Wee Shiong Lim

The Asia-Pacific clinical practice guidelines for the management of frailty

OBJECTIVE To develop Clinical Practice Guidelines for the screening, assessment and management of the geriatric condition of frailty. METHODS An adapted Grading of Recommendations, Assessment, Development, and Evaluation approach was used to develop the guidelines. This process involved detailed evaluation of the current scientific evidence paired with expert panel interpretation. Three categories of Clinical Practice Guidelines recommendations were developed: strong, conditional, and no recommendation. RECOMMENDATIONS Strong recommendations were (1) use a validated measurement tool to identify frailty; (2) prescribe physical activity with a resistance training component; and (3) address polypharmacy by reducing or deprescribing any inappropriate/superfluous medications. Conditional recommendations were (1) screen for, and address modifiable causes of fatigue; (2) for persons exhibiting unintentional weight loss, screen for reversible causes and consider food fortification and protein/caloric supplementation; and (3) prescribe vitamin D for individuals deficient in vitamin D. No recommendation was given regarding the provision of a patient support and education plan. CONCLUSIONS The recommendations provided herein are intended for use by healthcare providers in their management of older adults with frailty in the Asia Pacific region. It is proposed that regional guideline support committees be formed to help provide regular updates to these evidence-based guidelines.

Metabolic Syndrome and the Risk of Mild Cognitive Impairment and Progression to Dementia: Follow-up of the Singapore Longitudinal Ageing Study Cohort

IMPORTANCE The association of the metabolic syndrome (MetS) and component cardiovascular risk factors with the risk of developing mild cognitive impairment (MCI) and MCI progression to dementia is not well established. OBJECTIVE To investigate the association of the MetS and its component cardiovascular risk factors with the incidence of MCI and its progression to dementia. DESIGN, SETTING, AND PARTICIPANTS Prospective longitudinal study from September 1, 2003, through December 31, 2009, in communities in 5 districts in the South East region of Singapore. Study participants were a population-based sample of 1519 cognitively normal adults 55 years and older. MAIN OUTCOMES AND MEASURES Prespecified outcomes were incident MCI and MCI progression to dementia. RESULTS The study cohort comprised 1519 participants. Their mean (SD) age was 64.9 (6.8) years, and 64.8% (n = 984) were female. Baseline characteristics associated with an increased risk of incident MCI were MetS (hazard ratio [HR], 1.46; 95% CI, 1.02-2.09), central obesity (HR, 1.41; 95% CI, 1.01-1.98), diabetes mellitus (HR, 2.84; 95% CI, 1.92-4.19), dyslipidemia (HR, 1.48; 95% CI, 1.01-2.15), and 3 or more component cardiovascular risk factors (HR, 1.58; 95% CI, 1.13-2.33). Baseline characteristics associated with an increased risk of MCI progression to dementia were MetS (HR, 4.25; 95% CI, 1.29-14.00), diabetes mellitus (HR, 2.47; 95% CI, 1.92-4.19), and 3 or more component cardiovascular risk factors (HR, 4.92; 95% CI, 1.39-17.4). CONCLUSIONS AND RELEVANCE The MetS was associated with an increased incidence of MCI and progression to dementia. Identifying individuals with diabetes mellitus or the MetS with or without MCI is a promising approach in early interventions to prevent or slow progression to dementia.

Metabolic Syndrome and Amnestic Mild Cognitive Impairment: Singapore Longitudinal Ageing Study-2 Findings

