Relationships between the results of anorectal investigations and symptom severity in patients with faecal incontinence.

PURPOSE: Anorectal dysfunction is the focus of diagnostic investigations for faecal incontinence. However, severity of incontinence and anorectal investigation results can be discordant. The aim of this study was to define the relationships between anorectal investigation results and incontinence severity to determine which measures, if any, were predictive of incontinence severity. METHODS: Patients presenting for investigation of faecal incontinence completed a symptom questionnaire, anorectal manometry, rectal sensation, pudendal nerve terminal motor latency, and endoanal ultrasound. Bivariate analyses were conducted between the Jorge-Wexner score and investigation results. Subgroup analyses were performed for gender and symptom subtypes (urge, passive, mixed). A multiple regression analysis was performed. RESULTS: Five hundred and thirty-eight patients were included. There were weak correlations between the Jorge-Wexner score and maximal squeeze pressure [r = - 0.24, 95%CI(- 0.31, - 0.16), p < 0.001], and resting pressure [r = - 0.18, (95%CI(- 0.26, - 0.10), p < 0.001]. In men only, there were significant associations between the Jorge-Wexner score and endoanal sonography [IAS defects: t(113) = - 2.26, p = 0.03, d = 0.58, 95%CI(- 4.38, - 0.29)] and rectal sensation (MTV: rs = - 0.24, 95%CI(- 0.41, - 0.06), p = 0.01). No substantial differences were observed in the urge/passive/mixed subgroup analyses. Multiple regression analysis included three variables: age (ß = 0.02, p = 0.17), maximal resting pressure (ß = - 0.01, p = 0.28), and maximal squeeze pressure (ß = - 0.01, p < 0.01). The variance in the Jorge-Wexner score accounted for by this model was < 10%, (R2 = 0.07, p = < 0.01, adjusted R2 = 0.06). CONCLUSION: Anorectal investigations cannot predict the severity of faecal incontinence. This may be due to limitations of diagnostic modalities, the heterogeneity of anorectal dysfunction in these patients, or contributing factors which are extrinsic to the anorectum.

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).

Unhappiness, health and cognitive ability in old age.

BACKGROUND: To test whether scores on depression inventories on entry to a longitudinal study predict mental ability over the next 4-16 years. METHOD: Associations between scores on the Beck Depression Inventory and on tests of intelligence, vocabulary and memory were analysed in 5070 volunteers aged 49-93 years after differences in prescribed drug consumption, death and drop-out, sex, socio-economic advantage and recruitment cohort effects had also been considered. RESULTS: On all cognitive tasks Beck scores on entry, even in the range 0-7 indicating differences in above average contentment, affected overall levels of cognitive performance but not rates of age-related cognitive decline suggesting effects of differences in life satisfaction rather than in depression. CONCLUSIONS: A new finding is that, in old age, increments in life satisfaction are associated with better cognitive performance. Implications for interpreting associations between depression inventory scores and cognitive performance in elderly samples are discussed.

Brain-derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly.

A functional brain-derived neurotrophic factor (BDNF) gene polymorphism (Val66Met) that alters activity-dependent secretion has previously been reported to influence cognitive functioning. A large proportion of these reports suggest that the Met allele, which results in reduced secretion of BDNF, impairs long-term memory as a direct consequence of its influence on hippocampal function but has little influence on working memory. In contrast, other studies have found that the Met allele can also play a protective role in certain neurological conditions and is associated with improved non-verbal reasoning skills in the elderly suggesting effects that appear disease, domain and age specific. We have investigated six haplotype-tagging single nucleotide polymorphisms (SNPs) using a cohort of 722 elderly individuals who have completed cognitive tests that measured the domains of fluid intelligence, processing speed and memory. We found that the presence of the Met allele reduced cognitive performance on all cognitive tests. This reached nominal significance for tests of processing speed (P = 0.001), delayed recall (P = 0.037) and general intelligence (g) (P = 0.008). No association was observed between cognitive tests and any other SNPs once the Val66Met was adjusted for. Our results support initial findings that the Met allele is associated with reduced cognitive functioning. We found no evidence that the Met allele plays a protective role in older non-demented individuals. Magnetic resonance imaging data collected from a subgroup of 61 volunteers showed that the left and right hippocampus were 5.0% and 3.9% smaller, respectively, in those possessing the Met allele, although only a non-significant trend was observed.

