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Brain aging is typically associated with a significant decline in cognitive performance. Vascular risk factors (VRF) and subsequent atherosclerosis (AS) play a major role in this process. Brain resilience reflects the brain's ability to withstand external perturbations, but the relationship of brain resilience with cognition during the aging process remains unclear. Here, we investigated how brain topological resilience (BTR) is associated with cognitive performance in the face of aging and vascular risk factors. We used data from two cross-ethnicity community cohorts, PolyvasculaR Evaluation for Cognitive Impairment and Vascular Events (PRECISE, n = 2220) and Sydney Memory and Ageing Study (MAS, n = 246). We conducted an attack simulation on brain structural networks based on k-shell decomposition and node degree centrality. BTR was defined based on changes in the size of the largest subgroup of the network during the simulation process. Subsequently, we explored the negative correlations of BTR with age, VRF, and AS, and its positive correlation with cognitive performance. Furthermore, using structural equation modeling (SEM), we constructed path models to analyze the directional dependencies among these variables, demonstrating that aging, AS, and VRF affect cognition by disrupting BTR. Our results also indicated the specificity of this metric, independent of brain volume. Overall, these findings underscore the supportive role of BTR on cognition during aging and highlight its potential application as an imaging marker for objective assessment of brain cognitive performance., (Copyright © 2024 Science China Press. Published by Elsevier B.V. All rights reserved.)

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Increased efforts in neuroscience seek to understand how macro-anatomical and physiological connectomes cooperatively work to generate cognitive behaviors. However, the structure-function coupling characteristics in normal aging individuals remain unclear. Here, we developed an index, the Coupling in Brain Structural connectome and Functional connectome (C-BSF) index, to quantify regional structure-function coupling in a large community-based cohort. C-BSF used diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (fMRI) data from the Polyvascular Evaluation for Cognitive Impairment and Vascular Events study (PRECISE) cohort (2007 individuals, age: 61.15 ± 6.49 years) and the Sydney Memory and Ageing Study (MAS) cohort (254 individuals, age: 83.45 ± 4.33 years). We observed that structure-function coupling was the strongest in the visual network and the weakest in the ventral attention network. We also observed that the weaker structure-function coupling was associated with increased age and worse cognitive level of the participant. Meanwhile, the structure-function coupling in the visual network was associated with the visuospatial performance and partially mediated the connections between age and the visuospatial function. This work contributes to our understanding of the underlying brain mechanisms by which aging affects cognition and also help establish early diagnosis and treatment approaches for neurological diseases in the elderly., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cognitive, social, and physical activities, collectively linked to cognitive reserve, are associated with better late-life cognitive outcomes. To better understand the building of cognitive reserve, we investigated which of these activities, during which stages of life, had the strongest associations with late-life cognitive performance. From the Sydney Memory and Aging Study, 546 older Australians, who were community-dwelling and without a dementia diagnosis at recruitment (M age 80.13 years, 52.2% female), were asked about their engagement in social, physical, and cognitive activities throughout young adulthood (YA), midlife (ML), and late-life (LL). Comprehensive neuropsychological testing administered biennially over 6 years measured baseline global cognition and cognitive decline. In our study, YA, but not ML nor LL, cognitive activity was significantly associated with late-life global cognition ( β = 0.315, p  < .001). A follow-up analysis pointed to the formal education component of the YA cognitive activity measure, rather than YA cognitive leisure activities, as a significant predictor of better late-life global cognition ( β = 0.146, p  = .003). YA social activity and LL cognitive activity were significantly associated with less cognitive decline ( β = 0.023, p  < .001, and β =  0.016, p  = .022, respectively). Physical activity was not found to be associated with global cognition or cognitive decline. Overall, YA cognitive activity was associated with better late-life cognition, and YA social and LL cognitive activities were associated with less cognitive decline. Formal education emerges as the key contributor in the association between YA cognitive activity and late-life global cognition.

Objectives: The 10-item Kessler Psychological Distress Scale (K-10) is a widely applied distress measure; however, its psychometric properties were not established with older populations using advanced methodology. The aim of this study was to examine psychometric properties of the K-10 through application of Rasch methodology and if possible, develop an ordinal-to-interval conversion to improve its reliability in older populations., Method: The Partial Credit Rasch Model was applied to analyse K-10 scores of the sample including 490 participants (56.3 % females) aged 70 to 90 years and without dementia from the Sydney Memory and Ageing Study (MAS)., Results: The initial analysis of the K-10 showed poor reliability and significant deviation from the expectations of the Rasch model. The best model fit was evident after correcting disordered thresholds and creating two testlet models to address local dependency between items (χ 2 (35) = 29.87, p = 0.71). The modified K-10 demonstrated strict unidimensionality, enhanced reliability and scale invariance across personal factors, such as sex, age, and education and permitted development of ordinal-to-interval transformation algorithms., Limitations: Ordinal-to-interval conversion can only be applied for older adults with complete data., Conclusions: The K-10 satisfied principles of fundamental measurement defined by Rasch model after minor modifications. Clinicians and researchers can transform K-10 raw scores into interval-level data using converging algorithms published here without altering the original scale response format, which increases reliability of the K-10., Competing Interests: Conflict of interest The authors declare that there is no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Growing evidence suggests that there is an association between poor oral health and cognitive function in late adulthood. However, most studies to date have relied on cross-sectional research methods that do not permit inferences about the temporality of any association. Moreover, the few longitudinal studies that do exist have typically relied on small samples and quite limited cognitive or oral health assessments. The aim of the present study was therefore designed to provide the first direct evaluation of whether cognitive function is predictive of poor oral health in older adults., Methods: This longitudinal research included data from 339 participants aged 70 years or older from The Sydney Memory and Ageing Study (MAS), a large cohort of healthy community-dwelling older adults. Cognitive function was assessed using a battery of tests at baseline (Wave 1) in 2005 and six years later (Wave 4) in 2011. In 2015 (Wave 6), participants were assessed for oral health using the Oral Health Assessment Tool (OHAT), number of functional occluding pairs of natural teeth and sublingual resting saliva pH (SRSpH). Ordinal least squares regression analysis was used to model the effect of cognitive function on total OHAT score, and binomial logistic regression used for SRSpH and occluding pairs of functional teeth., Results: Two models were tested. In the partially adjusted model, age, gender and years of education were included. The fully adjusted model additionally included medical conditions, general health, depression, smoking, alcohol consumption, functionality, and dental care utilization. The key finding to emerge was that a six-year change in memory (from Wave 1 to Wave 4) was associated with lower sublingual resting saliva pH at Wave 6 in partially (Odds Ratio (OR) = 0.65) and fully adjusted model (OR = 0.63)., Conclusions: This longitudinal study provides further evidence that a relationship between cognitive function and oral health exists, and also points to this relationship potentially being bi-directional, as previous evidence suggests. The findings from the study also suggest that older adults who present with greater than normal memory decline at an earlier point in life were more likely to experience poor oral health when this was evaluated at a later time-point, four years later., (© 2022. The Author(s).)

