Biomedical subjects

N Pendleton

Publications and source records attributed to N Pendleton.

At least 19 recordsLinked to original sources

PubMed2006

Balance marks cognitive changes in old age because it reflects global brain atrophy and cerebro-arterial blood-flow.

In healthy old age biomarkers such as Balance robustly correlate with measures of mental abilities such as scores on tests of intelligence, reaction times and memory. A plausible explanation is that balance reflects general physiological fitness and so also neurophysiological integrity, but direct evidence is lacking. Brain scans measured age-associated loss of brain volume and cerebro-arterial blood flow (CBf) in 69 volunteers aged from 62 to 81 years who also took the Tinetti Balance test battery, 3 tests of fluid intelligence, 3 tests of decision speed and a memory test. Balance, but not atrophy or CBf, predicted intelligence test scores. Balance, atrophy, and CBf all independently predicted speed and memory scores but, after variance in atrophy and CBf had been considered, predictions from Balance were no longer significant. It appears that in these tests Balance marks cognitive performance in old age because it reflects gross age-related neurophysiological changes.

Aged↗

PubMed2006

Influence and interactions of cathepsin D, HLA-DRB1 and APOE on cognitive abilities in an older non-demented population.

Cathepsin D (CTSD), human leukocyte antigen DRB1 (HLA-DRB1) and apolipoprotein E (APOE) have all been associated with cognitive ability in both demented and non-demented individuals. CTSD is a pleiotrophic protein whose functions include the processing of proteins prior to presentation by HLA. Several studies have also reported that a functional exon 2 polymorphism in the CTSD gene interacts with APOEepsilon4 resulting in an increased risk of developing Alzheimer's disease (AD). We have previously reported that the CTSD exon 2 polymorphism regulates fluid intelligence. In this study, we extend this finding to other cognitive domains and investigate interactions with APOE and HLA-DRB1. Using a cohort of 766 non-demented volunteers, we found that the CTSD exon 2 T allele was associated with a decrease in several cognitive domains that comprise processing speed [random letters (RLs) test, P = 0.012; alphabet-coding task (ACT), P = 0.001], spatial recall (SR) (P = 0.016) and an additional test of fluid intelligence (P = 0.010). We also observed that the HLA-DR1 was associated with enhanced cumulative recall ability (P = 0.006), and conversely HLA-DR5 was associated with diminished delayed verbal recall and SR abilities (P = 0.014 and P = 0.003, respectively). When analysed independently, APOEepsilon4 did not influence any cognitive domains. In contrast, CTSD T/APOEepsilon4-positive volunteers scored lower on tests of fluid intelligence (P = 0.015), processing speed (ACT, P = 0.001; RL, P = 0.013) and immediate recall (P = 0.029). Scores were lower for all these tests than when CTSD and APOE were analysed independently. This supports previous findings in AD that have also reported an epistatic interaction. In addition, we found that CTSD T/HLA-DR2-positive volunteers had reduced processing speed (ACT, P = 0.040; RL, P = 0.014) and had significantly lower cumulative and SR abilities (P = 0.003 and P = 0.001, respectively). Biological interaction between these two proteins has previously been shown where HLA-DR2 binds more readily to the myelin basic protein (MBP) compared with other DR antigens, preventing MBP cleavage by CTSD.

Aged↗

PubMed2006

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.

Aged↗

PubMed2006

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.

Adult↗

PubMed2005

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.

Age Factors↗

PubMed2005

Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population.

Dysfunction of the serotonergic pathway disrupts normal cognitive functioning and is believed to be the underlying basis for a variety of psychiatric disorders. Two functional polymorphisms within the serotonin transporter (SLC6A4) gene (promoter 44 bp insertion/deletion (HTTLPR) and an intron two 16 or 17 bp variable number tandem repeat (VNTR2)) have been extensively studied in psychiatric conditions but not in the cognitive functioning of normal individuals. We have investigated these two polymorphisms for association with both the level of cognitive abilities and their decline with age using a cohort consisting of over 750 elderly nondemented individuals with a follow-up of up to 15 years. We found that volunteers homozygous for the VNTR2 12 allele had a faster rate of decline for all cognitive tests. This reached significance for both tests of fluid intelligence (novel problem solving) (AH1 P=0.002, AH2 P=0.014), the test of semantic memory (P=0.010) and general cognitive ability (P=0.006). No association was observed between the HTTLPR polymorphism and the rate of cognitive decline when analysed either independently or in combination with the VNTR2 polymorphism based on their influence on expression in vitro. No associations were observed between the two polymorphisms and the baseline level of cognitive abilities. This is only the second gene that has been reported to regulate the rate of cognitive decline in nondemented individuals and may be a target for the treatment of cognitive impairment in the elderly.

Aged↗

PubMed2003

Cathepsin D exon 2 polymorphism associated with general intelligence in a healthy older population.

