Alan J. Sinclair

Cytomegalovirus Seropositivity Drives the CD8 T Cell Repertoire Toward Greater Clonality in Healthy Elderly Individuals

The deterioration in immune function with aging is thought to make a major contribution to the increased morbidity and mortality from infectious disease in old age. One aspect of immune senescence is the reduction in CD8 T cell repertoire as due to the accumulation of oligoclonal, memory T cells and a reduction in the naive T cell pool. CD8 T cell clonal expansions accumulate with age, but their antigenic specificity remains unknown. In this study, we show that in elderly individuals seropositivity for human CMV leads to the development of oligoclonal populations of CMV-specific CTL that can constitute up to one-quarter of the total CD8 T cell population. Furthermore, CMV-specific CTL have a highly polarized membrane phenotype that is typical of effector memory cells (CD28−, CD57+, CCR7−). TCR analyses show that CMV-specific CTL have highly restricted clonality with greater restriction in the larger expansions. Clonal analysis of the total CD8 T cell repertoire was compared between CMV-seropositive and CMV-seronegative donors. Thirty-three percent more clonal expansions were observed in CMV-seropositive donors in comparison with seronegative individuals. These data implicate CMV as a major factor in driving oligoclonal expansions in old age. Such a dramatic accumulation of virus-specific effector CTL might impair the ability to respond to heterologous infection and may underlie the negative influence of CMV seropositivity on survival in the very elderly.

Searching for an Operational Definition of Frailty: A Delphi Method Based Consensus Statement. The Frailty Operative Definition-Consensus Conference Project

BACKGROUND There is no consensus regarding the definition of frailty for clinical uses. METHODS A modified Delphi process was used to attempt to achieve consensus definition. Experts were selected from different fields and organized into five Focus Groups. A questionnaire was developed and sent to experts in the area of frailty. Responses and comments were analyzed using a pre-established strategy. Statements with an agreement more than or equal to 80% were accepted. RESULTS Overall, 44% of the statements regarding the concept of frailty and 18% of the statements regarding diagnostic criteria were accepted. There was consensus on the value of screening for frailty and about the identification of six domains of frailty for inclusion in a clinical definition, but no agreement was reached concerning a specific set of clinical/laboratory biomarkers useful for diagnosis. CONCLUSIONS There is agreement on the usefulness of defining frailty in clinical settings as well as on its main dimensions. However, additional research is needed before an operative definition of frailty can be established.

Cognitive dysfunction in older subjects with diabetes mellitus: impact on diabetes self-management and use of care services

OBJECTIVE To determine whether cognitive impairment is associated with changes in self-care behaviour and use of health and social services in older subjects with diabetes mellitus. RESEARCH DESIGN AND METHODS This was a community based, case-control study of subjects registered with general practices participating in the All Wales Research into Elderly (AWARE) Diabetes Study. The 396 patients aged 65 years or older with known diabetes mellitus were compared with 393 age- and sex-matched, non-diabetic controls. Adjusted odds ratio estimates of normal performance on Mini-Mental State Examination (MMSE) and Clock Drawing Test (numbers and hands) were determined. Information on self-care behaviours and use of services was obtained. RESULTS A total of 283 (71%) diabetic subjects scored 24 or more on MMSE, compared with 323 (88%) of controls (OR 0.54, P<0.0005). The mean (S.D.) scores were 24.5 (5.1) and 25.7 (4.3), respectively (difference between means 1.22; 95% CI 0.56, 1.88; P<0. 001). Clock testing demonstrated that 257 (65%) and 286 (72%) diabetic subjects correctly placed the numbers and hands, respectively, compared with 299 (76%) and 329 (84%) of controls (OR 0.59, P<0.001 and P<0.52, P<0.0005, respectively). Both test scores declined with increasing age, earlier school leaving age and deteriorating visual acuity. Of other variables examined, only need for oral hypoglycaemic drugs or insulin, history of stroke, dementia or Parkinsons disease and symptoms of autonomic neuropathy significantly impaired one or more cognitive test scores. The odds ratios (95% CI) for normal cognitive test results in subjects with diabetes after adjusting for all significant variables was 0.74 (0. 56, 0.97), P=0.029 for MMSE scores and 0.63 (0.44, 0.93), P=0.019, and 0.58 (0.38, 0.89), P=0.013, for the numbers and hands parts of the clock test, respectively. In comparison with diabetic subjects with no evidence of cognitive impairment, diabetic subjects with an MMSE score <23 were significantly less likely to be involved in diabetes self-care (P<0.001) and diabetes monitoring (P<0.001). A low MMSE score was also significantly associated with higher hospitalisation in the previous year (P=0.001), reduced ADL (activities of daily living) ability (P<0.001) and increased need for assistance in personal care (P=0.001). CONCLUSIONS Elderly subjects with predominantly Type 2 diabetes mellitus display significant excess of cognitive dysfunction, associated with poorer ability in diabetes self-care and greater dependency. Routine screening of cognition in older subjects with diabetes is recommended.

