Sydney Memory Research Articles

57 The Use of the Physiological Profile Assessment to Improve Prediction of Fragility Fractures in Community-Dwelling Older People

Abstract Introduction The Physiological Profile Assessment (PPA) is a validated composite measure of sensorimotor function, known to predict falls with 75% accuracy. This work aimed to investigate whether PPA is also associated with fragility fractures. Method Participants were 489 community-dwelling older people (age=70-90) enrolled in the longitudinal population-based Sydney Memory and Ageing Study. Participants underwent comprehensive assessments at enrolment, including the 5-item PPA (visual contrast sensitivity, lower limb proprioception, knee extension strength, simple reaction time and postural sway). Participant records were linked to emergency department, hospital and death records (2005-2014) to identify fragility fractures following baseline assessment, with median follow-up duration of 7.5 years. Negative binomial regression, with observation time as the offset, was used to assess factors associated with fractures. Results At baseline assessment, 281 (57.5%) participants were assessed as having low/mild fall risk [PPA<1] and 208 (42.5%) as moderate/marked/very marked fall risk [PPA score >1]. Over the study period, 72 (14.7%) individuals sustained 1 fracture, and a further 39 (8.0%) sustained 2 or more fractures. Univariate analysis showed that increasing age (Incidence Rate Ratio (IRR) 1.1, 95%CI 1.0-1.1, p=0.0026), being female (IRR 1.8, 95%CI 1.3-2.8, p=0.0033), having osteoporosis (IRR 1.7, 95%CI 1.1-2.6, p=0.0340) and moderate/marked/very marked PPA (IRR 1.8, 95%CI 1.2-2.7, p=0.0025) were associated with fractures. In the multivariate analysis, only moderate/marked/very marked PPA (IRR 1.6, 95%CI 1.1-2.5, p=0.0159) and being female (IRR 1.8, 95%CI 1.1-2.8, p=0.0121) remained independently associated with fractures. Conclusion These findings show that people at increased risk of falls based on the Physiological Profile Assessment are also at increased risk of future fragility fractures regardless of the presence of osteoporosis. Early identification of this high risk population provides the opportunity to intervene with evidence based strategies to minimize falls risk as well as considering pharmacological management of bone health.

New avenue for the geriatric depression scale: Rasch transformation enhances reliability of assessment

BackgroundDepression is a common problem in older adults. The 15-item Geriatric Depression Scale (GDS-15) is a widely used psychometric tool for measuring depression in the elderly, but its psychometric properties have not been yet rigorously investigated. The aim was to evaluate psychometric properties of the GDS-15 and improve precision of the instrument by applying Rasch analysis and deriving conversion tables for transformation of raw scores into interval level data. MethodsThe data was extracted from the prospective cohort Sydney Memory and Ageing Study of initially not demented individuals aged 70 years and older. The GDS-15 items scores of 212 participants (47.2% males) were analysed using the dichotomous Rasch model. ResultsInitially poor reliability of the GDS-15, Person Separation Index (PSI) = 0.68, was improved by combining locally dependent items into seven super-items. These modifications improved reliability of the GDS-15 (PSI = 0.78) and resulted in the best Rasch model fit (χ2(28)=37.72, p = =0.104), strict unidimensionality and scale invariance across personal factors such as gender, diagnostic and language background. LimitationsPresence of participants with cognitive impairment may be a potential limitation. ConclusionsReliability and psychometric characteristics of the GDS-15 were improved by minor modifications and now satisfy expectations of the unidimensional Rasch model. By using Rasch transformation tables published here psychiatrists, psychologists and researchers can transform GDS raw scores into interval-level data, which improves reliability of the GDS-15 without the need to modify its original response format. These findings increase accuracy of clinical psychometric assessments, leading to more precise diagnosis of depression in the elderly.