The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sydney, Australia in 2019, highlighting the leadership of Australian researchers in advancing the understanding of and treatment developments for Alzheimer's disease (AD) and other dementias. This leadership includes the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), which has fueled the identification and development of many biomarkers and novel therapeutics. Two multimodal lifestyle intervention studies have been launched in Australia; and Australian researchers have played leadership roles in other global studies in diverse populations. Australian researchers have also played an instrumental role in efforts to understand mechanisms underlying vascular contributions to cognitive impairment and dementia; and through the Women's Healthy Aging Project have elucidated hormonal and other factors that contribute to the increased risk of AD in women. Alleviating the behavioral and psychological symptoms of dementia has also been a strong research and clinical focus in Australia., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objectives: This study assessed whether reciprocal relationships exist between cognitive function and the social network size of older adults, controlling for age, sex, education, medical conditions, and depressive symptoms., Methods: Data were collected at biennial follow-ups over 6 years in the Sydney Memory and Ageing Study, a longitudinal cohort study including 1,037 community-based Sydney residents aged 70-90 years without dementia at baseline. We used random intercept cross-lagged panel models to investigate reciprocal associations between social network size and scores in each of 7 cognitive domains including a global score., Results: Standardized models indicated that within-person deviation in expected language score predicted deviation in expected network size. Within-person deviation in prior expected social network size predicted deviation in expected executive function at year 6. Cross-lagged effects in models of both global cognition and memory, respectively, could not be attributed solely to within-person change., Discussion: Findings support a co-constitutive view of cognitive function and social relationships in older age. Although both cognition and network size declined over time, slower than expected decline in language ability predicted less than expected contraction in social networks. A similar influence of network size on executive functioning indicated that relationships with friends and family outside of the home contributed significantly to the maintenance of higher order cognitive abilities in older late life. Diverse patterns of influence between cognitive domains and social network size over 6 years underscore the importance of assessing the complex and nuanced interplay between brain health and social relationships in older age., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Diffusion weighted imaging (DWI) is a widely recognized neuroimaging technique to evaluate the microstructure of brain white matter. The objective of this study is to establish an improved automated DWI marker for estimating white matter integrity and investigating ageing related cognitive decline. The concept of Wasserstein distance was introduced to help establish a new measure: difference in distribution functions (DDF), which captures the difference of reshaping one's mean diffusivity (MD) distribution to a reference MD distribution. This new DWI measure was developed using a population-based cohort (n=19,369) from the UK Biobank. Validation was conducted using the data drawn from two independent cohorts: the Sydney Memory and Ageing Study, a community-dwelling sample (n=402), and the Renji Cerebral Small Vessel Disease Cohort Study (RCCS), which consisted of cerebral small vessel disease (CSVD) patients (n=171) and cognitively normal controls (NC) (n=43). DDF was associated with age across all three samples and better explained the variance of changes than other established DWI measures, such as fractional anisotropy, mean diffusivity and peak width of skeletonized mean diffusivity (PSMD). Significant correlations between DDF and cognition were found in the UK Biobank cohort and the MAS cohort. Binary logistic analysis and receiver operator characteristic curve analysis of RCCS demonstrated that DDF had higher sensitivity in distinguishing CSVD patients from NC than the other DWI measures. To demonstrate the flexibility of DDF, we calculated regional DDF which also showed significant correlation with age and cognition. DDF can be used as a marker for monitoring the white matter microstructural changes and ageing related cognitive decline in the elderly., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Ageing is associated with a decrease in odour identification. Additionally, deficits in olfaction have been linked to age-related disease and mortality. Heritability studies suggest genetic variation contributes to olfactory identification. The olfactory receptor (OR) gene family is the largest in the human genome and responsible for overall odour identification. In this study, we sought to find olfactory gene family variants associated with individual and overall odour identification and to examine the relationships between polygenic risk scores (PRS) for olfactory-related phenotypes and olfaction. Participants were Caucasian older adults from the Sydney Memory and Ageing Study and the Older Australian Twins Study with genome-wide genotyping data ( n = 1395, mean age = 75.52 ± 6.45). The Brief-Smell Identification Test (BSIT) was administered in both cohorts. PRS were calculated from independent GWAS summary statistics for Alzheimer's disease (AD), white matter hyperintensities (WMH), Parkinson's disease (PD), hippocampal volume and smoking. Associations with olfactory receptor genes ( n = 967), previously identified candidate olfaction-related SNPs ( n = 36) and different PRS with BSIT scores (total and individual smells) were examined. All of the relationships were analysed using generalised linear mixed models (GLMM), adjusted for age and sex. Genes with suggestive evidence for odour identification were found for 8 of the 12 BSIT items. Thirteen out of 36 candidate SNPs previously identified from the literature were suggestively associated with several individual BSIT items but not total score. PRS for smoking, WMH and PD were negatively associated with chocolate identification. This is the first study to conduct genetic analyses with individual odorant identification, which found suggestive olfactory-related genes and genetic variants for multiple individual BSIT odours. Replication in independent and larger cohorts is needed.

The relationships between aging and brain morphology have been reported in many previous structural brain studies. However, the trajectories of successful brain aging in the extremely old remain underexplored. In the limited research on the oldest old, covering individuals aged 85 years and older, there are very few studies that have focused on the cortical morphology, especially cortical sulcal features. In this paper, we measured sulcal width and depth as well as cortical thickness from T1-weighted scans of 290 nondemented community-dwelling participants aged between 76 and 103 years. We divided the participants into young old (between 76 and 84; mean = 80.35±2.44; male/female = 76/88) and oldest old (between 85 and 103; mean = 91.74±5.11; male/female = 60/66) groups. The results showed that most of the examined sulci significantly widened with increased age and that the rates of sulcal widening were lower in the oldest old. The spatial pattern of the cortical thinning partly corresponded with that of sulcal widening. Compared to females, males had significantly wider sulci, especially in the oldest old. This study builds a foundation for future investigations of neurocognitive disorders and neurodegenerative diseases in the oldest old, including centenarians., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2021. Published by Elsevier Inc.)

White matter hyperintensities (WMH) are generally considered to be associated with cerebral small vessel disease, especially, in older age. Although significant sex differences have been reported in the severity of WMH, it is not yet known if the risk factors for WMH differ in men and women. In this study, magnetic resonance imaging brain scans from 2 Australian cohorts were analyzed to extract WMH volumes. The objective of this study is to examine the moderation effect by sex in the association between known risk factors and WMH. The burden of WMH was significantly higher in women compared to men, especially in the deep WMH (DWMH). In the generalized linear model that included the interaction between sex and body mass index (BMI), there was a differential association of BMI with DWMH in men and women in the exploratory sample, that is, the Sydney Memory and Aging Study, n = 432, aged between 70 and 90. The finding of a higher BMI associated with a higher DWMH in men compared to women was replicated in the Older Australian Twins Study sample, n = 179, aged between 65 and 90. The risk factors of WMH pathology are suggested to have a different impact on the aging brains of men and women., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Non-pharmacological treatments (NPTs) have the potential to improve meaningful outcomes for older people at risk of, or living with dementia, but research often lacks methodological rigor and continues to produce mixed results., Methods: In the current position paper, experts in NPT research have specified treatment targets, aims, and ingredients using an umbrella framework, the Rehabilitation Treatment Specification System., Results: Experts provided a snapshot and an authoritative summary of the evidence for different NPTs based on the best synthesis efforts, identified main gaps in knowledge and relevant barriers, and provided directions for future research. Experts in trial methodology provide best practice principles and recommendations for those working in this area, underscoring the importance of prespecified protocols., Discussion: We conclude that the evidence strongly supports various NPTs in relation to their primary targets, and discuss opportunities and challenges associated with a unifying theoretical framework to guide future efforts in this area., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Data collected from clinical trials and cohort studies, such as dementia studies, are often high-dimensional, censored, heterogeneous and contain missing information, presenting challenges to traditional statistical analysis. There is an urgent need for methods that can overcome these challenges to model this complex data. At present there is no cure for dementia and no treatment that can successfully change the course of the disease. Machine learning models that can predict the time until a patient develops dementia are important tools in helping understand dementia risks and can give more accurate results than traditional statistical methods when modelling high-dimensional, heterogeneous, clinical data. This work compares the performance and stability of ten machine learning algorithms, combined with eight feature selection methods, capable of performing survival analysis of high-dimensional, heterogeneous, clinical data. We developed models that predict survival to dementia using baseline data from two different studies. The Sydney Memory and Ageing Study (MAS) is a longitudinal cohort study of 1037 participants, aged 70-90 years, that aims to determine the effects of ageing on cognition. The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a longitudinal study aimed at identifying biomarkers for the early detection and tracking of Alzheimer's disease. Using the concordance index as a measure of performance, our models achieve maximum performance values of 0.82 for MAS and 0.93 For ADNI.

