Reaction Time Measures Predict Incident Dementia in Community-Living Older Adults: The Sydney Memory and Ageing Study

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

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

Intraindividual Stepping Reaction Time Variability Predicts Falls in Older Adults With Mild Cognitive Impairment

Background: Reaction time measures have considerable potential to aid neuropsychological assessment in a variety of health care settings. One such measure, the intraindividual reaction time variability (IIV), is of particular interest as it is thought to reflect neurobiological disturbance. IIV is associated with a variety of age-related neurological disorders, as well as gait impairment and future falls in older adults. However, although persons diagnosed with Mild Cognitive Impairment (MCI) are at high risk of falling, the association between IIV and prospective falls is unknown. Methods: We conducted a longitudinal cohort study in cognitively intact (n = 271) and MCI (n = 154) community-dwelling adults aged 70–90 years. IIV was assessed through a variety of measures including simple and choice hand reaction time and choice stepping reaction time tasks (CSRT), the latter administered as a single task and also with a secondary working memory task. Results: Logistic regression did not show an association between IIV on the hand-held tasks and falls. Greater IIV in both CSRT tasks, however, did significantly increase the risk of future falls. This effect was specific to the MCI group, with a stronger effect in persons exhibiting gait, posture, or physiological impairment. Conclusions: The findings suggest that increased stepping IIV may indicate compromised neural circuitry involved in executive function, gait, and posture in persons with MCI increasing their risk of falling. IIV measures have potential to assess neurobiological disturbance underlying physical and cognitive dysfunction in old age, and aid fall risk assessment and routine care in community and health care settings

Risk factors for falls in community-dwelling older people with mild cognitive impairment: a prospective one-year study

Objective: Mild cognitive impairment (MCI) is considered an intermediate stage between normal cognitive function and dementia. Fall risk is increased in this group, but there is limited literature exploring specific fall risk factors that may be addressed in fall prevention strategies. The aim of this study was to examine risk factors for falls in older people with MCI, focusing on cognitive, psychological and physical factors. Methods: Participants (n = 266, 45% women) were community-dwelling older people aged 70–90 years who met the criteria for MCI. Cognitive, psychological, sensorimotor and physical assessments, physical activity levels, medication use, general health and disability were ascertained at baseline. Falls were monitored prospectively for 12 months. Results: During follow-up, 106 (40%) participants reported one or more falls. Poorer visual contrast sensitivity, increased postural sway, lower levels of weekly walking activity, higher levels of depressive symptoms and psychotropic medication use were significantly associated with faller status (≥1 falls) in univariable analyses. Of these factors, poor visual contrast sensitivity, increased postural sway and psychotropic medication use were found to be significant independent predictors of falls in multivariable analysis while controlling for age and sex. No measures of cognitive function were associated with falls. Conclusions: Poor visual contrast sensitivity, impaired balance and psychotropic medication use predicted falls in community-dwelling people with MCI. These risk factors may be amenable to intervention, so these factors could be carefully considered in fall prevention programs for this population

A Novel Approach to Investigate Depression Symptoms in the Aging Population Using Generalizability Theory

As depression is common in older people and confers significant risk for dementia, its accurate assessment is essential. The 15-item Geriatric Depression Scale (GDS-15) is a widely used assessment tool for measuring depression in aged populations, and its psychometric properties have been recently improved using Rasch analysis. However, its temporal reliability and ability to distinguish between dynamic and enduring symptoms of depression have not been examined using the appropriate methodology. Generalizability theory (G theory) is a suitable method to distinguish between enduring and dynamic symptoms of depression and to evaluate the reliability of the GDS-15 scores and sources of measurement error. We applied G theory to the longitudinal GDS-15 data of 354 participants from the Sydney Memory and Ageing Study, collected biennially over 10 years, from individuals aged 70 years and older. The GDS-15 demonstrated strong reliability and generalizability of its test scores in measuring enduring symptoms of depression (Ga = 0.82, Gr = 0.90) across the sample population and occasions, and indicated that depression scores significantly increased over time. In addition, three identified dynamic symptoms of depression, namely helplessness, hopelessness, and loss of interest in activities, did not affect the overall reliability of the GDS-15. Thus, the GDS-15 is a reliable measure for assessing enduring symptoms of depression and can be used to evaluate the efficacy of depression treatments and monitor depression levels over time in older adults

Reliability, Validity, and User-Experience of Remote Unsupervised Computerized Neuropsychological Assessments in Community-Living 55- to 75-Year-Olds

Background: Self-administered computerized neuropsychological assessments (CNAs) provide lower cost, more accessible alternatives to traditional in-person assessments but lack critical information on psychometrics and subjective experience of older adults in remote testing environments. Objective: We used an online brief battery of computerized tasks selected from the Cogstate Brief Battery (CBB) and Cambridge Brain Sciences (CBS) to 1) determine test-retest reliability in an unsupervised setting; 2) examine convergent validity with a comprehensive 'gold standard' paper-and-pencil neuropsychological test battery administered in-person; and 3) explore user-experience of remote computerized testing and individual tests. Methods: Fifty-two participants (mean age 65.8±5.7 years) completed CBB and CBS tests on their own computer, unsupervised from home, on three occasions, and visited a research center for an in-person paper-and-pencil assessment. They also completed a user-experience questionnaire. Results: Test-retest reliabilities varied for individual measures (ICCs = 0.20 to 0.83). Global cognition composites showed excellent reliability (ICCs > 0.8 over 1-month follow-up). A strong relationship between a combination of CNA measures and paper-and-pencil battery was found (canonical correlation R = 0.87, p = 0.04). Most tests were rated as enjoyable with easy-to-understand instructions. Ratings of general experience with online testing were mostly favorable; few had difficulty concentrating (17%) or using the computer for tasks (10%), although over one-third experienced performance anxiety (38%). Conclusion: A combined brief online battery selected from two CNAs demonstrated robust psychometric standards for reliability (global composite), and convergent validity with a gold standard battery, and mostly good usability and acceptability in the remote testing environment

