A multifactorial approach for understanding fall risk in older people

OBJECTIVE: To identify the interrelationships and discriminatory value of a broad range of objectively measured explanatory risk factors for falls. DESIGN: Prospective cohort study with 12-month follow-up period. SETTING: Community sample. PARTICIPANTS: Five hundred community-dwelling people aged 70 to 90. MEASUREMENTS: All participants underwent assessments on medical, disability, physical, cognitive, and psychological measures. Fallers were defined as people who had at least one injurious fall or at least two noninjurious falls during a 12-month follow-up period. RESULTS: Univariate regression analyses identified the following fall risk factors: disability, poor performance on physical tests, depressive symptoms, poor executive function, concern about falling, and previous falls. Classification and regression tree analysis revealed that balance-related impairments were critical predictors of falls. In those with good balance, disability and exercise levels influenced future fall risk-people in the lowest and the highest exercise tertiles were at greater risk. In those with impaired balance, different risk factors predicted greater fall risk-poor executive function, poor dynamic balance, and low exercise levels. Absolute risks for falls ranged from 11% in those with no risk factors to 54% in the highest-risk group. CONCLUSIONS: A classification and regression tree approach highlighted interrelationships and discriminatory value of important explanatory fall risk factors. The information may prove useful in clinical settings to assist in tailoring interventions to maximize the potential benefit of falls prevention strategies

Patterns of change in subjective cognitive complaints are associated with cognitive decline and dementia risk: Findings from the Sydney Memory and Ageing Study

Background Subjective cognitive complaints (SCCs) are now an established risk factor for dementia, however, little is known about whether changing patterns in SCCs over time are associated with cognitive decline and dementia risk. We examine the trajectory of SCCs over a 6‐year period to determine whether intraindividual patterns of reporting SCCs over time is related to cognitive decline and incident dementia. Method Participants were 1037 older adults without dementia (M age = 78.65 years; 55% females) from the Sydney Memory and Ageing Study who were followed‐up biennially. Global cognition was measured using a comprehensive neuropsychological battery, and clinical diagnoses were made by an expert consensus panel. SCCs were obtained as participants’ response to a single question concerning their subjective report of memory decline. Patterns of SCCs over time were modelled by conducting categorical latent growth curve analysis using the logit transformation (Figure 1). We examined the associations between average level of SCC likelihood and change in SCC likelihood, with global cognition over six years using latent growth curve analysis, and with risk of incident dementia over 10 years using Cox regression. Result In this community‐dwelling older adult sample, there was an annual 10% increase in the odds of reporting SCCs (Figure 2). After controlling for demographics, depression, and personality, results revealed a negative longitudinal association between the slope of SCCs and the slope of global cognition scores, such that participants with an increasing propensity of reporting SCCs over time also showed a steeper rate of decline in global cognition (Figure 4). Cox regression revealed an association between increased SCCs and incident dementia risk (Table 1). That is, participants with an increasing propensity of reporting SCCs over time are also at greater risk for developing dementia (Figure 5). Conclusion This is the first study to use latent growth curve analysis to examine patterns of change in SCCs overtime. Traditionally, studies examining SCCs longitudinally categorise people as ‘stable’ versus ‘not stable’, however, important information may be lost this way. Understanding patterns of change in SCC reporting over time has significant potential to identify individuals at greater risk of cognitive decline and incident dementia

Social cognitive abilities in older adults with mild cognitive impairment and dementia

Background Aging is associated with changes in general cognition and social cognition. Many studies have detailed these functions in isolation, comparing young and older adults. More information is needed on how social cognition, including theory of mind (ToM), affective empathy (AE), social perception (SP), and social behavior (SB), is affected at different cognitive stages in older adults. Method Cross‐sectional study of 305 older adults from the Sydney Memory and Ageing Study. Dementia was classified based on clinical consensus using DSM‐IV criteria, while mild cognitive impairment (MCI) was classified using the International Working Group criteria. Cognitively normal (CN), MCI, and dementia participants were compared on social cognitive domains including: ToM, via the Reading the Mind in the Eyes Test (RMET) and the Interpersonal Reactivity Index – Perspective Taking subscale (IRI‐PT); AE, via the IRI – Empathic Concern subscale (IRI‐EC); and SP, via the Emotion Recognition Task (ERT). Apathy, which is related to SB, was measured via the Apathy Evaluation Scale (AES). Result Mean age 87.00 ± 4.05 years, mean education 11.89 ± 3.36 years, 60.3% female. 141 were CN, 103 had MCI, and 61 had dementia. Across cognitive groups, significant differences were observed for the RMET, ERT (specifically for the recognition of anger, disgust, and happiness), AES, IRI‐PT, and IRI‐EC. In posthoc comparisons, RMET and ERT were significantly poorer in MCI and dementia compared to CN, but not between MCI and dementia. IRI ratings and AES were poorer for dementia compared to MCI and CN, but not between MCI and CN (Table 1). In multivariable logistic regression adjusting for significant risk factors for cognitive impairment, RMET and ERT disgust performance were associated with lower risk of MCI over CN. Only AES significantly differentiated dementia from MCI (Table 2). Conclusion Neurocognitive disorders are associated with social cognition changes. ToM and SP appear to be affected in MCI relative to CN. Apathy, known to be linked to SB, appears to be affected in dementia. MCI seems to be associated with impaired ability to recognize specific social cognitive cues, while dementia may be more associated with overall worse social cognitive functioning and observed behavioral changes

