The Dunedin Study - DMHDRU


Brain Neuroimaging (MRI)

Improving risk indexes for Alzheimer’s disease and related dementias for use in midlife | 2022
Aaron Reuben, Terrie E. Moffitt, Wickcliffe C. Abraham, Antony Ambler, Maxwell L. Elliott, ... Show all » Ahmad R. Hariri, Honalee Harrington, Sean Hogan, Renate M. Houts, David Ireland, Annchen R. Knodt, Joan Leung, Amber Pearson, Richie Poulton, Suzanne C. Purdy, Sandhya Ramrakha, Line J.H. Rasmussen, Karen Sugden, Peter R. Thorne, Benjamin Williams, Graham Wilson, Avshalom Caspi. « Hide
Brain Communications, 2022, 4(5), .
download pdf Our ref: RO790
Show abstract » 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.
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Diminished structural brain integrity in long-term cannabis users reflects a history of polysubstance use | 2022
Knodt, A.R., Meier, M.H., Ambler, ... Show all » A., Gehred, M.Z., Harrington, H., Ireland, D., Poulton, R., Ramrakha, S., Caspi, A., Moffitt, T.E., Hariri, A.R. « Hide
Biological Psychiatry, 2022, .
download pdf Our ref: RO784
Show abstract » Background
Cannabis legalization and use are outpacing our understanding of its long-term effects on brain and behavior, which is fundamental for effective policy and health practices. Existing studies are limited by small samples, cross-sectional measures, failure to separate long-term from recreational use, and inadequate control for other substance use. Here, we address these limitations by determining the structural brain integrity of long-term cannabis users in the Dunedin Study, a longitudinal investigation of a population-representative birth cohort followed to midlife.
We leveraged prospective measures of cannabis, alcohol, tobacco, and other illicit drug use, in addition to structural neuroimaging in 875 Study members at age 45 to test for differences in both global and regional grey and white matter integrity between long-term cannabis users and lifelong non-users. We additionally tested for dose-response associations between continuous measures of cannabis use and brain structure, including careful adjustments for use of other substances.
Long-term cannabis users had a thinner cortex, smaller subcortical grey matter volumes, and higher machine-learning-predicted brain age than non-users. However, these differences in structural brain integrity were explained by the propensity of long-term cannabis users to engage in polysubstance use, especially with alcohol and tobacco.
These findings suggest that diminished midlife structural brain integrity in long-term cannabis users reflects a broader pattern of polysubstance use, underlining the importance of understanding comorbid substance use in efforts to curb the negative effects of cannabis on brain and behavior as well as establish more effective policy and health practices.

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Association of Treatable Health Conditions During Adolescence With Accelerated Aging at Midlife | 2022
Bourassa, K., Moffitt, T.E., Ambler, ... Show all » A., Hariri, A.R., Harrington, H., Houts, R., Ireland, D., Knodt, A., Poulton, R., Ramrakha, S., Caspi, A. « Hide
JAMA Pediatrics , 2022, .
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Our ref: RO773
Show abstract » Importance Biological aging is a distinct construct from health; however, people who age quickly are more likely to experience poor health. Identifying pediatric health conditions associated with accelerated aging could help develop treatment approaches to slow midlife aging and prevent poor health in later life.

Objective To examine the association between 4 treatable health conditions in adolescence and accelerated aging at midlife.

Design, Setting, and Participants This cohort study analyzed data from participants in the Dunedin Study, a longitudinal investigation of health and behavior among a birth cohort born between April 1, 1972, and March 31, 1973, in Dunedin, New Zealand, and followed up until age 45 years. Participants underwent an assessment at age 45 years and had data for at least 1 adolescent health condition (asthma, smoking, obesity, and psychological disorders) and outcome measure (pace of aging, gait speed, brain age, and facial age). Data analysis was performed from February 11 to September 27, 2021.

Exposures Asthma, cigarette smoking, obesity, and psychological disorders were assessed at age 11, 13, and 15 years.