We aimed to examine the relationship between Apolipoprotein E ε4 (APOE*4) carriage on cognitive decline, and whether these associations were moderated by sex, baseline age, ethnicity, and vascular risk factors. Participants were 19,225 individuals aged 54-103 years from 15 longitudinal cohort studies with a mean follow-up duration ranging between 1.2 and 10.7 years. Two-step individual participant data meta-analysis was used to pool results of study-wise analyses predicting memory and general cognitive decline from carriage of one or two APOE*4 alleles, and moderation of these associations by age, sex, vascular risk factors, and ethnicity. Separate pooled estimates were calculated in both men and women who were younger (ie, 62 years) and older (ie, 80 years) at baseline. Results showed that APOE*4 carriage was related to faster general cognitive decline in women, and faster memory decline in men. A stronger dose-dependent effect was observed in older men, with faster general cognitive and memory decline in those carrying two versus one APOE*4 allele. Vascular risk factors were related to an increased effect of APOE*4 on memory decline in younger women, but a weaker effect of APOE*4 on general cognitive decline in older men. The relationship between APOE*4 carriage and memory decline was larger in older-aged Asians than Whites. In sum, APOE*4 is related to cognitive decline in men and women, although these effects are enhanced by age and carriage of two APOE*4 alleles in men, a higher numbers of vascular risk factors during the early stages of late adulthood in women, and Asian ethnicity., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

Centenarians without dementia can be considered as a model of successful ageing and resistance against age-related cognitive decline. Is there something special about their brain functional connectivity that helps them preserve cognitive function into the 11th decade of life? In a cohort of 57 dementia-free near-centenarians and centenarians (95-103 years old) and 66 cognitively unimpaired younger participants (76-79 years old), we aimed to investigate brain functional characteristics in the extreme age range using resting-state functional MRI. Using group-level independent component analysis and dual regression, results showed group differences in the functional connectivity of seven group-level independent component (IC) templates, after accounting for sex, education years, and grey matter volume, and correcting for multiple testing at family-wise error rate of 0.05. After Bonferroni correction for testing 30 IC templates, near-centenarians and centenarians showed stronger functional connectivity between right frontoparietal control network (FPCN) and left inferior frontal gyrus (Bonferroni-corrected p ​= ​0.024), a core region of the left FPCN. The investigation of between-IC functional connectivity confirmed the voxel-wise result by showing stronger functional connectivity between bilateral FPCNs in near-centenarians and centenarians compared to young-old controls. In addition, near-centenarians and centenarians had weaker functional connectivity between default mode network and fronto-temporo-parietal network compared to young-old controls. In near-centenarians and centenarians, stronger functional connectivity between bilateral FPCNs was associated with better cognitive performance in the visuospatial domain. The current study highlights the key role of bilateral FPCN connectivity in the reserve capacity against age-related cognitive decline., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fractal geometry provides a method of analyzing natural and especially biological morphologies. To investigate the relationship between the complexity measure, which is indexed as fractal dimensionality (FD), and the traditional Euclidean metrics, such as the volume and thickness, of the brain in older age, we analyzed 483 MRI scans of 161 community-dwelling, nondemented individuals aged 70-90 years at the baseline and their 2-year and 6-year follow-ups. We quantified changes in neuroimaging metrics in cortical lobes and subcortical structures and investigated the effects of age, sex, hemisphere, and education on FD. We also analyzed the mediating effects of these metrics for further investigation. FD showed significant age-related decline in all structures, and its trajectory was best modeled quadratically in the bilateral frontal, parietal, and occipital lobes, as well as in the bilateral caudate, putamen, hippocampus, amygdala, and accumbens. FD showed specific mediating effects on aging and cognitive decline in some regions. Our findings suggest that FD is reliable yet shows a different pattern of decline compared with volumetric measures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Exposures to life stressors accumulate across the lifespan, with possible impact on brain health. Little is known, however, about the mechanisms mediating age-related changes in brain structure. We use a lifespan sample of participants (n = 21 251; 4-97 years) to investigate the relationship between the thickness of cerebral cortex and the expression of the glucocorticoid- and the mineralocorticoid-receptor genes (NR3C1 and NR3C2, respectively), obtained from the Allen Human Brain Atlas. In all participants, cortical thickness correlated negatively with the expression of both NR3C1 and NR3C2 across 34 cortical regions. The magnitude of this correlation varied across the lifespan. From childhood through early adulthood, the profile similarity (between NR3C1/NR3C2 expression and thickness) increased with age. Conversely, both profile similarities decreased with age in late life. These variations do not reflect age-related changes in NR3C1 and NR3C2 expression, as observed in 5 databases of gene expression in the human cerebral cortex (502 donors). Based on the co-expression of NR3C1 (and NR3C2) with genes specific to neural cell types, we determine the potential involvement of microglia, astrocytes, and CA1 pyramidal cells in mediating the relationship between corticosteroid exposure and cortical thickness. Therefore, corticosteroids may influence brain structure to a variable degree throughout life., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Current research on the psychological health of near-centenarians (95-99 years old) and centenarians remains limited. Existing studies have mainly characterized their physical, cognitive, and social health. Results on the anxiety and depression of near-centenarians and centenarians (more than 95 years old) have been mixed with some studies, finding higher rates of anxiety and depression among those older than 95 years and others reporting no difference in rates compared with younger age groups. This study aims to synthesize the existing literature on the prevalence and predictors of anxiety and depression in near-centenarians and centenarians., Method: A systematic review was conducted using Ovid Medline, Embase, PsycINFO, CINAHL, SCOPUS, and the Cochrane database. Common and conflicting findings among the literature were examined., Results: Thirty-eight studies met the inclusion criteria. Six studies examined the prevalence and predictors of anxiety, and 37 studies investigated the prevalence and predictors of depression. Five studies examined both anxiety and depression in the same sample. Prevalence data on anxiety and depression varied significantly, as did comparisons with rates in younger populations. Findings on predictors of anxiety and depression were contradictory., Conclusion: There is a large degree of heterogeneity among studies of centenarians' psychological status. Findings conflict on the prevalence and predictors of anxiety and depression and rates compared with younger age groups. Variation in findings may result from the different inclusion criteria, sampling methods, and measurement tools. Better harmonization of centenarian study methodologies may improve consistency of findings to aid in developing clinical interventions.

Objectives: To follow-up a cohort of older people who self-harmed, their carer, and general practitioner (GP) and examine their reflections on the self-harm, care experiences, and outcomes., Design: Qualitative in-depth interviews., Setting: Two teaching hospitals and associated community services., Participants: Twelve-month follow-up of participants aged 80 or older who self-harmed, their nominated carers, and GPs., Measurements: A geriatric psychiatrist gathered data through patient and carer interviews using a narrative inquiry approach and from medical records. Interviews were audio recorded and transcribed. N-VIVO facilitated data organization for thematic analysis. Questionnaires sent to the patient's GP examined their perspectives and aspects of care relating to the self-harm., Results: Nineteen patients (63% baseline sample), 29 carers (90.6%), and 11 GPs (36.7%) were available at follow-up. Themes emerging from patients were "denial and secrets;" "endless suffering;" "more invalidation;" "being heard;" and "miserable in care." Themes from carer interviews were "denial and secrets;" "patient's persistent wish to die;" "abandonment by clinicians;" "unending burden for the carer;" and "distress regarding placement." General practitioner themes were "the problem is fixed;" "the troops have arrived;" and "I understand.", Conclusions: Factors contributing to self-harm persisted at follow-up. Positive and negative responses were identified in the older person's system, highlighting areas for potential intervention. A conceptual framework for understanding self-harm in the very old was derived that emphasized the importance of understanding individual needs, the interpersonal context of the older person, and carer burden. Interventions should improve communication, facilitate shared understanding of perspectives, and provide support at all levels.

