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Background and ObjectivesDNA methylation algorithms are increasingly used to estimate biological aging; however, how these proposed measures of whole-organism biological aging relate to aging in the brain is not known. We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Framingham Heart Study (FHS) Offspring Cohort to test the association between blood-based DNA methylation measures of biological aging and cognitive impairment and dementia in older adults.MethodsWe tested 3 “generations” of DNA methylation age algorithms (first generation: Horvath and Hannum clocks; second generation: PhenoAge and GrimAge; and third generation: DunedinPACE, Dunedin Pace of Aging Calculated from the Epigenome) against the following measures of cognitive impairment in ADNI: clinical diagnosis of dementia and mild cognitive impairment, scores on Alzheimer disease (AD) / Alzheimer disease and related dementias (ADRD) screening tests (Alzheimer's Disease Assessment Scale, Mini-Mental State Examination, and Montreal Cognitive Assessment), and scores on cognitive tests (Rey Auditory Verbal Learning Test, Logical Memory test, and Trail Making Test). In an independent replication in the FHS Offspring Cohort, we further tested the longitudinal association between the DNA methylation algorithms and the risk of developing dementia.ResultsIn ADNI (N = 649 individuals), the first-generation (Horvath and Hannum DNA methylation age clocks) and the second-generation (PhenoAge and GrimAge) DNA methylation measures of aging were not consistently associated with measures of cognitive impairment in older adults. By contrast, a third-generation measure of biological aging, DunedinPACE, was associated with clinical diagnosis of Alzheimer disease (beta [95% CI] = 0.28 [0.08–0.47]), poorer scores on Alzheimer disease/ADRD screening tests (beta [Robust SE] = −0.10 [0.04] to 0.08[0.04]), and cognitive tests (beta [Robust SE] = −0.12 [0.04] to 0.10 [0.03]). The association between faster pace of aging, as measured by DunedinPACE, and risk of developing dementia was confirmed in a longitudinal analysis of the FHS Offspring Cohort (N = 2,264 individuals, hazard ratio [95% CI] = 1.27 [1.07–1.49]).DiscussionThird-generation blood-based DNA methylation measures of aging could prove valuable for measuring differences between individuals in the rate at which they age and in their risk for cognitive decline, and for evaluating interventions to slow aging.

Although higher-order cognitive and lower-order sensorimotor abilities are generally regarded as distinct and studied separately, there is evidence that they not only covary but also that this covariation increases across the lifespan. This pattern has been leveraged in clinical settings where a simple assessment of sensory or motor ability (e.g. hearing, gait speed) can forecast age-related cognitive decline and risk for dementia. However, the brain mechanisms underlying cognitive, sensory, and motor covariation are largely unknown. Here, we examined whether such covariation in midlife reflects variability in common versus distinct neocortical networks using individualized maps of functional topography derived from BOLD fMRI data collected in 769 45-year-old members of a population-representative cohort. Analyses revealed that variability in basic motor but not hearing ability reflected individual differences in the functional topography of neocortical networks typically supporting cognitive ability. These patterns suggest that covariation in motor and cognitive abilities in midlife reflects convergence of function in higher-order neocortical networks and that gait speed may not be simply a measure of physical function but rather an integrative index of nervous system health.

Functional MRI (fMRI) has considerable potential as a translational tool for understanding risk, prioritizing interventions, and improving the treatment of brain disorders. However, recent studies have found that many of the most widely used fMRI measures have low reliability, undermining this potential. Here, we argue that many fMRI measures are unreliable because they were designed to identify group-effects, not to precisely quantify individual differences. We then highlight four emerging strategies (extended aggregation, reliability modeling, multi-echo fMRI, and stimulus design) that build on established psychometric properties to generate more precise and reliable fMRI measures. By adopting such strategies to improve reliability, we are optimistic that fMRI can fulfill its potential as a clinical tool.

Knowledge of a person’s risk for Alzheimer’s disease and related dementias (ADRDs) is required to triage candidates for preventive interventions, surveillance, and treatment trials. ADRD risk indexes exist for this purpose, but each includes only a subset of known risk factors. Information missing from published indexes could improve risk prediction. In the Dunedin Study of a population-representative New Zealand-based birth cohort followed to midlife (N = 938, 49.5% female), we compared associations of four leading risk indexes with midlife antecedents of ADRD against a novel benchmark index comprised of nearly all known ADRD risk factors, the Dunedin ADRD Risk Benchmark (DunedinARB). Existing indexes included the Cardiovascular Risk Factors, Aging, and Dementia index (CAIDE), LIfestyle for BRAin health index (LIBRA), Australian National University Alzheimer’s Disease Risk Index (ANU-ADRI), and risks selected by the Lancet Commission on Dementia. The Dunedin benchmark was comprised of 48 separate indicators of risk organized into 10 conceptually distinct risk domains. Midlife antecedents of ADRD treated as outcome measures included age-45 measures of brain structural integrity [magnetic resonance imaging-assessed: (i) machine-learning-algorithm-estimated brain age, (ii) log-transformed volume of white matter hyperintensities, and (iii) mean grey matter volume of the hippocampus] and measures of brain functional integrity [(i) objective cognitive function assessed via the Wechsler Adult Intelligence Scale-IV, (ii) subjective problems in everyday cognitive function, and (iii) objective cognitive decline measured as residualized change in cognitive scores from childhood to midlife on matched Weschler Intelligence scales]. All indexes were quantitatively distributed and proved informative about midlife antecedents of ADRD, including algorithm-estimated brain age (β's from 0.16 to 0.22), white matter hyperintensities volume (β's from 0.16 to 0.19), hippocampal volume (β's from −0.08 to −0.11), tested cognitive deficits (β's from −0.36 to −0.49), everyday cognitive problems (β's from 0.14 to 0.38), and longitudinal cognitive decline (β's from −0.18 to −0.26). Existing indexes compared favourably to the comprehensive benchmark in their association with the brain structural integrity measures but were outperformed in their association with the functional integrity measures, particularly subjective cognitive problems and tested cognitive decline. Results indicated that existing indexes could be improved with targeted additions, particularly of measures assessing socioeconomic status, physical and sensory function, epigenetic aging, and subjective overall health. Existing premorbid ADRD risk indexes perform well in identifying linear gradients of risk among members of the general population at midlife, even when they include only a small subset of potential risk factors. They could be improved, however, with targeted additions to more holistically capture the different facets of risk for this multiply determined, age-related disease.

