A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.

Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.

Genome-wide association studies establish that human intelligence is highly heritable and polygenic.

General intelligence is an important human quantitative trait that accounts for much of the variation in diverse cognitive abilities. Individual differences in intelligence are strongly associated with many important life outcomes, including educational and occupational attainments, income, health and lifespan. Data from twin and family studies are consistent with a high heritability of intelligence, but this inference has been controversial. We conducted a genome-wide analysis of 3511 unrelated adults with data on 549,692 single nucleotide polymorphisms (SNPs) and detailed phenotypes on cognitive traits. We estimate that 40% of the variation in crystallized-type intelligence and 51% of the variation in fluid-type intelligence between individuals is accounted for by linkage disequilibrium between genotyped common SNP markers and unknown causal variants. These estimates provide lower bounds for the narrow-sense heritability of the traits. We partitioned genetic variation on individual chromosomes and found that, on average, longer chromosomes explain more variation. Finally, using just SNP data we predicted ∼1% of the variance of crystallized and fluid cognitive phenotypes in an independent sample (P=0.009 and 0.028, respectively). Our results unequivocally confirm that a substantial proportion of individual differences in human intelligence is due to genetic variation, and are consistent with many genes of small effects underlying the additive genetic influences on intelligence.

Antioxidant and B vitamin intake in relation to cognitive function in later life in the Lothian Birth Cohort 1936.

BACKGROUND/OBJECTIVES: Cross-sectional and longitudinal studies provide some evidence for an association between intake of antioxidants and B vitamins, and cognitive function in later life, but intervention studies have not provided clear evidence of beneficial effects. The possibility that those with higher cognitive ability during earlier adult life consume more nutrient-rich diets in later life could provide an alternative explanation for the associations seen in observational studies. METHODS: Survey of 1091 men and women born in 1936 living in Edinburgh, Scotland, in whom previous cognitive ability was available from intelligence quotient (IQ) measurements at age 11 years. At age 70 years, participants carried out a range of cognitive tests and completed a semiquantitative food-frequency questionnaire (FFQ). RESULTS: A total of 882 participants returned completed FFQs from which intake of ß-carotene, vitamin C, B12, folate and riboflavin was estimated. IQ at age 11 years was positively associated with dietary intake of vitamin C (P=0.048) and inversely associated with dietary intake of riboflavin (P<0.001) at age 70 years, and was higher in those taking folate supplements at age 70 years (P<0.005). Weak associations between intake of vitamins B12, C, riboflavin and folate and cognitive performance at age 70 years were attenuated by adjustment for confounding variables, including IQ at age 11 years. In the fully adjusted models, the proportion of total variance in cognitive function at age 70 years accounted for by intake of these nutrients was less than 1%. CONCLUSION: These results provide no evidence for a clinically significant beneficial association between intake of these antioxidants and B vitamins, and cognitive function at age 70 years.

Difficulties in emotion regulation and impulse control in recently abstinent alcoholics compared with social drinkers.

BACKGROUND: Early abstinence from chronic alcohol dependence is associated with increased emotional sensitivity to stress-related craving as well as changes in brain systems associated with stress and emotional processing. The aim of the current study was to examine potential difficulties in emotion regulation during early alcohol abstinence using the recently validated Difficulties of Emotion Regulation Scale (DERS). METHOD: Recently abstinent treatment-seeking alcohol abusers (n=50) completed the DERS during their first week of inpatient treatment and at discharge (5 weeks later). These responses were compared to a group of social drinkers (n=62). RESULTS: Compared with social drinkers, alcohol-dependent patients reported significant differences in emotional awareness and impulse control during week 1 of treatment. Significant improvements in awareness and clarity of emotion were observed following 5 weeks of protracted abstinence. However, significant difficulties with impulse control persisted until discharge. CONCLUSION: Findings from the DERS indicate protracted stress-related impulse control problems in abstinent alcoholics, which may contribute to increased relapse vulnerability.

Difficulties in emotion regulation and impulse control during cocaine abstinence.

RATIONALE: Prior research has shown that cocaine dependence is associated with dysfunction of brain systems involved in emotions and motivational states. OBJECTIVES: To examine whether difficulties in emotion regulation are associated with early cocaine abstinence using the recently validated Difficulties in Emotion Regulation Scale (DERS). METHOD: Recently abstinent treatment-seeking cocaine patients (n=60) completed the DERS during their first week of inpatient treatment and at discharge (3-4 weeks later), and scores were compared with community controls (n=50). RESULTS: Compared with controls, cocaine-dependent individuals reported difficulties relating to understanding emotions, managing emotions and impulse control in the first week of abstinence. With continued abstinence, cocaine-dependent individuals showed continued difficulties only in impulse control. CONCLUSION: Cocaine-dependent individuals report emotion regulation difficulties, particularly during early abstinence. Additionally, protracted distress-related impulse control problems suggest potential relapse vulnerability.

Reliability of salivary cortisol assessments in cocaine dependent individuals.

The aim of this study was to assess the reliability of salivary cortisol as a measure of hypothalmic-pituitary-adrenal (HPA) axis function in cocaine dependent individuals. Saliva and total plasma samples were collected from 49 abusers on 3 testing days in the morning, across eight time points per day. Significant associations between saliva and plasma cortisol were observed across all time points collapsed across 3 days in both men and women. These moderately significant correlations suggest that salivary measurements represent a stable, non-invasive and broad indicator of HPA axis functioning in cocaine dependent individuals.

Persistent neuropsychological problems after 7 years of abstinence from recreational Ecstasy (MDMA): a case study.