SHRINKING AND GROWING SOCIAL NETWORKS IN THE SYDNEY MEMORY AND AGEING STUDY

Gerontological research suggests that shrinking social networks are characteristic of older age. Socioemotional selectivity theory suggests that older adults proactively reduce their networks over time. Core relationship networks consist of friends and family who are contacted at least monthly. Studies of perceived social support indicate that shrinking networks increase risk of isolation, loneliness, and associated ill health effects. Our research aimed to investigate change in size of older adults’ core relationship network over time, and to explore associations between network size and participant characteristics, using data from the first four waves of the Sydney Memory and Ageing Study. Participants completed: assessments of cognition, depression, personality; surveys of health-related quality of life, medical conditions, number of friends and relatives contacted at least monthly. Of 1037 participants aged 70 to 90 years surveyed at baseline 476 provided network data at all four time-points. Just over half of the participants (n=252, 52.9%) had smaller networks at wave 4 compared to baseline; nearly half of participants had stable (n=65, 13.7%) or larger networks (n=159, 33.4%), some doubling in size (n=65, 13.7%). Chi-square test indicated that more males (59.1%) had decreasing networks [X2(1, 476)=2.26, p=.02, phi=.11]. T-tests indicated: group differences in baseline neuroticism [t(276)=2.31, p=.02, Eta2=.02]; no significant difference in age, education, wave 4 global cognition, depression, quality of life, number of medical conditions. Results complement previous literature, yet challenge assumptions that shrinking social networks are a defining characteristic of older age. Future examination of our mental and physical engagement data may elucidate these differences.

Effects of Statins on Memory, Cognition, and Brain Volume in the Elderly

BackgroundThere is widespread consumer concern that statin use may be associated with impaired memory and cognitive decline. ObjectivesThis study sought to examine the association between statin use and changes in memory and global cognition in the elderly population over 6 years and brain volumes over 2 years. Interactions between statin use and known dementia risk factors were examined. MethodsProspective observational study of community-dwelling elderly Australians age 70 to 90 years (the MAS [Sydney Memory and Ageing Study], n = 1,037). Outcome measures were memory and global cognition (by neuropsychological testing every 2 years) and total brain, hippocampal and parahippocampal volumes (by magnetic resonance) in a subgroup (n = 526). Analyses applied linear mixed modeling, including the covariates of age, sex, education, body mass index, heart disease, diabetes, hypertension, stroke, smoking, and apolipoprotein Eε4 carriage. Interactions were sought between statin use and dementia risk factors. ResultsOver 6 years there was no difference in the rate of decline in memory or global cognition between statin users and never users. Statin initiation during the observation period was associated with blunting the rate of memory decline. Exploratory analyses found statin use was associated with attenuated decline in specific memory test performance in participants with heart disease and apolipoprotein Eε4 carriage. There was no difference in brain volume changes between statin users and never users. ConclusionsIn community-dwelling elderly Australians, statin therapy was not associated with any greater decline in memory or cognition over 6 years. These data are reassuring for consumers concerned about statin use and risk of memory decline.

Validation and Normative Data for the Modified Telephone Interview for Cognitive Status: The Sydney Memory and Ageing Study.

Telephone-based cognitive screens, such as the Telephone Interview for Cognitive Status (TICS), can potentially reduce the barriers and costs of assessing older adults. However, validation of clinically relevant psychometric properties is lacking in a large and comprehensively assessed sample of older adults. Furthermore, published normative data may lack sensitivity as they have not used regression-based demographic corrections or accounted for cases with subsequent dementia. We address these gaps using the modified TICS (TICS-M; a modified, 13-item, 39-point version) and provide an online norms calculator for clinicians and researchers. Prospective longitudinal study. Sydney, Australia. A total of 617 community-living older adults, aged from 71 to 91 years. The measures used included the TICS-M, the Mini-Mental State Examination (MMSE), Addenbrooke's Cognitive Examination-Revised (ACE-R), and a comprehensive neuropsychological test battery. Descriptive statistics, correlations, area under the curve, and regression analyses were used to determine the validity and normative properties of the TICS-M. TICS-M total scores (mean = 24.20; SD = 3.76) correlated well with the MMSE (0.70) and ACE-R (0.80) and moderately with neuropsychological tests tested noncontemporaneously. A cutoff score of 21 or lower reliably distinguished between those with and without incident dementia after 1 year (sensitivity = 77%; specificity = 88%) but was less reliable at distinguishing mild cognitive impairment from normal cognition. TICS-M scores decreased with age and increased with higher education levels. The robust normative sample, which excluded incident dementia cases, scored higher on the TICS-M and with less variability than the whole sample. An online calculator is provided to compute regression-based norms and reliable change statistics. In a large sample of community-dwelling older adults, the TICS-M performed well in terms of construct validity against typical screening tools and neuropsychological measures and diagnostic validity for incident dementia. The comprehensive, regression-based, and robust normative data provided will help improve the sensitivity, accessibility, and cost-effectiveness of cognitive testing with older adults. J Am Geriatr Soc 67:2108-2115, 2019.