Characterising Australian memory clinics: current practice and service needs informing national service guidelines

Background: Memory clinics (MCs) play a key role in accurate and timely diagnoses and treatment of dementia and mild cognitive impairment. However, within Australia, there are little data available on current practices in MCs, which hinder international comparisons for best practice, harmonisation efforts and national coordination. Here, we aimed to characterise current service profiles of Australian MCs. Methods: The ‘Australian Dementia Network Survey of Expert Opinion on Best Practice and the Current Clinical Landscape’ was conducted between August-September 2020 as part of a larger-scale Delphi process deployed to develop national MC guidelines. In this study, we report on the subset of questions pertaining to current practice including wait-times and post-diagnostic care. Results: Responses were received from 100 health professionals representing 60 separate clinics (45 public, 11 private, and 4 university/research clinics). The majority of participants were from clinics in metropolitan areas (79%) and in general were from high socioeconomic areas. While wait-times varied, only 28.3% of clinics were able to offer an appointment within 1-2 weeks for urgent referrals, with significantly more private clinics (58.3%) compared to public clinics (19.5%) being able to do so. Wait-times were less than 8 weeks for 34.5% of non-urgent referrals. Only 20.0 and 30.9% of clinics provided cognitive interventions or post-diagnostic support respectively, with 7.3% offering home-based reablement programs, and only 12.7% offering access to group-based education. Metropolitan clinics utilised neuropsychological assessments for a broader range of cases and were more likely to offer clinical trials and access to research opportunities. Conclusions: In comparison to similar countries with comprehensive government-funded public healthcare systems (i.e., United Kingdom, Ireland and Canada), wait-times for Australian MCs are long, and post-diagnostic support or evidence-based strategies targeting cognition are not common practice. The timely and important results of this study highlight a need for Australian MCs to adopt a more holistic service of multidisciplinary assessment and post-diagnostic support, as well as the need for the number of Australian MCs to be increased to match the rising number of dementia cases

The influence of rs53576 polymorphism in the oxytocin receptor (OXTR) gene on empathy in healthy adults by subtype and ethnicity: a systematic review and meta-analysis

Empathy is essential for navigating complex social environments. Prior work has shown associations between rs53576, a single nucleotide polymorphism (SNP) located in the oxytocin receptor gene (OXTR), and generalized empathy. We undertook a systematic review and meta-analysis to assess the effects of rs53576 on subdomains of empathy, specifically cognitive empathy (CE) and affective empathy (AE), in healthy adults. Twenty cohorts of 8933 participants aged 18-98 were identified, including data from the Sydney Memory and Ageing Study, a cohort of older community adults. Meta-analyses found G homozygotes had greater generalized empathic abilities only in young to middle-aged adults. While meta-analyses of empathy subdomains yielded no significant overall effects, there were differential effects based on ethnicity. G homozygotes were associated with greater CE abilities in Asian cohorts (standardized mean difference; SMD: 0.09 [2.8·10-3-0.18]), and greater AE performance in European cohorts [SMD: 0.12 (0.04-0.21)]. The current literature highlights a need for further work that distinguishes between genetic and ethnocultural effects and explores effects of advanced age on this relationship

Examining the validity of the Mini-Mental State Examination (MMSE) and its domains using network analysis

Background: The Mini-Mental State Examination (MMSE) is the most widely used standardised screener for impairments across a range of cognitive domains. However, the degree to which its domains (orientation, registration, attention, recall, language, and visuospatial) capture cognitive functioning measured using standardised neuropsychological tests is unclear. Method: A longitudinal research design with four biannual assessments over a 6-year period was used with an initial sample of 1037 older adults (aged above 70 years). Participants completed MMSE and neuropsychological tests at each assessment. Network analysis was utilised to investigate unique associations among the MMSE and its domains and neuropsychological test performance at each time point. Results: The total MMSE and two of its domains, language and recall, were associated with neuropsychological memory performance. The MMSE orientation, registration and visuospatial domains did not have any unique associations with neuropsychological performance. No stable internal interconnections between MMSE domains were found over time. The association of total MMSE as well as its recall domain with neuropsychological memory performance remained very similar over the 6-year period. Conclusions: The present study adds evidence to the validity of the MMSE and supports the clinical usage of the MMSE, whereby the total score is used for screening patients with or without cognitive impairments, with repeated administration to monitor cognitive changes over time, to inform intervention. However, the tool is not able to diagnose the cases for changes in specific cognitive domains and as such, should not replace a complete neuropsychological assessment

Polygenic resilience scores capture protective genetic effects for Alzheimer’s disease

Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer’s disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast “resilient” unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk