Mei Sian Chong

Preclinical Alzheimer's disease: diagnosis and prediction of progression

BACKGROUND From the modest but important breakthroughs in the treatment of Alzheimers disease (AD), diagnostic focus has increasingly shifted to the accurate detection of the earliest phase of the illness. The challenge of distinguishing preclinical AD from changes of normal ageing or established AD, has been recognised in several attempts at clinical classification. Of these attempts, Mayo Clinics mild cognitive impairment (MCI) has received significant attention, although it has not been internationally accepted. Not all people diagnosed as having MCI will develop AD, hence there is a need to reliably predict progression. RECENT DEVELOPMENTS Research in the identification of people with MCI who will develop AD via the use of neuropsychological tests, neuroimaging (both structural and functional), CSF analysis, and other biomarkers, either in isolation or in combination, has progressed rapidly. In this article we summarise findings from relevant recent longitudinal studies. WHERE NEXT?: There are increasing calls to recognise the pathological nature of MCI and to develop international diagnostic guidelines. Such uniform application of MCI criteria can then lead to clearer evidence of its diagnostic and therapeutic benefit. In developing these guidelines, the crucial presence of functional deficit arising from cognitive decline (which diagnoses dementia and excludes MCI) needs to be investigated in a standardised manner. Also needed are good-quality normal-values data on the various tests used to predict progression in preclinical AD.

Utility of the clinical dementia rating in Asian populations.

Consistent with the worldwide demographic trend of population aging, dementia is expected to become a burgeoning public health problem in Asian populations. Thus, there is a pressing need for reliable and valid methods of dementia diagnosis and staging that are applicable in heterogeneous Asian populations. The Clinical Dementia Rating (CDR) is an informant-based global assessment scale with established reliability and validity that has been widely utilized as a severity-ranking scale in many studies of Asian populations. From a diagnostic standpoint, the CDR is congruent with the Diagnostic and Statistical Manual of Mental Disorders approach of dementia diagnosis. It exhibits excellent discriminatory ability in the very mild stages of dementia, a useful property that is germane to the surging interest in mild cognitive impairment and related concepts. Limitations of the CDR include its length of administration, reliance on clinical judgment and collateral source information, and relative insensitivity as a measure of change in interventional studies. Since the exercise of clinical judgment is inherent in scoring, CDR raters should be mindful of the influence of cultural factors on premorbid lifestyle, informant reliability and performance in certain CDR test items (especially those pertaining to the categories of judgment and problem solving, community, and home and hobbies). Thus, in future studies that involve the nascent use of the CDR in Asian populations, it is recommended that any transcultural adaptation of CDR items be described in detail and appropriate validation studies be carried out before adopting the CDR as a yardstick measure of assessment. The potential of adapted versions of the CDR in chronic care settings and advanced cases should be explored. An integrative approach, combining brief informant interview in conjunction with brief objective cognitive testing, could be a viable strategy for dementia screening in the clinical and research setting that warrants further evaluation in Asian populations.

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.

Bright light therapy as part of a multicomponent management program improves sleep and functional outcomes in delirious older hospitalized adults

Objective Delirium is associated with poor outcomes following acute hospitalization. A specialized delirium management unit, the Geriatric Monitoring Unit (GMU), was established. Evening bright light therapy (2000–3000 lux; 6–10 pm daily) was added as adjunctive treatment, to consolidate circadian activity rhythms and improve sleep. This study examined whether the GMU program improved sleep, cognitive, and functional outcomes in delirious patients. Method A total of 228 patients (mean age = 84.2 years) were studied. The clinical characteristics, delirium duration, delirium subtype, Delirium Rating Score (DRS), cognitive status (Chinese Mini–Mental State Examination), functional status (modified Barthel Index [MBI]), and chemical restraint use during the initial and predischarge phase of the patient’s GMU admission were obtained. Nurses completed hourly 24-hour patient sleep logs, and from these, the mean total sleep time, number of awakenings, and sleep bouts (SB) were computed. Results The mean delirium duration was 6.7 ± 4.6 days. Analysis of the delirium subtypes showed that 18.4% had hypoactive delirium, 30.2% mixed delirium, and 51.3% had hyperactive delirium. There were significant improvements in MBI scores, especially for the hyperactive and mixed delirium subtypes (P < 0.05). Significant improvements were noted on the DRS sleep–wake disturbance subscore, for all delirium-subtypes. The mean total sleep time (7.7 from 6.4 hours) (P < 0.05) and length of first SB (6.0 compared with 5.3 hours) (P < 0.05) improved, with decreased mean number of SBs and awakenings. The sleep improvements were mainly seen in the hyperactive delirium subtype. Conclusion This study shows initial evidence for the clinical benefits (longer total sleep time, increased first SB length, and functional gains) of incorporating bright light therapy as part of a multicomponent delirium management program. The benefits appear to have occurred mainly in patients with hyperactive delirium, which merits further in-depth, randomized controlled studies.

