modified version of the Eriksen flanker task and underwent structural magnetic resonance imaging and diffusion tensor imaging (DTI). PES was positively related to WM volume in the caudal and rostral middle and superior frontal, medial orbitofrontal gyri and pars orbitalis. DTI analyses with tract-based spatial statistics (TBSS) showed that mean diffusivity in the superior longitudinal fasciculus, inferior fronto-occipital fasciculus and anterior thalamic radiation, as well as axial diffusivity in the corpus callosum, was negatively related to PES. Path analysis demonstrated that WM micro- and macrostructure were complementary in accounting for PES. It is concluded that individual differences in WM characteristics can partly explain why some people are better at adjusting their behavior in response to poor performance than others., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Increased performance variability has been demonstrated in several groups and conditions, including aging and cognitive decline. Structural brain characteristics underlying this phenomenon have so far been elusive. However, there is reason to expect that disconnectivity in associative pathways, whether caused by immature or degraded white matter (WM) tracts, will increase performance variability by neural noise. The aim of this study was to test whether the quality of WM, measured by diffusion tensor imaging, is related to performance variability in healthy adults. Intraindividual standard deviation of the reaction time (sdRT) across trials and median reaction time (mRT) from 270 participants were obtained from a speeded continuous performance task (Eriksen flanker task) with two conditions (congruent, incongruent). Tract-based spatial statistics was used to test the relationship with diffusion characteristics [fractional anisotropy (FA), mean diffusion (MD), radial diffusion (RD), axial diffusion (AD)]. Robust relationships between sdRT and all diffusion measures were found in most WM areas, independently of mRT, age, and sex. The effects were anatomically more widespread in the congruent than the incongruent condition, covering almost 50% of the voxels for RD and MD, and >25% of the voxels for FA and AD. Partial betas were in the range 0.45-0.55, and the strength of the relationships increased significantly with age. For mRT, the effects were smaller and unstable across condition. We concluded that performance variability is a likely consequence of individual differences in WM integrity, and that it is a promising behavioral correlate of individual differences in WM microstructure.

It is suggested that reductions in a medial temporo-parietal episodic memory network characterize Alzheimer's disease (AD), while changes in a fronto-striatal executive network characterize healthy aging. In the present study, magnetic resonance imaging (MRI) was used to test this directly. MRI scans of 372 participants from two samples were analyzed: Sample 1 consisted of 96 very mild to moderate AD patients, 93 healthy elderly (HE), and 137 young (HY), all with available MR scans, while Sample 2 consisted of 46 MCI patients, with available MR scans and measures of CSF biomarkers Abeta42 and tau protein. Substantial morphometric reductions of the medial temporo-parietal network were found in AD, while the fronto-striatal network was less affected. Both networks were affected by healthy aging, but the fronto-striatal to a greater degree than the medial temporo-parietal. Further exploratory analyses of 49 cortical and subcortical structures indicated no overlap between predictors of AD vs. HE and predictors of HE vs. HY. CSF biomarker pathology correlated with the medial temporo-parietal but not fronto-striatal network. Likewise, the AD-prone structures from the exploratory analyses were related to CSF biomarkers, while the aging-prone structures were not. It is concluded that the pattern of macrostructural brain changes in very mild to moderate AD can be clearly delineated from that of healthy aging.