Predicting cognitive ability in ageing cohorts using Type 2 diabetes genetic risk.

AIMS: To investigate whether there is overlap in the genetic determinants of Type 2 diabetes and cognitive ageing by testing whether a genetic risk score for Type 2 diabetes can predict variation in cognitive function in older people without dementia. METHODS: Type 2 diabetes genetic risk scores were estimated using various single nucleotide polymorphism significance inclusion criteria from an initial genome-wide association study, the largest in Type 2 diabetes to date. Scores were available for 2775-3057 individuals, depending on the cognitive trait. RESULTS: Type 2 diabetes genetic risk was associated with self-reported diabetes mellitus. Across varying single nucleotide polymorphism-inclusion levels, a significant association between Type 2 diabetes genetic risk and change in general cognitive function was found (median r = 0.04); however, this was such that higher Type 2 diabetes genetic risk related to higher cognitive scores. CONCLUSIONS: To investigate more fully the source of the often observed comorbidity between Type 2 diabetes and cognitive impairment, one direction for future research will be to use cognitive ability polygenic risk scores to predict Type 2 diabetes in line with the reverse causation hypothesis that people with lower pre-morbid cognitive ability are more likely to develop Type 2 diabetes.

Clinical correlates of cerebral white matter hyperintensities in cognitively normal older adults.

Many research studies have demonstrated asymptomatic white matter hyperintensities (WMHs) in older adults, which are postulated to be ischemic in origin. We hypothesized that certain clinical predictors, measured in a population of healthy older adults, would have a positive relationship with WMH scoring on magnetic resonance imaging (MRI). As part of a longitudinal study of cognitive aging we have performed MRI on healthy older adults. In a group of 46 volunteers (25 females; median age 73, range 63-84 years), we have calculated of the Hachinski score and Framingham Stroke Risk Profile (FSRP). Volunteers also provided self-reported health information using the Cornell Medical Index (CMI). These were compared against the total Age Related White Matter Changes (ARWMC) score. The mean total ARWMC score was 7.4 + or - 5.27 (+ or - S.D.) and only 3 (6.5%) individuals had no evidence of WMH. Regression analysis of individual variables identified self-report of cardiovascular disease from the CMI, section C as the only significant predictor of ARWMC. A multivariate linear regression model also identified FSRP at 1 year as a second independently significant predictor. The multivariate model accounted for 19% of the variance in total ARWMC score. The only 6.5% of individuals who had no WMH is in keeping with previous studies. The important finding was the positive relationship with self-reported cardiovascular disease, which is a possible biomarker of sub-clinical cerebrovascular disease (CVD).

Genetic associations between cathepsin D exon 2 C-->T polymorphism and Alzheimer's disease, and pathological correlations with genotype.

Genetic variations represent major risk factors for Alzheimer's disease (AD). While familial early onset AD is associated with mutations in the amyloid precursor protein and presenilin genes, only the e4 allele of the apolipoprotein E (APOE) gene has so far been established as a genetic risk factor for late onset familial and sporadic AD. It has been suggested that the C-->T (224Ala-->Val) transition within exon 2 of the cathepsin D gene (CTSD) might represent a risk factor for late onset AD. The objective of this study was to investigate whether possession of the CTSD exon 2 T allele increases the risk of developing AD, and to determine whether this modulates the amyloid pathology of the disease in conjunction with, or independent of, the APOE e4 allele. Blood samples were obtained from 412 patients with possible or probable AD and brain tissues from a further 148 patients with AD confirmed by postmortem examination. CTSD and APOE genotyping were performed by PCR on DNA extracted from blood, or from frontal cortex or cerebellum in the postmortem cases. Pathological measures of amyloid beta protein (Abeta), as plaque Abeta40 and Abeta42(3) load and degree of cerebral amyloid angiopathy were made by image analysis or semiquantitative rating, respectively. CTSD genotype frequencies in AD were not significantly different from those in control subjects, nor did these differ between cases of early or late onset AD or between younger and older controls. There was no gene interaction between the CTSD T and APOE e4 alleles. The amount of plaque Abeta40 was greater in patients carrying the CTSD T allele than in non-carriers, and in patients bearing APOE e4 allele compared with non-carriers. Possession of both these alleles acted synergistically to increase levels of plaque Abeta40, especially in those individuals who were homozygous for the APOE e4 allele. Possession of the CTSD T allele had no effect on plaque Abeta42(3) load or degree of CAA. Possession of the CTSD T allele does not increase the risk of developing AD per se, but has a modulating effect on the pathogenesis of the disorder by increasing, in concert with the APOE e4 allele, the amount of Abeta deposited as senile plaques in the brain in the form of Abeta40.