Main Outcomes and Measures The outcome was a midlife aging factor composite score comprising 4 measures of biological aging: pace of aging, gait speed, brain age (specifically, BrainAGE score), and facial age.

Results A total of 910 participants (459 men [50.4%]) met the inclusion criteria, including an assessment at age 45 years. Participants who had smoked daily (0.61 [95% CI, 0.43-0.79] SD units), had obesity (0.82 [95% CI, 0.59-1.06] SD units), or had a psychological disorder diagnosis (0.43 [95% CI, 0.29-0.56] SD units) during adolescence were biologically older at midlife compared with participants without these conditions. Participants with asthma were not biologically older at midlife (0.02 [95% CI, −0.14 to 0.19] SD units) compared with those without asthma. These results remained unchanged after adjusting for childhood risk factors such as poor health, socioeconomic disadvantage, and adverse experiences.

Conclusions and Relevance This study found that adolescent smoking, obesity, and psychological disorder diagnoses were associated with older biological age at midlife. These health conditions could be treated during adolescence to reduce the risk of accelerated biological aging later in life.

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Midlife Cardiovascular Fitness Is Reflected in the Brain's White Matter | 2021
d'Arbeloff, T., Elliott, M. L., Knodt, ... Show all » A. R., Sison, M., Melzer, T. R., Ireland, D., Ramrakha, S., Poulton, R., Caspi, A., Moffitt, T. E., Hariri, A. R. « Hide
Frontiers in Aging Neuroscience, 2021, 13 .
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Our ref: RO768
Show abstract » Disappointing results from clinical trials designed to delay structural brain decline and the accompanying increase in risk for dementia in older adults have precipitated a shift in testing promising interventions from late in life toward midlife before irreversible damage has accumulated. This shift, however, requires targeting midlife biomarkers that are associated with clinical changes manifesting only in late life. Here we explored possible links between one putative biomarker, distributed integrity of brain white matter, and two intervention targets, cardiovascular fitness and healthy lifestyle behaviors, in midlife. At age 45, fractional anisotropy (FA) derived from diffusion weighted MRI was used to estimate the microstructural integrity of distributed white matter tracts in a population-representative birth cohort. Age-45 cardiovascular fitness (VO2Max; N = 801) was estimated from heart rates obtained during submaximal exercise tests; age-45 healthy lifestyle behaviors were estimated using the Nyberg Health Index (N = 854). Ten-fold cross-validated elastic net predictive modeling revealed that estimated VO2Max was modestly associated with distributed FA. In contrast, there was no significant association between Nyberg Health Index scores and FA. Our findings suggest that cardiovascular fitness levels, but not healthy lifestyle behaviors, are associated with the distributed integrity of white matter in the brain in midlife. These patterns could help inform future clinical intervention research targeting ADRDs.
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Association of subcortical gray-matter volumes with life-course-persistent antisocial behavior in a population- representative longitudinal birth cohort | 2021
Carlisi, Christina O., Moffitt, Terrie E., Knodt, ... Show all » Annchen R., Harrington, HonaLee, Langevin, Stephanie, Ireland, David, Melzer, Tracy R., Poulton, Richie, Ramrakha, Sandhya, Caspi, Avshalom, Hariri, Ahmad R., Viding, Essi « Hide
Development and Psychopathology, 2021, 1-11.
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Our ref: RO767
Show abstract » Neuropsychological evidence supports the developmental taxonomy theory of antisocial behavior, suggesting that abnormal brain development distinguishes life-course-persistent from adolescence-limited antisocial behavior. Recent neuroimaging work confirmed that prospectively- measured life-course-persistent antisocial behavior is associated with differences in cortical brain structure. Whether this extends to subcortical brain structures remains uninvestigated. This study compared subcortical gray-matter volumes between 672 members of the Dunedin Study previously defined as exhibiting life-course-persistent, adolescence-limited or low-level antisocial behavior based on repeated assessments at ages 7–26 years. Gray-matter volumes of 10 subcortical structures were compared across groups. The lifecourse- persistent group had lower volumes of amygdala, brain stem, cerebellum, hippocampus, pallidum, thalamus, and ventral diencephalon compared to the low-antisocial group. Differences between life-course-persistent and adolescence-limited individuals were comparable in effect size to differences between life-course-persistent and low-antisocial individuals, but were not statistically significant due to less statistical power. Gray-matter volumes in adolescence-limited individuals were near the norm in this population-representative cohort and similar to volumes in low-antisocial individuals. Although this study could not establish causal links between brain volume and antisocial behavior, it constitutes new biological evidence that all people with antisocial behavior are not the same, supporting a need for greater developmental and diagnostic precision in clinical, forensic, and policy-based interventions.