Injury-related hospitalisation in community-dwelling older people across the cognitive spectrum: A population based study

ObjectivesTo describe the injury profile, hospitalisation rates and health outcomes for older people with cognitive impairment and to determine whether these differ from those with normal cognition. MethodsParticipants were 867 community-dwelling 70–90 year olds enrolled in the population-based longitudinal Sydney Memory and Ageing Study (MAS). Participant’s cognitive status was classified as normal, mild cognitive impairment (MCI) and dementia at baseline, then 2, 4 and 6 years’ follow-up. MAS records were linked to hospital and death records to identify injury-related hospitalisations for the 2-year period following each assessment. ResultsThere were 335 injury-related hospitalisations for participants; 222 (25.6%) participants had at least one injury-related hospitalisation. The injury-related hospitalisation rate for participants with MCI (63.0 [95%CI 51.6–74.4] per 1000 person-years) was higher than for people with normal cognition (39.3 [95%CI 32.4–46.1] per 1000 person-years) but lower than people with dementia (137.1 [95%CI 87.2–186.9] per 1000 person-years).Upper limb fractures (22.1%) were the most common injuries for participants with normal cognition, and non-fracture head injuries for participants with MCI and dementia (25.9% and 23.3% respectively). Participants with dementia had a higher proportion of hip fractures (20.0%, p = 0.0483) than participants with normal cognition. There was no difference in 30-day mortality between participants with normal cognition, MCI and dementia (3.9%, 1.7%, 3.3% respectively). ConclusionOlder people with objectively defined MCI are at higher risk of injury-related hospitalisation than their cognitively intact peers, but lower risk than people with dementia. Falls-risk screening and fall prevention initiatives may be indicated for older people with MCI.

Cross-sectional and prospective inter-relationships between depressive symptoms, vascular disease and cognition in older adults.

It has been proposed that vascular disease is the mechanism linking depression and cognition, but prospective studies have not supported this hypothesis. This study aims to investigate the inter-relationships between depressive symptoms, cognition and cerebrovascular disease using a well-characterised prospective cohort. Data came from waves 1 (2005-2007) and 2 (2007-2009) of the Sydney Memory and Ageing Study (n = 462; mean age = 78.3 years). At wave 1, there was an association between depressive symptoms and white matter hyperintensity (WMH) volume [b = 0.016, t(414) = 2.34, p = 0.020]. Both depressive symptoms [b = -0.058, t(413) = -2.64, p = 0.009] and WMH volume [b = -0.011, t(413) = -3.77, p < 0.001], but not stroke/transient ischaemic attack (TIA) [b = -0.328, t(413) = -1.90, p = 0.058], were independently associated with lower cognition. Prospectively, cerebrovascular disease was not found to predict increasing depressive symptoms [stroke/TIA: b = -0.349, t(374.7) = -0.76, p = 0.448; WMH volume: b = 0.007, t(376.3) = 0.875, p = 0.382]. Depressive symptoms predicted increasing WMH severity [b = 0.012, t(265.9) = -3.291, p = 0.001], but not incident stroke/TIA (odds ratio = 0.995; CI 0.949-1.043; p = 0.820). When examined in separate models, depressive symptoms [b = -0.027, t(373.5) = -2.16, p = 0.032] and a history of stroke/TIA [b = -0.460, t(361.2) = -4.45, p < 0.001], but not WMH volume [b = 0.001, t(362.3) = -0.520, p = 0.603], predicted declines in cognition. When investigated in a combined model, a history of stroke/TIA remained a predictor of cognitive decline [b = -0.443, t(360.6) = -4.28, p < 0.001], whilst depressive symptoms did not [b = -0.012, t(359.7) = -0.96, p = 0.336]. This study is contrasted with previous prospective studies which indicate that depressive symptoms predict cognitive decline independently of vascular disease. Future research should focus on further exploring the vascular mechanisms underpinning the relationship between depressive symptoms and cognition.