Metabolic syndrome (MetS) is reported to be associated with cognitive decline and dementia, in particular vascular dementia. However, the evidence linking MetS to Alzheimers disease (AD) and amnestic mild cognitive impairment (aMCI), a precursor of AD, is inconsistent and limited. This study examined the association of MetS and its components with aMCI and how APOE-εe4 and younger age influenced this association. Participants with aMCI (n = 98) and cognitively normal controls (n = 802) were identified from baseline data in a second wave cohort of older subjects aged 55 and over in the Singapore Longitudinal Ageing Study-2 (SLAS-2) in 2009/2010. The associations of MetS and its individual components with aMCI were analyzed using logistic regression controlling for age, gender, education, current smoking, alcohol drink, leisure time activities score, Geriatric Depression Scale score, APOE-ε4, and heart disease or stroke. The analysis was repeated for associations stratified by age and APOE-ε4 status. In multivariate analysis, MetS was associated with an elevated risk of aMCI (OR = 1.79; 95% CI 1.15-2.77). Among MetS components, central obesity showed a significant association with aMCI (OR = 1.77; 95% CI 1.11-2.82). The association between MetS and aMCI remained significant on repeated analysis among subjects free of heart disease and stroke. This association was particularly stronger among participants with APOE-ε4 allele (OR = 3.35; 95% CI, 1.03-10.85) and younger (<65 years) participants with APOE-ε4 (OR = 6.57; 95% CI, 1.03-41.74). MetS was found to be associated with aMCI, especially in individuals with APOE-ε4 at younger age in this middle-aged and older cohort.

Physical Frailty, Cognitive Impairment, and the Risk of Neurocognitive Disorder in the Singapore Longitudinal Ageing Studies

Background The independent and combined effects of physical and cognitive domains of frailty in predicting the development of mild cognitive impairment (MCI) or dementia are not firmly established. Methods This study included cross-sectional and longitudinal analyses of physical frailty (Cardiovascular Health Study criteria), cognitive impairment (Mini-Mental State Examination [MMSE]), and neurocognitive disorder (DSM-5 criteria) among 1,575 community-living Chinese older adults from the Singapore Longitudinal Ageing Studies. Results At baseline, 2% were frail, 32% were prefrail, and 9% had cognitive impairment (MMSE score < 23). Frailty at baseline was significantly associated with prevalent cognitive impairment. Physical frailty categories were not significantly associated with incident NCD, but continuous physical frailty score and MMSE score showed significant individual and joint associations with incident mild NCD and dementia. Compared with those who were robust and cognitively normal, prefrail or frail old adults without cognitive impairment had no increased risk of incident NCD, but elevated odds of association with incident NCD were observed for robust with cognitive impairment (odds ratio [OR] = 4.04, p < .001), prefrail with cognitive impairment (OR = 2.22, p = .044), and especially for frail with cognitive impairment (OR = 6.37, p = .005). The prevalence of co-existing frailty and cognitive impairment (cognitive frailty) was 1% (95% confidence interval [CI]: 0.5-1.4), but was higher among participants aged 75 and older at 5.0% (95% CI: 1.8-8.1). Conclusions Physical frailty is associated with increased prevalence and incidence of cognitive impairment, and co-existing physical frailty and cognitive impairment confers additionally greater risk of incident NCD.

Clinical and Safety Outcomes of Oral Antithrombotics for Stroke Prevention in Atrial Fibrillation: A Systematic Review and Network Meta-analysis.

INTRODUCTION Novel oral anticoagulants (NOACs) expanded the options for stroke prevention in atrial fibrillation (AF). Earlier studies comparing their relative effectiveness and safety typically do not incorporate age-related differences or postmarketing studies. This study aimed to summarize and compare clinical and safety outcomes of oral antithrombotics for stroke prevention in AF in younger (65-74 years) and older (≥75 years) elderly. METHODS We searched PubMed, Embase, and The Cochrane Library from inception through May 1, 2015, for randomized and nonrandomized studies comparing NOACs, warfarin, and aspirin in elderly with AF. Stroke and systemic embolism (SSE) and major bleeding (MB) are the main outcomes. We also studied secondary outcomes of ischemic stroke, all-cause mortality, intracranial bleeding, and gastrointestinal bleeding. RESULTS Of 5255 publications identified, 25 randomized controlled trials and 24 nonrandomized studies of 897,748 patients were included. NOACs reduced the risk of SSE compared with warfarin (rate ratios [RRs] range from 0.78-0.82). Relative to SSE, NOACs demonstrated a smaller benefit for ischemic stroke (dabigatran 110 mg, RR 1.08; edoxaban, 1.00; apixaban, 0.99). On the contrary, aspirin was associated with a significantly higher risk of SSE, ischemic stroke, and mortality than warfarin or NOACs (RR > 1), particularly in older elderly. Regarding safety, medium-dose aspirin (100-300 mg daily) and aspirin/clopidogrel combination showed an increased risk of MB compared with warfarin (RR 1.17 and 1.15, respectively), as per dabigatran 150 mg and rivaroxaban in older elderly (RR 1.17 and 1.12, respectively). Among the NOACs, dabigatran 150 mg conferred greater gastrointestinal bleeding risk compared with warfarin (RR 1.51), whereas rivaroxaban (RR 0.73) demonstrated less benefit of reduced intracranial bleeding than other NOACs (RRs range 0.39-0.46). CONCLUSIONS Lower rates of SSE and intracranial bleeding were observed with the NOACs compared with warfarin. Dabigatran 150 mg and rivaroxaban were associated with higher rates of MB in older elderly.