The apolipoprotein E epsilon4 allele selectively increases the risk of frontotemporal lobar degeneration in males.

OBJECTIVE: To determine whether polymorphic variations in the apolipoprotein E gene (APOE) are associated with increased risk of frontotemporal lobar degeneration (FTLD) when mutation in tau gene is absent. METHODS: The APOE gene was genotyped by polymerase chain reaction from DNA routinely extracted from blood or brain tissues. The APOE epsilon4 allele frequency in 198 patients with FTLD not associated with mutations in tau gene was compared with that of a control group of 756 normal individuals drawn from the same geographical region. Analyses were done according to clinical subtype or sex. RESULTS: The APOE epsilon4 allele frequency (19.4%) was increased (p = 0.01) in FTLD v the whole control group (14.1%), while the APOE epsilon2 allele frequency in FTLD (6.5%) was slightly lower than in controls (8.0%) (NS). The APOE epsilon4 allele frequency in men with FTLD (22.3%) was greater (p = 0.002) than in male controls (12.3%); the frequency in women (16.3%) was similar to that in female controls (14.8%) (NS). The APOE epsilon2 allele frequency in men with FTLD was 4.9% while in male controls it was 9.5% (p = 0.06), but there was no difference in women (7.5% v 7.9%, NS). Neither the APOE epsilon2 nor APOE epsilon4 allele frequency varied significantly between any of the clinical subtypes. CONCLUSIONS: In FTLD not associated with mutations in tau gene, possession of APOE epsilon4 allele in men roughly doubles the chances of developing disease, whereas this has no impact upon disease risk in women.

Relationship between self-reported prevalence of diabetes mellitus using the Cornell Medical Index (CMI) and prevalence determined by glycosylated hemoglobin (HbA(1c)) in an elderly community-dwelling population.

Reports of diabetes mellitus samples in community-dwelling unselected populations suggest a prevalence of 6%. A further 3% of unknown diabetes mellitus subjects are suggested when using formal biochemical methods of diagnosis. In this study, we present the prevalence of diabetes mellitus by self-reports using the CMI and concomitant biochemical detection in 436 community-dwelling older adults who have participated in a 20-year-study of age and cognitive performance in Manchester, UK. Twenty-three of the group reported that they had diagnosed diabetes mellitus, three individuals had a raised HbA(1c) of greater than 7.0% on random testing, but no knowledge of having diabetes mellitus. These individuals were re-contacted and three said they subsequently had a diagnosis of diabetes mellitus made within the two years following the questionnaire. We conclude that in an older population of community-dwelling subjects the numbers of undiagnosed cases of diabetes mellitus is lower than anticipated, based on large unselected population samples. The greater opportunity to interact with health care professionals who may consider screening for diabetes mellitus may explain these findings.

Cortisol kinetics in elderly women with persistently high cortisol concentrations after proximal femur fracture.