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.

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.

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.

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.

Sentinel node biopsy for squamous-cell carcinoma of the anus and anal margin.

PURPOSE: The majority of anal tumors are squamous-cell carcinomas. These may be tumors of the anal canal or margin. They are best treated by combination of chemotherapy and radiotherapy. T1 and T2 tumors in this regime do not receive radiotherapy to the inguinal regions despite approximately 5 to 10 percent incidence of inguinal lymph node involvement. If the nodal status of the inguinal region could be accurately assessed, then a more tailored radiotherapy regime may be given. This article describes a novel method of assessment of the status of the inguinal lymph nodes in patients. METHODS: Patients with anal squamous-cell carcinoma had four injections of 0.2 ml of antimony sulfide (30 MBq) around the tumor. Under a gamma camera, a distant high-intensity signal was located, and this point was marked on the overlying skin using an indelible ink pen. In the operating theater, patent blue dye was injected all around the tumor. The localized lymph node was removed and sent for histopathology. RESULTS: This procedure was performed on 12 patients. The sentinel node was localized to the inguinal region and removed in eight of these patients. In two patients, metastatic squamous-cell carcinoma was identified histologically in the sentinel node. CONCLUSION: We advocate that this as a safe technique for detecting metastatic disease in the inguinal nodes in patients with anal squamous-cell carcinoma.

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.

Individual inconsistency across measures of inhibition: an investigation of the construct validity of inhibition in older adults.

Inhibition is a central construct to the frontal lobe theory of ageing, yet its construct validity remains unproven. Furthermore, age effects on measures of inhibition are often reported without adequate control for the effects of global slowing on performance. We investigated inhibitory function in older adults in two experiments. In Experiment 1, 49 people with ages between 59 and 86 (mean=70 years 9 months S.D.=7.54) completed four analogues of the Stroop interference paradigm. To control for global slowing and to enable comparisons across all measures, we used a random effects model based on log-transformed response times. Age did not contribute significantly to the model and the estimated correlation between tasks was not significant. In Experiment 2, 33 people with ages between 62 and 86 (mean=73 years 4 months, S.D.=6.57) were compared on two measures of Stroop-like interference which were very similar in surface task demands. Age did not contribute significantly to the model but the estimated correlation between tasks was robust (r=0.714). We conclude that age may make little contribution to inhibitory function independently of other factors such as speed and intelligence. Second, that the level of individual consistency in the performance of measures of inhibition will depend on the similarity of the tasks used.

Identifying and separating the effects of practice and of cognitive ageing during a large longitudinal study of elderly community residents.

In protracted longitudinal studies of cognitive changes in old age volunteers must be repeatedly tested. Even with intervals of several years between assessment, this raises the possibility that improvements due to practice mask other changes. This problem is much more acute in brief studies of cognitive changes associated with progressive pathologies such as Alzheimer's disease or the effects of clinical interventions. Both types of study also encounter problems of selective dropout of frail and less able individuals leaving relatively 'elite' survivors. An analysis of data from repeated testing at 2-3 years intervals on the AH4 (1) intelligence test is presented to illustrate how a random effects model can be used to identify and disassociate age-related changes and practice effects at the population level, after effects of selective dropout and of background demographical variables have been taken into consideration. This analysis also provides some new, substantive empirical findings. Age-related changes are relatively slight between 49 and 70 years but much more marked between 70 and 80 years. Even with assessment points, several years apart the population average effect of practice is large relative to that of age-related change. Variation between individuals increases as samples age, providing the first clear evidence from a longitudinal study for marked individual differences in trajectories of cognitive ageing.

There are stable individual differences in performance variability, both from moment to moment and from day to day.