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Long-term Neural Embedding of Childhood Adversity in a Population-Representative Birth Cohort Followed for 5 Decades | 2021
Gehred, M. Z. Knodt, A. R. Ambler, A. Bourassa, K. J. Danese, ... Show all » A. Elliott, M. L. Hogan, S. Ireland, D. Poulton, R. Ramrakha, S. Reuben, A. Sison, M. L. Moffitt, T. E. Hariri, A. R. Caspi, A. « Hide
Biological Psychiatry, 2021, 90(3), 182-193.
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Our ref: RO761
Show abstract » 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.
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Disparities in the pace of biological aging among midlife adults of the same chronological age have implications for future frailty risk and policy | 2021
Maxwell L. Elliott, Avshalom Caspi, Renate M. Houts, Antony Ambler, Jonathan M. Broadbent, ... Show all » Robert J. Hancox, HonaLee Harrington, Sean Hogan, Ross Keenan, Annchen Knodt, Joan H. Leung, Tracy R. Melzer, Suzanne C. Purdy, Sandhya Ramrakha, Leah S. Richmond-Rakerd, Antoinette Righarts, Karen Sugden, Murray Thomson, Peter R. Thorne, Benjamin S. Williams, Graham Wilson, Ahmad R. Hariri, Richie Poulton, Terrie E. Moffitt « Hide
Nature Aging, 2021, 1 295–308.
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Our ref: RO751
Show abstract » 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.
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Childhood self-control forecasts the pace of midlife aging and preparedness for old age | 2021
Richmond-Rakerd, L. S. Caspi, A. Ambler, A. d'Arbeloff, T. de Bruine, ... Show all » M. Elliott, M. Harrington, H. Hogan, S. Houts, R. M. Ireland, D. Keenan, R. Knodt, A. R. Melzer, T. R. Park, S. Poulton, R. Ramrakha, S. Rasmussen, L. J. H. Sack, E. Schmidt, A. T. Sison, M. L. Wertz, J. Hariri, A. R. Moffitt, T. E. « Hide
PNAS, 2021, 118(3), .
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Our ref: RO748
Show abstract » 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.
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Is cardiovascular fitness associated with structural brain integrity in midlife? Evidence from a population-representative birth cohort study | 2020
d'Arbeloff, T., Cooke, M., Knodt, ... Show all » A. R., Sison, M., Melzer, T. R., Ireland, D., Poulton, R., Ramrakha, S., Moffitt, T. E., Caspi, A., Hariri, A. R. « Hide
Aging, 2020, 12(20), .
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Our ref: RO744
Show abstract » Improving cardiovascular fitness may buffer against age-related cognitive decline and mitigate dementia risk by staving off brain atrophy. However, it is unclear if such effects reflect factors operating in childhood (neuroselection) or adulthood (neuroprotection). Using data from 807 members of the Dunedin Study, a population-representative birth cohort, we investigated associations between cardiovascular fitness and structural brain integrity at age 45, and the extent to which associations reflected possible neuroselection or neuroprotection by controlling for childhood IQ. Higher fitness, as indexed by VO2Max, was not associated with average cortical thickness, total surface area, or subcortical gray matter volume including the hippocampus. However, higher fitness was associated with thicker cortex in prefrontal and temporal regions as well as greater cerebellar gray matter volume. Higher fitness was also associated with decreased hippocampal fissure volume. These associations were unaffected by the inclusion of childhood IQ in analyses. In contrast, a higher rate of decline in cardiovascular fitness from 26 to 45 years was not robustly associated with structural brain integrity. Our findings are consistent with a neuroprotective account of adult cardiovascular fitness but suggest that effects are not uniformly observed across the brain and reflect contemporaneous fitness more so than decline over time
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Association of childhood lead exposure with MRI measurements of structural brain integrity in midlife | 2020
Reuben, A. Elliott, M.L. Abraham, C. Broadbent, J. Houts, ... Show all » R.M. Ireland, D. Knodt, A.R. Poulton, R. Ramrakha, S. Hariri, A.R. Caspi, A. Moffitt, T.E. « Hide
JAMA, 2020, 324(19), 1970-1979.
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Our ref: RO742
Show abstract » 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).