Objective: While near-centenarians (95-99) and centenarians are the fastest growing sectors of the population in many countries, few studies have investigated their psychological health. We aimed to compare levels of psychological distress and life satisfaction in individuals aged 95 or above (95+) with younger age groups and identify the factors associated with psychological distress and life satisfaction in near-centenarians and centenarians., Methods: We assessed the physical, cognitive, social and psychological health of 207 participants aged 95+ in the Sydney Centenarian Study. Psychological distress and life satisfaction were rated on the Kessler Psychological Distress Scale (K10) and Satisfaction with Life Scale, respectively. Cross-sectional univariate comparisons were performed with participants aged 70-90 years from the Sydney Memory and Ageing Study. Factors associated with psychological distress and life satisfaction among Sydney Centenarian Study participants were examined using multiple regression analyses., Results: In Sydney Centenarian Study and Memory and Ageing Study, mean K10 scores were 15.3 (±5.9) and 13.4 (±3.6), and clinical levels of psychological distress (K10 ⩾ 20) were 19% and 7%, respectively. Sydney Centenarian Study participants demonstrated significantly higher levels and rates of psychological distress ( t  = 3.869, p  < 0.001; χ 2  = 27.331, p  < 0.001). In Sydney Centenarian Study, more psychotropic medications and having fewer relatives and friends were associated with higher psychological distress. Sydney Centenarian Study participants reported significantly higher levels of life satisfaction than Memory and Ageing Study participants, mean scores 6.0 (±1.5) and 5.6 (±1.3); t  = 5.835, p  < 0.001. Lower Mini-Mental State Examination scores and having fewer relatives and friends were associated with lower life satisfaction in Sydney Centenarian Study., Conclusion: Despite showing higher levels of psychological distress in the prior 4 weeks than younger age groups, near-centenarians and centenarians remained highly satisfied with their overall lives. The identification of risk and protective factors for psychological distress and life satisfaction provides opportunities for interventions to maintain good psychological health in this vulnerable population.

Objectives: The study aimed to examine the validity, reliability, and practicality of the Persian version of the General Practitioner Assessment of Cognition (P-GPCOG) as a brief, efficient cognitive assessment instrument in Iranian older adults. Method: The sample comprised 151 community-dwelling older adults and 79 nursing home residents (aged ≥60 years). The English GPCOG was translated, back-translated, and revised to prepare the final P-GPCOG. The Abbreviated Mental Test score (AMTs) and the Depression in Old Age Scale (DIA-S) were administered to the two different samples to establish the convergent and discriminant validity of the P-GPCOG. Results: The mean age of the sample was 70.67 (SD = 9.51); 57.4% were male. The mean P-GPCOG scores for the total, cognitive and informant subscales were 7.67 (SD = 4.59), 4.18 (SD = 2.73), and 3.49 (SD = 2.24), respectively. Cognitive ( P < 0.001), informant ( P < 0.001) and total scores ( P < 0.001) differed significantly between community-dwelling participants and nursing home residents. Worse cognitive performance on the P-GPCOG correlated significantly with worse scores on the AMTs ( r = 0.61, P < 0.001) and less so with depressive symptoms as measured with the DIA-S ( r = -0.20, P < 0.05). Cronbach's alpha for the P-GPCOG cognitive and informant subscales were 0.90 and 0.83 respectively, indicating a high degree of internal consistency and homogeneity between items. The test-retest correlation for the total P-GPCOG score was 0.82 in 30 participants after 19 days. P-GPCOG cognitive scores correlated significantly with education. Conclusion: The P-GPCOG displayed strong psychometric properties, offering healthcare professionals a quick and efficient cognitive instrument for older Persian speakers. As with other cognitive assessment tools, the P-GPCOG cognitive score is affected by a person's level of education.

Objectives: The aim of this study was to investigate physical decline over 1-year in a cohort of older people across the cognitive spectrum., Methods: Physical function was assessed using the Physiological Profile Assessment (PPA) in 593 participants (cognitively normal [CN]: n = 342, mild cognitive impairment [MCI]: n = 77, dementia: n = 174) at baseline and in 490 participants available for reassessment 1-year later. Neuropsychological performance and physical activity (PA) were assessed at baseline., Results: Median baseline PPA scores for CN, MCI and dementia groups were 0.41 (IQR = -0.09-1.02), 0.66 (IQR = -0.06-1.15) and 2.37 (IQR = 0.93-3.78) respectively. All baseline neuropsychological domains and PA were significantly associated with baseline PPA. There were significant interaction terms (Time × Cognitive Group, Global Cognition, Processing Speed, Executive Function and PA) in the models investigating PPA decline. In multivariate analysis the Time × Executive Function and PA interaction terms were significant, indicating that participants with poorer baseline executive function and reduced PA demonstrated greater physical decline when compared to individuals with better executive function and PA respectively., Discussion: Having MCI or dementia is associated with greater physical decline compared to CN older people. Physical inactivity and executive dysfunction were associated with physical decline in this sample, which included participants with MCI and dementia. Both factors influencing physical decline are potentially amenable to interventions e.g. exercise.

Objective: To examine the insights of carers to better understand self-harm in their older relatives., Methods: An in-depth interview was conducted with the nominated relative/friend (carer) of a person over 80 who had self-harmed within the last month. Carer interpretation and experience of the self-harm and clinical care were explored qualitatively. Audio recordings were transcribed and the content thematically analyzed using N-VIVO., Results: Thirty-two carers of 30 older people who self-harmed were interviewed. Physical, social, and psychological issues were identified as contributory to self-harm. Themes relating to the perceived barriers to seeking help included "they can't communicate," "suicide and secrets," and "invalidation." Themes for the intent of self-harm were "attention seeking" and "wanting to die." Themes which emerged for consequences of self-harm for carers were "anger," "guilt and self-blame," and "it made us ill." Themes for solutions to address the underlying factors leading to self-harm were "more practical support and structure," "improving communication," "removing means of self-harm," "advance care directives as a solution for suffering," and "ignoring self-harm." Clinical care themes were "shared shame and stigma," "safety and supervision vs being locked up," "clinicians dismissing the carer," and "relief and support.", Conclusions: Validation of carer perspectives and understanding family dynamics may improve communication at various system levels and inform interventions for older persons, concurrently support families, and potentially reduce risk of repeat self-harm. Good care must be holistic, be person-centred, and relieve carer burden. A shared understanding and psychotherapeutic approaches to management of self-harm in late life should be considered., (© 2018 John Wiley & Sons, Ltd.)