New DSM-V Neurocognitive Disorders Criteria and Their Impact on Diagnostic Classifications of Mild Cognitive Impairment and Dementia in a Memory Clinic Setting

OBJECTIVE To examine diagnostic agreement between Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) Neurocognitive Disorders (NCDs) criteria and DSM, Fourth Edition (DSM-IV) criteria for dementia and International Working Group (IWG) criteria for mild cognitive impairment (MCI) and DSM-Vs impact on diagnostic classifications of NCDs. The authors further examined clinical factors for discrepancy in diagnostic classifications between the different operational definitions. METHODS Using a cross-sectional study in tertiary memory clinic, the authors studied consecutive new patients aged 55 years or older who presented with cognitive symptoms. Dementia severity was scored based on the Clinical Dementia Rating scale (CDR). All patients completed neuropsychological evaluation. Agreement in diagnostic classifications between DSM-IV/IWG and DSM-V was examined using the kappa test and AC1 statistic, with multinomial logistic regression for factors contributing to MCI reclassification as major NCDs as opposed to diagnostically concordant MCI and dementia groups. RESULTS Of 234 patients studied, 166 patients achieved concordant diagnostic classifications, with overall kappa of 0.41. Eighty-six patients (36.7%) were diagnosed with MCI and 131 (56.0%) with DSM-IV-defined dementia. With DSM-V, 40 patients (17.1%) were classified as mild NCDs and 183 (78.2%) as major NCDs, representing a 39.7% increase in frequency of dementia diagnoses. CDR sum-of-boxes score contributed independently to differentiation of MCI patients reclassified as mild versus major NCDs (OR: 0.01; 95% CI: 0-0.09). CDR sum-of-boxes score (OR: 5.18; 95% CI: 2.04-13.15), performance in amnestic (OR: 0.14; 95% CI: 0.06-0.34) and language (Boston naming: OR: 0.52; 95% CI: 0.29-0.94) tests, were independent determinants of diagnostically concordant dementia diagnosis. CONCLUSION The authors observed moderate agreement between the different operational definitions and a 40% increase in dementia diagnoses with operationalization of the DSM-V criteria.

Worry about performance: a unique dimension of caregiver burden.

BACKGROUND Recent studies that describe the multidimensionality of the Zarit Burden Interview (ZBI) challenge the traditional dual-factor paradigm of personal and role strains (Whitlatch et al., 1991). These studies consistently reported a distinct dimension of worry about caregiver performance (WaP) comprising items 20 and 21.The present study aims to compare WaP against conventional ZBI domains in a predominantly Chinese multi-ethnic Asian population. METHODS We studied 130 consecutive dyads of family caregivers and patients. Factor analysis of the 22-item ZBI revealed four factors of burden. We compared WaP (factor 4) with the other three factors, personal strain, and role strain via: internal consistency; inter-factor correlation; item-to-total ratio across Clinical Dementia Rating (CDR) stages; predictors of burden; and interaction effect on total ZBI score using two-way analysis of variance. RESULTS WaP correlated poorly with the other factors (r = 0.05-0.21). It had the highest internal consistency (Cronbachs α = 0.92) among the factors. Unlike other factors, WaP was highly endorsed in mild cognitive impairment and did not increase linearly with disease severity, peaking at CDR 1. Multiple regression revealed younger caregiver age as the major predictor of WaP, compared with behavioral and functional problems for other factors. There was a significant interaction between WaP and psychological strain (p = 0.025). CONCLUSION Our results corroborate earlier studies that WaP is a distinct burden dimension not correspondent with traditional ZBI domains. WaP is germane to many Asian societies where obligation values to care for family members are strongly influential. Further studies are needed to better delineate the construct of WaP.