Individual differences in decision speed have been regarded as direct reflections of a "primitive" functional neurophysiological characteristic, which affects performance on all cognitive tasks and so may be regarded as the "biological basis of intelligence", or of age-related changes in mental abilities. More detailed analyses show that variability within an experimental session (WSV) is a stable individual difference characteristic and that mean choice reaction times (CRTs) are gross summary statistics that reflect variability, rather than maximum speed of performance. A total of 98 people aged from 60 to 80 years completed 36 weekly sessions on six different letter categorization tasks. After effects of practice and of circadian variability had been eliminated, individuals with lower scores on the Cattell Culture Fair intelligence test had slower CRTs and greater WSV on all tasks. A simulation study showed that the greater WSVs of low Cattell scorers led directly to the significantly greater variability of their mean CRTs from session to session. However because CRTs on tasks co-varied from session to session it was apparent that, besides being affected by WSV, individuals' between-session variabilities (BSVs) also vary because of state changes that affect their performance from day to day. It seems that both variability in performance from trial to trial during a session and variability in average performance from day to day are correlated, stable, individual difference characteristics that vary inversely with intelligence test performance. Methodological consequences of these results for interpretations of age-related cognitive changes, for variability between as well as within individuals, for individual differences in decision speed, and for circadian variability in performance are discussed.

Elderly drivers and their accidents: the Aging Driver Questionnaire.

The Manchester Driver Behavior Questionnaire (DBQ) was included as part of a questionnaire survey of 1989 drivers aged 50 or over. Previous research has differentiated three main types of aberrant driver behavior: errors, lapses and violations. Each of these has different psychological origins, and different implications for road safety interventions [Reason et al., 1990. Ergonomics 33, 1315-1312]. It has also been shown that, using a full age-range sample of drivers, reported violations were statistically associated with accident involvement, whereas errors and lapses were not [Parker et al., 1995a. Ergonomics 38, 1036-1048; Parker et al., 1995b. Accident Analysis and Prevention 27, 571-581]. Although factor analysis of the DBQ responses of this sample produced five factors, the original three-way distinction was preserved. However the pattern of relationships between factor scores and accident involvement was different. Relatively high scores on the error factor and the lapse factor were predictive of involvement in an active accident, while passive accident involvement was associated with high scores on the lapse factor.

Patterns of cognitive ageing.

Neuroanatomical evidence suggests that normal ageing affects some brain areas, and the "local" functions they support, earlier and more severely than others. Changes appear to be especially marked in the hippocampus, temporal association and prefrontal cortex. Evidence from classical neuropsychological studies suggests that these brain areas are associated with memory and "executive" functions, respectively. We may, therefore, expect that tests purported to measure these functions may be disproportionately affected in old age and that there may be evidence for some separation of these functions even within neurologically normal populations. What we also know, however, is that measures reflecting general fluid ability also decline with increasing age, so any hypothesis relating to specific "local" deficits must acknowledge and account for any "globar" changes in performance. Volunteers (n = 162) aged between 60-80 years who had completed the Cattell and Cattell Culture Fair Intelligence Test (CCF) completed the Cambridge Automated Neuropsychological Test Battery (CANTAB). The CANTAB has been administered to several patient populations and tests from the battery have been shown to be sensitive to damage in both temporal and prefrontal areas (Owen et al., 1996). Results from the test battery showed that both the Paired Associate Learning and Spatial Recognition tests were the most sensitive to normal ageing even when CCF is accounted for. In contrast, this performance on the "executive" tests, shown to be sensitive to frontal lobe damage was not related to age, and CCF scores predicted performance on these tests. These results are discussed in relation to theories of cognitive ageing and patterns of change and in relation to several important methodological and theoretical considerations for the study of executive function.

Diabetes mellitus and the rate of cognitive ageing.

OBJECTIVES: There is some evidence that besides affecting peripheral neural function diabetes may also cause more widespread changes in the central nervous system which reduce cognitive efficiency and so, also, independence and quality of life. The present study explores whether diabetes mellitus is a compounding factor in average declines in cognitive performance observed in old age. DESIGN: A sample of diabetics and controls were compared on a battery of cognitive tasks previously used in cognitive ageing research. METHODS: Thirty-three insulin dependent (IDDM), 135 non-insulin dependent (NIDDM) diabetics and 2191 non-diabetics aged between 50 and 91 years were compared on two tests of general intellectual ability, and on three tests of verbal memory. RESULTS: Overall, the combined IDDM and NIDDM groups had significantly lower average scores than the controls group on all cognitive tasks. Detailed analyses revealed most cognitive impairment for the NIDDM sub-group whose condition was managed by hypoglycaemic drugs, slightly less for those managed by diet, and no impairment for the IDDM group. These effects were independent of age, depression, socio-economic status, and presence of other illnesses. CONCLUSIONS: Together with other recent studies these data emphasize the need for early detection and effective management of diabetes in older patients.