General intelligence is a heritable trait that is a risk factor for both the onset of dementia and the rate of cognitive decline in community-dwelling older persons. Previous studies screening for quantitative trait loci (QTLs) that influence general intelligence in healthy individuals have identified four loci, two of which are located within the genes insulin-like growth factor 2 receptor (IGF2R) and the Msx1 homeobox. Here, we report the finding of another QTL associated with general intelligence that is located within exon 2 of the cathepsin D (CTSD) gene. A group of 767 healthy adults with a follow-up period of over 15 years have been analyzed for cross-sectional and longitudinal trends in cognitive change using the Heim intelligence test score (AH4-1). We observed a significant association (P = 0.01) between a functional C > T (Ala > Val) transition within exon 2 of the CTSD gene that increases the secretion of pro-CTSD from the cell, and the AH4-1 score at initial testing on entry to the longitudinal study. Interestingly, CTSD is transported by IGF2R from the trans Golgi network to the lysosome.

Aged↗

PubMed2001

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.

Accidental Falls↗

PubMed2001

Prognostic value of vascularity and vascular endothelial growth factor expression in non-small cell lung cancer.

AIMS: High expression of the angiogenic factor vascular endothelial growth factor (VEGF) in tumours has been found to be associated with poor prognosis in some studies, but not in others. The aims of this study were to determine the prognostic value of VEGF in operable non-small cell lung cancer (NSCLC) and its possible association with vascularity. METHODS: Sections from 81 NSCLC archival specimens were stained with antibodies to von Willebrand factor (vWF) and VEGF. Vascularity was measured by the average density of vWF positive vessels. VEGF expression in tumour cells was assessed by consensus of two independent observers according to three indices, namely: (1) percentage of area stained, (2) intensity of staining, and (3) final score (product of area and intensity). RESULTS: VEGF immunoreactivity was present in all tumours and adjacent normal lung tissue. None of the three VEGF indices was associated with vascularity or the clinical parameters examined. Mean survival times were shorter in patients with high VEGF expression, but the difference was not significant. This applied to the full cohort of patients, or when analysed separately according to tumour type or stage. However, high VEGF expression was associated with poor survival in patients with high vascularity (p = 0.02). VEGF had no discriminant value among patients with low vascularity. Vascularity had no prognostic value, except for late stage patients (UICC stages II and IIIa combined; n = 36), where high vascularity was associated with longer survival (p = 0.01). CONCLUSIONS: VEGF on its own has no prognostic value in NSCLC, but may become a useful indicator when combined with vascularity. VEGF may play a physiological role in the normal lung.

Aged↗

PubMed2000

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.

Accidental Falls↗

PubMed1999

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.

Aged↗

PubMed1999

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.

Aging↗

PubMed1998

Assessment of vascularity in histological sections: effects of methodology and value as an index of angiogenesis in breast tumours.

The aims of this study were to (a) determine how the quantification of blood vessels in histological sections (vascularity) is affected by the methodology used and (b) assess the value of vascularity as an index of angiogenesis by comparing tumour and normal breast tissue. Archival specimens of breast, lung and oral carcinoma, oral dysplasia and normal breast tissue were used to test the effects of the following experimental variables on vascularity: pretreatment of the sections (enzymatic digestion, heating), endothelial markers (von Willebrand factor and CD31 antibodies), method of quantification (highest microvascular density, average microvascular density and microvascular volume) and interobserver variations. All the variables examined significantly affected the estimated vascularity; this depended on the type of tissue and method used. The pretreatment of the sections before staining was the most important variable, altering the vascularity ranking of the tumours. Vascularity in breast tumours was similar to that of the normal breast intralobular stroma, suggesting that an area of high microvascular density in the tumour does not necessarily represent tumour-induced angiogenesis. Contradictory results have been published regarding the value of vascularity as a tumour prognostic factor. Our results suggest that statistically significant differences in vascularity values are most likely to arise from failure to optimize the staining protocol and from the method used to assess vascularity.

Blood Vessels↗

PubMed1998

Heterogeneity in microvascular density in lung tumours: comparison with normal bronchus.

The aim of this study was to test the hypotheses that (a) microvascular density (MVD) measured in histological sections of resected non-small cell lung carcinomas is an index of angiogenesis and (b) the measurement of MVD in a single block is representative of the overall MVD of the tumour. MVD was quantitated in one block per specimen of 60 lung tumours and nine normal lung tissues, and in 47 blocks taken from different regions of four tumours. Blood vessels were stained with antibody to von Willebrand Factor and MVD was quantitated using two methods: average density throughout the section (a-MVD) and density in the most vascularized area or 'hot spot' (h-MVD). Similar h-MVD values were found in tumours and in normal bronchus, whereas a-MVD was greater in the latter (P < 0.01). When 47 blocks from four tumours were analysed, inter-tumour variation was significant (P < 0.001) in spite of significant intra-tumour variation. The highest MVD value was not necessarily found in the periphery of the tumour. The four tumours were ranked into either two or four tiers according to their overall MVD. In 50 random selections of one block per tumour, the correct ranking was achieved in 68-74% of cases with the two-tier ranking and in 6-16% of cases with the four-tier ranking (h-MVD and a-MVD values respectively). These results suggest that elevated MVD values do not necessarily represent angiogenesis in non-small cell lung carcinomas. When only one block per tumour is examined, the chance of obtaining an accurate estimate of the vascularity of that tumour may be lower than 68%.

