An estimate of the longitudinal pace of aging from a single brain scan predicts dementia conversion, morbidity, and mortality.

To understand how aging affects functional decline and increases disease risk, it is necessary to develop accurate and reliable measures of how fast a person is aging. Epigenetic clocks measure aging but require DNA methylation data, which many studies lack. Using data from the Dunedin Study, we introduce an accurate and reliable measure for the rate of longitudinal aging derived from cross-sectional brain MRI: the Dunedin Pace of Aging Calculated from NeuroImaging or DunedinPACNI. Exporting this measure to the Alzheimer's Disease Neuroimaging Initiative and UK Biobank neuroimaging datasets revealed that faster DunedinPACNI predicted participants' cognitive impairment, accelerated brain atrophy, and conversion to diagnosed dementia. Underscoring close links between longitudinal aging of the body and brain, faster DunedinPACNI also predicted physical frailty, poor health, future chronic diseases, and mortality in older adults. Furthermore, DunedinPACNI followed the expected socioeconomic health gradient. When compared to brain age gap, an existing MRI aging biomarker, DunedinPACNI was similarly or more strongly related to clinical outcomes. DunedinPACNI is a "next generation" MRI measure that will be made publicly available to the research community to help accelerate aging research and evaluate the effectiveness of dementia prevention and anti-aging strategies.

Trajectories of Hearing From Childhood to Adulthood.

OBJECTIVES: The Dunedin Multidisciplinary Health and Development Study provides a unique opportunity to document the progression of ear health and hearing ability within the same cohort of individuals from birth. This investigation draws on hearing data from 5 to 13 years and again at 45 years of age, to explore the associations between childhood hearing variables and hearing and listening ability at age 45. DESIGN: Multiple linear regression analyses were used to assess associations between childhood hearing (otological status and mid-frequency pure-tone average) and (a) age 45 peripheral hearing ability (mid-frequency pure-tone average and high-frequency pure-tone average), and (b) age 45 listening ability (listening in spatialized noise and subjective questionnaire on listening experiences). Sex, childhood socioeconomic status, and adult IQ were included in the model as covariates. RESULTS: Peripheral hearing and listening abilities at age 45 were consistently associated with childhood hearing acuity at mid-frequencies. Otological status was a moderate predicting factor for high-frequency hearing and utilization of spatial listening cues in adulthood. CONCLUSIONS: We aim to use these findings to develop a foundational model of hearing trajectories. This will form the basis for identifying precursors, to be investigated in a subsequent series of analyses, that may protect against or exacerbate hearing-associated cognitive decline in the Dunedin Study cohort as they progress from mid-life to older age.

Childhood blood-lead level predicts lower general, non-selective hippocampal subfield volumes in midlife.

Millions of adults and children are exposed to high levels of lead, a neurotoxicant, each year. Recent evidence suggests that lead exposure may precipitate neurodegeneration, particularly if the exposure occurs early or late in life, with unique alterations to the structure or function of specific subfields of the hippocampus, a region involved in memory and Alzheimer's disease. It has been proposed that specific hippocampal subfields may thus be useful biomarkers for lead-associated neurological disease. We turned to a population-representative New Zealand birth cohort where the extent of lead exposure was not confounded by social class (the Dunedin Study; born 1972-1973 and followed to age 45) to test the hypothesis that early life lead exposure (blood-lead level at age 11 years) is associated with smaller MRI-assessed gray matter volumes of specific subfields of the hippocampus at age 45 years. Among the 508 Dunedin Study members with childhood lead data and adult MRI data passing quality control (93.9 % of those with lead data who attended the age-45 assessment wave, 240[47.2 %] female), childhood blood-lead levels ranged from 4 to 31 µg/dL (M[SD]=10.9[4.6]). Total hippocampal volumes were lower among adults with higher childhood blood-lead levels (b=-102.6 mm3 per 5 ug/dL-unit greater blood-lead level, 95 %CI: -175.4 to -29.7, p=.006, ß=-.11), as were all volumes of the 24 hemisphere-specific subfields of the hippocampus. Of these 24 subfields, 20 demonstrated negative lead-associations greater than ß=-.05 in size, 14 were statistically significant after adjustment for multiple comparisons (pFDR<.05), and 9 remained significant after adjustment for potential confounders and multiple comparisons. Children exposed to lead demonstrate smaller volumes across all subfields of the hippocampus in midlife. The hypothesis that lead selectively impairs specific subfields of the hippocampus, or that specific subfields may be markers for lead-associated neurological disease, requires further evaluation.