Smoking, drinking, and other life style factors and cognitive function in men in the Caerphilly cohort.

STUDY OBJECTIVES: To examine the cognitive function in a large, ongoing cohort study of older men, and to identify associations with social and lifestyle factors. DESIGN: A cross sectional study of cognitive function was conducted within the Caerphilly Prospective Study of Heart Disease and stroke. SETTING: The Caerphilly Study was originally set up in 1979-83 when the men were 45-59 years of age. Extensive data are available on a wide range of lifestyle and other factors of possible relevance to cognitive decline. Associations between some of these and cognitive function are reported. PARTICIPANTS: A representative sample of 1870 men aged 55-69 years. MAIN RESULTS: Age, social class, medication, and mood were found to be powerful determinants of performance. Self report data on the involvement of the men in leisure pursuits were examined by factor analysis. This indicated that the more intellectual leisure pursuits are the most strongly linked with performance. A measure of social contact showed a weak positive association with the test scores. Current cigarette smokers gave lower test cognitive function scores than either men who had never smoked, or ex-smokers. There was however no evidence of any gradient in function with the total lifetime consumption of tobacco. The disparity between these two data sets suggests that there had been prior selection of men who had originally started to smoke, but more particularly selection of those who later quit smoking. There was no significant association between alcohol consumption and cognitive function, though ex-drinkers had markedly lower test scores than either current drinkers or men who had never drunk alcohol. This seemed probably to be a consequence of an high prevalence of illness among the ex-drinkers. CONCLUSIONS: Age and social class show strong associations with cognitive function. Leisure persuits and social contact are also both positively associated. Neither tobacco smoking nor the drinking of alcohol seem to be associated with cognitive function, though there is evidence suggestive of self selection of both men who had never smoked and ex-smokers.

Cognitive function in the Caerphilly study: associations with age social class, education and mood.

Baseline cognitive function was established for a study of pre-symptomatic cognitive decline in 1870 men from the general population aged 55-69 years as part of the third examination of the Caerphilly Study. Cognitive assessment included the AH4, a four choice serial reaction time task, a modified CAMCOG, MMSE, NART and various memory tests. Distributions and relationships with age, social class, education and mood at time of testing are presented for a younger population than has previously been available. Multiple linear regression showed cognitive function to be independently associated with all four factors. The age effect was equivalent to one half of a standard deviation (SD) in CRT and AH4 scores. Only the NART score was not associated with age, supporting the use of NART score as an estimate of pre-morbid IQ. The largest age adjusted differences between men with low and normal mood were for the AH4 (3 points, t = 5.6, p < 0.0001) and the CAMCOG (2 points, t = 5.8, p < 0.0001). The smallest age adjusted effect of mood was for the CRT (33 ms, t = 2.14, p = 0.32) and the MMSE (0.4 points, t = 2.97, p = 0.003). Age, mood and education adjusted social class effects were very large ranging between around 0.5 SD for the CRT, and 1.0 SD for the AH4 and NART, respectively. For educational status age, mood and social class adjusted differences were also substantial with tests for trend showing the largest differences for the NART (t = 12, p < 0.0001) and modified CAMCOG (t = 10.6, p < 0.0001) with the smallest differences for the CRT (t = 2.73, p = 0.006).

Contribution of cognitive abilities to performance and improvement on a substitution coding task.

Age-related performance variance on substitution coding tests has been found to account for much of the age-related variance in tests of fluid and other abilities, leading to the conclusion that cognitive decline is due to slowing. Although it is an easy task, which could easily be performed accurately given adequate time, the substitution coding task is not a pure measure of cognitive speed. Evidence from growth curve analyses involving 3,708 volunteers (49-95 years of age) from the Manchester and Newcastle Studies of Cognitive Aging (P. Rabbitt, C. Donlan, N. Bent, L. McInnes, & V. Abson, 1993) indicates that, with practice on this task, improvement is related more to memory than to age, reasoning, vocabulary, or perceptual speed. In other words, faster performances are related primarily to memory. Operational similarities between speeded measures and measures of higher order abilities, which weaken the argument for causal relationships, are discussed.