OBJECTIVES: Elderly women with proximal femur fracture show abnormal persistence of increased cortisol concentrations, which could contribute to the high morbidity associated with this injury. Two weeks after injury, the authors found substantially increased urinary free cortisol excretion, which usually reflects the integrated concentration of free (bioactive) cortisol in plasma. However, there was a proportionally smaller increase in cortisol production rate. The authors have now tested the hypothesis that this was caused by a decreased metabolic clearance rate (MCR) rather than increased renal clearance, because the latter but not the former would invalidate free cortisol excretion as an index. SETTING: Orthopaedic wards in a teaching hospital. PATIENTS: Thirteen women aged seventy-one to ninety-two years who had sustained a proximal femur fracture approximately two weeks earlier were compared with ten healthy women aged sixty-seven to eighty-three years. These subjects are similar to those in the authors' previous study. MAIN OUTCOME MEASUREMENTS: The authors used single injections of [3H] cortisol to measure its MCR and estimated hepatic blood flow with indocyanine green. RESULTS: The patients with hip fractures had higher plasma cortisol concentrations than did the healthy subjects, as expected. Cortisol MCR was approximately 20 percent lower in the patients, and estimated hepatic blood flow was approximately 35 percent lower in the patients. Analysis of covariance showed that the difference in MCR was the result of the small difference in age between the groups rather than to injury per se. CONCLUSIONS: A lower cortisol MCR in the patients with hip fractures explains the authors' previous results and validates urinary free cortisol excretion as an index. The data suggest a roughly threefold mean increase in plasma cortisol bioactivity two weeks after hip fracture.

Cardiovascular response to graded lower body negative pressure in young and elderly man.

Lower body negative pressure (LBNP) reduces central venous pressure (CVP) and cardiac output. The elderly are reported to have a limited capacity to increase cardiac output by increasing heart rate (HR), are especially dependent on end diastolic volume to maintain stroke volume and therefore should be especially vulnerable to LBNP. The present study compared the effects of LBNP in the young and old. Stroke volume was assessed non-invasively as stroke distance (SD) by aortovelography. Two groups of healthy male volunteers were studied: eight young (29.7 +/- 2.0 years, mean +/- S.E.M.) and nine old (70.1 +/- 0.9 years). LBNP was applied progressively at 17.5, 35 and 50 mmHg in 20 min steps, with measurements taken during each steady state. There were similar, significant, falls in CVP in both groups. SD fell significantly in both groups from respective control values of 24.8 +/- 1.6 and 16.6 +/- 0.9 cm to 12.5 +/- 1.3 and 8.9 +/- 0.4 cm at a LBNP of 50 mmHg. Although SD in the elderly was significantly lower than in the young, the LBNP-induced changes were not different between groups. Both groups produced similar significant increases in vascular resistance, HR, plasma vasopressin (AVP) and noradrenaline. Mean arterial blood pressure (MBP) and plasma adrenaline did not change significantly. Therefore healthy old men respond to LBNP in a similar manner to the young, although MBP and SD are regulated around different baselines in the two groups.

Clinical features of dementia associated with apolipoprotein epsilon4: discrimination with a neural network genetic algorithm.

BACKGROUND: It is unclear whether the APOE epsilon4 allele is associated with distinct clinical features in dementia. METHOD: 100 cases meeting ICD criteria for dementia were interviewed using standardized instruments and genotyped for APOE. The presence of the epsilon4 allele was used by a genetic algorithm neural network (GANN) to discriminate symptoms and signs. RESULTS: The GANN selected six features: gender, systolic blood pressure, absence of ankle tendon reflexes, history of weight loss, history of falls, and interviewer observed lability of mood. Using these features, a neural network discriminated cases according to epsilon4 highly accurately (area under receiver operating characteristic=0.83, sensitivity=0.78, specificity=0.78). CONCLUSIONS: A GANN is able to discriminate a clinically distinct group of features among dementia patients who express the epsilon4 allele.

Hypocapnia and its relation to fear of falling.