Improving Predictability, Test-Retest Reliability and Generalisability of Brain-Wide Associations for Cognitive Abilities via Multimodal Stacking.

Brain-wide association studies (BWASs) have attempted to relate cognitive abilities with brain phenotypes, but have been challenged by issues such as predictability, test-retest reliability, and cross-cohort generalisability. To tackle these challenges, we proposed "stacking" that combines brain magnetic resonance imaging of different modalities, from task-fMRI contrasts and functional connectivity during tasks and rest to structural measures, into one prediction model. We benchmarked the benefits of stacking, using the Human Connectome Projects: Young Adults and Aging and the Dunedin Multidisciplinary Health and Development Study. For predictability, stacked models led to out-of-sample r ∼.5-.6 when predicting cognitive abilities at the time of scanning and 36 years earlier. For test-retest reliability, stacked models reached an excellent level of reliability (ICC>.75), even when we stacked only task-fMRI contrasts together. For generalisability, a stacked model with non-task MRI built from one dataset significantly predicted cognitive abilities in other datasets. Altogether, stacking is a viable approach to undertake the three challenges of BWAS for cognitive abilities.

Dementia, dementia's risk factors and premorbid brain structure are concentrated in disadvantaged areas: National register and birth-cohort geographic analyses.

INTRODUCTION: Dementia risk may be elevated in socioeconomically disadvantaged neighborhoods. Reasons for this remain unclear, and this elevation has yet to be shown at a national population level. METHODS: We tested whether dementia was more prevalent in disadvantaged neighborhoods across the New Zealand population (N = 1.41 million analytic sample) over a 20-year observation. We then tested whether premorbid dementia risk factors and MRI-measured brain-structure antecedents were more prevalent among midlife residents of disadvantaged neighborhoods in a population-representative NZ-birth-cohort (N = 938 analytic sample). RESULTS: People residing in disadvantaged neighborhoods were at greater risk of dementia (HR per-quintile-disadvantage-increase = 1.09, 95% confidence interval [CI]:1.08-1.10) and, decades before clinical endpoints typically emerge, evidenced elevated dementia-risk scores (CAIDE, LIBRA, Lancet, ANU-ADRI, DunedinARB; ß's 0.31-0.39) and displayed dementia-associated brain structural deficits and cognitive difficulties/decline. DISCUSSION: Disadvantaged neighborhoods have more residents with dementia, and decades before dementia is diagnosed, residents have more dementia-risk factors and brain-structure antecedents. Whether or not neighborhoods causally influence risk, they may offer scalable opportunities for primary dementia prevention.

A blood biomarker of the pace of aging is associated with brain structure: replication across three cohorts.

Biological aging is the correlated decline of multi-organ system integrity central to the etiology of many age-related diseases. A novel epigenetic measure of biological aging, DunedinPACE, is associated with cognitive dysfunction, incident dementia, and mortality. Here, we tested for associations between DunedinPACE and structural MRI phenotypes in three datasets spanning midlife to advanced age: the Dunedin Study (age=45 years), the Framingham Heart Study Offspring Cohort (mean age=63 years), and the Alzheimer's Disease Neuroimaging Initiative (mean age=75 years). We also tested four additional epigenetic measures of aging: the Horvath clock, the Hannum clock, PhenoAge, and GrimAge. Across all datasets (total N observations=3380; total N individuals=2322), faster DunedinPACE was associated with lower total brain volume, lower hippocampal volume, greater burden of white matter microlesions, and thinner cortex. Across all measures, DunedinPACE and GrimAge had the strongest and most consistent associations with brain phenotypes. Our findings suggest that single timepoint measures of multi-organ decline such as DunedinPACE could be useful for gauging nervous system health.