Effects of Different Exercise Interventions on Risk of Falls, Gait Ability, and Balance in Physically Frail Older Adults: A Systematic Review

The aim of this review was to recommend training strategies that improve the functional capacity in physically frail older adults based on scientific literature, focusing specially in supervised exercise programs that improved muscle strength, fall risk, balance, and gait ability. Scielo, Science Citation Index, MEDLINE, Scopus, Sport Discus, and ScienceDirect databases were searched from 1990 to 2012. Studies must have mentioned the effects of exercise training on at least one of the following four parameters: Incidence of falls, gait, balance, and lower-body strength. Twenty studies that investigated the effects of multi-component exercise training (10), resistance training (6), endurance training (1), and balance training (3) were included in the present revision. Ten trials investigated the effects of exercise on the incidence of falls in elderly with physical frailty. Seven of them have found a fewer falls incidence after physical training when compared with the control group. Eleven trials investigated the effects of exercise intervention on the gait ability. Six of them showed enhancements in the gait ability. Ten trials investigated the effects of exercise intervention on the balance performance and seven of them demonstrated enhanced balance. Thirteen trials investigated the effects of exercise intervention on the muscle strength and nine of them showed increases in the muscle strength. The multi-component exercise intervention composed by strength, endurance and balance training seems to be the best strategy to improve rate of falls, gait ability, balance, and strength performance in physically frail older adults.

European Diabetes Working Party for Older People 2011 clinical guidelines for type 2 diabetes mellitus. Executive summary.

AIM The Clinical Guidelines provide an opportunity to summarise the interpretation of relevant clinical trial evidence for older people with diabetes. They are intended to support clinical decisions in older people with diabetes and the primary focus is enhancing high quality diabetes care by the use of best available evidence. METHODS The principles used for developing the recommendations are drawn from the Scottish Intercollegiate Guidelines Network (SIGN) based in Edinburgh, Scotland. Using SIGN 50, the Guidelines developers handbook, each reviewer evaluated relevant and appropriate studies which have attempted to answer key clinical questions identified by the Working Party. Searches were generally limited to English language citations over the previous 15 years but the wide experience and multinational nature of the Working party ensured that citations in Italian, French Spanish, and German were considered if relevant. All relevant published articles were identified from the following databases: Embase, Medline/PubMed, Cochrane Trials Register, Cinahl, and Science Citation. Hand searching of 13 key major peer-reviewed journals was undertaken by two reviewers and included the Lancet, Diabetes, Diabetologia, Diabetes Care, Diabetes and Metabolism, British Medical Journal, New England Journal of Medicine, and the Journal of the American Medical Association. RESULTS Key evidenced-based recommendations were made in 18 clinical domains of interest and Good Clinical Practice points identified. A glucose-lowering algorithm has been provided for frail older patients with diabetes. CONCLUSION We have provided an up-to-date evidenced-based approach to practical clinical decision-making for older adults with type 2 diabetes of 70 years and over. We have included a user-friendly set of recommendations to aid clinical decision-making in primary, community-based and secondary care settings.