Past research on the brain correlates of trait anger has been limited by small sample sizes, a focus on relatively few regions-of-interest, and poor test-retest reliability of functional brain measures. To address these limitations, we conducted a data-driven analysis of variability in connectome-wide general functional connectivity, which has good test-retest reliability, in a sample of 1,048 young adult volunteers. Multi-dimensional matrix regression analysis showed that individual differences in self-reported trait anger maps onto variability in the whole-brain functional connectivity patterns of three brain regions that serve action-related functions: bilateral supplementary motor area (SMA) and the right lateral frontal pole. Follow-up seed-based analysis confirmed that high trait anger is associated with hyperconnectivity between these three regions and the somatomotor network as well as hyperconnectivity and hypoconnectivity between SMA and default mode and visual networks, respectively. Supplementary targeted analyses based on theoretical and empirical grounds further revealed that high trait anger is associated with hyperconnectivity between the amygdala and dorsomedial prefrontal cortex, dorsal anterior cingulate cortex, and striatum. These patterns suggest that the dispositional tendency to more easily experience frustration and anger is associated with variability in the functional connectivity of brain networks supporting somatomotor, affective, self-referential, and visual information processes. The emergence of action-related brain regions from our connectome-wide analysis is consistent with trait anger as reflecting a greater propensity to provoked action.

Some humans age faster than others. Variation in biological aging can be measured in midlife, but the implications of this variation are poorly understood. We tested associations between midlife biological aging and indicators of future frailty risk in the Dunedin cohort of 1,037 infants born the same year and followed to age 45. Participants’ ‘Pace of Aging’ was quantified by tracking declining function in 19 biomarkers indexing the cardiovascular, metabolic, renal, immune, dental and pulmonary systems across ages 26, 32, 38 and 45 years. At age 45 in 2019, participants with faster Pace of Aging had more cognitive difficulties, signs of advanced brain aging, diminished sensory–motor functions, older appearances and more pessimistic perceptions of aging. People who are aging more rapidly than same-age peers in midlife may prematurely need supports to sustain independence that are usually reserved for older adults. Chronological age does not adequately identify need for such supports. A cohort study tracking 20-year age-related declines in multiple organ systems finds that, already by midlife, those aging fastest showed cognitive declines, signs of brain aging, diminished sensory–motor function and negative views about aging.

IMPORTANCE: Childhood lead exposure has been linked to disrupted brain development, but long-term consequences for structural brain integrity are unknown. OBJECTIVE: To test the hypothesis that childhood lead exposure is associated with magnetic resonance imaging (MRI) measurements of lower structural integrity of the brain in midlife. DESIGN, SETTING, AND PARTICIPANTS: The Dunedin Study followed a population-representative 1972-1973 birth cohort in New Zealand (N = 564 analytic sample) to age 45 years (until April 2019). EXPOSURES: Childhood blood lead levels measured at age 11 years. MAIN OUTCOMES AND MEASURES: Structural brain integrity at age 45 years assessed via MRI (primary outcomes): gray matter (cortical thickness, surface area, hippocampal volume), white matter (white matter hyperintensities, fractional anisotropy [theoretical range, 0 {diffusion is perfectly isotropic} to 100 {diffusion is perfectly anisotropic}]), and the Brain Age Gap Estimation (BrainAGE), a composite index of the gap between chronological age and a machine learning algorithm–estimated brain age (0 indicates a brain age equivalent to chronological age; positive and negative values represent an older and younger brain age, respectively). Cognitive function at age 45 years was assessed objectively via the Wechsler Adult Intelligence Scale IV (IQ range, 40-160, standardized to a mean of 100 [SD, 15]) and subjectively via informant and self-reports (z-score units; scale mean, 0 [SD, 1]). RESULTS: Of 1037 original participants, 997 were alive at age 45 years, of whom 564 (57%) had received lead testing at age 11 years (302 [54%] male) (median follow-up, 34 [interquartile range, 33.7-34.7] years). Mean blood lead level at age 11 years was 10.99 (SD, 4.63) μg/dL. After adjusting for covariates, each 5-μg/dL higher childhood blood lead level was significantly associated with 1.19-cm(2) smaller cortical surface area (95% CI, −2.35 to −0.02 cm(2); P = .05), 0.10-cm(3) smaller hippocampal volume (95% CI, −0.17 to −0.03 cm(3); P = .006), lower global fractional anisotropy (b = −0.12; 95% CI, −0.24 to −0.01; P = .04), and a BrainAGE index 0.77 years older (95% CI, 0.02-1.51 years; P = .05) at age 45 years. There were no statistically significant associations between blood lead level and log-transformed white matter hyperintensity volume (b = 0.05 log mm(3); 95% CI, −0.02 to 0.13 log mm(3); P = .17) or mean cortical thickness (b = −0.004 mm; 95% CI, −0.012 to 0.004 mm; P = .39). Each 5-μg/dL higher childhood blood lead level was significantly associated with a 2.07-point lower IQ score at age 45 years (95% CI, −3.39 to −0.74; P = .002) and a 0.12-point higher score on informant-rated cognitive problems (95% CI, 0.01-0.23; P = .03). There was no statistically significant association between childhood blood lead levels and self-reported cognitive problems (b = −0.02 points; 95% CI, −0.10 to 0.07; P = .68). CONCLUSIONS AND RELEVANCE: In this longitudinal cohort study with a median 34-year follow-up, higher childhood blood lead level was associated with differences in some MRI measures of brain structure that suggested lower structural brain integrity in midlife. Because of the large number of statistical comparisons, some findings may represent type I error.