Recent advances in mass spectrometry-based techniques have inspired research into lipidomics, a subfield of '-omics', which aims to identify and quantify large numbers of lipids in biological extracts. Although lipidomics is becoming increasingly popular as a screening tool for understanding disease mechanisms, it is largely unknown how the lipidome naturally varies by age and sex in healthy individuals. We aimed to identify cross-sectional associations of the human lipidome with 'physiological' ageing, using plasma from 100 subjects with an apolipoprotein E (APOE) E3/E3 genotype, and aged between 56 to 100 years. Untargeted analysis was performed by liquid chromatography coupled-mass spectrometry (LC-MS/MS) and data processing using LipidSearch software. Regression analyses confirmed a strong negative association of age with the levels of various lipid, which was stronger in males than females. Sex-related differences include higher LDL-C, HDL-C, total cholesterol, particular sphingomyelins (SM), and docosahexaenoic acid (DHA)-containing phospholipid levels in females. Surprisingly, we found a minimal relationship between lipid levels and body mass index (BMI). In conclusion, our results suggest substantial age and sex-related variation in the plasma lipidome of healthy individuals during the second half of the human lifespan. In particular, globally low levels of blood lipids in the 'oldest old' subjects over 95 years could signify a unique lipidome associated with extreme longevity., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To examine the perspectives of people aged 80 years or older who self-harmed regarding their reasons for self-harm and its consequences, and their perceptions of care., Design: A qualitative study using in-depth interviews., Setting: Participants were recruited from two teaching hospitals and associated community services., Participants: People aged 80 years or older who had self-harmed within the previous month., Methods: Structured psychiatric assessment including cognitive testing, DSM-5 diagnosis, and an in-depth qualitative interview focusing upon the reasons for and consequences of self-harm. Narrative enquiry was used to guide the discussion. All interviews were undertaken by a geriatric psychiatrist, audio recorded, transcribed verbatim, and subjected to thematic analysis using N-VIVO., Results: Themes that emerged for the reasons for self-harm included "enough is enough"; "loneliness"; "disintegration of self"; "being a burden"; "cumulative adversity"; "hopelessness and endless suffering"; "helplessness with rejection"; and "the untenable situation". Themes for the consequences of self-harm were "becoming engaged with or distanced from family"; "the problem was solved"; "gaining control"; "I"m worse off now"; "rejection by health professionals"; and "tension in the role of the inpatient clinical environment"., Conclusions: Self-harm may communicate a need that cannot otherwise be expressed. An individualized person-centered approach is required to respond to self-harm, including a combination of practical, medical, and psychological approaches as indicated. Involvement of families in the process of understanding the meaning of and responding to self-harm through education and family therapy, as well as education of healthcare professionals beyond risk factor notation may be indicated., (Copyright © 2018 American Association for Geriatric Psychiatry. All rights reserved.)

Emerging evidence from lesion-symptom mapping (LSM) studies suggested that regional white matter lesions (WML) on strategic white matter (WM) fiber tracts are significantly associated with specific cognitive domains, independent of global WML burden. However, previous LSM investigations were mostly carried out in disease cohorts, with little evidence from community-based older individuals, making findings difficult to generalize. Moreover, most LSM studies applied a threshold to the probabilistic atlas, leading to the loss of information and threshold-dependent findings. Furthermore, it is still unclear whether associations between regional WML and cognition are independent of global grey matter (GM) and WM volumes, which have also been linked to cognition. In the current study, we undertook a region of interest (ROI) LSM study to examine the relationship between regional WML on strategic WM tracts and cognitive performance in a large community-based cohort of older individuals ( N  = 461; 70-90 years). WML were extracted using a publicly available pipeline, UBO Detector (https://cheba.unsw.edu.au/group/neuroimaging-pipeline). Mapping of WML to the Johns Hopkins University WM atlas was undertaken using an automated TOolbox for Probabilistic MApping of Lesions (TOPMAL), which we introduce here, and is implemented in UBO Detector. The results show that different patterns of brain structural volumes in the ageing brain were associated with different cognitive domains. Regional WML were associated with processing speed, executive function, and global cognition, independent of total GM, WM and WML volumes. Moreover, regional WML explained more variance in executive function, compared to total GM, WM and WML volumes. The current study highlights the importance of studying regional WML in age-related cognitive decline.

Sulcal morphology has been reported to change with age-related neurological diseases, but the trajectories of sulcal change in normal ageing in the elderly is still unclear. We conducted a study of sulcal morphological changes over seven years in 132 normal elderly participants aged 70-90 years at baseline, and who remained cognitively normal for the next seven years. We examined the fold opening and sulcal depth of sixteen (eight on each hemisphere) prominent sulci based on T1-weighted MRI using automated methods with visual quality control. The trajectory of each individual sulcus with respect to age was examined separately by linear mixed models. Fold opening was best modelled by cubic fits in five sulci, by quadratic models in six sulci and by linear models in five sulci, indicating an accelerated widening of a number of sulci in older age. Sulcal depth showed significant linear decline in three sulci and quadratic trend in one sulcus. Turning points of non-linear trajectories towards accelerated widening of the fold were found to be around the age between 75 and 80, indicating an accelerated atrophy of brain cortex starting in the age of late 70s. Our findings of cortical sulcal changes in normal ageing could provide a reference for studies of neurocognitive disorders, including neurodegenerative diseases, in the elderly., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Prospective memory (PM) is crucial to the maintenance of functional independence in late adulthood and is consistently impaired in mild cognitive impairment (MCI). There remains a need for brief but valid measures of this construct that can be used as part of a comprehensive clinical assessment of cognition. Since the distinctiveness of PM cues is argued to determine the degree of strategic, controlled demands of PM paradigms, two variants of a brief measure were developed, one of which presented low-salience and the other high-salience PM cues., Method: A large cohort of older adults with normal cognition or MCI was assessed with one of the two variants of our brief, novel measure of PM. Participants were asked to remember to execute PM tasks where the target cue was either high or low in salience, while concurrently engaged in an ongoing task of olfactory assessment., Results: The task was able to discriminate between groups of participants with MCI or no cognitive impairment, albeit with a small effect size. The high-salience cue improved performance on the PM task; however, there was no interaction of cue salience with group., Conclusions: These results suggest that the temporal reliability and construct validity of very brief measures of the type used in this study need further exploration to determine their potential to provide meaningful insights into PM function. This measure may have utility as a brief screening tool, with identified deficits being followed up with a more comprehensive PM assessment.

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.

Apolipoproteins play a crucial role in lipid metabolism with implications in cardiovascular disease, obesity, diabetes, Alzheimer's disease, and longevity. We quantified 7 apolipoproteins in plasma in 1067 individuals aged 56-105 using immunoassays and explored relationships with APOE polymorphism ε2/3/4, vascular health, frailty, and cognition. ApoA1, ApoA2, ApoB, ApoC3, ApoE, ApoH, and ApoJ decreased from mid-life, although ApoE and ApoJ had U-shaped trends. Centenarians had the highest ApoE levels and the lowest frequency of APOE ε4 allele relative to younger groups. Apolipoprotein levels trended lower in APOE ε4 homozygotes and heterozygotes compared with noncarriers, with ApoE and ApoJ being significantly lower. Levels of all apolipoproteins except ApoH were higher in females. Sex- and age-related differences were apparent in the association of apolipoproteins with cognitive performance, as only women had significant negative associations of ApoB, ApoE, ApoH, and ApoJ in mid-life, whereas associations at older age were nonsignificant or positive. Our findings suggest levels of some apolipoproteins, especially ApoE, are associated with lifespan and cognitive function in exceptionally long-lived individuals., (Copyright © 2017 Elsevier Inc. All rights reserved.)

An active cognitive lifestyle has been suggested to have a protective role in the long-term maintenance of cognition. Amongst healthy older adults, more managerial or supervisory experiences in midlife are linked to a slower hippocampal atrophy rate in late life. Yet whether similar links exist in individuals with Mild Cognitive Impairment (MCI) is not known, nor whether these differences have any functional implications. 68 volunteers from the Sydney SMART Trial, diagnosed with non-amnestic MCI, were divided into high and low managerial experience (HME/LME) during their working life. All participants underwent neuropsychological testing, structural and resting-state functional MRI. Group comparisons were performed on hippocampal volume, morphology, hippocampal seed-based functional connectivity, memory and executive function and self-ratings of memory proficiency. HME was linked to better memory function (p = 0.024), mediated by larger hippocampal volume (p = 0.025). More specifically, deformation analysis found HME had relatively more volume in the CA1 sub-region of the hippocampus (p < 0.05). Paradoxically, this group rated their memory proficiency worse (p = 0.004), a result correlated with diminished functional connectivity between the right hippocampus and right prefrontal cortex (p < 0.001). Finally, hierarchical regression modelling substantiated this double dissociation.