Co-expression network analysis of peripheral blood transcriptome identifies dysregulated protein processing in endoplasmic reticulum and immune response in recurrent MDD in older adults

The molecular factors involved in the pathophysiology of major depressive disorder (MDD) remain poorly understood. One approach to examine the molecular basis of MDD is co-expression network analysis, which facilitates the examination of complex interactions between expression levels of individual genes and how they influence biological pathways affected in MDD. Here, we applied an unsupervised gene-network based approach to a prospective experimental design using microarray genome-wide gene expression from the peripheral whole blood of older adults. We utilised the Sydney Memory and Ageing Study (sMAS, N = 521) and the Older Australian Twins Study (OATS, N = 186) as discovery and replication cohorts, respectively. We constructed networks using Weighted Gene Co-expression Network Analysis (WGCNA), and correlated identified modules with four subtypes of depression: single episode, current, recurrent, and lifetime MDD. Four modules of highly co-expressed genes were associated with recurrent MDD (N = 27) in our discovery cohort (FDR<0.2), with no significant findings for a single episode, current or lifetime MDD. Functional characterisation of these modules revealed a complex interplay between dysregulated protein processing in the endoplasmic reticulum (ER), and innate and adaptive immune response signalling, with possible involvement of pathogen-related pathways. We were underpowered to replicate findings at the network level in an independent cohort (OATS), however; we found a significant overlap for 9 individual genes with similar co-expression and dysregulation patterns associated with recurrent MDD in both cohorts. Overall, our findings support other reports on dysregulated immune response and protein processing in the ER in MDD and provide novel insights into the pathophysiology of depression.

People with mild cognitive impairment are at increased risk of serious injury

IntroductionData-linkage studies using administrative hospital data have shown that people with dementia have double the rate of injury-related hospitalisations and poorer health outcomes than those without. No previous research has explored whether people with mild cognitive impairment are also at increased risk of serious injury requiring hospitalisation.&#x0D; Objectives and ApproachA major barrier to the use of administrative hospital data for undertaking research focusing on people with MCI is that MCI cannot be reliably identified from ICD-10 coded administrative data. To overcome this limitation, hospitalisation and death data was linked to data from participants (community-dwelling 70-90 year olds) enrolled in the population-based longitudinal Sydney Memory and Ageing Study (MAS). MAS participants underwent comprehensive neuropsychological assessments at baseline, then 2, 4 and 6 years’ follow-up to accurately determine cognitive status at each time-period. Linkage to hospital records allowed identification of injury-related hospitalisations and outcomes for the 2-year period following each assessment.&#x0D; ResultsThere were 335 injury-related hospitalisations for the 867 participants; 222 (25.6%) participants had at least one injury-related hospitalisation. After adjusting for age-and-sex, participants in a state of MCI had 1.7 (95%CI 1.2-2.4) times higher odds of an injury-related hospitalisation than participants in a state of normal cognition, whilst participants with dementia had 2.3 (95%CI 1.2-4.4) times higher odds. There was no difference in odds between participants with MCI and dementia.&#x0D; Of the 116 hospitalisations for people with MCI, the majority (79.3%) were due to falls. Non-fracture head injuries (25.9%), upper limb and trunk fractures (13.8% respectively) were the most common injury type. There were no differences in injury type, mean length of stay, or 30-day mortality between people with normal cognition, MCI and dementia.&#x0D; Conclusion/ImplicationsOlder people with objectively defined MCI are at higher risk of injury, predominantly as a result of falls, than their cognitively intact peers. Falls-risk screening and fall prevention initiatives may be indicated for people with MCI. Further research is required to determine which cognitive domains contribute to this increased risk.