Children at a higher risk of lead exposure develop smaller brain cortical surface area and volume, but only if they are from low-income families.

Williams syndrome is a rare genetic disorder caused by hemizygous deletion of ∼1.6 Mb affecting 26 genes on chromosome 7 (7q11.23) and is clinically typified by two cognitive/behavioural hallmarks: marked visuospatial deficits relative to verbal and non-verbal reasoning abilities and hypersocial personality. Clear knowledge of the circumscribed set of genes that are affected in Williams syndrome, along with the well-characterized neurobehavioural phenotype, offers the potential to elucidate neurogenetic principles that may apply in genetically and clinically more complex settings. The intraparietal sulcus, in the dorsal visual processing stream, has been shown to be structurally and functionally altered in Williams syndrome, providing a target for investigating resting-state functional connectivity and effects of specific genes hemideleted in Williams syndrome. Here, we tested for effects of the LIMK1 gene, deleted in Williams syndrome and important for neuronal maturation and migration, on intraparietal sulcus functional connectivity. We first defined a target brain phenotype by comparing intraparietal sulcus resting functional connectivity in individuals with Williams syndrome, in whom LIMK1 is hemideleted, with typically developing children. Then in two separate cohorts from the general population, we asked whether intraparietal sulcus functional connectivity patterns similar to those found in Williams syndrome were associated with sequence variation of the LIMK1 gene. Four independent between-group comparisons of resting-state functional MRI data (total n = 510) were performed: (i) 20 children with Williams syndrome compared to 20 age- and sex-matched typically developing children; (ii) a discovery cohort of 99 healthy adults stratified by LIMK1 haplotype; (iii) a replication cohort of 32 healthy adults also stratified by LIMK1 haplotype; and (iv) 339 healthy adolescent children stratified by LIMK1 haplotype. For between-group analyses, differences in intraparietal sulcus resting-state functional connectivity were calculated comparing children with Williams syndrome to matched typically developing children and comparing LIMK1 haplotype groups in each of the three general population cohorts separately. Consistent with the visuospatial construction impairment and hypersocial personality that typify Williams syndrome, the Williams syndrome cohort exhibited opposite patterns of intraparietal sulcus functional connectivity with visual processing regions and social processing regions: decreased circuit function in the former and increased circuit function in the latter. All three general population groups also showed LIMK1 haplotype-related differences in intraparietal sulcus functional connectivity localized to the fusiform gyrus, a visual processing region also identified in the Williams syndrome-typically developing comparison. These results suggest a neurogenetic mechanism, in part involving LIMK1, that may bias neural circuit function in both the general population and individuals with Williams syndrome.

Significance We followed a population-representative cohort of children from birth to their mid-forties. As adults, children with better self-control aged more slowly in their bodies; showed fewer signs of brain aging; and were more equipped to manage later-life health, financial, and social demands. The effects of children’s self-control were separable from their socioeconomic origins and intelligence. Children changed in their rank order of self-control across age, suggesting the hypothesis that it is a malleable intervention target. Adults’ self-control was associated with their aging outcomes independently of their childhood self-control, indicating that midlife might offer another intervention window. Programs that are successful in increasing self-control might extend both the length (life span) and quality (health span) of life., The ability to control one’s own emotions, thoughts, and behaviors in early life predicts a range of positive outcomes in later life, including longevity. Does it also predict how well people age? We studied the association between self-control and midlife aging in a population-representative cohort of children followed from birth to age 45 y, the Dunedin Study. We measured children’s self-control across their first decade of life using a multi-occasion/multi-informant strategy. We measured their pace of aging and aging preparedness in midlife using measures derived from biological and physiological assessments, structural brain-imaging scans, observer ratings, self-reports, informant reports, and administrative records. As adults, children with better self-control aged more slowly in their bodies and showed fewer signs of aging in their brains. By midlife, these children were also better equipped to manage a range of later-life health, financial, and social demands. Associations with children’s self-control could be separated from their social class origins and intelligence, indicating that self-control might be an active ingredient in healthy aging. Children also shifted naturally in their level of self-control across adult life, suggesting the possibility that self-control may be a malleable target for intervention. Furthermore, individuals’ self-control in adulthood was associated with their aging outcomes after accounting for their self-control in childhood, indicating that midlife might offer another window of opportunity to promote healthy aging.

