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Biomedical subjects

John M Starr

Publications and source records attributed to John M Starr.

At least 19 recordsLinked to original sources
PubMed2007

The ongoing adaptive evolution of ASPM and Microcephalin is not explained by increased intelligence.

Recent studies have made great strides towards identifying putative genetic events underlying the evolution of the human brain and its emergent cognitive capacities. One of the most intriguing findings is the recurrent identification of adaptive evolution in genes associated with primary microcephaly, a developmental disorder characterized by severe reduction in brain size and intelligence, reminiscent of the early hominid condition. This has led to the hypothesis that the adaptive evolution of these genes has contributed to the emergence of modern human cognition. As with other candidate loci, however, this hypothesis remains speculative due to the current lack of methodologies for characterizing the evolutionary function of these genes in humans. Two primary microcephaly genes, ASPM and Microcephalin, have been implicated not only in the adaptive evolution of the lineage leading to humans, but in ongoing selective sweeps in modern humans as well. The presence of both the putatively adaptive and neutral alleles at these loci provides a unique opportunity for using normal trait variation within humans to test the hypothesis that the recent selective sweeps are driven by an advantage in cognitive abilities. Here, we report a large-scale association study between the adaptive alleles of these genes and normal variation in several measures of IQ. Five independent samples were used, totaling 2393 subjects, including both family-based and population-based datasets. Our overall findings do not support a detectable association between the recent adaptive evolution of either ASPM or Microcephalin and changes in IQ. As we enter the post-genomic era, with the number of candidate loci underlying human evolution growing rapidly, our findings highlight the importance of direct experimental validation in elucidating their evolutionary role in shaping the human phenotype.

Adolescent↗
PubMed2006

Physical fitness and lifetime cognitive change.

OBJECTIVE: To test the hypothesis that physical fitness is associated with more successful cognitive aging. METHODS: Surviving participants (N = 460) of the Scottish Mental Survey of 1932 were tested on the same general cognitive test at age 11 and 79 years. Measures of grip strength, 6-meter walk time, and lung function (forced expiratory volume from the lungs in 1 second [FEV1]) were assessed at age 79 years. RESULTS: A latent physical fitness trait, derived by principal components analysis of the three fitness measures, was significantly associated with successful cognitive aging. Cognitive score at age 11, sex, social class, and APOE-epsilon4 genotype were included as covariables. Higher childhood IQ was associated with better lung function in old age. CONCLUSIONS: Physical fitness is associated with cognitive reserve. Intervention studies aimed at making older people fitter are good candidates to improve cognitive aging.

Adaptation, Physiological↗
PubMed2006

The association between telomere length, physical health, cognitive ageing, and mortality in non-demented older people.

Telomeres are nucleo-protein complexes that protect the ends of chromosomes. The telomeric DNA component shortens each time a somatic cell replicates, eventually leading to cell senescence. Telomere length has been associated with morbidity and mortality rates from age-related diseases. We tested the hypotheses that mean peripheral blood leukocyte telomere length, at age 79 years, is associated with physical health at age 79, cognitive ability at age 79, lifetime cognitive change, smoking, alcohol consumption, social class in adulthood, and mortality in a cohort of people without dementia (the Lothian Birth Cohort 1921: LBC1921). There was a small, significant association between telomere length and verbal fluency (a test of executive function) before (r=-0.16, p=0.027) and after (r=-0.17, p=0.022) adjustment for mental ability at age 11. This might be a type 1 error. Otherwise, we find that telomere length in old age does not have a significant association with age-related physical and cognitive decline or mortality.

Aged↗
PubMed2006

Smoking and cognitive change from age 11 to 66 years: a confirmatory investigation.