Mild Traumatic Brain Injury Does Not Significantly Affect Midlife Cognitive Functioning Within the General Population: Findings From a Prospective Longitudinal Birth Cohort Study.

OBJECTIVE: To determine whether differences exist in mid-adulthood cognitive functioning in people with and without history of mild traumatic brain injury (mTBI). SETTING: Community-based study. PARTICIPANTS: People born between April 1, 1972, and March 31, 1973, recruited into the Dunedin Multidisciplinary Health and Development Longitudinal Study, who completed neuropsychological assessments in mid-adulthood. Participants who had experienced a moderate or severe TBI or mTBI in the past 12 months were excluded. DESIGN: Longitudinal, prospective, observational study. MAIN MEASURES: Data were collected on sociodemographic characteristics, medical history, childhood cognition (between 7 and 11 years), and alcohol and substance dependence (from 21 years of age). mTBI history was determined from accident and medical records (from birth to 45 years of age). Participants were classified as having 1 mTBI and more in their lifetime or no mTBI. The Wechsler Adult Intelligence Scale (WAIS-IV) and Trail Making Tests A and B (between 38 and 45 years of age) were used to assess cognitive functioning. T tests and effect sizes were used to identify any differences on cognitive functioning domains between the mTBI and no mTBI groups. Regression models explored the relative contribution of number of mTBIs and age of first mTBI and sociodemographic/lifestyle variables on cognitive functioning. RESULTS: Of the 885 participants, 518 (58.5%) had experienced at least 1 mTBI over their lifetime, with a mean number of 2.5 mTBIs. The mTBI group had significantly slower processing speed ( P < .01, d = 0.23) in mid-adulthood than the no TBI controls, with a medium effect size. However, the relationship no longer remained significant after controlling for childhood cognition, sociodemographic and lifestyle factors. No significant differences were observed for overall intelligence, verbal comprehension, perceptual reasoning, working memory, attention, or cognitive flexibility. Childhood cognition was not linked to likelihood of sustaining mTBI later in life. CONCLUSION: mTBI histories in the general population were not associated with lower cognitive functioning in mid-adulthood once sociodemographic and lifestyle factors were taken into account.

Who Australasians trusted during COVID-19: lessons from the pandemic response.

AIM: Public trust in authoritative information sources is a key element of a successful public health response to a pandemic. This study investigated which sources of COVID-19 advice were most trusted by a primarily New Zealand-based cohort and considers implications for policy and practice regarding future pandemics. METHOD: Data were from a COVID-19 vaccine intention survey presented to Australia- and New Zealand-based members of the longitudinal Dunedin Study (n=832) between ages 48 and 49, immediately before vaccines became available for the general population within New Zealand. We assessed participants' trust in specific sources of COVID-19 advice and investigated whether the pattern of responses differed by sex, socio-economic status (SES) or education. RESULTS: Doctors and healthcare providers were the most trusted source of COVID-19 advice, over and above other institutional sources. This pattern was consistent across sex, SES and education. Institutional experts were trusted significantly more by those with higher SES compared to those with lower SES, and by those with formal qualifications compared to those without formal qualifications. CONCLUSION: Our findings suggest that it is important to empower healthcare providers early in a pandemic to share advice with the public alongside other trusted sources, such as the government.

Childhood caries is associated with poor health and a faster pace of aging by midlife.