OBJECTIVE: To determine if hypocapnia occurs in patients with fear of falling and to explore potential causes of hypocapnia. DESIGN: Observational study in patients who fall with and without fear of falling. SETTING: Rehabilitation wards of an elderly care unit. PATIENTS: Consecutive fallers with (n = 20) and without (n = 10) fear of falling. MAIN OUTCOME MEASURES: End-tidal CO2 (PETCO2) and respiratory rate (RR) responses were measured during sustained isometric muscle contraction (SIMC) (40% of maximum voluntary contraction of quadriceps for 2 min) and during a 5-meter walk. Falls efficacy scale (FES) and Hospital anxiety and depression scale (HAD). RESULTS: Patients with fear of falling had significantly higher FES and HAD scores (p < .01). During SIMC, baseline and nadir PETCO2 levels were significantly lower in patients with a fear of falling (p < .01). During the 5-meter walk, PETCO2 was lower at baseline, at nadir, and at the end of the walk in the fear of falling group than in controls (p < .01). RR was higher at nadir and end of the walk in the fear of falling group than in controls (p < .02). CONCLUSIONS: Hypocapnia may occur in patients with a fear of falling during SIMC and walking. Anxiety seems to be the main cause, but muscle weakness may contribute. Breathing or relaxation techniques and reconditioning may have a role in treating fear of falling in the rehabilitation setting.

New approach to risk determination: development of risk profile for new falls among community-dwelling older people by use of a Genetic Algorithm Neural Network (GANN).

BACKGROUND: Falls risk in older people is multifactorial and complex. There is uncertainty about the importance of specific risk factors. Genetic algorithm neural networks (GANNs) can examine all available data and select the best nonlinear combination of variables for predicting falls. The aim of this work was to develop a risk profile for operationally defined new falls in a random sample of older people by use of a GANN approach. METHODS: A random sample of 1042 community-dwelling people aged 65 and older, living in Nottingham, England, were interviewed at baseline (1985) and survivors reinterviewed at a 4-year follow-up (n = 690). The at-risk group (n = 435) was defined as those survivors who had not fallen in the year before the baseline interview. A GANN was used to examine all available attributes and, from these, to select the best nonlinear combination of variables that predicted those people who fell 4 years later. RESULTS: The GANN selected a combination of 16 from a potential 253 variables and correctly predicted 35/114 new fallers (sensitivity = 31%; positive predictive value = 57%) and 295/321 nonfallers (specificity = 92%; negative predictive value = 79%); total correct = 76%. The variables selected by the GANN related to personal health, opportunity, and personal circumstances. CONCLUSIONS: This study demonstrates the capacity of GANNs to examine all available data and then to identify the best 16 variables for predicting falls. The risk profile complements risk factors in the current literature identified by use of standard and conventional statistical methods. Additional data about environmental factors might enhance the sensitivity of the GANN approach and help identify those older people who are at risk of falling.

Disrupted cortisol-ACTH relationships in elderly women given corticotrophin-releasing hormone two weeks after proximal femur fracture.

OBJECTIVE: In elderly women with hip fractures plasma cortisol is persistently higher than in healthy elderly women, possibly causing undesirable catabolic effects. A lack of corresponding changes in plasma ACTH or in the cortisol response to exogenous ACTH has prompted us to study cortisol-ACTH relationships after giving corticotrophin-releasing hormone (CRH) to such subjects. SUBJECTS: Seventeen women aged 70-90 years who had sustained a hip fracture about two weeks previously were compared with 19 healthy women aged 68-85 years. MEASUREMENTS: 100 microg CRH was injected into each subject and ACTH and cortisol concentrations were measured at intervals for 90 minutes beforehand and 180 minutes afterwards. The concentrations of vasopressin and various cytokines and related peptides were also measured during the baseline period. RESULTS: Under baseline conditions plasma cortisol was higher and plasma ACTH lower in the injured patients than in the healthy subjects. The patients showed smaller incremental ACTH and cortisol responses to CRF but because of the higher baseline value the peak cortisol concentration was enhanced. A strong correlation between the cortisol and ACTH responses in the healthy subjects was completely lost in the patients and the slope of the ACTH-cortisol dose-response relationship varied greatly between individuals, with no overall increase. The concentrations of vasopressin, interleukin-1 receptor antagonist and soluble tumour necrosis factor receptors were higher in the patients but did not correlate with the responses to CRH. CONCLUSIONS: The results are not consistent with increased sensitivity to ACTH and suggest an independent stimulus to the adrenals of hip-fracture patients. Its identity is unknown as the non-ACTH stimuli proposed hitherto are reported to enhance sensitivity to ACTH.