NUMBER OF FACE-TO-FACE CONTACTS PREDICTS VARIANCE IN COGNITIVE FUNCTION IN HEALTHY OLDER ADULTS

Personal social networks are composed of hierarchical layers. The innermost layer typically contains five friends/relatives (Sutcliffe, Dunbar, Binder, & Arrow, 2012). Subsequent layers increase in relationship number by a multiple of 3 and decrease in emotional closeness, and contact frequency (i.e. 5 ‘intimate’, 15 ‘good’ friends). Associations exist between cognitive function and social relationships according to relationship type, frequency, and number (Kelly et al., 2017). This research investigated the ability of three social engagement indicators to predict performance in cognitive domains, controlling for sociodemographic and health-related variables. Baseline data were from the Sydney Memory and Ageing Study. Cognitive domains were Attention/Processing Speed (Digit Symbol-Coding; Trail Making Test A), Language (30-item Boston Naming Test; Semantic Fluency—Animals), Executive (Controlled Oral Word Association Test-FAS; Trail Making Test B), Visuo-spatial (Block Design), Verbal Memory (Logical Memory Story A delayed recall; Rey Auditory Verbal Learning Tests, trials 1-7), Memory (ibid. plus Benton Visual Retention Test—recognition), and Global Cognition. Engagement indicators were number of friends/relatives contacted monthly, number of monthly face-to-face contacts with friends/relatives, and having a confidant. Covariates were age, sex, years of education, and Geriatric Depression Scale score (Sheikh & Yesavage, 1986). Respondents were 873 Sydney residents aged 70 to 91 years, 56% were female. Multiple regression analysis indicated that age, years of education, Geriatric Depression Scale score and number of face-to-face contacts predicted variance in cognitive domain scores. Total variance explained by the models ranged from 14.9% to 26.5%. Reporting < 1 (n = 19) face-to-face contact each month (vs. reference ≥ 11, n = 540) predicted lower Executive function (beta = - .09, p < .01), controlling for covariates. Reporting 1 to 4 (n = 85) face-to-face contacts predicted lower Attention/Processing Speed (beta = -.09, p = .01) and Language (beta = - .09, p = .01) and Global Cognition (beta = - .08, p = .01). Fewer than five regular face-to-face contacts was associated with lower cognitive function. Type, frequency and number of social relationships should be considered in predictive models of cognitive function for older adults.

Body mass index and waist circumference predict health-related quality of life, but not satisfaction with life, in the elderly.

While obesity has been linked with lower quality of life in the general adult population, the prospective effects of present obesity on future quality of life amongst the elderly is unclear. This article investigates the cross-sectional and longitudinal relationships between obesity and aspects of quality of life in community-dwelling older Australians. A 2-year longitudinal sample of community dwellers aged 70-90years at baseline, derived from the Sydney Memory and Ageing Study (MAS), was chosen for the study. Of the 1037 participants in the original MAS sample, a baseline (Wave 1) sample of 926 and a 2-year follow-up (Wave 2) sample of 751 subjects were retained for these analyses. Adiposity was measured using body mass index (BMI) and waist circumference (WC). Quality of life was measured using the Assessment of Quality of Life (6 dimensions) questionnaire (AQoL-6D) as well as the Satisfaction with Life Scale (SWLS). Linear regression and analysis of covariance (ANCOVA) were used to examine linear and non-linear relationships between BMI and WC and measures of health-related quality of life (HRQoL) and satisfaction with life, adjusting for age, sex, education, asthma, osteoporosis, depression, hearing and visual impairment, mild cognitive impairment, physical activity, and general health. Where a non-linear relationship was found, established BMI or WC categories were used in ANCOVA. Greater adiposity was associated with lower HRQoL but not life satisfaction. Regression modelling in cross-sectional analyses showed that higher BMI and greater WC were associated with lower scores for independent living, relationships, and pain (i.e. worse pain) on the AQoL-6D. In planned contrasts within a series of univariate analyses, obese participants scored lower in independent living and relationships, compared to normal weight and overweight participants. Longitudinal analyses found that higher baseline BMI and WC were associated with lower independent living scores at Wave 2. Obesity is associated with and predicts lower quality of life in elderly adults aged 70-90years, and the areas most affected are independent living, social relationships, and the experience of pain.

The relationship of cerebral microbleeds to cognition and incident dementia in non-demented older individuals.

Cerebral microbleeds (CMB), suspected markers of hemorrhage-prone microangiopathy, are common in patients with cerebrovascular disease and in those with cognitive impairment. Their longitudinal relationship with cognitive decline and incident dementia in non-demented community-dwelling older individuals has been insufficiently examined. 302 adults aged 70-90 participating in the population-based Sydney Memory and Ageing Study underwent a susceptibility-weighted imaging (SWI) MRI sequence. The relationship of CMB with performance on neuropsychological tests was examined both cross-sectionally and longitudinally, over a mean of 4years. The association with cases of incident dementia during this period was also examined. The prevalence of CMB was 20%. In cross-sectional analysis, after adjusting for demographics and vascular risk factors, there was a significant association between the presence of CMB and poorer executive function. CMB were not associated with global cognition or other cognitive domains. On longitudinal analysis, after adjusting for demographics and vascular risk factors, there was a greater decline in visuospatial ability in those with CMB compared to those without. The presence of CMB was not associated with increased progression to dementia. CMB are associated with impairments in specific cognitive domains: executive function and decline in visuospatial ability, independent of other markers of CVD including white matter hyperintensities. This suggests a direct contribution of CMB to cognitive impairment although no significant difference in incident dementia rates was observed.

Is intraindividual reaction time variability an independent cognitive predictor of mortality in old age? Findings from the Sydney Memory and Ageing Study.

Intraindividual variability of reaction time (IIVRT), a proposed cognitive marker of neurobiological disturbance, increases in old age, and has been associated with dementia and mortality. The extent to which IIVRT is an independent predictor of mortality, however, is unclear. This study investigated the association of IIVRT and all-cause mortality while accounting for cognitive level, incident dementia and biomedical risk factors in 861 participants aged 70–90 from the Sydney Memory and Ageing Study. Participants completed two computerised reaction time (RT) tasks (76 trials in total) at baseline, and comprehensive medical and neuropsychological assessments every 2 years. Composite RT measures were derived from the two tasks—the mean RT and the IIVRT measure computed from the intraindividual standard deviation of the RTs (with age and time-on-task effects partialled out). Consensus dementia diagnoses were made by an expert panel of clinicians using clinical criteria, and mortality data were obtained from a state registry. Cox proportional hazards models estimated the association of IIVRT and mean RT with survival time over 8 years during which 191 (22.2%) participants died. Greater IIVRT but not mean RT significantly predicted survival time after adjusting for age, sex, global cognition score, cardiovascular risk index and apolipoprotein ɛ4 status. After excluding incident dementia cases, the association of IIVRT with mortality changed very little. Our findings suggest that greater IIVRT uniquely predicts shorter time to death and that lower global cognition and prodromal dementia in older individuals do not explain this relationship.

Effects of MCI subtype and reversion on progression to dementia in a community sample.

We sought to understand the trajectory of mild cognitive impairment (MCI) better by examining longitudinally different MCI subtypes and progression to dementia and reversion to normal cognition in a community sample. We evaluated the stability of MCI subtypes and risk of dementia over 4 biennial assessments as part of an ongoing prospective cohort study, the Sydney Memory and Ageing Study. While prevalence of MCI and different MCI subtypes remains relatively stable across all assessments, reversion from MCI and transitions between different MCI subtypes were common. Up to 46.5% of participants classified with MCI at baseline reverted at some point during follow-up. The majority (83.8%) of participants with incident dementia were diagnosed with MCI 2 years prior to their dementia diagnosis. Both reverters and participants with stable MCI were at an increased risk of progression to dementia compared to those without MCI at baseline (HR 6.4, p = 0.02, and HR 24.7, p < 0.001, respectively); however, the risk of dementia in participants with MCI who did not revert was higher than in reverters (HR 2.5, p = 0.01). This effect was specific to amnestic subtypes (MCI reverters vs nonreverters: amnestic MCI HR 3.3, p = 0.006; nonamnestic MCI: HR 1.3, p = 0.67). Our findings indicate that the relevance of reversion for progression risk depends on the MCI subtype. Subtype specificity and longitudinal characterization are required for the reliable identification of individuals at high risk of developing dementia.

Prospective memory function and cue salience in mild cognitive impairment: Findings from the Sydney Memory and Ageing Study

ABSTRACTObjective: 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.