Previously we reported that smoking is associated with a small relative decline in cognition from childhood to old age. In this study we perform confirmatory analyses on a further wave of data collected from 298 of the participants, all with age 11 IQ scores, at age 66years, 2years after the original observations. Non-smokers scored a mean 4.9 memory test and 2.6 information processing speed test points and ex-smokers 3.5 memory test and 1.9 information processing speed test points higher than current smokers respectively over the two waves of testing, equivalent to 4-8% of mean test scores, adjusted for the effects of childhood IQ. Across tests a 100l/min higher Peak Expiratory Flow Rate was associated with a 3-4% higher test score at ages 64 and 66years. These data confirm the adverse effect of smoking on information processing speed, and provide new evidence for a similar adverse effect on memory for people in their mid-sixties.

Aged↗
PubMed2006

Smaller left anterior cingulate cortex volumes are associated with impaired hypothalamic-pituitary-adrenal axis regulation in healthy elderly men.

CONTEXT: Studies in animals suggest that the limbic prefrontal cortex, including the anterior cingulate cortex, is involved in regulation of the hypothalamic-pituitary-adrenal (HPA) axis, but human data are lacking. OBJECTIVE: This study tested the hypothesis that smaller anterior cingulate cortex volumes are associated with HPA axis dysregulation in healthy older men. DESIGN AND PARTICIPANTS: Comparison was made of volumes of bilateral anterior cingulate cortex, hippocampus, and superior frontal gyrus (control region) volumes in two groups of 10 healthy men, aged 65-70 yr, who showed nonsuppression or suppression of cortisol levels in response to low dose (250 microg) dexamethasone. Analysis of brain volumes was performed blind to the cortisol levels. SETTING: This study was performed at a tertiary care clinical research center. RESULTS: Nonsuppressors had significantly smaller left anterior cingulate cortex volumes than suppressors (5757 vs. 7817 mm(3); P = 0.01). Right anterior cingulate cortex, bilateral hippocampus, and bilateral superior frontal gyrus volumes were not significantly different between nonsuppressors and suppressors. CONCLUSIONS: Smaller left anterior cingulate cortex volumes may be associated with HPA axis dysregulation in humans. These results substantiate evidence from animal studies indicating an important role for the anterior cingulate cortex in suprahypothalamic feedback regulation of the HPA axis. The results also have implications for disorders in which HPA axis dysregulation and abnormalities of the anterior cingulate cortex are frequently observed, such as depression and Alzheimer's disease.

Aged↗
PubMed2005

Polymorphisms in the gene encoding 11B-hydroxysteroid dehydrogenase type 1 (HSD11B1) and lifetime cognitive change.

A rare polymorphism in the gene encoding 11B-hydroxysteroid dehydrogenase type 1 (HSD11B1: rs846911-C/A) has been associated with an increased risk of Alzheimer's disease. We tested the hypothesis that this and 2 other HSD11B1 polymorphisms (rs12086634-G/T and rs846910-A/G) were associated with lifetime cognitive change in humans. Subjects were 194 participants of the Scottish Mental Survey of 1932 who took the same well-validated mental test at age 11 and age 79. The subjects represented the highest and lowest quintiles with respect to cognitive decline between ages 11 and 79. Despite having non-significantly different IQs at age 11, by age 79 the groups had mean (S.D.) IQs of 80.3 (14.1) and 109.6 (9.1), respectively (p<.001). The polymorphism rs846911-C/A was absent from both groups. There were no significant differences in the frequency of polymorphisms of rs12086634-G/T (p=.91) and rs846910-A/G (p=.90) between the groups. We conclude that these variants in HSD11B1 are not significant contributors to the range of cognitive ageing examined here.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2005

Genetic influences on oxidative stress and their association with normal cognitive ageing.