Frailty, Sarcopenia and Diabetes

It is estimated that 26.9% of persons 65 years and older in the United States have diabetes mellitus (www.cdc.gov/diabetes/pubs/ estimates11.htm).1 A systematic review has shown that persons with diabetes are at increased risk of mobility disability and disability in instrumental activities of daily living and activities of daily living.2 Frailty has been defined as a predisability state, which increases the vulnerability of a person to have a poorer outcome (eg, disability, hospitalization, nursing home placement, or death) when exposed to a stressor.3,4 The major cause of frailty is sarcopenia. Modern definitions have redefined sarcopenia as lacking muscle strength, as measured by gait speed or grip strength, in the presence of a low muscle mass.5e8 In this review, we explore the relationship of frailty and sarcopenia to diabetes mellitus.

Diabetes is associated with a slower rate of cognitive decline in Alzheimer disease

Background: Previous epidemiologic studies indicate that diabetes mellitus (DM) is associated with cognitive decline and an increased risk of developing Alzheimer disease (AD) in people who do not have dementia. However, little is known about the effect of DM on the rate of cognitive decline in established AD. Our objective was to determine whether DM influences the rate of cognitive decline in patients with AD. Methods: A total of 608 patients with a probable diagnosis of AD and a Mini-Mental State Examination (MMSE) score between 10 and 26 were enrolled in a prospective multicenter study. Participants were followed up to 52 (mean 26) months. DM was assessed at baseline (history of DM or antidiabetic medication use). Cognitive function was assessed twice yearly with the MMSE. Results: Sixty-three participants (10.4%) had DM at baseline. In a mixed model adjusted for sex, age, educational level, dementia severity, cholinesterase inhibitor use, and vascular factors (hypertension, atrial fibrillation, coronary heart disease, and hypercholesterolemia), there were no differences between the groups in MMSE baseline scores (−0.75, p = 0.20), but cognitive decline was slower in the group with DM (0.38, p = 0.01). Conclusions: In a cohort of community-dwelling patients with Alzheimer disease (AD), the presence of diabetes mellitus (DM) was associated with a lower rate of cognitive decline. Future studies will need to address the potential impact of DM in the cerebral aging process and to assess the neuropathologic variations in patients with AD with DM.

Observations of diabetes care in long-term institutional settings with measures of cognitive function and dependency

OBJECTIVE To document the prevalence of known diabetes and quantity of diabetes care delivered in long-term institutional settings in South Glamorgan, Wales; to measure physical and mental performance of diabetic residents; and to ascertain the level of basic diabetes knowledge of both staff and diabetic residents. RESEARCH DESIGN AND METHODS A postal questionnaire survey was sent to 31 nursing or dual registered homes and 88 residential homes in South Wales to determine the prevalence of known diabetes. Medical examination and a semistructured interview of 109 diabetic and 106 age- and sex-matched nondiabetic residents was followed by assessment of dependency (Barthel Activities of Daily Living Scale [15]; Behavioral Rating Scale [16]) and cognitive performance (Mini-Mental State Exam [12]). RESULTS The prevalence of known diabetes was 7.2%. Forty percent of diabetic residents were taking long-acting sulfonylureas. Only half of the residents in both homes had regular blood glucose monitoring. Less than 1 in 10 diabetic residents were being followed in a hospital-based diabetic clinic. Diabetic residents had had more hospital admissions in the preceding year than nondiabetic control subjects, and their length of stay was double that of nondiabetic control subjects (P < 0.05). Health professional input was fragmented, with involvement of community nurses and dietitians being rare. Diabetic residents had significantly higher levels of arterial disease (P < 0.05), foot ulceration (P < 0.01), and dementia (P < 0.01), and more severe cognitive impairment and higher levels of dependency (P < 0.01). Knowledge of diabetes was poor among both diabetic and nondiabetic residents and care staff. CONCLUSIONS There is an important need for a reappraisal of diabetes care in institutional settings.