Adenocarcinoma↗

PubMed1998

Prediction of hemorrhagic blood loss with a genetic algorithm neural network.

There is no established method for accurately predicting how much blood loss has occurred during hemorrhage. In the present study, we examine whether a genetic algorithm neural network (GANN) can predict volume of hemorrhage in an experimental model in rats and we compare its accuracy to stepwise linear regression (SLR). Serial measurements of heart period; diastolic, systolic, and mean blood pressures; hemoglobin; pH; arterial PO2; arterial PCO2; bicarbonate; base deficit; and blood loss as percent of total estimated blood volume were made in 33 male Wistar rats during a stepwise hemorrhage. The GANN and SLR used a randomly assigned training set to predict actual volume of hemorrhage in a test set. Diastolic blood pressure, arterial PO2, and base deficit were selected by the GANN as the optimal predictors set. Root mean square error in prediction of estimated blood volume by GANN was significantly lower than by SLR (2.63%, SD 1.44, and 4.22%, SD 3.48, respectively; P < 0.001). A GANN can predict highly accurately and significantly better than SLR volume of hemorrhage without knowledge of prehemorrhage status, rate of blood loss, or trend in physiological variables.

Algorithms↗

PubMed1998

Evolution of artificial neural network architecture: prediction of depression after mania.

Artificial neural networks (ANNs) are compared to standard statistical methods for outcome prediction in biomedical problems. A general method for using genetic algorithms to "evolve" ANN architecture (EANN) is presented. Accuracy of logistic regression, a fully interconnected ANN, and an EANN for predicting depression after mania are examined. All methods showed very good agreement (training set accuracy, chi-square all p < 0.01). However, significant differences were found for stability (test set accuracy); logistic regression being the most unstable and EANN being significantly more stable than a fully interconnected ANN (McNemar p < 0.01). We conclude that the EANN method enhances ANN stability. This approach may have particular relevance for biomedical prediction problems, such as predicting depression after mania.

Algorithms↗

PubMed1997

Comparison of a genetic algorithm neural network with logistic regression for predicting outcome after surgery for patients with nonsmall cell lung carcinoma.

BACKGROUND: Neural networks have been used to predict outcome in cancer patients. Their accuracy compared with standard statistical methods has not been fully assessed. METHODS: In this study, the authors examined the ability to predict the outcome of surgery in 620 patients with nonsmall cell lung carcinoma (NSCLC) by a genetic algorithm neural network (GANN) using Bayes' theorem compared with logistic regression, and the predictive value of tumor volume measures in addition to standard indices such as histologic type and stage. Predictive methods were compared by examining accuracy of classifying target outcome of patients living or dead at 6, 12, 18, and 24 months after surgery. RESULTS: GANN was a significantly better predictor of outcome than logistic regression at all time points (McNemar, P < 0.01). Measures of tumor volume produced significant improvement in the prediction of 12-, 18-, and 24-month time points with GANN, and at 18- and 24-month time points with logistic regression (Wilcoxon matched pairs signed rank test, P < 0.02). CONCLUSIONS: In this study of surgically treated NSCLC patients, outcome predictions were significantly improved by including measures of tumor volume. For predicting individual patient outcome, GANN was found to be highly accurate and significantly better than logistic regression.

Aged↗

PubMed1997

Relationship between vascularity, age and survival in non-small-cell lung cancer.

Lung tumours in the elderly show reduced growth potential; impaired angiogenesis may contribute to this phenomenon. Recent studies have suggested that the angiogenic potential of a tumour may be inferred by the vascularity measured in histological sections. The purpose of this study has been to determine whether vascularity is related to age, survival or other clinical parameters in resected non-small-cell lung cancer (NSCLC). A group of 88 consecutive patients with a follow-up period of at least 5 years was selected. The group exhibited a wide age range (37-78 years) and similar survival characteristics to those of the general NSCLC population. Tumour sections were stained with a pan-endothelial antibody (vWF) and vascularity was quantitated, without knowledge of the clinical details, by three methods: highest microvascular density; average microvascular density; and average microvascular volume. The results were analysed by non-parametric statistical tests. A correlation was found between all three methods of quantitation. Vascularity was not associated with age, sex, tumour type, stage, volume, size (TNM-T) nodal status (TNM-N) or survival. However, survival time was generally longer for patients with higher vascularity, reaching borderline significance (P = 0.06) for the average microvascular density values. Higher tumour volume (P = 0.02) and stage (P = 0.05) were associated with lower survival times. Using multivariate survival analysis, tumour volume was the only factor related to survival. We conclude that vascularity is not associated with age and has no significant prognostic value in NSCLC.

Adult↗