Exposure. Childhood blood-lead levels measured at age 11 years.

Main Outcomes and Measures. Structural brain integrity at age 45 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)-100(diffusion is perfectly anisotropic)]), and 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). Age-45 cognitive function was assessed objectively via the Wechsler Adult Intelligence Scale–IV [IQ range, 40-160, standardized to mean(SD)=100(15)] and subjectively via informant and self-reports [z-score units, scale mean(SD)=0(1)].

Results. Of 1037 original participants, 997 were alive at age 45, of whom 564(57%) had received lead testing at age 11 years (302[54%] male) (median follow-up 34 years, IQR 33.7-34.7). Mean(SD) age-11 blood-lead level was 10.99(4.63) µg/dL. After adjusting for covariates, each 5µg/dL higher childhood blood-lead level was significantly associated with 1.19 cm2 smaller cortical surface area (95%CI:-2.35,-0.02, P=.05), 0.10 cm3 smaller hippocampal volume (95%CI:-0.17,-0.03, P=.006), lower global fractional anisotropy (b=-0.12, 95%CI:-0.24,-0.01, P=.04), and 0.77 years older brainAGE (95%CI:0.02, 1.51, P=.05). There were no statistically significant associations between blood-lead level and log-transformed white matter hyperintensity volume (b=0.05 log mm3, 95%CI:-0.02, 0.13, P=.17) or mean cortical thickness (b=-0.004 mm, 95%CI:-0.012, 0.004, P=.39). Each 5µg/dL higher childhood blood-lead level was significantly associated with a 2.07-point lower score (95%CI:-3.39,-0.74, P=.002) in age-45 IQ, and a 0.12-point higher score (95%CI:0.01, 0.23, P=.03) on informant-rated cognitive problems. There was no statistically significant association between childhood blood-lead levels and self-reported cognitive problems (b=-0.02 points, 95%CI: -0.10, 0.07, P=.68).

Conclusion 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 mid-life. Because of the large number of statistical comparisons, some findings may represent type I error.

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What is the test-retest reliability of common task-fMRI measures? New empirical evidence and a meta-analysis | 2020
Maxwell L. Elliott, Annchen R. Knodt, David Ireland, Meriwether L. Morris, Richie Poulton, ... Show all » Sandhya Ramrakha, Maria L. Sison, Terrie E. Moffitt, Avshalom Caspi, Ahmad R. Hariri « Hide
Psychological Science, 2020, 31(7), .
download pdf Our ref: RO734
Show 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 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.
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Pervasively Thinner Neocortex as a Transdiagnostic Feature of General Psychopathology | 2020
Adrienne L. Romer, Maxwell L. Elliott, Annchen R. Knodt, Maria L. Sison, David Ireland, ... Show all » Renate Houts, Sandhya Ramrakha, Richie Poulton, Ross Keenan, Tracy R. Melzer, Terrie E. Moffitt, Avshalom Caspi, Ahmad R. Hariri « Hide
Am J Psychiatry, 2020, .
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Our ref: RO737
Show abstract » Objective:
Neuroimaging 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. The authors 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.

Analyses were conducted on structural MRI and psychopathology data collected from 861 members of the population-representative Dunedin Multidisciplinary Health and Development Study at age 45.