OBJECTIVES: Childhood caries is associated with poorer self-rated general health in adulthood, but it remains unclear whether that holds for physical health and aging. The aim of this study was to identify whether age-5 caries is associated with (a) biomarkers for poor physical health, and (b) the pace of aging (PoA) by age 45 years. METHODS: Participants are members of the Dunedin Multidisciplinary Health and Development Study birth cohort. At age 45, 94.1% (n = 938) of those still alive took part. Data on age-5 caries experience and age-45 health biomarkers were collected. The PoA captures age-related decline across the cardiovascular, metabolic, renal, immune, dental and pulmonary systems from age 26 to 45 years. We used (a) generalized estimating equations to examine associations between age-5 caries and poor physical health by age 45 years, and (b) ordinary least squares regression to examine whether age-5 caries was associated with the PoA. Analyses adjusted for sex, perinatal health, childhood SES and childhood IQ. RESULTS: High caries experience at age-5 was associated with higher risk for some metabolic abnormalities, including BMI ≥30, high waist circumference, and high serum leptin. Those with high caries experience at age-5 were aging at a faster rate by age 45 years than those who had been caries-free. CONCLUSIONS: Oral health is essential for wellbeing. Poor oral health can be an early signal of a trajectory towards poor health in adulthood. Management for both conditions should be better-integrated; and integrated population-level prevention strategies should be foundational to any health system.

Test-retest reliability and predictive utility of a macroscale principal functional connectivity gradient.

Mapping individual differences in brain function has been hampered by poor reliability as well as limited interpretability. Leveraging patterns of brain-wide functional connectivity (FC) offers some promise in this endeavor. In particular, a macroscale principal FC gradient that recapitulates a hierarchical organization spanning molecular, cellular, and circuit level features along a sensory-to-association cortical axis has emerged as both a parsimonious and interpretable measure of individual differences in behavior. However, the measurement reliabilities of this FC gradient have not been fully evaluated. Here, we assess the reliabilities of both global and regional principal FC gradient measures using test-retest data from the young adult Human Connectome Project (HCP-YA) and the Dunedin Study. Analyses revealed that the reliabilities of principal FC gradient measures were (1) consistently higher than those for traditional edge-wise FC measures, (2) higher for FC measures derived from general FC (GFC) in comparison with resting-state FC, and (3) higher for longer scan lengths. We additionally examined the relative utility of these principal FC gradient measures in predicting cognition and aging in both datasets as well as the HCP-aging dataset. These analyses revealed that regional FC gradient measures and global gradient range were significantly associated with aging in all three datasets, and moderately associated with cognition in the HCP-YA and Dunedin Study datasets, reflecting contractions and expansions of the cortical hierarchy, respectively. Collectively, these results demonstrate that measures of the principal FC gradient, especially derived using GFC, effectively capture a reliable feature of the human brain subject to interpretable and biologically meaningful individual variation, offering some advantages over traditional edge-wise FC measures in the search for brain-behavior associations.

A blood biomarker of accelerated aging in the body associates with worse structural integrity in the brain: replication across three cohorts.

Biological aging is the correlated decline of multi-organ system integrity central to the etiology of many age-related diseases. A novel epigenetic measure of biological aging, DunedinPACE, is associated with cognitive dysfunction, incident dementia, and mortality. Here, we tested for associations between DunedinPACE and structural MRI phenotypes in three datasets spanning midlife to advanced age: the Dunedin Study (age=45 years), the Framingham Heart Study Offspring Cohort (mean age=63 years), and the Alzheimer's Disease Neuroimaging Initiative (mean age=75 years). We also tested four additional epigenetic measures of aging: the Horvath clock, the Hannum clock, PhenoAge, and GrimAge. Across all datasets (total N observations=3,380; total N individuals=2,322), faster DunedinPACE was associated with lower total brain volume, lower hippocampal volume, and thinner cortex. In two datasets, faster DunedinPACE was associated with greater burden of white matter hyperintensities. Across all measures, DunedinPACE and GrimAge had the strongest and most consistent associations with brain phenotypes. Our findings suggest that single timepoint measures of multi-organ decline such as DunedinPACE could be useful for gauging nervous system health.