Oxidative stress is hypothesised to play a major role in ageing processes. Reactive oxygen species produced during normal aerobic metabolism damage cellular macromolecules. The brain is particularly susceptible to oxidative stress due to its high rate of aerobic metabolism. We hypothesised that polymorphisms in genes contributing to antioxidant defences are associated with variation in normal cognitive ageing in the absence of dementia. We examined associations between two SNPs (rs2073495 and rs743658) in Lactotransferrin (LTF), a gene involved in iron absorption, and the common M129V SNP in the prion protein gene, PRNP (rs1799990), with cognitive ability and cognitive ageing in a cohort of non-demented individuals born in 1921. All had cognitive ability measured at age 11 in the Scottish Mental Survey of 1932, and again at age 79. No association was identified with LTF. PRNP M129V was significantly related to Moray House Test (MHT) IQ scores at age 79, adjusted for sex and age 11 IQ (p=0.006). Individuals homozygous for the methionine allele performed significantly better than heterozygotes. This study supports the hypothesis that genetic variations in antioxidant defence genes, specifically PRNP, are important influences on the trajectory of normal cognitive ageing. An interaction between PRNP and klotho (KL) genotypes was also identified (p=0.015), highlighting the importance of analysing gene interactions when investigating associations with quantitative traits.

Aged↗
PubMed2005

The functional COMT polymorphism, Val 158 Met, is associated with logical memory and the personality trait intellect/imagination in a cohort of healthy 79 year olds.

A polymorphism (Val 158 Met) in the gene for catechol-O-methyl transferase (COMT) was previously associated with differences in cognitive ability and personality. Here we examine associations between this polymorphism and cognitive ability, cognitive aging, personality and mood in 460 relatively healthy people born in 1921. All had cognitive ability measured at age 11 in the Scottish Mental Survey of 1932, and again at age 79. COMT genotype was not associated with childhood IQ. At age 79, COMT genotype was significantly related to differences in verbal declarative memory (scores on the Logical Memory test; p=0.028) and to scores on the personality trait of intellect/imagination (p=0.023), adjusted for sex and childhood IQ. In both cases the Val/Met heterozygotes had higher scores than both homozygous groups. There were trends toward the heterozygotes having higher scores on the personality traits of agreeableness and conscientiousness. The effect of COMT genotype on Logical Memory scores was independent of the effect of APOE genotype, and similar in effect size. Therefore, COMT genotype may contribute to differences in normal cognitive aging and to differences in some of the major personality traits in old age.

Aged↗
PubMed2005

Brain white matter hyperintensities: relative importance of vascular risk factors in nondemented elderly people.

PURPOSE: To prospectively determine whether there is an association between brain white matter signal hyperintensities on magnetic resonance (MR) images and potential risk factors for cerebral ischemia in a well-characterized narrow age cohort of nondemented community-dwelling elderly people. MATERIALS AND METHODS: The study population consisted of surviving members of the Aberdeen 1921 Birth Cohort, a subsample of participants in the 1932 Scottish Mental Survey who were born in 1921. With the permission of the local ethics committee and with informed written consent, 106 nondemented subjects (62 men, 44 women) aged 78-79 years underwent T2-weighted brain MR imaging. Brain MR images were scored semiquantitatively for deep white matter hyperintensities and periventricular hyperintensities. Vascular risk factors and clinical measures potentially associated with cerebral ischemia included hypertension, diabetes, cerebrovascular disease, smoking, body mass index grade, respiratory function levels (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and peak expiratory flow rate [PEFR]) normalized for subject's height, plasma lipid levels (cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein), glycated hemoglobin level, and mean fasting blood glucose level. Pearson correlation coefficients were calculated for correlations between potential vascular risk factors and scores for deep white matter and periventricular hyperintensities, and stepwise multiple linear regression analysis was performed for factors with a statistically significant correlation. RESULTS: Significant Pearson correlations with deep white matter hyperintensities were found for glycated hemoglobin level (r = 0.31), hypertension (r = 0.27), normalized FEV1 (r = -0.27), normalized FVC (r = -0.22), normalized PEFR (r = -0.27), low-density lipoprotein (r = 0.24), and cholesterol (r = 0.20), and with periventricular hyperintensities for glycated hemoglobin level (r = 0.28) and normalized PEFR (r = -0.23). Multiple linear regression analysis showed that glycated hemoglobin level and hypertension were predictive of 16.2% of the variance in deep white matter hyperintensities. When subjects with non-insulin-dependent (type 2) diabetes mellitus (n = 11) were excluded, hypertension and decreased normalized PEFR were predictive of 11.7% of the variance. CONCLUSION: White matter hyperintensities are associated with elevated levels of glycated hemoglobin in nondemented community-dwelling elderly subjects. Hypertension and decreased normalized PEFR are the principal predictors of deep white matter hyperintensities in nondiabetic subjects.