Diabetes in older people: new insights and remaining challenges

Diabetes in ageing communities imposes a substantial personal and public health burden by virtue of its high prevalence, its capacity to cause disabling vascular complications, the emergence of new non-vascular complications, and the effects of frailty. In this Review, we examine the current state of knowledge about diabetes in older people (aged ≥ 75 years) and discuss how recognition of the effect of frailty and disability is beginning to lead to new management approaches. A multidimensional and multidisciplinary assessment process is essential to obtain information on medical, psychosocial, and functional capabilities, and also on how impairments of these functions could limit activities. Major aims of diabetes care include maintenance of independence, functional status, and quality of life by reduction of symptom and medicine burden, and active identification of risks. Linking of therapeutic targets to individual functional status is mandatory and very tight glucose control is often not necessary. Hypoglycaemia remains an important avoidable iatrogenic event. Quality diabetes care in older people remains an important challenge for health professionals.

Glutathione: in sickness and in health

There is increasing evidence that free radical damage may be an important cause of some of the adverse effects of disease and advancing age. Much of the clinical evidence to support this hypothesis is based on the protective effect sometimes observed in those on diets high in antioxidants and those given antioxidants therapeutically. Further support would be obtained if plasma markers for oxidative damage such as lipid peroxidation products (lipid hydroperoxide [LHP]) were raised and antioxidants such as glutathione were low in the old and the sick, particularly in those who are acutely and severely ill. We have therefore measured plasma glutathione and LHP in healthy young individuals, healthy older individuals, and two groups of elderly patients, one with chronic ill-health attending outpatients and one acutely ill and in hospital. We studied 66 young healthy volunteers (mean 24· 5 [SD 4· 7] years) and 58 community-based healthy elderly individuals (70· 7 [4· 8] years). Health was defined as an absence of major medical or surgical illness in the previous 5 years, no hospital admissions, no current medication, and a subjective perception of good health. We also studied 49 patients attending general medical clinics (75· 7 [8· 3] years) with a variety of chronic illnesses including ischaemic heart disease, arthritis, diabetes, and hypertension. Finally, 47 hospitalised elderly patients (77· 2 [8· 6] years) were studied during the course of an acute illness within the first week of admission. Non-fasting venous blood was sampled into standard edetic acid (glutathione) and lithium heparin (LHP) tubes. Samples were all taken by one person (SN) and care was taken to minimise haemolysis. They were centrifuged immediately at 3500 rpm, 4oC for 15 min, and plasma stored at -80oC until analysis. Plasma for glutathione was pre-treated with 30% perchloric acid to stabilise thiol groups. Total plasma glutathione was determined by enzyme-rate assay and plasma LHP by ferrous oxidation of xylenol orange. A sample size of at least 47 in each group was needed to detect a 20% change in plasma glutathione with 80% power at the 95% confidence limit. Statistical difference between groups was determined by ANOVA and the level of significance taken as p<0· 05. The results are presented in the figure. The plasma glutathione in young healthy adults was 0· 54 (SE 0· 02) μmol/L. In the healthy elderly glutathione was significantly lower (0· 29 [0· 01] μmol/L, p<0· 0001). The age-adjusted values for elderly outpatients were significantly lower than in the healthy elderly (0· 24 [0· 01] μmol/L, p<0· 0001) and values for elderly inpatients were lower than for elderly outpatients (0· 17 [0· 01] μmol/L, p<0· 01). The marker for oxidative damage, LHP, was low in the healthy young adults (2· 14 [0· 17] μmol/L) and higher in the healthy elderly (3· 14 [0· 20] μmol/L, p<0· 01). It was higher in the sick elderly (8· 51 [0· 66] and 8· 84 [0· 63] μmol/L in outpatients and inpatients, respectively [p<0· 0001 compared with healthy elderly]).