In old age, a relationship has been reported between intraindividual variability (IIV) in reaction time and white matter integrity as evidenced by white matter hyperintensities (WMH). However, it is unclear how far such associations are due to incipient neurodegenerative pathology in the samples investigated. The present study examined the relationship between IIV and WMH in older individuals (N=526) drawn from the Sydney Memory and Ageing Study. Using a complex reaction time (RT) task, greater IIV and mean-RT were related to a higher WMH burden in the frontal lobe. Critically, significant associations remained having taken future dementia into account suggesting that they were not explained by incipient dementia. Additionally, independent measures of executive function accounted for the association between RT metrics and WHM. The results are consistent with the view that frontally-supported cognitive processes are involved in IIV-WMH relations, and that RT measures are sensitive to compromise in white matter structures in non-demented older individuals., (Copyright © 2017. Published by Elsevier Ltd.)

Successful brain aging in the oldest old (≥90 years) is underexplored. This study examined cross-sectional brain morphological differences from 8th to 11th decades of life in nondemented individuals by high-resolution magnetic resonance imaging. Two hundred seventy-seven nondemented community-dwelling participants (71-103 years) from Sydney Memory and Ageing Study and Sydney Centenarian Study comprised the sample, including a subsample of 160 cognitively high-functioning elders. Relationships between age and magnetic resonance imaging-derived measurements were studied using general linear models; and structural profiles of the ≥90 years were delineated. In full sample and the subsample, significant linear negative relationship of gray matter with age was found, with the greatest age effects in the medial temporal lobe and parietal and occipital cortices. This pattern was further confirmed by comparing directly the ≥90 years to the 71-89 years groups. Significant quadratic age effects on total white matter and white matter hyperintensities were observed. Our study demonstrated heterogeneous differences across brain regions between the oldest old and young old, with an emphasis on hippocampus, temporoposterior cortex, and white matter hyperintensities., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Apolipoprotein H (ApoH) is a multi-functional plasma glycoprotein that has been associated with negative health outcomes. ApoH levels have high heritability. We undertook a genome-wide association study of ApoH levels using the largest sample to date and replicated the results in an independent cohort (total N = 1,255). In the discovery phase, a meta-analysis of two cohorts, the Sydney Memory and Ageing Study (Sydney MAS) and the Older Australian Twins Study (OATS) (n = 942) revealed genome-wide significant results in or near the APOH gene on chromosome 17 (top SNP, rs7211380, p = 1 × 10(-11)). The results were replicated in an independent cohort, the Hunter Community Study (p < 0.002) (n = 313). Conditional and joint analysis (COJO) confirmed the association of the chromosomal 17 region with ApoH levels. The set of independent SNPs identified by COJO explained 23% of the variance. The relationships between the top SNPs and cardiovascular/lipid/cognition measures and diabetes were assessed in Sydney MAS, with suggestive results observed for diabetes and cognitive performance. However, replication of these results in the smaller OATS cohort was not found. This work provides impetus for future research to better understand the contribution of genetics to ApoH levels and its possible impacts on health.

Objective: To examine the utility of intraindividual variability of reaction times (IIVRT) and mean reaction time (RT) as behavioral markers of incident all-cause dementia., Methods: A longitudinal cohort study followed biennially for 4 years, the community-based Sydney Memory and Ageing Study, 861 initially nondemented participants aged 70-90. Incident all-cause dementia determined by consensus, RT measures from simple and complex tasks, Mini-Mental State Exam and neuropsychological tests, Geriatric Depression Scale and Goldberg Anxiety Scale, cardiovascular risk score, apolipoprotein ε4 status, and the Bayer ADL Scale were used. Associations of baseline IIVRT and mean RT with time to dementia were evaluated with hazard ratios (HRs) using Cox proportional-hazards models with and without controlling for dementia risk factors., Results: Forty-eight cases developed dementia. Greater complex IIVRT predicted a 40% (HR: 1.43) and mean RT a 50%-60% (simple RT: HR 1.53; complex RT: HR 1.59) per standard deviation increased risk of developing dementia, remaining significant after controlling for age, education, sex, general cognitive function, mood, cerebrovascular disease, and genetic susceptibility. Prediction of incident dementia using demographical information and RT measures combined was comparable with several traditional neuropsychological measures (AUC 0.75), although lower than a full neuropsychological battery (AUC 0.90). Prediction of functional decline by RT measures combined was equal to the neuropsychological battery (multiple Rs of .233 and .238, respectively)., Conclusion: Brief RT measures provided information on risk of imminent dementia and functional decline within 4 years in older adults at a population level, with mean RT the stronger predictor., (Copyright © 2016 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: Determine whether (1) a relationship exists between plasma amyloid-β (Aβ)1- 40 and 1-42 peptide levels, brain volumetrics and cognitive performance in elderly individuals with and without amnestic mild cognitive impairment (aMCI), (2) plasma Aβ peptide levels differ between apolipoprotein E (APOE) ε4 carriers and non-carriers and (3) longitudinal changes in cognition and brain volume relate to Aβ levels., Methods: Subjects with aMCI (n = 89) and normal cognition (n = 126) were drawn from the Sydney Memory and Aging Study (Sydney MAS), a population based study of non-demented 70-90 year old individuals; 39 Alzheimer's disease (AD) patients were recruited from a specialty clinic. Sydney MAS participants underwent brain MRI scans and were assessed on 19 cognitive measures and were APOE ε4 genotyped. Plasma levels of Aβ1-40 and 1-42 were quantified using ELISA., Results: Wave1 plasma levels of Aβ peptides and Aβ1-42/1-40 ratio were lower in aMCI and AD, and Aβ1-42 was positively associated with global cognition and hippocampal volume and negatively with white matter hyperintensities. The relationships of Aβ1-40 and Aβ1-42 were predominantly observed in ε4 allele carriers and non-carriers respectively. Longitudinal analysis revealed greater decline in global cognition and memory for the highest quintiles of Aβ1-42 and the ratio measure., Conclusion: Plasma Aβ levels and the Aβ1-42/1-40 ratio are related to cognition and hippocampal volumes, with differential associations of Aβ1-40 and Aβ1-42 in ε4 carriers and non-carriers. These data support the Aβ sink model of AD pathology, and suggest that plasma Aβ measures may serve as biomarkers of AD.