Background Childhood adversity has been previously associated with alterations in brain structure, but heterogeneous designs, methods, and measures have contributed to mixed results and have impeded progress in mapping the biological embedding of childhood adversity. We sought to identify long-term differences in structural brain integrity associated with childhood adversity. Methods Multiple regression was used to test associations between prospectively ascertained adversity during childhood and adversity retrospectively reported in adulthood with structural magnetic resonance imaging measures of midlife global and regional cortical thickness, cortical surface area, and subcortical gray matter volume in 861 (425 female) members of the Dunedin Study, a longitudinal investigation of a population-representative birth cohort. Results Both prospectively ascertained childhood adversity and retrospectively reported adversity were associated with alterations in midlife structural brain integrity, but associations with prospectively ascertained childhood adversity were consistently stronger and more widely distributed than associations with retrospectively reported childhood adversity. Sensitivity analyses revealed that these associations were not driven by any particular adversity or category of adversity (i.e., threat or deprivation) or by childhood socioeconomic disadvantage. Network enrichment analyses revealed that these associations were not localized but were broadly distributed along a hierarchical cortical gradient of information processing. Conclusions Exposure to childhood adversity broadly is associated with widespread differences in midlife gray matter across cortical and subcortical structures, suggesting that biological embedding of childhood adversity in the brain is long lasting, but not localized. Research using retrospectively reported adversity likely underestimates the magnitude of these associations. These findings may inform future research investigating mechanisms through which adversity becomes embedded in the brain and influences mental health and cognition.

Identifying brain biomarkers of disease risk is a growing priority in neuroscience. The ability to identify meaningful biomarkers is limited by measurement reliability; unreliable measures are unsuitable for predicting clinical outcomes. Measuring brain activity using task functional MRI (fMRI) is a major focus of biomarker development; however, the reliability of task fMRI has not been systematically evaluated. We present converging evidence demonstrating poor reliability of task-fMRI measures. First, a meta-analysis of 90 experiments ( N = 1,008) revealed poor overall reliability—mean intraclass correlation coefficient (ICC) = .397. Second, the test-retest reliabilities of activity in a priori regions of interest across 11 common fMRI tasks collected by the Human Connectome Project ( N = 45) and the Dunedin Study ( N = 20) were poor (ICCs = .067–.485). Collectively, these findings demonstrate that common task-fMRI measures are not currently suitable for brain biomarker discovery or for individual-differences research. We review how this state of affairs came to be and highlight avenues for improving task-fMRI reliability.

Key Points Question Do mental disorder life histories shift among different successive disorders? Findings In this cohort study of 1037 participants in the Dunedin Study birth cohort, with assessments from ages 11 to 45 years, mental disorder life histories shifted among different successive internalizing, externalizing, and thought disorders. Mental disorder life histories are better described by age of onset, duration, and diversity of disorder than by any particular diagnosis. Meaning The finding that most mental disorder life histories involve different successive disorders helps to account for genetic and neuroimaging findings pointing to transdiagnostic causes and cautions against overreliance on diagnosis-specific research and clinical protocols., This cohort study describes mental disorder life histories across 4 decades among participants in the Dunedin Study., Importance Mental health professionals typically encounter patients at 1 point in patients’ lives. This cross-sectional window understandably fosters focus on the current presenting diagnosis. Research programs, treatment protocols, specialist clinics, and specialist journals are oriented to presenting diagnoses, on the assumption that diagnosis informs about causes and prognosis. This study tests an alternative hypothesis: people with mental disorders experience many different kinds of disorders across diagnostic families, when followed for 4 decades. Objective To describe mental disorder life histories across the first half of the life course. Design, Setting, and Participants This cohort study involved participants born in New Zealand from 1972 to 1973 who were enrolled in the population-representative Dunedin Study. Participants were observed from birth to age 45 years (until April 2019). Data were analyzed from May 2019 to January 2020. Main Outcomes and Measures Diagnosed impairing disorders were assessed 9 times from ages 11 to 45 years. Brain function was assessed through neurocognitive examinations conducted at age 3 years, neuropsychological testing during childhood and adulthood, and midlife neuroimaging-based brain age. Results Of 1037 original participants (535 male [51.6%]), 1013 had mental health data available. The proportions of participants meeting the criteria for a mental disorder were as follows: 35% (346 of 975) at ages 11 to 15 years, 50% (473 of 941) at age 18 years, 51% (489 of 961) at age 21 years, 48% (472 of 977) at age 26 years, 46% (444 of 969) at age 32 years, 45% (429 of 955) at age 38 years, and 44% (407 of 927) at age 45 years. The onset of the disorder occurred by adolescence for 59% of participants (600 of 1013), eventually affecting 86% of the cohort (869 of 1013) by midlife. By age 45 years, 85% of participants (737 of 869) with a disorder had accumulated comorbid diagnoses. Participants with adolescent-onset disorders subsequently presented with disorders at more past-year assessments (r = 0.71; 95% CI, 0.68 to 0.74; P