The effect of aging on skeletal muscle capillarization in a murine model.

Capillarization of skeletal muscle has been reported to be both maintained and reduced with advancing age. This conflict may represent methodological differences between biopsy studies. We have examined capillarization throughout two muscles, soleus and extensor digitorum longus (EDL), from a well-established colony of aging mice, and related this to fiber number (C/F ratio) and type. Labeling of muscle capillaries was performed with the biotinylated Griffonia (Bandeiraea) simplicifolia lectin (GSL 1) using immunochemistry. The results showed a significant increase in the C/F ratio in the aged mice when compared with the younger (6-month mice soleus = 1.296, 95% CI 1.226-1.366 vs 28-month mice soleus = 1.530, 95% CI 1.488-1.572, p <.001; 6-month mice EDL = 0.881, 95% CI 0.751-1.011 vs 28-month mice EDL = 1.124, 95% CI 1.028-1.220, p = .017). These differences could not be accounted for by changes in fiber type but may reflect loss of fibers. Alternatively, there may be increased angiogenic drive or a failure of downregulation of angiogenesis.

A study of infection in elderly nursing/residential home and community-based residents.

It is commonly believed that patients admitted to hospital from nursing homes/residential homes (NHRH) with infections are less likely to respond to treatment and have a higher fatality rate than counterparts admitted from their own homes ('the Community'). It is also believed that NHRH's harbour a reservoir of unusual and resistant organisms. These preconceptions may influence how these patients are managed. A database of 10593 sequential admissions to a Geriatric Medical unit over a three-year period was used to identify NHRH and community populations with a principal diagnosis of infection. They were investigated using the Department of Microbiology's database. The admission rate in the NHRH group was twice that of the community group. There were no significant differences in length of stay (LOS) [16 +/- 2 vs 17 +/- 2 days (s.e.m.)], or mean survival time (ST)(61 days (37-84) vs 48 days (25-72): 95% confidence intervals) between the two groups. Subgroups of the NHRH group did have significantly different survival times. Fatality rate was not significantly different between the NHRH (40%) or Community (35%) groups. Both the NHRH and community group underwent very similar levels of investigation (189 vs 200 investigations performed). The types and frequencies of pathogen seen in the two groups were very similar.

Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response.

The effects of intrinsic aging on the cutaneous wound healing process are profound, and the resulting acute and chronic wound morbidity imposes a substantial burden on health services. We have investigated the effects of topical estrogen on cutaneous wound healing in healthy elderly men and women, and related these effects to the inflammatory response and local elastase levels, an enzyme known to be up-regulated in impaired wound healing states. Eighteen health status-defined females (mean age, 74.4 years) and eighteen males (mean age, 70.7 years) were randomized in a double-blind study to either active estrogen patch or identical placebo patch attached for 24 hours to the upper inner arm, through which two 4-mm punch biopsies were made. The wounds were excised at either day 7 or day 80 post-wounding. Compared to placebo, estrogen treatment increased the extent of wound healing in both males and females with a decrease in wound size at day 7, increased collagen levels at both days 7 and 80, and increased day 7 fibronectin levels. In addition, estrogen enhanced the strength of day 80 wounds. Estrogen treatment was associated with a decrease in wound elastase levels secondary to reduced neutrophil numbers, and decreased fibronectin degradation. In vitro studies using isolated human neutrophils indicate that one mechanism underlying the altered inflammatory response involves both a direct inhibition of neutrophil chemotaxis by estrogen and an altered expression of neutrophil adhesion molecules. These data demonstrate that delays in wound healing in the elderly can be significantly diminished by topical estrogen in both male and female subjects.