The latent construct of dementia phenotype: Validation and longitudinal examination in the Sydney Memory and Ageing Study

Background The latent continuous construct delta (δ) has been proposed as a novel approach to model dementia phenotype using structural equation modelling that reflects the “cognitive correlates of functional status” (Royall & Palmer, 2012. J Neuropsychiatry Clin Neurosci; Royall et al., 2012. J Alzheimers Dis). This δ factor has been demonstrated to be associated with clinically diagnosed dementia status and severity of dementia. However, thus far there are few studies validating the model longitudinally and these are in American samples. To establish the potential research and clinical utility of δ, the current research constructs and validates this latent dementia factor over a 6‐year period in a community sample of Australian older adults. Method A community‐dwelling sample of Australian older adults without dementia (at baseline) from the Sydney Memory and Ageing Study was used (n = 1037; M age = 78.65 years; 55% females). Biennially, participants completed a battery of neuropsychological tests measuring performance in four major cognitive domains, and informants rated their functional status on instrumental activities of daily living. Dementia status and severity were established through consensus diagnosis by an expert panel of clinicians and the Clinical Dementia Rating Scale Sum of Boxes (CDR‐SOB), respectively. Result A latent growth curve model of δ and Spearman’s general intelligence factor (g) built on four waves of cognitive and function data revealed good fit: CFI = 0.97, RMSEA = 0.04, SRMR = 0.06. A significant increase in δ over time was observed, and this latent change in δ (Δδ) was significantly associated with CDR‐SOB at wave 4 after controlling for demographics, APOE*4, and baseline CDR‐SOB. Cox regression revealed a significant association between Δδ and incident dementia. Further, Δδ accurately discriminated diagnosed dementia cases at wave 4 (ROC area under the curve = 0.91, 95% CI [0.88, 0.95]). Conclusion This study tests and validates the δ framework in Australian older adults by demonstrating that the change in δ over 6 years is associated with dementia risk and prospective severity of dementia. Future research should further test the model using longitudinal data from geographically and ethnoculturally diverse samples

Interfering with DNA Decondensation as a Strategy Against Mycobacteria

Tuberculosis is once again a major global threat, leading to more than 1 million deaths each year. Treatment options for tuberculosis patients are limited, expensive and characterized by severe side effects, especially in the case of multidrug-resistant forms. Uncovering novel vulnerabilities of the pathogen is crucial to generate new therapeutic strategies. Using high resolution microscopy techniques, we discovered one such vulnerability of Mycobacterium tuberculosis. We demonstrate that the DNA of M. tuberculosis can condense under stressful conditions such as starvation and antibiotic treatment. The DNA condensation is reversible and specific for viable bacteria. Based on these observations, we hypothesized that blocking the recovery from the condensed state could weaken the bacteria. We showed that after inducing DNA condensation, and subsequent blocking of acetylation of DNA binding proteins, the DNA localization in the bacteria is altered. Importantly under these conditions, Mycobacterium smegmatis did not replicate and its survival was significantly reduced. Our work demonstrates that agents that block recovery from the condensed state of the nucleoid can be exploited as antibiotic. The combination of fusidic acid and inhibition of acetylation of DNA binding proteins, via the Eis enzyme, potentiate the efficacy of fusidic acid by 10 and the Eis inhibitor to 1,000-fold. Hence, we propose that successive treatment with antibiotics and drugs interfering with recovery from DNA condensation constitutes a novel approach for treatment of tuberculosis and related bacterial infections

Classifying MCI Subtypes in Community-Dwelling Elderly Using Cross-Sectional and Longitudinal MRI-Based Biomarkers

Amnestic MCI (aMCI) and non-amnestic MCI (naMCI) are considered to differ in etiology and outcome. Accurately classifying MCI into meaningful subtypes would enable early intervention with targeted treatment. In this study, we employed structural magnetic resonance imaging (MRI) for MCI subtype classification. This was carried out in a sample of 184 community-dwelling individuals (aged 73–85 years). Cortical surface based measurements were computed from longitudinal and cross-sectional scans. By introducing a feature selection algorithm, we identified a set of discriminative features, and further investigated the temporal patterns of these features. A voting classifier was trained and evaluated via 10 iterations of cross-validation. The best classification accuracies achieved were: 77% (naMCI vs. aMCI), 81% (aMCI vs. cognitively normal (CN)) and 70% (naMCI vs. CN). The best results for differentiating aMCI from naMCI were achieved with baseline features. Hippocampus, amygdala and frontal pole were found to be most discriminative for classifying MCI subtypes. Additionally, we observed the dynamics of classification of several MRI biomarkers. Learning the dynamics of atrophy may aid in the development of better biomarkers, as it may track the progression of cognitive impairment

Applying generalizability theory to examine assessments of subjective cognitive complaints: whose reports should we rely on - participant versus informant?