Background To understand and measure the association between chronic inflammation, aging, and age-related diseases, broadly applicable standard biomarkers of systemic chronic inflammation are needed. We tested whether elevated blood levels of the emerging chronic inflammation marker soluble urokinase plasminogen activator receptor (suPAR) were associated with accelerated aging, lower functional capacity, and cognitive decline. Methods We used data from the Dunedin Study, a population-representative 1972–1973 New Zealand birth cohort (n = 1037) that has observed participants to age 45 years. Plasma suPAR levels were analyzed at ages 38 and 45 years. We performed regression analyses adjusted for sex, smoking, C-reactive protein, and current health conditions. Results Of 997 still-living participants, 875 (88%) had plasma suPAR measured at age 45. Elevated suPAR was associated with accelerated pace of biological aging across multiple organ systems, older facial appearance, and with structural signs of older brain age. Moreover, participants with higher suPAR levels had greater decline in physical function and cognitive function from childhood to adulthood compared to those with lower suPAR levels. Finally, improvements in health habits between ages 38 and 45 (smoking cessation or increased physical activity) were associated with less steep increases in suPAR levels over those years. Conclusions Our findings provide initial support for the utility of suPAR in studying the role of chronic inflammation in accelerated aging and functional decline.

An individual’s brainAGE is the difference between chronological age and age predicted from machine-learning models of brain-imaging data. BrainAGE has been proposed as a biomarker of age-related deterioration of the brain. Having an older brainAGE has been linked to Alzheimer’s, dementia, and mortality. However, these findings are largely based on cross-sectional associations which can confuse age differences with cohort differences. To illuminate the validity of brainAGE as a biomarker of accelerated brain aging, a study is needed of a large cohort all born in the same year who nevertheless vary on brainAGE. In the Dunedin Study, a population-representative 1972–73 birth cohort, we measured brainAGE at age 45 years, as well as the pace of biological aging and cognitive decline in longitudinal data from childhood to midlife (N = 869). In this cohort, all chronological age 45 years, brainAGE was measured reliably (ICC = 0.81) and ranged from 24 to 72 years. Those with older midlife brainAGEs tended to have poorer cognitive function in both adulthood and childhood, as well as impaired brain health at age 3. Furthermore, those with older brainAGEs had an accelerated pace of biological aging, older facial appearance, and early signs of cognitive decline from childhood to midlife. These findings help to validate brainAGE as a potential surrogate biomarker for midlife intervention studies that seek to measure dementia-prevention efforts in midlife. However, the findings also caution against the assumption that brainAGE scores represent only age-related deterioration of the brain as they may also index central nervous system variation present since childhood.

Background Low replication rates are a concern in most, if not all, scientific disciplines. In psychiatric genetics specifically, targeting intermediate brain phenotypes, which are more closely associated with putative genetic effects, was touted as a strategy leading to increased power and replicability. In the current study, we attempted to replicate previously published associations between single nucleotide polymorphisms and threat-related amygdala reactivity, which represents a robust brain phenotype not only implicated in the pathophysiology of multiple disorders, but also used as a biomarker of future risk. Methods We conducted a literature search for published associations between single nucleotide polymorphisms and threat-related amygdala reactivity and found 37 unique findings. Our replication sample consisted of 1117 young adult volunteers (629 women, mean age 19.72 ± 1.25 years) for whom both genetic and functional magnetic resonance imaging data were available. Results Of the 37 unique associations identified, only three replicated as previously reported. When exploratory analyses were conducted with different model parameters compared to the original findings, significant associations were identified for 28 additional studies: eight of these were for a different contrast/laterality; five for a different gender and/or race/ethnicity; and 15 in the opposite direction and for a different contrast, laterality, gender, and/or race/ethnicity. No significant associations, regardless of model parameters, were detected for six studies. Notably, none of the significant associations survived correction for multiple comparisons. Conclusions We discuss these patterns of poor replication with regard to the general strategy of targeting intermediate brain phenotypes in genetic association studies and the growing importance of advancing the replicability of imaging genetics findings.

ObjectiveNeuroimaging research has revealed that structural brain alterations are common across broad diagnostic families of disorders rather than specific to a single psychiatric disorder. Such overlap in the structural brain correlates of mental disorders mirrors already well-documented phenotypic comorbidity of psychiatric symptoms and diagnoses, which can be indexed by a general psychopathology or p factor. We hypothesized that if general psychopathology drives the convergence of structural alterations common across disorders then 1) there should be few associations unique to any one diagnostic family of disorders, and 2) associations with the p factor should overlap with those for the broader diagnostic families.MethodsAnalyses were conducted on structural MRI and psychopathology data collected from 861 members of the population representative Dunedin Study at age 45.ResultsStudy members with high scores across three broad diagnostic families of disorders (Externalizing, Internalizing, Thought Disorder) exhibited highly overlapping patterns of reduced global and widely distributed parcel-wise neocortical thickness. Study members with high p factor scores exhibited patterns of reduced global and parcel-wise neocortical thickness nearly identical to those associated with the three broad diagnostic families.ConclusionsA pattern of pervasively reduced neocortical thickness appears common across all forms of mental disorders and may represent a transdiagnostic feature of general psychopathology. As has been documented with regard to symptoms and diagnoses, the underlying brain structural correlates of mental disorders may not exhibit specificity, the continued pursuit of which may limit progress toward more effective strategies for etiological understanding, prevention, and intervention.