Study 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.

A pattern of pervasively reduced neocortical thickness appears to be 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, and the continued pursuit of such specific correlates may limit progress toward more effective strategies for etiological understanding, prevention, and intervention.

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Association between elevated suPAR, a new biomarker of inflamation, and accelerated aging | 2020
Line Jee Hartmann Rasmussen, Avshalom Caspi, Antony Ambler, Andrea Danese, Maxwell Elliott, ... Show all » Jesper Eugen-Olsen, Ahmad R. Hariri, HonaLee Harrington, Renate Houts, Richie Poulton, Sandhya Ramrakha, Karen Sugden, Benjamin Williams, Terrie E. Moffitt « Hide
The Journals of Gerontology: Series A, 2020, .
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Our ref: RO732
Show abstract » 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.

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.

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.

Our findings provide initial support for the utility of suPAR in studying the role of chronic inflammation in accelerated aging and functional decline.

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Associations between life-course-persistent antisocial behaviour and brain structure in a population-representative longitudinal birth cohort | 2020
Christina O Carlisi, Terrie E Moffitt, Annchen R Knodt, Honalee Harrington, David Ireland, ... Show all » Tracy R Melzer, Richie Poulton, Sandhya Ramrakha, Avshalom Caspi, Ahmad R Hariri, Essi Viding « Hide
Lancet Psychiatry , 2020, 7 245-53.
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Our ref: RO731
Show abstract » Summary
Background Studies with behavioural and neuropsychological tests have supported the developmental taxonomy theory of antisocial behaviour, which specifies abnormal brain development as a fundamental aspect of life-coursepersistent antisocial behaviour, but no study has characterised features of brain structure associated with lifecourse-persistent versus adolescence-limited trajectories, as defined by prospective data. We aimed to determine whether life-course-persistent antisocial behaviour is associated with neurocognitive abnormalities by testing the hypothesis that it is also associated with brain structure abnormalities.
We used structural MRI data collected at 45 years of age from participants in the Dunedin Study, a populationrepresentative longitudinal birth cohort of 1037 individuals born between April 1, 1972, and March 31, 1973, in Dunedin, New Zealand, who were resident in the province and who participated in the first assessment at 3 years of age. Participants underwent MRI, and mean global cortical surface area and cortical thickness were extracted for each participant. Participants had been previously subtyped as exhibiting life-course-persistent, adolescence-limited, or no history of persistent antisocial behaviour (ie, a low trajectory group) based on informant-reported and self-reported conduct problems from the ages of 7 years to 26 years. Study personnel who processed the MRI images were masked to antisocial group membership. We used linear estimated ordinary least squares regressions to compare each antisocial trajectory group (life-course persistent and adolescence limited) with the low trajectory group to examine whether antisocial behaviour was related to abnormalities in mean global surface area and mean cortical thickness. Next, we used parcel-wise linear regressions to identify antisocial trajectory group differences in surface area and cortical thickness. All results were controlled for sex and false discovery rate corrected. Findings Data from 672 participants were analysed, and 80 (12%) were classified as having life-course-persistent antisocial behaviour, 151 (23%) as having adolescence-limited antisocial behaviour, and 441 (66%) as having low antisocial behaviour. Individuals on the life-course-persistent trajectory had a smaller mean surface area (standardised β=–0·18 [95% CI –0·24 to –0·11]; p<0·0001) and lower mean cortical thickness (standardised β=–0·10 [95% CI –0·19 to –0·02]; p=0·020) than did those in the low group. Compared with the low group, the life-course-persistent group had reduced surface area in 282 of 360 anatomically defined parcels and thinner cortex in 11 of 360 parcels encompassing circumscribed frontal and temporal regions associated with executive function, affect regulation, and motivation. Widespread differences in brain surface morphometry were not observed for the adolescence-limited group compared with either non-antisocial behaviour or life-course-persistent groups.
These analyses provide initial evidence that differences in brain surface morphometry are associated with life-course-persistent, but not adolescence-limited, antisocial behaviour. As such, the analyses are consistent with the developmental taxonomy theory of antisocial behaviour and highlight the importance of using prospective longitudinal data to define different patterns of antisocial behaviour development.