OBJECTIVES: This study aimed to apply the generalizability theory (G-theory) to investigate dynamic and enduring patterns of subjective cognitive complaints (SCC), and reliability of two widely used SCC assessment tools. DESIGN: G-theory was applied to assessment scales using longitudinal measurement design with five assessments spanning 10 years of follow-up. SETTING: Community-dwelling older adults aged 70-90 years and their informants, living in Sydney, Australia, participated in the longitudinal Sydney Memory and Ageing Study. PARTICIPANTS: The sample included 232 participants aged 70 years and older, and 232 associated informants. Participants were predominantly White Europeans (97.8%). The sample of informants included 76 males (32.8%), 153 females (65.9%), and their age ranged from 27 to 86 years, with a mean age of 61.3 years (SD = 14.38). MEASUREMENTS: The Memory Complaint Questionnaire (MAC-Q) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). RESULTS: The IQCODE demonstrated strong reliability in measuring enduring patterns of SCC with G = 0.86. Marginally acceptable reliability of the 6-item MAC-Q (G = 0.77-0.80) was optimized by removing one item resulting in G = 0.80-0.81. Most items of both assessments were measuring enduring SCC with exception of one dynamic MAC-Q item. The IQCODE significantly predicted global cognition scores and risk of dementia incident across all occasions, while MAC-Q scores were only significant predictors on some occasions. CONCLUSIONS: While both informants' (IQCODE) and self-reported (MAC-Q) SCC scores were generalizable across sample population and occasions, self-reported (MAC-Q) scores may be less accurate in predicting cognitive ability and diagnosis of each individual

Age-related cognitive decline and associations with sex, education and apolipoprotein E genotype across ethnocultural groups and geographic regions: a collaborative cohort study