Aged↗
PubMed2005

Plasma cortisol levels, brain volumes and cognition in healthy elderly men.

PURPOSE: In ageing animals, exposure to chronic high levels of glucocorticoids is associated with cognitive impairment and hippocampal atrophy. However, there are few studies examining relationships among glucocorticoids, brain volumes and cognitive function in healthy older humans. This study examined the hypotheses that higher plasma cortisol levels and altered sensitivity to glucocorticoids are associated with worse cognition and more brain atrophy in elderly men. MATERIALS AND METHODS: Ninety-seven healthy men aged 65-70 had plasma cortisol measured at 09:00, 14:30 h, and post-dexamethasone (0.25mg, 09:00 h), and had dermal sensitivity to glucocorticoids measured. They also underwent cognitive testing, with scores adjusted for estimated prior mental ability, and had MRI measurements of intracranial area (a validated estimate of intracranial capacity), and hippocampus, temporal lobe and frontal lobe volumes. RESULTS: Plasma cortisol levels at 09:00 h were significantly and negatively correlated with a summary General Cognitive Factor accounting for 51% of the variance of cognitive function (rho=-0.22, p=0.035), and specific cognitive tests: delayed paragraph recall (rho=-0.28, p=0.036) and processing speed (rho=-0.23, p=0.026). Regional brain volumes adjusted for intracranial area generally did not correlate with cortisol levels. Tissue glucocorticoid sensitivity did not correlate with any measure of cognition or brain volume. CONCLUSIONS: In healthy older men, higher plasma cortisol levels are associated with worse ageing-related overall cognitive change but not ageing-related brain atrophy.

Aged↗
PubMed2005

KLOTHO genotype and cognitive ability in childhood and old age in the same individuals.

This study examined the influence of a variation in the KLOTHO gene on cognitive ability at age 11 and age 79 in 464 people from the Lothian Birth Cohort 1921 (LBC1921), and at age 11 and age 64 in 451 people in the Aberdeen Birth Cohort 1936 (ABC1936). In the LBC1921, people with the KLOTHO V/V genotype had lower verbal reasoning ability at age 11 and age 79, and lower non-verbal reasoning at age 79, than those with the F/F genotype, or heterozygotes. The effect of the KLOTHO polymorphism on cognition at age 79 was non-significant when adjusted for IQ at age 11. In this sample, KLOTHO V allele status accounts for about 2% of the variance in life-long traits related to verbal and non-verbal reasoning, but not to age-related cognitive change. These results were not replicated in the ABC1936 sample. In a combined analysis of the LBC1921 and the ABC1936 cohorts there was a significant KLOTHOxsex interaction: women with the V/V genotype had lower non-verbal reasoning scores at age 79, after adjustment for cognitive ability at age 11. Variation in the KLOTHO gene is a possible contributor to life-long reasoning differences in humans and/or to the ageing of non-verbal reasoning, especially in women.

Aged↗
PubMed2005

Nicastrin gene polymorphisms, cognitive ability level and cognitive ageing.