This case study concerns a 26-yr.-old male who had consumed large amounts of Ecstasy seven years previously. He stated that his increasingly intensive use of ecstasy over a 4-yr. period had led to the emergence of multiple psychiatric and psychological problems. Given these problems, he stopped using Ecstasy, but the problems had not resolved despite seven years of abstinence. The neurocognitive profile was very similar to that shown by current heavy Ecstasy users, with deficits in immediate and delayed verbal recall, moderately impaired memory function, but normal expressive language ability and perceptual functioning. Extremely high pathology was evident, including depression and phobic anxiety. Severe problems with sleep and sex were also reported. Further studies involving larger groups of abstinent former users are needed; adverse sequelae associated with intensive Ecstasy use may sometimes be enduring.

Dietary supplement use in old age: associations with childhood IQ, current cognition and health.

AIMS: Dietary supplement (DS) use is actively promoted among old people but there is little evidence in favour of DS use or information about the demographic, health and cognitive characteristics of DS users. METHOD: We examined 176 healthy, old people without dementia all born in 1921 and living independently in the community. IQ scores aged about 11 years were available for all subjects. DS users were more often female, had a lower BMI and were taking fewer prescribed medications than non-users. RESULTS: Usual dietary intake, as measured by food frequency questionnaire, did not differ between DS users and DS non-users. DS users were seen to have higher Vitamin C (p<0.05), alpha-carotene (p<0.05) and lower gamma-tocopherol (p<0.001) and homocysteine (p<0.01). DS users did not differ from DS non-users in years of education, indices of occupational code, current socio-economic category or parameters of cardiovascular or respiratory functions. DS users had higher (p<0.05) childhood IQ scores but did not differ in current Mini-Mental State Examination (MMSE) score or performance on Raven's Progressive Matrices (RPM) either before or after adjustment for childhood IQ. CONCLUSIONS: DS users may enjoy somewhat better general health than non-users but the source of this difference is unknown. Possible health benefits of DS use merit further study.

Neuropsychological evidence of a relatively selective profile of temporal dysfunction in drug-free MDMA ("ecstasy") polydrug users.

RATIONALE: Experimental evidence has shown that 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") can act as a serotonergic neurotoxin in laboratory animals. The serotonin system predominantly innervates frontal and limbic regions of the brain and has been associated with consolidatory learning and mnemonic processes in humans. OBJECTIVES: The aim of the present study was to investigate the cognitive neuropsychological profile of drug-free ecstasy users by employing a selection of tasks previously associated with lesion or neurodegenerative damage to the temporal lobe or fronto-striatal regions. METHODS: The study comprised 40 participants: 20 ecstasy polydrug users and 20 polydrug users who had never taken ecstasy. RESULTS: Ecstasy users were significantly impaired on a recognition task for complex visual patterns and spatial working memory, as a function of task difficulty rather than systematic search strategy. They also showed a trend towards impairment on several learning paradigms. Ecstasy users remained relatively unimpaired on most measures associated with prefrontal functioning, with the exception of verbal fluency "letter" generation. CONCLUSIONS: Initial cognitive deficits in ecstasy polydrug users may be more apparent in tasks known to be sensitive to temporal functioning.

Auditory verbal learning in drug-free Ecstasy polydrug users.

Drug-free Ecstasy polydrug users have shown impairment on tasks of verbal working memory and memory span. Current research aims to investigate how these deficits may affect the learning of verbal material by administration of the Auditory Verbal Learning Task (AVLT) (Rey, 1964). The task provides a learning curve by assessing immediate memory span over multiple trials. Learning strategies are further analysed by tendencies to confabulate as well as demonstrate either proactive or retroactive interference elicited by a novel 'distractor' list. Three groups completed the task: two groups of 14 Ecstasy users (short- and long-term) and one group of 14 polydrug controls. Compared with controls both Ecstasy groups recalled significantly fewer words and made more confabulation errors on the initial three recall trials as well as a delayed recall trial. Long-term users demonstrated increased confabulation on the initial trials and the novel 'distractor7' trial, compared with short-term users. Only following repeated presentations were both short- and long-term users shown to perform at control levels. As such, deficits in verbal learning may be more related to storage and/or retrieval problems than problems associated with capacity per se. No interference errors were demonstrated by either of the Ecstasy groups. However, a high level of intrusion errors may indicate selective working memory problems associated with longer-term use of the drug. Copyright 2001 John Wiley & Sons, Ltd.

Ecstasy use: cognitive deficits related to dosage rather than self-reported problematic use of the drug.

Previous research has shown drug-free Ecstasy users to demonstrate selective cognitive impairment. However, there seems to be a degree of individual variation in the occurrence of such deficits. The present study aimed to assess whether these cognitive deficits are related to an awareness of problematic Ecstasy use, or to past drug dosage. Twenty regular Ecstasy users who reported experiencing Ecstasy-related problems were compared with 20 Ecstasy users who had not reported any previous problems. The two groups displayed similar past histories in relation to a range of illicit drugs, and were divided into low, medium and high users. The controls comprised 20 illicit recreational drug users who had never taken Ecstasy. Executive task measures comprised the Tower of London (TOL), the Wisconsin Card Sorting Task (WCST) and spatial working memory. Immediate and delayed word recall, matched verbal recognition and recall and simple reaction time were also included. Both Ecstasy groups performed significantly worse than controls on two executive measures: TOL planning time and spatial working memory score. There were no differences in cognitive impairment between the Ecstasy users who complained of problems and those who did not. In both groups, decrement on executive tasks was demonstrated as a function of previous drug dose. The study confirms that heavy Ecstasy polydrug use may culminate in selective executive deficits. It also demonstrates that two differently self-perceived Ecstasy groups showed similar cognitive impairment, despite only one group complaining of problems. Because all Ecstasy participants also consumed a range of other illicit drugs, the results are reflective of Ecstasy polydrug use in individuals who use Ecstasy as a drug of preference.