Differential Unmet Needs and Experience of Restorative Dental Care in Trajectories of Dental Caries Experience: A Birth Cohort Study.

Dental caries is a chronic and cumulative disease but little has been reported on the continuity of the disease and its treatment through life. Group-based multi-trajectory modeling was used to identify developmental trajectories of untreated carious tooth surfaces (DS), restored tooth surfaces (FS), and teeth extracted due to caries (MT) from ages 9 to 45 years in a New Zealand longitudinal birth cohort, the Dunedin Multidisciplinary Health and Development Study (n = 975). Associations between early-life risk factors and trajectory group membership were examined by specifying the probability of group membership according to a multinomial logit model. Six trajectory groups were identified and labeled: "low caries rate"; "moderate caries rate, maintained"; "moderate caries rate, unmaintained"; "high caries rate, restored"; "high caries rate, tooth loss"; and "high caries rate, untreated caries". The two moderate-caries-rate groups differed in count of FS. The three high-caries-rate groups differed in the relative proportion of accumulated DS, FS, and MT. Early childhood risk factors associated with less favorable trajectories included higher dmfs scores at age 5, lack of exposure to community water fluoridation during the first 5 years of life, lower childhood IQ, and low childhood socioeconomic status. Parent self-ratings of their own or their child's oral health as "poor" were associated with less favorable caries experience trajectories. Children who had clinical signs of dental caries together with a parent rating of child's oral health as poor were more likely to follow a less favorable caries trajectory. Higher deciduous dentition caries experience at age 5 years was associated with less favorable caries trajectories, as were children whose parents gave "poor" ratings of their own or their child's oral health. These findings highlight the considerable intergenerational continuity in dental caries experience from early childhood to midlife. Subjective measures of child oral health are informative and might aid as predictors of adult caries experience in cases where childhood dental clinical data were not available.

Tracing the origins of midlife despair: association of psychopathology during adolescence with a syndrome of despair-related maladies at midlife.

BACKGROUND: Midlife adults are experiencing a crisis of deaths of despair (i.e. deaths from suicide, drug overdose, and alcohol-related liver disease). We tested the hypothesis that a syndrome of despair-related maladies at midlife is preceded by psychopathology during adolescence. METHODS: Participants are members of a representative cohort of 1037 individuals born in Dunedin, New Zealand in 1972-73 and followed to age 45 years, with 94% retention. Adolescent mental disorders were assessed in three diagnostic assessments at ages 11, 13, and 15 years. Indicators of despair-related maladies across four domains - suicidality, substance misuse, sleep problems, and pain - were assessed at age 45 using multi-modal measures including self-report, informant-report, and national register data. RESULTS: We identified and validated a syndrome of despair-related maladies at midlife involving suicidality, substance misuse, sleep problems, and pain. Adults who exhibited a more severe syndrome of despair-related maladies at midlife tended to have had early-onset emotional and behavioral disorders [ß = 0.23, 95% CI (0.16-0.30), p < 0.001], even after adjusting for sex, childhood SES, and childhood IQ. A more pronounced midlife despair syndrome was observed among adults who, as adolescents, were diagnosed with a greater number of mental disorders [ß = 0.26, 95% CI (0.19-0.33), p < 0.001]. Tests of diagnostic specificity revealed that associations generalized across different adolescent mental disorders. CONCLUSIONS: Midlife adults who exhibited a more severe syndrome of despair-related maladies tended to have had psychopathology as adolescents. Prevention and treatment of adolescent psychopathology may mitigate despair-related maladies at midlife and ultimately reduce deaths of despair.

Cross-National and Cross-Generational Evidence That Educational Attainment May Slow the Pace of Aging in European-Descent Individuals.