Ageing is characterized by chronically elevated inflammatory markers (IMs). Peripheral IM levels have been found in negative correlations with brain structural measures including global and lobar volumes and the hippocampus. This study investigated the relationship between 10 peripheral IMs and voxel-based gray matter (GM) volumes in nondemented older adults (n = 463). Two proinflammatory cytokines (tumor necrosis factor-α [TNF-α] and interleukin-1β) and 2 vascular IMs (vascular cellular adhesion molecule-1 and plasminogen activator inhibitor-1) were negatively correlated with regional GM volumes. TNF-α and interleukin-1β were both significantly correlated with GM volumes in the left occipitotemporal area, left superior occipital gyrus, and left inferior parietal lobule; TNF-α was also significantly correlated with the bilateral medial prefrontal cortices and approached significance for the correlations with the bilateral hippocampi. Significant GM correlations with vascular cellular adhesion molecule-1 were located in the bilateral anterior cingulate cortices, and with plasminogen activator inhibitor-1 in the cerebellum and right hippocampus. The neuroanatomical correlation patterns of 2 proinflammatory cytokines and 2 vascular IMs might be reflective of the effects of neurodegenerative and vascular pathological processes in the ageing brain., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Macrophage inhibitory cytokine-1 (MIC-1/GDF15) is a marker of inflammation that has been associated with atherosclerosis. We have previously demonstrated its relationships with cognitive decline and cerebral gray matter volumes, suggesting its role as a biomarker of cognitive impairment. Considering that it is widely distributed in the brain, and both inflammation and vascular pathology impact on white matter (WM) integrity, we examined the relationship between MIC-1/GDF15 and measures of WM integrity, including WM volumes, mean fractional anisotropy (FA) values and WM hyperintensity (WMH) volumes in a community-dwelling non-demented sample of older individuals (n=327, 70-90 years old). We found that the mean FA values were negatively associated with MIC-1/GDF15 serum levels, after Bonferroni correction. The voxel-wise analysis showed negative relationships between MIC-1/GDF15 serum levels and FA values in corticospinal tract, corpus callosum (including genu, body and splenium parts), superior longitudinal fasciculus, cingulum, as well as anterior and posterior thalamic radiation. Whole brain WMH volumes, especially deep WMH volumes, showed a non-significant trend for a positive association with MIC-1/GDF15 serum levels. The associations between MIC-1/GDF15 serum levels and WM integrity showed a non-significant trend of being stronger for the individuals classified as mild cognitive impairment, compared to the normal ageing participants. The findings suggest that high serum MIC-1/GDF15 levels indicate reduced WM integrity and possibly greater WM pathology., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: There is limited understanding of the usefulness of subjective cognitive complaint(s) (SCC) in predicting longitudinal outcome because most studies focus solely on memory (as opposed to nonmemory cognitive) complaints, do not collect data from both participants and informants, do not control for relevant covariates, and have limited outcome measures. Therefore the authors investigate the usefulness of participant and informant SCCs in predicting change in cognition, functional abilities, and diagnostic classification of mild cognitive impairment or dementia in a community-dwelling sample over 4 years., Methods: Nondemented participants (N = 620) in the Sydney Memory and Ageing Study aged between 70 and 90 years completed 15 memory and 9 nonmemory SCC questions. An informant completed a baseline questionnaire that included 15 memory and 4 nonmemory SCC questions relating to the participant. Neuropsychological, functional, and diagnostic assessments were carried out at baseline and again at 4-year follow-up. Cross-sectional and longitudinal analyses were carried out to determine the association between SCC indices and neuropsychological, functional, and diagnostic data while controlling for psychological measures., Results: Once participant characteristics were controlled for, participant complaints were generally not predictive of cognitive or functional decline, although participant memory-specific complaints were predictive of diagnostic conversion. Informant-related memory questions were associated with global cognitive and functional decline and with diagnostic conversion over 4 years., Conclusion: Informant memory complaint questions were better than participant complaints in predicting cognitive and functional decline as well as diagnoses over 4 years., (Copyright © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: DNA methylation variation has been implicated in memory, cognitive performance, and dementia. Plasma apolipoprotein-A1 (ApoA1) levels may act as a biomarker of age-associated cognitive performance and decline., Objectives: To estimate the heritability of plasma ApoA1 protein levels; to examine DNA methylation variation within the APOA1 gene; and to investigate whether APOA1 methylation is associated with plasma ApoA1 levels and episodic memory performance., Method: Heritability of ApoA1 protein levels in Older Australian Twins Study (OATS) was assessed using structural equation modelling. APOA1 methylation levels were assayed in two cohorts of cognitively normal older individuals. The methylation status of 12 CpGs in 24 twin pairs from OATS was assayed using the Illumina 450K methylation array. Candidate CpGs were assayed in 454 individuals from Sydney Memory and Ageing Study (Sydney MAS) using pyrosequencing. Regression analyses assessed associations between APOA1 methylation levels, ApoA1 plasma levels, and memory performance., Results: No significant heritability was observed for ApoA1 protein levels. APOA1 candidate-gene analyses revealed CpG sites associated with memory performance in the twin study (p < 0.050). Replication of an association between methylation of a specific CpG (cg03010018) in APOA1 and memory performance was observed in Sydney MAS (β = -0.145, p = 0.010). Methylation of this CpG site was also significantly correlated with ApoA1 protein levels (β = 0.161, p = 0.019). However, no relationship between a composite memory domain score and methylation was observed (p = 0.389)., Conclusion: Findings demonstrated that epigenetic control of APOA1 expression and DNA methylation levels are associated with episodic memory performance in older adults.

Background: Prospective memory refers to memory for future intentions and is a critical predictor of functional capacity in late adulthood. For many other cognitive abilities, self- and informant-rated methods of assessment are routinely used to guide clinical decision-making. However, little is known about the validity (and consequently the clinical utility) of subjective reports of prospective memory difficulties., Objective: The aim of this study was to compare clinical [mild cognitive impairment (MCI), dementia] and nonclinical older adults (healthy controls) on self- and informant-rated versions of prospective and retrospective memory function, as well as objective measures of prospective memory. Critical here was not only the assessment of between-group differences, but also whether these different methods of assessing memory function would show appropriate convergent and discriminant validity., Methods: A total of 138 participants aged between 64 and 92 years, diagnosed with dementia (n=37), MCI (n=48) or no impairment (n=53), were asked to complete self- and informant-rated versions of the Prospective and Retrospective Memory Questionnaire (PRMQ). Participants also completed behavioural measures of global cognitive function [the Mini-Mental State Examination (MMSE)], as well as a behavioural measure of prospective memory (Virtual Week)., Results: Self-reported impairments were equivalent across the three groups, and informant reports of impairment, while higher for those with dementia, did not distinguish MCI from controls. For the combined sample and for all three groups separately, both self- and informant reports of prospective memory showed poor convergent validity, at best correlating only weakly with Virtual Week. Self-reported prospective memory was correlated with informant report only in the dementia group, not in the control or MCI groups. Convergent and discriminant validity were poor, with self- and informant-rated prospective memory more strongly related to self- and informant-rated retrospective memory than to scores on Virtual Week., Conclusion: These data indicate that self-report and informant report may neither accurately measure prospective memory of older people, nor be sensitive to objective prospective memory difficulties in people with MCI and dementia. These data have potentially important implications for clinical practice., (© 2015 S. Karger AG, Basel)

Background: Late-life depression has been associated with white matter changes in studies using the regions of interest approach., Aims: To investigate the cross-sectional and longitudinal relationship between white matter integrity and depression in community-dwelling individuals using diffusion tensor imaging with tract-based spatial statistics., Method: The sample comprised 381 participants aged between 72 and 92 years who were assessed twice within 2 years. Depressive symptoms were measured with the Geriatric Depression Scale. Tract-based spatial statistics were applied to investigate white matter integrity in currently depressed v. non-depressed elderly people and in those with a history of depression v. no history of depression. The relationship between white matter integrity and development of depressive symptoms after 2 years were analysed with logistic regression., Results: Individuals with current depression had widespread white matter integrity reduction compared with non-depressed elderly people. Significant fractional anisotropy reductions were found in 45 brain areas with the most notable findings in the frontal lobe, association and projection fibres. A history of depression was not associated with reduced fractional anisotropy. White matter changes in the superior frontal gyrus, posterior thalamic radiation, superior longitudinal fasciculus and in the body of corpus callosum predicted depression at follow-up., Conclusions: Reduced white matter integrity is associated with late-life depression and predicts future depressive symptoms whereas a history of depression is not related to white matter changes. Disruption to white matter integrity may be a biomarker to predict late-life depression., (Royal College of Psychiatrists.)