Background: The prevalence of dementia varies around the world, potentially contributed to by international differences in rates of age-related cognitive decline. Our primary goal was to investigate how rates of age-related decline in cognitive test performance varied among international cohort studies of cognitive aging. We also determined the extent to which sex, educational attainment, and apolipoprotein E ε4 allele (APOE*4) carrier status were associated with decline. Methods and findings: We harmonized longitudinal data for 14 cohorts from 12 countries (Australia, Brazil, France, Greece, Hong Kong, Italy, Japan, Singapore, Spain, South Korea, United Kingdom, United States), for a total of 42,170 individuals aged 54–105 y (42% male), including 3.3% with dementia at baseline. The studies began between 1989 and 2011, with all but three ongoing, and each had 2–16 assessment waves (median = 3) and a follow-up duration of 2–15 y. We analyzed standardized Mini-Mental State Examination (MMSE) and memory, processing speed, language, and executive functioning test scores using linear mixed models, adjusted for sex and education, and meta-analytic techniques. Performance on all cognitive measures declined with age, with the most rapid rate of change pooled across cohorts a moderate -0.26 standard deviations per decade (SD/decade) (95% confidence interval [CI] [-0.35, -0.16], p < 0.001) for processing speed. Rates of decline accelerated slightly with age, with executive functioning showing the largest additional rate of decline with every further decade of age (-0.07 SD/decade, 95% CI [-0.10, -0.03], p = 0.002). There was a considerable degree of heterogeneity in the associations across cohorts, including a slightly faster decline (p = 0.021) on the MMSE for Asians (-0.20 SD/decade, 95% CI [-0.28, -0.12], p < 0.001) than for whites (-0.09 SD/decade, 95% CI [-0.16, -0.02], p = 0.009). Males declined on the MMSE at a slightly slower rate than females (difference = 0.023 SD/decade, 95% CI [0.011, 0.035], p < 0.001), and every additional year of education was associated with a rate of decline slightly slower for the MMSE (0.004 SD/decade less, 95% CI [0.002, 0.006], p = 0.001), but slightly faster for language (-0.007 SD/decade more, 95% CI [-0.011, -0.003], p = 0.001). APOE*4 carriers declined slightly more rapidly than non-carriers on most cognitive measures, with processing speed showing the greatest difference (-0.08 SD/decade, 95% CI [-0.15, -0.01], p = 0.019). The same overall pattern of results was found when analyses were repeated with baseline dementia cases excluded. We used only one test to represent cognitive domains, and though a prototypical one, we nevertheless urge caution in generalizing the results to domains rather than viewing them as test-specific associations. This study lacked cohorts from Africa, India, and mainland China. Conclusions: Cognitive performance declined with age, and more rapidly with increasing age, across samples from diverse ethnocultural groups and geographical regions. Associations varied across cohorts, suggesting that different rates of cognitive decline might contribute to the global variation in dementia prevalence. However, the many similarities and consistent associations with education and APOE genotype indicate a need to explore how international differences in associations with other risk factors such as genetics, cardiovascular health, and lifestyle are involved. Future studies should attempt to use multiple tests for each cognitive domain and feature populations from ethnocultural groups and geographical regions for which we lacked dataFunding for each of the contributing studies is as follows: The Brazilian Ministry of Health and Ministry of Science and Technology (MFLC, ECC); Major awards from the UK Medical Research Council and the Department of Health (CB, FEM, BCMS); National Institute on Health/National Institute on Aging grants (5P01 AG003949, 1R03 AG045474; RBL, MJK); Novartis (KR, JS, MLA); Alzheimer’s Association (IIRG-09- 133014), ESPA-EU program Excellence Grant (ARISTEIA), which is co-funded by the European Social Fund and Greek National resources (189 10276/8/9/2011), and Ministry for Health and Social Solidarity, Greece (ΔY2β/οικ.51657/ 14.4.2009; NS, MY, ED); Mr. Lai Seung Hung & Mrs. Lai Chan Pui Ngong Dementia in Hong Kong Research Fund, and an educational fund from Eisai (LCWL, CHYW, AWTF); Fondazione Golgi Cenci and Federazione Alzheimer Italia (AG, RV, AD); Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea [Grant No. HI09C1379 (A092077); KWK, JWH, THK]; National Health and Medical Research Council of Australia (Grants 973302, 179805, 157125 and 1002160; KJA, NC, PB); Wellcome Trust (grant code GR066133MA) and FAPESP-Brazil (grant code 2004/12694-8; MS); Health and Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare of Japan (H25-Ninchisho-Ippan-004) and a research grant from Sasaguri town, Fukuoka, Japan (SK, SC, KN); Research grants (No. 03/ 121/17/214 and No. 08/1/21/19/567) from the Biomedical Research Council, Agency for Science, Technology and Research (A_STAR) in Singapore (TPN, QG); National Health & Medical Research Council of Australia Program Grant (ID 350833; PSS, DML, NAK, JDC, AT, GA, SR, HB); Fondo de Investigacio´n Sanitaria, Instituto de Salud Carlos III, Spanish Ministry of Health, Madrid, Spain (Grants 94/ 1562, 97/1321E, 98/0103, 01/0255, 03/0815, 06/0617, and G03/128) and Pfizer Foundation, Madrid (AL, RLA, JS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Age-Related Changes of Peak Width Skeletonized Mean Diffusivity (PSMD) Across the Adult Lifespan: A Multi-Cohort Study

Parameters of water diffusion in white matter derived from diffusion-weighted imaging (DWI), such as fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AD, and RD), and more recently, peak width of skeletonized mean diffusivity (PSMD), have been proposed as potential markers of normal and pathological brain ageing. However, their relative evolution over the entire adult lifespan in healthy individuals remains partly unknown during early and late adulthood, and particularly for the PSMD index. Here, we gathered and analyzed cross-sectional diffusion tensor imaging (DTI) data from 10 population-based cohort studies in order to establish the time course of white matter water diffusion phenotypes from post-adolescence to late adulthood. DTI data were obtained from a total of 20,005 individuals aged 18.1 to 92.6 years and analyzed with the same pipeline for computing skeletonized DTI metrics from DTI maps. For each individual, MD, AD, RD, and FA mean values were computed over their FA volume skeleton, PSMD being calculated as the 90% peak width of the MD values distribution across the FA skeleton. Mean values of each DTI metric were found to strongly vary across cohorts, most likely due to major differences in DWI acquisition protocols as well as pre-processing and DTI model fitting. However, age effects on each DTI metric were found to be highly consistent across cohorts. RD, MD, and AD variations with age exhibited the same U-shape pattern, first slowly decreasing during post-adolescence until the age of 30, 40, and 50 years, respectively, then progressively increasing until late life. FA showed a reverse profile, initially increasing then continuously decreasing, slowly until the 70s, then sharply declining thereafter. By contrast, PSMD constantly increased, first slowly until the 60s, then more sharply. These results demonstrate that, in the general population, age affects PSMD in a manner different from that of other DTI metrics. The constant increase in PSMD throughout the entire adult life, including during post-adolescence, indicates that PSMD could be an early marker of the ageing process

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