Associations between reaction time measures and white matter hyperintensities in very old age

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.

Measurement of Functional Cognition and Complex Everyday Activities in Older Adults with Mild Cognitive Impairment and Mild Dementia: Validity of the Large Allen's Cognitive Level Screen

To explore the validity of the Large Allen's Cognitive Level Screen-5 (LACLS-5) as a performance-based measure of functional cognition, representing an ability to perform complex everyday activities in older adults with mild cognitive impairment (MCI) and mild dementia living in the community. Using cross-sectional data from the Sydney Memory and Ageing Study, 160 community-dwelling older adults with normal cognition (CN; N = 87), MCI (N = 43), or dementia (N = 30) were studied. Functional cognition (LACLS-5), complex everyday activities (Disability Assessment for Dementia [DAD]), Assessment of Motor and Process Skills [AMPS]), and neuropsychological measures were used. Participants with dementia performed worse than CN on all clinical measures, and MCI participants were intermediate. Correlational analyses showed that LACLS-5 was most strongly related to AMPS Process scores, DAD instrumental activities of daily living subscale, Mini-Mental State Exam, Block Design, Logical Memory, and Trail Making Test B. Multiple regression analysis indicated that both cognitive (Block Design) and functional measures (AMPS Process score) and sex predicted LACLS-5 performance. Finally, LACLS-5 was able to adequately discriminate between CN and dementia and between MCI and dementia but was unable to reliably distinguish between CN and MCI. Construct validity, including convergent and discriminative validity, was supported. LACLS-5 is a valid performance-based measure for evaluating functional cognition. Discriminativevalidity is acceptable for identifying mild dementia but requires further refinement for detecting MCI.

Genome-Wide Gene Expression Signature Of Depression

Background Many studies have attempted to identify the molecular signature of depression. The results, however, are inconsistent. The small sample sizes, choice of tissue/cell types and suboptimal statistical methods are the major limitations that might contribute to this inconsistency. In our study, to identify the whole blood transcriptome signature of geriatric depression, we utilized two large population cohorts aged over 65 -The Sydney Memory and Aging Study, MAS (N=521) and The Older Australian Twin Study, OATS (N=324) as discovery and replication cohorts, respectively. Major Depression was assessed according to DSM-IV criteria. Methods The genome-wide gene expression data were obtained using Illumina HT-12 v4. After quality control and pre-processing, the application of stringent filtering criteria (by detection p-value (p Results The eigengenes of two modules were associated with the depression phenotype (p=0.01 and p=0.02). Closer inspection of the modules of interest revealed that only 37 out of 82 genes in one module and 17 out of 64 genes in another module were significantly associated with the phenotype of depression. Correlational analyses of individual genes within the depression relevant modules revealed that 8 out of 37 significant genes in one module were protein coding genes, involved in various translational, metabolic and immune processes (PCYOX1L, RPL14, MCTS1, GIMAP7, NDUFB9, BOLA2, EIF3M, RPL7A). The second module contained 5 protein coding genes out of 17 associated with depression, the known molecular functions of which include catalytic, enzyme regulation, transcription factor and translational regulation activities (PRCP, POLR2J2, ATF4, TAOK3, EIF2B5). The two top genes from both modules are known to be involved in metabolic process regulation by reactive oxygen species (PCYOX1L, prenylcysteine oxidase-like (p Discussion Our results support the oxidative stress hypothesis of depression and provide new insights into pathophysiological mechanisms of geriatric depression. In addition, we will present the results from pathway analyses (Ingenuity Pathway Analysis software, IPA) performed on genes identified as relevant to depression in this study. To bridge genotype with whole blood transcriptome and identify genomic loci that influence the identified gene expression signature of depression, we will present results from genome-wide eQTL analyses, which are ongoing.