OBJECTIVES: Individuals with more education are at lower risk of developing multiple, different age-related diseases than their less-educated peers. A reason for this might be that individuals with more education age slower. There are 2 complications in testing this hypothesis. First, there exists no definitive measure of biological aging. Second, shared genetic factors contribute toward both lower educational attainment and the development of age-related diseases. Here, we tested whether the protective effect of educational attainment was associated with the pace of aging after accounting for genetic factors. METHODS: We examined data from 5 studies together totaling almost 17,000 individuals with European ancestry born in different countries during different historical periods, ranging in age from 16 to 98 years old. To assess the pace of aging, we used DunedinPACE, a DNA methylation algorithm that reflects an individual's rate of aging and predicts age-related decline and Alzheimer's disease and related disorders. To assess genetic factors related to education, we created a polygenic score based on the results of a genome-wide association study of educational attainment. RESULTS: Across the 5 studies, and across the life span, higher educational attainment was associated with a slower pace of aging even after accounting for genetic factors (meta-analysis effect size = -0.20; 95% confidence interval [CI]: -0.30 to -0.10; p = .006). Further, this effect persisted after taking into account tobacco smoking (meta-analysis effect size = -0.13; 95% CI: -0.21 to -0.05; p = .01). DISCUSSION: These results indicate that higher levels of education have positive effects on the pace of aging, and that the benefits can be realized irrespective of individuals' genetics.

Which Types of Stress Are Associated With Accelerated Biological Aging? Comparing Perceived Stress, Stressful Life Events, Childhood Adversity, and Posttraumatic Stress Disorder.

OBJECTIVE: Stress and stressful events are associated with poorer health; however, there are multiple ways to conceptualize and measure stress and stress responses. One physiological mechanism through which stress could result in poorer health is accelerated biological aging. This study tested which types of stress were associated with accelerated biological aging in adulthood. METHODS: Studying 955 participants from the Dunedin Longitudinal Study, we tested whether four types of stress assessed from ages 32 to 45 years-perceived stress, number of stressful life events, adverse childhood experiences, and posttraumatic stress disorder-were associated with accelerated biological aging. RESULTS: Higher levels of all four measures of stress were significantly associated with accelerated aging in separate models. In a combined model, more perceived stress and more stressful life events remained associated with faster aging, and the stress measures explained 6.9% of the variance in aging. The magnitudes of the associations between the four measures of stress and biological aging were comparable to associations for smoking and low education, two established risk factors for accelerated aging. People with high levels of perceived stress, numerous adverse childhood experiences (4+), high stressful life event counts, or posttraumatic stress disorder were aging an additional estimated 2.4 months, 1.1 additional months, 1.4 months, and 1.4 months per year, respectively. CONCLUSIONS: Assessing stress, particularly perceived stress, could help identify people at risk of accelerated aging. Intervening to treat stress or the health-relevant sequelae of stress could potentially slow the rate at which people are aging, improving their health as they age.

Functional topography of the neocortex predicts covariation in complex cognitive and basic motor abilities.

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.

Associations Between Thinner Retinal Neuronal Layers and Suboptimal Brain Structural Integrity in a Middle-Aged Cohort.

