Mark Chan

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.

Stage-Independent and Stage-Specific Phenotypic Differences between Vascular Dementia and Alzheimer’s Disease

Aims: We examined the effect of stratification by dementia severity on clinical and neuropsychological differences observed between vascular dementia (VaD) and Alzheimer’s disease (AD) to ascertain whether any observed phenotypic differences would differ between the early and late stages. Methods: The phenotypic features at presentation of 219 newly diagnosed VaD (n = 103) and AD (n = 116) patients were analyzed. All patients underwent clinical, neuropsychological and neuroimaging evaluation. Severity of dementia was staged using the Clinical Dementia Rating (CDR) scale. Results: VaD can be clinically distinguished from AD by criterion-related features that span across all stages of dementia. We also identified non-criterion-related features that differed according to dementia severity. In the CDR 0.5–1 stage, VaD patients demonstrated increased reading difficulty, loss of insight, apathy, and greater impairment in executive function compared with delayed and recognition memory. Unique distinguishing features for VaD in the CDR 2–3 stage included higher Geriatric Depression Scale scores, lower Barthel scores, gait apraxia and parkinsonism. Conclusions: Phenotypic differences between VaD and AD can be conceptualized as either criterion-related stage-independent features, or stage-specific features (comprising cognitive and neuropsychological elements in the mild stages, and physical, affective and functional components in the later stages).

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.

Differential perceptions of quality of life (QoL) in community-dwelling persons with mild-to-moderate dementia

BACKGROUND Discordance between patient- and caregiver-reported quality of life (QoL) is well recognized. This study sought to (i) identify predictors of discrepancy between patient- and caregiver-rated QoL amongst community-dwelling persons with mild-to-moderate dementia, and (ii) differentiate between patients who systematically rate their QoL lower versus those who rate their QoL higher relative to their caregiver ratings. METHODS We recruited 165 patient-caregiver dyads with mild-to-moderate dementia. Quality of life in Alzheimers disease (QoL-AD) scale was administered separately to patients and caregivers. Data on socio-demographics, interpersonal relationship, and disease-related characteristics (cognitive performance, mood, neuropsychiatric symptoms, functional ability, and caregiver burden) were collected. Patient-caregiver dyads were categorized based on whether patient-rated QoL was lower or higher than their respective caregiver ratings. Univariate analyses and multiple regression models were performed to identify predictors of dyadic rating discrepancy. RESULTS Mean patient-rated QoL was significantly higher than caregiver rating (mean difference: 3.8 ± 7.1, p < 0.001). Majority (111 (67.2%)) of patients had more positive self-perceived QoL (QoL-ADp (QoL-AD self rated by the patient) > QoL-ADc (QoL-AD proxy-rated by a caregiver)), compared with those (44 (26.7%)) with poorer self-perceived QoL (QoL-ADp < QoL-ADc). Patients education level, depressive symptoms, and severity of neuropsychiatric symptoms predicted magnitude of discrepancy. Depression (OR = 1.17, 95% CI = 1.02-1.35) and being cared for by other relative (non-spouse/adult child; OR = 7.54, 95% CI = 1.07-53.03) predicted poorer self-perceived QoL. CONCLUSIONS Dyadic rating discrepancy in QoL should draw the clinicians attention to patient depression and neuropsychiatric symptoms. Consideration should also be given to nature of patient-caregiver relationship when discordance between patient and caregiver assessments of QoL is observed.

Prospective Observational Study of Delirium Recovery Trajectories and Associated Short-Term Outcomes in Older Adults Admitted to a Specialized Delirium Unit

To describe the recovery trajectories of delirium and to determine factors predicting the course of recovery and adverse outcome.

Cost of informal care for community-dwelling mild-moderate dementia patients in a developed Southeast Asian country.

BACKGROUND Cost of informal care constitutes an important component of total dementia care cost. It also reflects resource utilization by patients and caregivers. We aim to quantify the informal cost of care for mild to moderate dementia patients. METHODS We recruited 165 patient-caregiver dyads with mild to moderate dementia. Informal care burden was assessed using the Resource Utilization in Dementia (RUD)-Lite instrument. A generalized linear model was fitted for association between cost of informal care and cognitive impairment, taking into account patient demographics, disease factors, and use of paid domestic help. Marginal estimates were obtained from the model for the purpose of illustration and discussion. RESULTS Total hours of informal care by primary caregiver doubled in moderate dementia patients, with 57.9% having paid domestic help to assist in care. Functional factors and use of paid domestic help were significantly associated with informal care costs. Costs were consistently higher for patients without paid domestic help for mild- and moderate dementia. CONCLUSION This study demonstrates the informal care costs of caring for mild-moderate dementia patients in Singapore, with the unique cost savings provided by live-in paid domestic help, and potentially may aid policy-makers in allocation of resources and support to caregivers.