Transcriptome Signature of Depression

Previous studies aiming to identify the transcriptome signature of depression show inconsistent results with low replicability at the single gene level in both brain and peripheral tissues. The complexity of the depression phenotype may contribute to this inconsistency. An advance in this field could be made by utilising systems biology approach. In this study, we analysed whole blood transcriptomes of 521 elderly people from the general population (The Sydney Memory and Aging Study, MAS) to identify molecular networks involved in geriatric depression. Depression was assessed according to DSM-IV criteria yielding both categorical and continuous depression phenotypes.Pre-processing of 47,323 probes (Illumina HT-12 v4) resulted in the 11,018 top-varying genes for downstream analyses. Pre-processing included maximum likelihood estimation (MLE) background correction, variance-stabilising (VST) transformation, quantile normalisation and filtering by detection p-value (p<0.01 in ≥50% of samples) and coefficient of variation (0.01).Using WGCNA package (R) we constructed the co-expression network consisting of 29 modules, two of which were associated with depressive symptoms. Both modules showed a highly significant correlation between module membership (MM) and gene significance (GS) measures (r=0.55, p=1e-07, r=0.4, p=0.0011), indicating that genes in these modules are highly significantly associated with depression. Further analysis showed that 37 and 17 genes respectively from the two “depression modules” are significantly associated with depressive symptoms (p<0.05), the top in each module being two protein-coding genes involved in metabolic process regulation by reactive oxygen species PCYOX1L, prenylcysteine oxidase-like (p<0.001) and PRCP, prolylcarboxypeptidase (p<0.05). Our results are in line with the oxidative stress hypothesis of depression. In addition, using IPA software we will present the results from pathway analyses performed on genes identified as relevant to depression in this study. A replication study (Older Australian Twins Study, OATS) is currently underway in a sample of 324 subject of similar age, gender and ethnicity.

Pharmacogenomics of Mood Disorders

Overall Abstract Single gene and GWAS analyses of pharmacological treatment response in depression and bipolar disorder have had varying success in identifying functionally relevant genes associated with pharmacological treatment response such as response to SSRI in depression and lithium in bipolar disorder. Hence, the need to better understand the complex genetic underpinnings of pharmacoresponse may include methodologies such as RNA-seq and microarray analyses. Such approaches contribute to a more in in-depth functional characterization of risk loci related to treatment response and to characterize the genetic underpinnings of both adverse events (e.g. induction of mania by antidepressants) and of medical comorbidity contributing to poor treatment response. In addition, gene expression profile and eQTLs can assist an improved understanding of the functional genomics of mood disorders. Specifically, recent large-scale GWAS meta-analyses (ConLiGen) have implicated multiple novel loci, two of which met the threshold for genome-wide significance: GADL1 (Chen et al., 2014) and an intergenic locus on chromosome 21 (Hou et al., 2016). The functional implications of the related genes remain to be described. In a first presentation, results will be presented from whole blood RNA-seq-data in a subsample of ConLiGen to validate and characterize these associations with clinical lithium treatment response and how these loci impact gene function and lithium response (David Stacey). Addressing the need to investigate the genetic underpinning of a broader range of treatment outcomes and adverse events, the genetic contribution of a potential induction of mania by antidepressants will be discussed in a second presentation, that shows results from a GWAS of antidepressant-induced mania (Joanna Biernacka). Among other factors, the co-morbidity of depression with other psychiatric and cardiometabolic disorders may negatively influence antidepressants treatment outcome. Moreover, response to antidepressants is a complex trait with substantial contribution from a large number of common genetic variants of small effect. Hence, use of polygenic scores (PGS) could be a better alternative to estimate the overall effect of genetic factors on treatment response and assess the importance of co-morbidities and related phenotypes. To investigate this further, we evaluated whether PGS derived from 25 recognized comorbid cardiometabolic and psychiatric disorders, personality traits and educational attainment predict treatment outcome to SSRIs in major depressive disorder using the ISPC data (Bernhard Baune). Previous studies aiming to identify the transcriptome signature of depression are inconsistent with low replicability at the single gene level in both brain and peripheral tissues. In a fourth presentation, results from analyses of whole blood transcriptomes of 521 elderly people from the general population (The Sydney Memory and Age Study, MAS, Sydney) are shown to describe molecular networks involved in geriatric depression. Functional characterisation of two out of 29 modules of the co-expression network indicated that abnormalities in structural constituents of ribosome may be involved in the pathophysiology of geriatric depression. In addition, results of pathway analyses using Ingenuity Pathway Analysis software will be shown (Liliana Ciobanu).