The hypothesis that polymorphisms in the gene for nicastrin (NCSTN) are associated with differences in cognitive level and ageing was tested in 462 relatively healthy surviving participants of the Scottish Mental Survey 1932. None had a history of dementia. They were tested on the Moray House Test of verbal reasoning at age 11 in 1932 and at age 79 between 1999 and 2001. At age 79 they also took tests of non-verbal reasoning, short- and long-term verbal declarative memory, Verbal Fluency, and a short screening test for dementia. Subjects who possessed at least one copy of the NCSTN B haplotype (Hap B) had higher scores on the Moray House Test (a test principally of verbal reasoning) at age 11 (p=0.036) and age 79 (p=0.027). The effect of Hap B on cognition at age 79 was non-significant after adjusting for the effect at age 11. Therefore, the effect of Hap B in this sample is on the life-long stable trait of cognitive ability, and not on age-related cognitive change. The possibility that this result might be a selection effect was not supported by the samples being in Hardy-Weinberg equilibrium with respect to the distribution of NCSTN genotypes.

Aged↗
PubMed2005

Childhood IQ, smoking, and cognitive change from age 11 to 64 years.

We investigated whether smoking is a risk factor for relative cognitive decline from age 11 to 64 years. The potentially confounding effects of childhood IQ, occupational status, level of education, presence of heart disease, hypertension, and lung function were examined. Subjects were nondemented and living independently. They were all born in 1936, had been participants in the same Scottish national IQ survey in 1947, and were reexamined at age about 64 years in 2000-2002. Current smokers and nonsmokers had significantly different mental test scores at age 64. This difference remained after adjustment for childhood IQ. Multiple linear regression identified childhood IQ, level of education, occupational code, lung function, and smoking history as significant independent predictors of mental function at age 64. In this sample, smoking makes a small (<1% variance) independent negative contribution to cognitive aging.

Aging↗
PubMed2005

Childhood IQ and social factors on smoking behaviour, lung function and smoking-related outcomes in adulthood: linking the Scottish Mental Survey 1932 and the Midspan studies.

OBJECTIVE: To investigate the associations of childhood IQ and adult social factors, and smoking behaviour, lung function (forced expiratory volume in one second; FEV(1)), and smoking-related outcomes in adulthood. DESIGN: Retrospective cohort study. METHOD: Participants were from the Midspan prospective studies conducted on Scottish adults in the 1970s. The sample consisted of 938 Midspan participants born in 1921 who were successfully matched with their cognitive ability test results on the Scottish Mental Survey 1932. RESULTS: Structural equation modelling showed that age 11 IQ was not directly associated with smoking consumption, but that IQ and adult social class had indirect effects on smoking consumption via deprivation category. The influence of IQ on FEV(1) was partly indirect via social class. Gender influenced smoking consumption and also IQ and social class. There was a 21% higher risk of having a smoking-related hospital admission, cancer, or death during 25 years of follow-up for each standard deviation disadvantage in IQ. Adjustment for adult social class, deprivation category, and smoking reduced the association to 10%. CONCLUSION: Childhood IQ was associated with social factors which influenced lung function in adulthood, but was not associated directly with smoking consumption. In future studies, it is important to consider other pathways which may account for variance in the link between childhood IQ and health in later life.

Adult↗
PubMed2004

Differential cognitive outcomes in the Hypertensive Old People in Edinburgh study.