Background: White matter hyperintensities increase the risk of multiple falls in older people, but the effect of sub-cortical infarcts is unknown., Aims: By pooling data from two Australian population-based studies, we aimed to investigate the association between sub-cortical infarcts and multiple falls and whether this relationship, and that of white matter hyperintensities, is mediated or modified by cognitive or sensorimotor factors., Methods: Participants underwent structural magnetic resonance imaging and cognitive and sensorimotor assessments. Falls were prospectively measured over 12 months. Sub-cortical infarcts were detected visually. Total white matter hyperintensity volume was quantified using automated segmentation methods. Generalized linear models were used to examine if sub-cortical infarcts and white matter hyperintensities predicted falls., Results: The mean age of the sample (n = 655) was 74·5 (standard deviation 6·7) years, 336 (51·3%) males. Overall, 114 (17·4%) had multiple falls. The majority had no sub-cortical infarcts (n = 491, 75·0%), while 90 had one (13·7%), 41 had two (6·3%), and 33 had more than or equal to three sub-cortical infarcts (5·0%). The risk of multiple falls was elevated in people with more than or equal to three sub-cortical infarcts (adjusted relative risk 1·89, 95% confidence interval 1·03, 3·46) and in the highest quarter of white matter hyperintensity volume (adjusted relative risk 1·46, 95% confidence interval 1·00, 2·13). The effect of sub-cortical infarcts on falls was amplified by poorer vision (P = 0·03). The effect of white matter hyperintensities was amplified by poorer vision (P = 0·008), proprioception (P = 0·03), and muscle strength (P = 0·008). There was no modifying effect of cognitive function., Conclusions: Increasing burdens of sub-cortical infarcts and white matter hyperintensities are associated with a risk of falling. Interventions targeting sensorimotor factors along with strategies to prevent sub-cortical infarcts and white matter hyperintensities may reduce the risk of falls., (© 2014 The Authors. International Journal of Stroke © 2014 World Stroke Organization.)

Type 2 diabetes predicts accelerated cognitive decline and brain atrophy. We hypothesized that impaired fasting glucose (IFG) and incident glucose disorders have detrimental effects on global cognition and brain volume. We further hypothesized that metabolic and inflammatory derangements accompanying hyperglycaemia contribute to change in brain structure and function. This was a longitudinal study of a community-dwelling elderly cohort with neuropsychological testing (n = 880) and brain volumes by magnetic resonance imaging (n = 312) measured at baseline and 2 years. Primary outcomes were global cognition and total brain volume. Secondary outcomes were cognitive domains (processing speed, memory, language, visuospatial and executive function) and brain volumes (hippocampal, parahippocampal, precuneus and frontal lobe). Participants were categorised as normal, impaired fasting glucose at both assessments (stable IFG), baseline diabetes or incident glucose disorders (incident diabetes or IFG at 2 years). Measures included inflammatory cytokines and oxidative metabolites. Covariates were age, sex, education, non-English speaking background, smoking, blood pressure, lipid-lowering or antihypertensive medications, mood score, apolipoprotein E genotype and baseline cognition or brain volume. Participants with incident glucose disorders had greater decline in global cognition and visuospatial function compared to normal, similar to that observed in baseline diabetes. Homocysteine was independently associated with the observed effect of diabetes on executive function. Apolipoprotein E genotype did not influence the observed effects of diabetes on cognition. Incident glucose disorders and diabetes were also associated with greater 2-year decline in total brain volume, compared to normal (40.0 ± 4.2 vs. 46.7 ± 5.7 mm(3) vs. 18.1 ± 6.2, respectively, p < 0.005). Stable IFG did not show greater decline in global cognition or brain volumes compared to normal. Incident glucose disorders, like diabetes, are associated with accelerated decline in global cognition and brain volumes in non-demented elderly, whereas stable IFG is not. Preventing deterioration in glucose metabolism in the elderly may help preserve brain structure and function.

Most previous neuroimaging studies of age-related brain structural changes in older individuals have been cross-sectional and/or restricted to clinical samples. The present study of 345 community-dwelling non-demented individuals aged 70-90years aimed to examine age-related brain volumetric changes over two years. T1-weighted magnetic resonance imaging scans were obtained at baseline and at 2-year follow-up and analyzed using the FMRIB Software Library and FreeSurfer to investigate cortical thickness and shape and volumetric changes of subcortical structures. The results showed significant atrophy across much of the cerebral cortex with bilateral transverse temporal regions shrinking the fastest. Atrophy was also found in a number of subcortical structures, including the CA1 and subiculum subfields of the hippocampus. In some regions, such as left and right entorhinal cortices, right hippocampus and right precentral area, the rate of atrophy increased with age. Our analysis also showed that rostral middle frontal regions were thicker bilaterally in older participants, which may indicate its ability to compensate for medial temporal lobe atrophy. Compared to men, women had thicker cortical regions but greater rates of cortical atrophy. Women also had smaller subcortical structures. A longer period of education was associated with greater thickness in a number of cortical regions. Our results suggest a pattern of brain atrophy with non-demented people that resembles a less extreme form of the changes associated with Alzheimer's disease (AD)., (© 2013 Elsevier Inc. All rights reserved.)

Purpose: We examined whether differences in findings of studies examining mild cognitive impairment (MCI) were associated with recruitment methods by comparing sample characteristics in two contemporaneous Australian studies, using population-based and convenience sampling., Method: The Sydney Memory and Aging Study invited participants randomly from the electoral roll in defined geographic areas in Sydney. The Australian Imaging, Biomarkers and Lifestyle Study of Ageing recruited cognitively normal (CN) individuals via media appeals and MCI participants via referrals from clinicians in Melbourne and Perth. Demographic and cognitive variables were harmonized, and similar diagnostic criteria were applied to both samples retrospectively., Results: CN participants recruited via convenience sampling were younger, better educated, more likely to be married and have a family history of dementia, and performed better cognitively than those recruited via population-based sampling. MCI participants recruited via population-based sampling had better memory performance and were less likely to carry the apolipoprotein E ε4 allele than clinically referred participants but did not differ on other demographic variables., Conclusion: A convenience sample of normal controls is likely to be younger and better functioning and that of an MCI group likely to perform worse than a purportedly random sample. Sampling bias should be considered when interpreting findings., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Folate fortification of food aims to reduce the number of babies born with neural tube defects, but has been associated with cognitive impairment when vitamin B12 levels are deficient. Given the prevalence of low vitamin B12 levels among the elderly, and the global deployment of food fortification programs, investigation of the associations between cognitive impairment, vitamin B12, and folate are needed., Objective: To investigate the associations of serum vitamin B12, red cell folate, and cognitive impairment., Methods: Data were collected on 1,354 subjects in two studies investigating cognitive impairment, and from patients attending for assessment or management of memory problems in the Barwon region of south eastern Australia between 2001 and 2011. Eligible subjects who had blood measurements of vitamin B12 and red cell folate taken within six months of cognitive testing were included. Subjects with stroke or neurodegenerative diseases other than Alzheimer's disease were excluded. A Mini-Mental State Examination score of <24 was used to define impaired cognitive function., Results: Participants with low serum vitamin B12 (<250 pmol/L) and high red cell folate (>1,594 nmol/L) levels were more likely to have impaired cognitive performance (adjusted odds ratio (AOR) 3.45, 95% confidence interval (CI): 1.60-7.43, p = 0.002) when compared to participants with biochemical measurements that were within the normal ranges. Participants with high folate levels, but normal serum vitamin B12, were also more likely to have impaired cognitive performance (AOR 1.74, 95% CI: 1.03-2.95, p = 0.04)., Conclusions: High folate or folic acid supplements may be detrimental to cognition in older people with low vitamin B12 levels. This topic is of global significance due to the wide distribution of food fortification programs, so prospective studies should be a high priority.