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Brain-age in midlife is associated with accelerated biological aging and cognitive decline in a longitudinal birth cohort | 2019
Elliott, M.L. Belsky, D.W., Knodt, A.R., ... Show all » Ireland, D., Melzer, T.R., Poulton, R., Ramrakha, S., Caspi, A., Moffitt, T.E., Hariri, A.R « Hide
Molecular Psychiatry, 2019, .
download pdf Our ref: RO733
Show abstract » 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 crosssectional 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.
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White matter hyperintensities are common in midlife and already associated with cognitive decline | 2019
Tracy d’Arbeloff, Maxwell L. Elliott, Annchen R. Knodt, Tracy R. Melzer, Ross Keenan, ... Show all » David Ireland, Sandhya Ramrakha, Richie Poulton, Tim Anderson, Avshalom Caspi, Terrie E. Moffitt, Ahmad R. Hariri « Hide
Brain Communications, 2019, 1(1), .
download pdf Our ref: RO728
Show abstract » 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 < 0.001). Moreover, white matter hyperintensity volume was associated with greater cognitive decline from childhood to midlife (ß=−0.09, P < 0.001). Our results demonstrate that a link between white matter hyperintensities and early signs of cognitive decline is detectable decades before clinical symptoms of dementia emerge. Thus, white matter hyperintensities may be a useful surrogate biomarker for identifying individuals in midlife at risk for future accelerated cognitive decline and selecting participants for dementia prevention trials.
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Replicability of structural brain alterations associated with general psychopathology: evidence from a population-representative birth cohort | 2019
Romer, A. L., Knodt, A. R., Sison, ... Show all » M., Ireland, D., Ramrakha, S., Poulton, R., Keenan, R., Melzer, T. R., Moffitt, T. E., Caspi, A., Hariri, A. R. « Hide
Molecular Psychiatry, 2019, .
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Show abstract » Transdiagnostic research has identified a general psychopathology factor – often called the ‘p’
factor – that accounts for shared liability to internalizing, externalizing, and thought disorders in
diverse samples. It has been argued that the p factor may reflect dysfunctional thinking present
in serious mental illness. In support of this, we previously used a theory-free, data-driven
multimodal neuroimaging approach to find that higher p factor scores are associated with
structural deficits within a cerebello-thalamo-cortical circuit (CTCC) and visual association
cortex, both of which are important for monitoring and coordinating information processing in
the service of executive control. Here we attempt to replicate these associations by conducting
region-of-interest analyses of the CTCC and visual association cortex using data from 831
members of the Dunedin Multidisciplinary Health and Development Study, a five-decade
longitudinal study of a population-representative birth cohort now 45 years old. We further
sought to replicate a more recent report that p factor scores can be predicted by patterns of
distributed cerebellar morphology as estimated through independent component analysis. We
successfully replicated associations between higher p factor scores and both reduced grey
matter volume of the visual association cortex and fractional anisotropy of pontine white
matter pathways within the CTCC. In contrast, we failed to replicate prior associations between
cerebellar structure and p factor scores. Collectively, our findings encourage further focus on
the CTCC and visual association cortex as core neural substrates and potential biomarkers of
transdiagnostic risk for mental illness.