The independent role of inflammation in physical frailty among older adults with mild cognitive impairment and mild-to-moderate Alzheimer’s disease

ObjectivesTo examine the independent and combined effects of inflammation and endocrine dysregulation on (i) baseline frailty status and (ii) frailty progression at one year, among cognitively impaired community dwelling older adults.DesignProspective cohort study.SettingTertiary Memory Clinic.MethodsWe recruited patients with mild cognitive impairment and mild-moderate Alzheimer’s disease. Physical frailty status was assessed at baseline and 1-year. Blood biomarkers of systemic inflammation [interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α)] and anabolic hormones [insulin-like growth factor-1 (IGF-1), dehydroepiandrosterone sulphate (DHEAS)] were measured at baseline and examined in relation to physical frailty status at baseline and progression at 1-year. Each subject was categorized as (i) neither pro-inflammatory nor endocrine deficient, (ii) pro-inflammatory (IL-6 or TNF-α, or both, being in highest quartile) but not endocrine deficient, (iii) endocrine deficient (IGF-1 or DHEAS, or both, being in lowest quartile) but not pro-inflammatory and (iv) both pro-inflammatory and endocrine deficient.ResultsTwenty (20.2%) of 99 subjects were physically frail at baseline. There was no association between severity of cognitive impairment and baseline frailty status, but the frail group had significantly greater hippocampal atrophy (median MTA: 2 (2–3) vs 1 (1–2), p=0.010). TNF-α was significantly higher in subjects who were physically frail at baseline (median TNF-α: 1.30 (0.60–1.40) vs 0.60 (0.50–1.30) pg/mL, p=0.035). In multiple logistic regression adjusted for age and gender, a pro-inflammatory state in the absence of concomitant endocrine deficiency was significantly associated with physical frailty at baseline (OR=4.99, 95% C.I 1.25–19.88, p=0.023); this was no longer significant when MTA score was included in the model. Isolated pro-inflammatory state (without endocrine deficiency) significantly increased the odds of frailty progression (OR=4.06, 95% CI 1.09–15.10, p=0.037) at 1-year. The combination pro-inflammatory and endocrine deficient state was not significantly associated with either baseline or progressive physical frailty.ConclusionA pro-inflammatory state exerts differential effects on physical frailty, contributing to the increased risk of baseline and progressive frailty only in the absence of a concomitant endocrine deficient state, with potential mediation via neurodegeneration.

Outcomes of an innovative model of acute delirium care: the Geriatric Monitoring Unit (GMU)

Objective Delirium is associated with poor outcomes following acute hospitalization. The Geriatric Monitoring Unit (GMU) is a specialized five-bedded unit for acute delirium care. It is modeled after the Delirium Room program, with adoption of core interventions from the Hospital Elder Life Program and use of evening light therapy to consolidate circadian rhythms and improve sleep in older inpatients. This study examined whether the GMU program improved outcomes in delirious patients. Method A total of 320 patients, including 47 pre-GMU, 234 GMU, and 39 concurrent control subjects, were studied. Clinical characteristics, cognitive status, functional status (Modified Barthel Index [MBI]), and chemical restraint-use data were obtained. We also looked at in-hospital complications of falls, pressure ulcers, nosocomial infection rate, and discharge destination. Secondary outcomes of family satisfaction (for the GMU subjects) were collected. Results There were no significant demographic differences between the three groups. Pre-GMU subjects had longer duration of delirium and length of stay. MBI improvement was most evident in the GMU compared with pre-GMU and control subjects (19.2±18.3, 7.5±11.2, 15.1±18.0, respectively) (P<0.05). The GMU subjects had a zero restraint rate, and pre-GMU subjects had higher antipsychotic dosages. This translated to lower pressure ulcer and nosocomial infection rate in the GMU (4.1% and 10.7%, respectively) and control (1.3% and 7.7%, respectively) subjects compared with the pre-GMU (9.1% and 23.4%, respectively) subjects (P<0.05). No differences were observed in mortality or discharge destination among the three groups. Caregivers of GMU subjects felt the multicomponent intervention to be useful, with scheduled activities voted the most beneficial in patient’s recovery from the delirium episode. Conclusion This study shows the benefits of a specialized delirium management unit for older persons. The GMU model is thus a relevant system of care for rapidly “graying” nations with high rates of frail elderly hospital admissions, which can be easily transposed across acute care settings.

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.