Purpose: The retina has potential as a biomarker of brain health and Alzheimer's disease (AD) because it is the only part of the central nervous system which can be easily imaged and has advantages over brain imaging technologies. Few studies have compared retinal and brain measurements in a middle-aged sample. The objective of our study was to investigate whether retinal neuronal measurements were associated with structural brain measurements in a middle-aged population-based cohort. Participants and Methods: Participants were members of the Dunedin Multidisciplinary Health and Development Study (n=1037; a longitudinal cohort followed from birth and at ages 3, 5, 7, 9, 11, 13, 15, 18, 21, 26, 32, 38, and most recently at age 45, when 94% of the living Study members participated). Retinal nerve fibre layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) thickness were measured by optical coherence tomography (OCT). Brain age gap estimate (brainAGE), cortical surface area, cortical thickness, subcortical grey matter volumes, white matter hyperintensities, were measured by magnetic resonance imaging (MRI). Results: Participants with both MRI and OCT data were included in the analysis (RNFL n=828, female n=413 [49.9%], male n=415 [50.1%]; GC-IPL n=825, female n=413 [50.1%], male n=412 [49.9%]). Thinner retinal neuronal layers were associated with older brain age, smaller cortical surface area, thinner average cortex, smaller subcortical grey matter volumes, and increased volume of white matter hyperintensities. Conclusion: These findings provide evidence that the retinal neuronal layers reflect differences in midlife structural brain integrity consistent with increased risk for later AD, supporting the proposition that the retina may be an early biomarker of brain health.

Functional Topography of the Neocortex Predicts Covariation in Complex Cognitive and Basic Motor Abilities.

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.

Are macular drusen in midlife a marker of accelerated biological ageing?

CLINICAL RELEVANCE: Macular drusen are associated with age-related maculopathy but are not an ocular manifestation or biomarker of systemic ageing. BACKGROUND: Macular drusen are the first sign of age-related maculopathy, an eye disease for which age is the strongest risk factor. The aim of this cohort study was to investigate whether macular drusen in midlife - a sign of the earliest stages of age-related macular degeneration (AMD) - are associated with accelerated biological ageing more generally. METHODS: Members of the long-running Dunedin Multidisciplinary Health and Development Study (hereafter the Dunedin Study, n = 1037) underwent retinal photography at their most recent assessment at the age of 45 years. Images were graded for the presence of AMD using a simplified scale from the Age-Related Eye Disease Study (AREDS). Accelerated ageing was assessed by (i) a measure of Pace of Ageing defined from a combination of clinical and serum biomarkers obtained at ages 26, 32, 38, and 45 years and (ii) Facial Ageing, defined from photographs obtained at age 38 and 45 years. RESULTS: Of the 938 participants who participated at the age 45 assessments, 834 had gradable retinal photographs, and of these 165 (19.8%) had macular drusen. There was no significant difference in Pace of Ageing (p = .743) or Facial Ageing (p = .945) among participants with and without macular drusen. CONCLUSIONS: In this representative general population sample, macular drusen in midlife were not associated with accelerated ageing. Future studies tracking longitudinal changes in drusen number and severity at older ages may reveal whether drusen are a biomarker of accelerated ageing.

Childhood Adversity and Midlife Health: Shining a Light on the Black Box of Psychosocial Mechanisms.

Adverse childhood experiences (ACEs) are associated with poorer health, which has spurred public health efforts to reduce the number of adverse events children experience. Unfortunately, it is unlikely that all ACEs can be prevented. For adults who already experienced ACEs in childhood, what psychological, social, and behavioral intervention targets might reduce risk for negative health outcomes? To provide insight into the "black box" of psychosocial mechanisms linking ACEs to poor health, our study used data from the Dunedin Study, a longitudinal cohort assessed from birth to age 45. Mediation models (N = 859) were used to examine whether candidate psychosocial variables in adulthood explained the association between childhood ACEs and health in midlife. Potential psychosocial mediators included stressful life events, perceived stress, negative emotionality, and health behaviors. Children who experienced more ACEs had poorer health in midlife. They also had significantly more stressful life events, more perceived stress, more negative emotionality, and unhealthier behaviors as adults. These mediators were each independently associated with poorer health in midlife and statistically mediated the association between ACEs and midlife health. Health behaviors evidenced the strongest indirect effect from ACEs to midlife health. Together, these psychosocial mediators accounted for the association between ACEs in childhood and health three decades later. Public health efforts to mitigate the health consequences of ACEs could aim to reduce the stressful life events people experience, reduce negative emotionality, reduce perceived stress, or improve health behaviors among adults who experienced childhood adversity.