Diagnostic Performance of the Chinese Frontal Assessment Battery in Early Cognitive Impairment in an Asian Population

Background: The Frontal Assessment Battery (FAB) has been shown to be useful in evaluating frontal dysfunction. There is a paucity of studies validating cutoffs in the early cognitive impairment. We aim to validate the Chinese FAB in Asian subjects with mild cognitive impairment (MCI) and early dementia. Methods: Eighty subjects with MCI and mild dementia and 100 cognitively healthy community subjects were studied. ROC analysis was done to determine the Chinese FAB’s optimal cutoff scores for age- and education-adjusted subgroups. Results: Chinese FAB scores were significantly lower in early cognitive impairment compared with cognitively normal controls. The optimal cutoff score was 12/13 (sensitivity 92%, specificity 78.7%). A similar cutoff score was obtained following age-adjustment and for subjects with <6 years’ education. Of note, the optimal cutoff for subjects with ≧6 years’ education was 13/14 (sensitivity 91.8%, specificity 70.3%), an improved diagnostic performance compared to the earlier reported 11/12 cutoff. In comparison, the Mini-Mental Status Examination (MMSE) had lower rule-out accuracy (77% sensitivity, 91.2% specificity). The combination of the Chinese FAB and MMSE was superior to either test in isolation. Conclusion: The education-adjusted Chinese FAB has good diagnostic performance, which can supplement the MMSE in early cognitive impairment evaluation with construct differences observed between the Chinese FAB and MMSE.

Gene Expression Profiling of Peripheral Blood Leukocytes Shows Consistent Longitudinal Downregulation of TOMM40 and Upregulation of KIR2DL5A, PLOD1, and SLC2A8 Among Fast Progressors in Early Alzheimer's Disease

We previously reported TOMM40 was significantly down-regulated in whole blood of Alzheimers disease (AD) subjects. In this study, we examined whole blood gene profiling differences over a one-year period comparing early AD subjects based on disease progression. 6-monthly assessments and blood sampling on 29 probable AD subjects compared with age- and gender-matched controls were performed. AD subjects with change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score of ≥2 points/year were classified as fast-progressors and those with CDR-SB change of <2 points/year were classified as slow-progressors. We found statistically significant upregulation in KIR2DL5A, SLC2A8, and PLOD1 for fast- (n = 8) compared with slow-progressors (n = 21) across the time-points. TOMM40 gene expression remained significantly lower in AD patients at all time-points compared to controls, supporting our previous findings. Our novel findings of specific gene expression differences between fast- and slow-progressors in combination with consistently lower TOMM40 expression, suggest their potential role as prognostic blood biomarkers to predict progression in early AD.

Downregulation of TOMM40 expression in the blood of Alzheimer disease subjects compared with matched controls.

Translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene has been reported in several GWAS to be associated with Alzheimer disease (AD). Gene expression studies thus far only showed TOMM40 differential expression in one study on brain cortex and not in peripheral blood. We studied the gene expression profiles of AD blood versus controls in an Asian population in Singapore. In this first analysis we focused on genes that have been previously reported on GWAS. We found TOMM40 to be significantly down-regulated in blood samples of AD in one discovery and two validation sets, totalling 45 subjects (mean age 76.90, SD 6.46) and 45 controls (mean age 76.23, SD 5.09), matched for ethnicity and gender. The function of TOMM40 is not yet fully characterized but is believed to be involved in import and trafficking of protein into mitochondria. Therefore TOMM40 downregulation, found in the brain in severe AD and in our blood profile, may be a potential marker for AD, disease severity or progression and merit further investigation.