Difficulties in measuring the effect of testosterone replacement therapy on muscle function in older men.

Muscle wasting in older men may be related to androgen deficiency. We have assessed the effect of testosterone replacement therapy on muscle function in the upper and lower limbs of older (age > 60 years) men with blood testosterone levels < 14 nmol/L. Subjects (n = 7 per group) received testosterone enanthate 200 mg i.m. or placebo every 2 weeks in a double blind study over a 12-week period and underwent muscle testing every 4 weeks. A significant increase in blood levels of testosterone and a reduction in levels of sex hormone binding globulin occurred in the treatment group. Total body mass, haemoglobin and packed cell volume also increased significantly (p < 0.05). No improvements in handgrip strength, isometric strength of knee flexors and extensors or leg extensor power were seen in either group. Wide variability in all measures of muscle function were observed in these elderly men suggesting that very large study groups would be required to determine potential treatment benefits on muscle function.

Opinions of elderly people on treatment for end-stage renal disease.

BACKGROUND: As more people survive into old age, a greater number are becoming eligible for dialysis treatment for end-stage renal failure. In the UK the elderly have previously been excluded from treatment programmes, and continuing financial constraints are unlikely to improve this situation. There are few data on the views of elderly subjects on renal replacement treatment. We have, therefore, explored the views of elderly subjects in this study. METHODS: 50 subjects were selected from hospital geriatric wards and nursing homes. A short clinical vignette about a 75-year-old patient with renal failure was presented, and the subjects were asked to give their opinion on choices made by the patient to different treatment options. The subjects were then asked what choice they would make if in the same situation. They were asked what level of symptoms they would tolerate and for their views on cost and treatment allocation. Important contributors to quality of life were also determined for each subject using visual analogue scales. RESULTS: 84% of the subjects would choose dialysis treatment, and 78% of all elderly would attend hospital as necessary, if their symptoms could be relieved. 54% of the in-patient elderly and 83.3% of nursing home elderly even when physically disabled and living in a nursing home would want dialysis for end-stage renal failure. 74% of all elderly preferred to have home dialysis treatment. Only 36% of the subjects thought cost was important when allocating dialysis to the elderly. Being independent and free from major symptoms was regarded as important for a good quality of life. CONCLUSIONS: In this survey, elderly subjects wanted dialysis treatment. Neither age nor cost were considered important determinants for resource allocation. Symptom relief and maintaining independence were considered the main goals of treatment.

Serum transferrin receptor assay in iron deficiency anaemia and anaemia of chronic disease in the elderly.

The most common cause of anaemia in the elderly is anaemia of chronic disease (ACD). However, iron deficiency anaemia (IDA) may coexist, and can be difficult to diagnose. The serum transferrin receptor (sTfR) blood test may be a better indicator of iron status as it is not affected by inflammation nor by advancing age. We evaluated it in four groups (10 males, 10 females each): 'young' controls, 'elderly' controls, IDA and ACD. All patients in the IDA group had elevated sTfR levels (mean +/- SD 65.2 +/- 17.7 nmol/l). All 'young' controls had normal sTfR (22.3 +/- 7.3 nmol/l) and ferritin levels (92.7 +/- 61.1 micrograms/l). Although all subjects in the 'elderly' controls and ACD group had normal, and raised or normal serum ferritin, respectively (88 +/- 62.3 micrograms/l; 631.2 +/- 509.5 micrograms/l), three (15%) 'elderly' controls and four (20%) ACD patients had raised sTfR levels, suggesting depleted iron stores. Bone-marrow aspirates were available in 3/4 ACD patients with raised sTfR. Haemosiderin was absent in two. The sTfR blood test is comparable to serum ferritin in diagnosing IDA in the elderly but also seems capable of differentiating ACD from IDA. Its potential as a non-invasive test of iron status, especially in elderly anaemic patients, deserves further evaluation.