Introduction Previous research has identified specific brain regions associated with regulating emotion using common strategies such as expressive suppression and cognitive reappraisal. However, most research focuses on a priori regions and directs participants how to regulate, which may not reflect how people naturally regulate outside the laboratory. Method Here, we used a data‐driven approach to investigate how individual differences in distributed intrinsic functional brain connectivity predict emotion regulation tendency outside the laboratory. Specifically, we used connectome‐based predictive modeling to extract functional connections in the brain significantly related to the dispositional use of suppression and reappraisal. These edges were then used in a predictive model and cross‐validated in novel participants to identify a neural signature that reflects individual differences in the tendency to suppress and reappraise emotion. Results We found a significant neural signature for the dispositional use of suppression, but not reappraisal. Within this whole‐brain signature, the intrinsic connectivity of the default mode network was most informative of suppression tendency. In addition, the predictive performance of this model was significant in males, but not females. Conclusion These findings help inform how whole‐brain networks of functional connectivity characterize how people tend to regulate emotion outside the laboratory., Here, we used a data‐driven approach to investigate how individual differences in distributed intrinsic functional brain connectivity predict emotion regulation tendency. We found a significant neuromarker of dispositional use of suppression, but not reappraisal. These findings help inform how whole‐brain networks of functional connectivity characterize how people tend to regulate emotion outside the laboratory.

White matter hyperintensities proliferate as the brain ages and are associated with increased risk for cognitive decline as well as Alzheimer’s disease and related dementias. As such, white matter hyperintensities have been targeted as a surrogate biomarker in intervention trials with older adults. However, it is unclear at what stage of aging white matter hyperintensities begin to relate to cognition and if they may be a viable target for early prevention. In the Dunedin Study, a population-representative cohort followed since birth, we measured white matter hyperintensities in 843 45-year-old participants using T2-weighted magnetic resonance imaging and we assessed cognitive decline from childhood to midlife. We found that white matter hyperintensities were common at age 45 and that white matter hyperintensity volume was modestly associated with both lower childhood (ß = −0.08, P = 0.013) and adult IQ (ß=−0.15, P, White matter hyperintensities, which are associated with dementia risk in older adults, were found to be common in a population-representative birth cohort at age 45 and already associated with cognitive decline since childhood. This suggests they may be useful as surrogate biomarkers in dementia prevention trials targeting midlife., Graphical Abstract Graphical Abstract

Identifying brain biomarkers of disease risk is a growing priority in neuroscience. The ability to identify meaningful biomarkers is limited by measurement reliability; unreliable measures are unsuitable for predicting clinical outcomes. Measuring brain activity using task-fMRI is a major focus of biomarker development; however, the reliability of task-fMRI has not been systematically evaluated. We present converging evidence demonstrating poor reliability of task-fMRI measures. First, a meta-analysis of 90 experiments (N=1,008) revealed poor overall reliability (mean ICC=.397). Second, the test-retest reliabilities of activity in a priori regions of interest across 11 common fMRI tasks collected in the context of the Human Connectome Project (N=45) and the Dunedin Study (N=20) were poor (ICCs=.067-.485). Collectively, these findings demonstrate that common task-fMRI measures are not currently suitable for brain biomarker discovery or individual differences research. We review how this state of affairs came to be and highlight avenues for improving task-fMRI reliability.

Accumulating research suggests that the pro-inflammatory cytokine interleukin-1β (IL-1β) has a modulatory effect on the hippocampus, a brain structure important for learning and memory as well as linked with both psychiatric and neurodegenerative disorders. Here, we used an imaging genetics strategy to test an association between an IL-1β polygenic score and hippocampal volume in two independent samples. Our polygenic score was derived using summary statistics from a recent genome-wide association study of circulating cytokines that included IL-1β (N = 3,309). In the first sample of 512 non-Hispanic Caucasian university students (274 women, mean age 19.78 ± 1.24 years) from the Duke Neurogenetics Study, we identified a significant positive correlation between IL-1β polygenic scores and hippocampal volume. This positive association was successfully replicated in a second sample of 7,960 white British volunteers (4,158 women, mean age 62.63 ± 7.45 years) from the UK Biobank. Our results lend further support in humans, to the link between IL-1β and the structure of the hippocampus.

Accumulating research suggests that the pro-inflammatory cytokine interleukin-1β (IL-1β) has a modulatory effect on the hippocampus, a brain structure important for learning and memory as well as linked with both psychiatric and neurodegenerative disorders. Here, we use an imaging genetics strategy to test an association between an IL-1β polygenic score, derived from summary statistics of a recent genome-wide association study (GWAS) of circulating cytokines, and hippocampal volume, in two independent samples. In the first sample of 512 non-Hispanic Caucasian university students (274 women, mean age 19.78 ± 1.24 years) from the Duke Neurogenetics Study, we identified a significant positive correlation between higher polygenic scores, which presumably reflect higher circulating IL-1β levels, and average hippocampal volume. This positive association was successfully replicated in a second sample of 7,960 white British volunteers (4,158 women, mean age 62.63±7.45 years) from the UK Biobank. Collectively, our results suggest that a functional GWAS-derived score of IL-1β blood circulating levels affects hippocampal volume, and lend further support in humans, to the link between IL-1β and the structure of the hippocampus.