Hypertension is associated with cognitive impairment in older adults. The Hypertensive Old People in Edinburgh (HOPE) study reported improved scores in two psychometric tests in those subjects with the greatest fall in diastolic blood pressure during a 24-week randomised, double-blind trial of captopril versus bendrofluazide in 81 elderly hypertensive people with mild cognitive impairment. Three hundred and eighty-seven of the original sample of 603 older people with and without hypertension and/or cognitive impairment from which the trial subsample was drawn were available for adequate psychometric testing 4 years later. Blood pressure was related prospectively to Raven's Progressive Matrices (RPM), a measure of fluid intelligence, but not memory differences. RPM scores were obtained at baseline, 6 weeks, 12 weeks and at the end of the randomised controlled trial. For subjects on captopril mean scores at each time point adjusted for blood pressure change were 27.6 (95% CI 25.5-29.6), 27.2 (95% CI 25.1-29.2), 28.4 (95% CI 26.6-30.3) and 28.9 (95% CI 26.9-30.9), and for bendrofluazide 27.1 (95% CI 25.1-29.0), 28.9 (95% CI 26.9-30.9), 28.9 (95% CI 27.2-30.7) and 28.7 (95% CI 26.8-30.6). There was a significant improvement in scores for those on bendrofluazide compared with captopril at week 6 (F=8.10, p=0.006, partial eta2=0.11). There were no significant effects for either drug or blood pressure at any time point for tests of memory. Future trials of the effects of antihypertensive therapy on cognition should focus more on outcomes other than memory. Early differential effects of therapeutic agents may not be maintained.

Aged↗
PubMed2004

Age at natural menopause and cognition.

OBJECTIVES: To examine associations between age at natural menopause, childhood IQ and cognition at age 65 years. To determine if lower age at menopause partly mediates the effect of childhood IQ on cognition at age 65 years. METHODS: Data were provided by a sub-cohort of women participating in a longitudinal study of brain ageing and health. Main variables were childhood IQ from a 1947 national survey of children born in 1936, age at natural menopause and five cognitive tests measured in 2000-2001. RESULTS: Age at menopause was associated with childhood IQ (r = 0.221, P = 0.008) and with general cognitive function age 65 years (r = 0.246, P = 0.004). Multiple regression showed 44.4% of the reliable variance in cognitive ability age 65 years is contributed by IQ at an age of 11 years to which, years of education contributed an additional 3.9%. Structural equation modelling suggested that childhood IQ differences contribute 4.8% of the variance to age at natural menopause and that the relation between age at menopause and cognition at age 65 years was accounted for by childhood IQ. CONCLUSION: Childhood IQ and age at menopause each have significant relations with general cognitive function age 65 years but the link between cognition age 65 years and age at menopause might be wholly explained by childhood IQ. The association between childhood IQ and age at menopause may be attributed to central neural mechanisms or, as argued here, to the effects of childhood IQ on adult general health.

Adult↗
PubMed2004

Life long changes in cognitive ability are associated with prescribed medications in old age.

OBJECTIVES: To determine the association between prescribed medication and life long changes in cognitive ability. DESIGN: Retrospective cohort study. SETTING: Community residents of a largely urban region of South East Scotland. PARTICIPANTS: Four hundred and seventy-eight survivors of the 1932 Scottish Mental Health Survey (n=87,498) without dementia. MEASUREMENTS: The Moray House Test (MHT) of intelligence administered at age 11 and age 80 years. Hospital Anxiety and Depression Scale (HADS) score, history of disease and current prescribed medications age 80 years. RESULTS: After adjusting for sex, neuroactive drugs had a detrimental effect on life long cognitive change age (F=12.2, p=0.001, partial eta-squared=0.026), statins a beneficial effect (F=5.78, p=0.017, partial eta-squared=0.013) and polypharmacy a detrimental effect (F=6.46, p=0.011, partial eta-squared=0.014). In the optimal model estimated marginal means revealed: a relative improvement for statin users, IQ age 11=93.2 (95% CI 87.9-98.4) and age 80=100.6 (95% CI 95.3-105.9); compared with non-users, IQ age 11=100.9 (95% CI 99.4-102.3) and age 80=100.0 (95% CI 98.6-101.5). CONCLUSIONS: Clinically, the degree to which drugs impair cognition in relatively fit, older people may not be apparent. However, in population terms, medication use, particularly polypharmacy, is important. Statins, used as currently indicated for cardiovascular disease, appear promising in ameliorating cognitive decline in older people. However, firm recommendation of their use should await the outcome of ongoing randomised clinical trials.

Aged↗