Laura Tay

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.

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.

Monocyte chemoattractant protein-1: a proinflammatory cytokine elevated in sarcopenic obesity

Objective Sarcopenic obesity (SO) is associated with poorer physical outcomes and functional status in the older adult. A proinflammatory milieu associated with central obesity is postulated to enhance muscle catabolism. We set out to examine associations of the chemokine monocyte chemoattractant protein-1 (MCP-1) in groups of older adults, with sarcopenia, obesity, and the SO phenotypes. Methods A total of 143 community dwelling, well, older adults were recruited. Cross-sectional clinical data, physical performance, and muscle mass measurements were collected. Obesity and sarcopenia were defined using revised National Cholesterol Education Program (NCEP) obesity guidelines and those of the Asian Working Group for Sarcopenia. Serum levels of MCP-1 were measured by enzyme-linked immunosorbent assay (ELISA). Results In all, 25.2% of subjects were normal, 15.4% sarcopenic, 48.3% obese, and 11.2% were SO. The SO groups had the lowest appendicular lean mass, highest percentage body fat, and lowest performance scores on the Short Physical Performance Battery and grip strength. The MCP-1 levels were significantly different, with the highest levels found in SO participants (P<0.05). Conclusion Significantly raised MCP-1 levels in obese and SO subjects support the theory of chronic inflammation due to excess adiposity. Longitudinal studies will reveal whether SO represents a continuum of obesity causing accelerated sarcopenia and cardiovascular events, or the coexistence of two separate conditions with synergistic effects affecting functional performance.

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.

TOMM40 Alterations in Alzheimer's Disease Over a 2-Year Follow-Up Period

We previously reported TOMM40 to be significantly down-regulated in whole blood of Alzheimers disease (AD) subjects at baseline and after one-year. In this longitudinal follow-up study of TOMM40 expression up to 2 years, we performed 6-monthly assessments for the first year and 2nd year blood sampling on 27 probable AD subjects compared with age- and gender-matched controls. TOMM40 gene expression remained significantly lower in AD patients at all time-points compared to controls, supported by confirmatory RT-PCR results. Our findings of consistently lower TOMM40 expression on longitudinal 2-year sampling support its potential role as a diagnostic blood AD biomarker.

Impact of frailty and residual subsyndromal delirium on 1-year functional recovery: A prospective cohort study

To investigate the association between frailty and incomplete delirium recovery at discharge (residual subsyndromal delirium [RSSD]), and to examine the mediating role of RSSD in the relationship between frailty and functional recovery at 12 months post‐delirium.

The Case for Stage-Specific Frailty Interventions Spanning Community Aging to Cognitive Impairment

OBJECTIVES To explore factors associated with frailty across the continuum of healthy aging to cognitive impairment (mild cognitive impairment [MCI], mild and moderate Alzheimer disease [AD]). DESIGN Cross-sectional study. SETTING Senior activity centers and the outpatient memory clinic of a tertiary hospital. PARTICIPANTS Community-dwelling and functionally independent adults aged 50 years and older and older adults attending the memory clinic with MCI, and mild and moderate AD diagnoses. METHODS We recruited 299 participants comprising 200 cognitively healthy individuals, 16 with MCI, 68 with mild AD, and 15 with moderate AD. We collected measures of comorbidities, cognitive and functional performance, physical activity level, and anthropometric and nutritional status. Frailty was defined using Buchmann criteria, and sarcopenic obesity (SO) was defined using the Asian Working Group for Sarcopenia criteria and the revised National Cholesterol and Education Panel-obesity definition of waist circumference. Multiple logistic regression was performed to identify factors associated with frailty as a whole group and separately based on cognitive subgroups. RESULTS There were 16.7% of patients who met frailty criteria. Frailty prevalence was lowest in the well elderly (3.5%) and subsequently followed a U-shaped prevalence from MCI to mild and moderate AD, respectively. Specific univariate differences were noted in age, hypertension, ischemic heart disease, depressive symptoms, social differences, and functional scores. Multivariable logistic regression showed age, cognitive status, and SO to be significantly associated with frailty status. Subgroup analysis showed only SO to be significant (odds ratio [OR] 15.55, 95% confidence interval [CI] 1.63-148.42) in well elderly and only cognition to be associated with frailty (OR 0.89, 95% CI 0.80-0.99) among the cognitively impaired. CONCLUSION Our findings lend initial support to the case for stage-specific interventions for physical frailty with the focus on SO in healthy community-dwelling older persons and cognitive-based measures in older adults with cognitive impairment. The accurate clinical phenotyping would then set the stage for future potential investigative therapies along these specific lines, rather than an undifferentiated approach.