The global population is aging, leading to an increasing burden of age-related neurodegenerative disease. Efforts to intervene against age-related dementias in older adults have generally proven ineffective. These failures suggest that a lifetime of brain aging may be difficult to reverse once widespread deterioration has occurred. To test interventions in younger populations, biomarkers of brain aging are needed that index subtle signs of accelerated brain deterioration that are part of the putative pathway to dementia. Here I review potential MRI-based biomarkers that could connect midlife brain aging to later life dementia. I survey the literature with three questions in mind, 1) Does the biomarker index age-related changes across the lifespan? 2) Does the biomarker index cognitive ability and cognitive decline? 3) Is the biomarker sensitive to known risk factors for dementia? I find that while there is preliminary support for some midlife MRI-based biomarkers for accelerated aging, the longitudinal research that would best answer these questions is still in its infancy and needs to be further developed. I conclude with suggestions for future research.

Amongst a number of negative life sequelae associated with childhood adversity is the later expression of a higher dispositional tendency to experience anger and frustration to a wide range of situations (i.e., trait anger). We recently reported that an association between childhood adversity and trait anger is moderated by individual differences in both threat-related amygdala activity and executive control-related dorsolateral prefrontal cortex (dlPFC) activity, wherein individuals with relatively low amygdala and high dlPFC activity do not express higher trait anger even when having experienced childhood adversity. Here, we examine possible structural correlates of this functional dynamic using diffusion magnetic resonance imaging data from 647 young adult men and women volunteers. Specifically, we tested whether the degree of white matter microstructural integrity as indexed by fractional anisotropy modulated the association between childhood adversity and trait anger. Our analyses revealed that higher microstructural integrity of multiple pathways was associated with an attenuated link between childhood adversity and adult trait anger. Amongst these pathways was the uncinate fasciculus, which not only provides a major anatomical link between the amygdala and prefrontal cortex but also is associated with individual differences in regulating negative emotion through top-down cognitive reappraisal. These findings suggest that higher microstructural integrity of distributed white matter pathways including but not limited to the uncinate fasciculus may represent an anatomical foundation serving to buffer against the expression of childhood adversity as later trait anger, which is itself associated with multiple negative health outcomes.

People who score higher on intelligence tests tend to have larger brains. Twin studies suggest the same genetic factors influence both brain size and intelligence. This has led to the hypothesis that genetics influence intelligence partly by contributing to development of larger brains. We tested this hypothesis with molecular genetic data using discoveries from a genome-wide association study (GWAS) of educational attainment, a correlate of intelligence. We analyzed genetic, brain imaging, and cognitive test data from the UK Biobank, the Dunedin Study, the Brain Genomics Superstruct Project (GSP), and the Duke Neurogenetics Study (DNS) (combined N=8,271). We measured genetics using polygenic scores based on published GWAS. We conducted meta-analysis to test associations among participants’ genetics, total brain volume (i.e., brain size), and cognitive test performance. Consistent with previous findings, participants with higher polygenic scores achieved higher scores on cognitive tests, as did participants with larger brains. Participants with higher polygenic scores also had larger brains. We found some evidence that brain size partly mediated associations between participants’ education polygenic scores and their cognitive test performance. Effect-sizes were larger in the population-based UK Biobank and Dunedin samples than in the GSP and DNS samples. Sensitivity analysis suggested this effect-size difference partly reflected restricted range of cognitive performance in the GSP and DNS samples. Recruitment and retention of population-representative samples should be a priority for neuroscience research. Findings suggest promise for studies integrating GWAS discoveries with brain imaging data to understand neurobiology linking genetics with individual differences in cognitive performance.

Background High rates of comorbidity, shared risk, and overlapping therapeutic mechanisms have led psychopathology research toward transdiagnostic dimensional investigations of clustered symptoms. One influential framework accounts for these transdiagnostic phenomena through a single general factor, sometimes referred to as the p factor, associated with risk for all common forms of mental illness. Methods We build on previous research identifying unique structural neural correlates of the p factor by conducting a data-driven analysis of connectome-wide intrinsic functional connectivity (n = 605). Results We demonstrate that higher p factor scores and associated risk for common mental illness maps onto hyperconnectivity between visual association cortex and both frontoparietal and default mode networks. Conclusions These results provide initial evidence that the transdiagnostic risk for common forms of mental illness is associated with patterns of inefficient connectome-wide intrinsic connectivity between visual association cortex and networks supporting executive control and self-referential processes, networks that are often impaired across categorical disorders.