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Association of Neurocognitive and Physical Function With Gait Speed in Midlife | 2019
Line Jee Hartmann Rasmussen, Avshalom Caspi, Antony Ambler, Jonathan M. Broadbent, Harvey J. Cohen, ... Show all » Tracy d’Arbeloff, Maxwell Elliott, Robert J. Hancox, HonaLee Harrington, Sean Hogan, Renate Houts, David Ireland, Annchen R. Knodt, Kim Meredith-Jones, Miriam C. Morey, Lynda Morrison, Richie Poulton, Sandhya Ramrakha, Leah Richmond-Rakerd, Maria L. Sison, Kate Sneddon, W. Murray Thomson, Ahmad R. Hariri, Terrie E. Moffitt « Hide
JAMA Network Open, 2019, .
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Our ref: RO725
Show abstract » 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 < .001), poorer physical functions (ie, weak grip strength [β, 0.36; 95%CI, 0.25 to 0.46], poor balance [β, 0.28; 95%CI, 0.21 to 0.34], poor visualmotor coordination [β, 0.24; 95%CI, 0.17 to 0.30], and poor performance on the chair-stand [β, 0.34; 95%CI, 0.27 to 0.40] or 2-minute step tests [β, 0.33; 95%CI, 0.27 to 0.39]; all P < .001), accelerated biological aging across multiple organ systems (β, −0.33; 95%CI, −0.40 to −0.27; P < .001), older facial appearance (β, −0.25; 95%CI, −0.31 to −0.18; P < .001), smaller brain volume (β, 0.15; 95%CI, 0.06 to 0.23; P < .001), more cortical thinning (β, 0.09; 95%CI, 0.02 to 0.16; P = .01), smaller cortical surface area (β, 0.13; 95%CI, 0.04 to 0.21; P = .003), and more white matter hyperintensities (β, −0.09; 95%CI, −0.15 to −0.02; P = .01) had slower gait speed. Participants with lower IQ in midlife (β, 0.38; 95%CI, 0.32 to 0.44; P < .001) and participants who exhibited cognitive
decline from childhood to adulthood (β, 0.10; 95%CI, 0.04 to 0.17; P < .001) had slower gait at age 45 years. Those with poor neurocognitive functioning as early as age 3 years had slower gait in midlife (β, 0.26; 95%CI, 0.20 to 0.32; P < .001).

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General functional connectivity: Shared features of resting-state and task fMRI drive reliable and heritable individual differences in functional brain networks | 2019
Maxwell L. Elliott, Annchen R. Knodt, Megan Cooke, M. Justin Kim, Tracy R. Melzer, ... Show all » Ross Keenan, David Ireland, Sandhya Ramrakha, Richie Poulton, Avshalom Caspi, Terrie E. Moffitt, Ahmad R. Hariri « Hide
NeuroImage, 2019, 189 516-532.
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Our ref: RO719
Show abstract » Intrinsic connectivity, measured using resting-state fMRI, has emerged as a fundamental tool in the study of the human brain. However, due to practical limitations,
many studies do not collect enough resting-state data to generate reliable measures of intrinsic connectivity necessary for studying individual differences. Here we
present general functional connectivity (GFC) as a method for leveraging shared features across resting-state and task fMRI and demonstrate in the Human Connectome
Project and the Dunedin Study that GFC offers better test-retest reliability than intrinsic connectivity estimated from the same amount of resting-state data
alone. Furthermore, at equivalent scan lengths, GFC displayed higher estimates of heritability than resting-state functional connectivity. We also found that predictions
of cognitive ability from GFC generalized across datasets, performing as well or better than resting-state or task data alone. Collectively, our work suggests that GFC can improve the reliability of intrinsic connectivity estimates in existing datasets and, subsequently, the opportunity to identify meaningful correlates of individual differences in behavior. Given that task and resting-state data are often collected together, many researchers can immediately derive more reliable measures of intrinsic connectivity through the adoption of GFC rather than solely using resting-state data. Moreover, by better capturing heritable variation in intrinsic connectivity, GFC represents a novel endophenotype with broad applications in clinical neuroscience and biomarker discovery.

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A Polygenic Score for Higher Educational Attainment is Associated with Larger Brains | 2019
Elliott, M. L. Belsky, D. W. Anderson, K. Corcoran, D. L. Ge, ... Show all » T. Knodt, A. Prinz, J. A. Sugden, K. Williams, B. Ireland, D. Poulton, R. Caspi, A. Holmes, A. Moffitt, T.E. Hariri, A. R. « Hide
Cerebal Cortex, 2019, 1-9.
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Show abstract » 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.
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