Sleep disturbances represent one risk factor for depression. Reward-related brain function, particularly the activity of the ventral striatum (VS), has been identified as a potential buffer against stress-related depression. We were therefore interested in testing whether reward-related VS activity would moderate the effect of sleep disturbances on depression in a large cohort of young adults. Data were available from 1129 university students (mean age 19.71 ± 1.25 years; 637 women) who completed a reward-related functional MRI task to assay VS activity and provided self-reports of sleep using the Pittsburgh Sleep Quality Index and symptoms of depression using a summation of the General Distress/Depression and Anhedonic Depression subscales of the Mood and Anxiety Symptoms Questionnaire-short form. Analyses revealed that as VS activity increased the association between sleep disturbances and depressive symptoms decreased. The interaction between sleep disturbances and VS activity was robust to the inclusion of sex, age, race/ethnicity, past or present clinical disorder, early and recent life stress, and anxiety symptoms, as well as the interactions between VS activity and early or recent life stress as covariates. We provide initial evidence that high reward-related VS activity may buffer against depressive symptoms associated with poor sleep. Our analyses help advance an emerging literature supporting the importance of individual differences in reward-related brain function as a potential biomarker of relative risk for depression.SIGNIFICANCE STATEMENTSleep disturbances are a common risk factor for depression. An emerging literature suggests that reward-related activity of the ventral striatum (VS), a brain region critical for motivation and goal-directed behavior, may buffer against the effect of negative experiences on the development of depression. Using data from a large sample of 1129 university students we demonstrate that as reward-related VS activity increases, the link between sleep disturbances and depression decreases. This finding contributes to accumulating research demonstrating that reward-related brain function may be a useful biomarker of relative risk for depression in the context of negative experiences.

BackgroundHigh rates of comorbidity, shared risk, and overlapping therapeutic mechanisms have led psychopathology research towards transdiagnostic dimensional investigations of clustered symptoms. One influential framework accounts for these transdiagnostic phenomena through a single general factor, sometimes referred to as the ‘p’ factor, associated with risk for all common forms of mental illness.MethodsHere we build on past research identifying unique structural neural correlates of the p factor by conducting a data-driven analysis of connectome wide intrinsic functional connectivity (n = 605).ResultsWe demonstrate that higher p factor scores and associated risk for common mental illness maps onto hyper-connectivity between visual association cortex and both frontoparietal and default mode networks.ConclusionsThese results provide initial evidence that the transdiagnostic risk for common forms of mental illness is associated with patterns of inefficient connectome wide intrinsic connectivity between visual association cortex and networks supporting executive control and self-referential processes, networks which are often impaired across categorical disorders.

Key Points Question Is gait speed measured at age 45 years associated with accelerated biological aging, neurocognitive function, and cognitive decline? Findings In this 5-decade cohort study of 904 participants in New Zealand, physical and biological indicators of accelerated aging, including compromised brain integrity (eg, reduced brain volume and cortical thickness), were associated with slow gait measured at age 45 years. Lifelong compromised brain health—including poor neurocognitive functioning as early as age 3 years and childhood-to-adulthood decline in cognitive functioning—was associated with slower gait at midlife. Meaning Gait speed at midlife may be a summary index of lifelong aging with possible origins in childhood central nervous system deficits., This 5-decade cohort study of a New Zealand population examines whether slow gait speed in middle age is associated with accelerated biological aging, as well as poor neurocognitive functioning in childhood and cognitive decline from childhood to middle age., Importance Gait speed is a well-known indicator of risk of functional decline and mortality in older adults, but little is known about the factors associated with gait speed earlier in life. Objectives To test the hypothesis that slow gait speed reflects accelerated biological aging at midlife, as well as poor neurocognitive functioning in childhood and cognitive decline from childhood to midlife. Design, Setting, and Participants This cohort study uses data from the Dunedin Multidisciplinary Health and Development Study, a population-based study of a representative 1972 to 1973 birth cohort in New Zealand that observed participants to age 45 years (until April 2019). Data analysis was performed from April to June 2019. Exposures Childhood neurocognitive functions and accelerated aging, brain structure, and concurrent physical and cognitive functions in adulthood. Main Outcomes and Measures Gait speed at age 45 years, measured under 3 walking conditions: usual, dual task, and maximum gait speeds. Results Of the 1037 original participants (91% of eligible births; 535 [51.6%] male), 997 were alive at age 45 years, of whom 904 (90.7%) had gait speed measured (455 [50.3%] male; 93% white). The mean (SD) gait speeds were 1.30 (0.17) m/s for usual gait, 1.16 (0.23) m/s for dual task gait, and 1.99 (0.29) m/s for maximum gait. Adults with more physical limitations (standardized regression coefficient [β], −0.27; 95% CI, −0.34 to −0.21; P

Auditory enhancement refers to the perceptual phenomenon that a target sound is heard out more readily from a background sound if the background is presented alone first. Here we used stimulus-frequency otoacoustic emissions (SFOAEs) to test the hypothesis that activation of the medial olivocochlear efferent system contributes to auditory enhancement effects. The SFOAEs were used as a tool to measure changes in cochlear responses to a target component and the neighboring components of a multitone background between conditions producing enhancement and conditions producing no enhancement. In the “enhancement” condition, the target and multitone background were preceded by a precursor stimulus with a spectral notch around the signal frequency; in the control (no-enhancement) condition, the target and multitone background were presented without the precursor. In an experiment using a wideband multitone stimulus known to produce significant psychophysical enhancement effects, SFOAEs showed no changes consistent with enhancement, but some aspects of the results indicated possible contamination of the SFOAE magnitudes by the activation of the middle-ear-muscle reflex. The same SFOAE measurements performed using narrower-band stimuli at lower sound levels also showed no SFOAE changes consistent with either absolute or relative enhancement despite robust psychophysical enhancement effects observed in the same listeners with the same stimuli. The results suggest that cochlear efferent control does not play a significant role in auditory enhancement effects.