Brain age predicts mortality.

Age-associated disease and disability are placing a growing burden on society. However, ageing does not affect people uniformly. Hence, markers of the underlying biological ageing process are needed to help identify people at increased risk of age-associated physical and cognitive impairments and ultimately, death. Here, we present such a biomarker, 'brain-predicted age', derived using structural neuroimaging. Brain-predicted age was calculated using machine-learning analysis, trained on neuroimaging data from a large healthy reference sample (N=2001), then tested in the Lothian Birth Cohort 1936 (N=669), to determine relationships with age-associated functional measures and mortality. Having a brain-predicted age indicative of an older-appearing brain was associated with: weaker grip strength, poorer lung function, slower walking speed, lower fluid intelligence, higher allostatic load and increased mortality risk. Furthermore, while combining brain-predicted age with grey matter and cerebrospinal fluid volumes (themselves strong predictors) not did improve mortality risk prediction, the combination of brain-predicted age and DNA-methylation-predicted age did. This indicates that neuroimaging and epigenetics measures of ageing can provide complementary data regarding health outcomes. Our study introduces a clinically-relevant neuroimaging ageing biomarker and demonstrates that combining distinct measurements of biological ageing further helps to determine risk of age-related deterioration and death.

An epigenome-wide association study meta-analysis of educational attainment.

The epigenome is associated with biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here we provide evidence on the associations between epigenetic modifications-in our case, CpG methylation-and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10 767 individuals. We find nine CpG probes significantly associated with EA. However, robustness analyses show that all nine probes have previously been found to be associated with smoking. Only two associations remain when we perform a sensitivity analysis in the subset of never-smokers, and these two probes are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, the effect sizes of the associations with EA are far smaller than the known associations with the biologically proximal environmental factors alcohol consumption, body mass index, smoking and maternal smoking during pregnancy. Follow-up analyses that combine the effects of many probes also point to small methylation associations with EA that are highly correlated with the combined effects of smoking. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.

Common polygenic risk for autism spectrum disorder (ASD) is associated with cognitive ability in the general population.

Cognitive impairment is common among individuals diagnosed with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). It has been suggested that some aspects of intelligence are preserved or even superior in people with ASD compared with controls, but consistent evidence is lacking. Few studies have examined the genetic overlap between cognitive ability and ASD/ADHD. The aim of this study was to examine the polygenic overlap between ASD/ADHD and cognitive ability in individuals from the general population. Polygenic risk for ADHD and ASD was calculated from genome-wide association studies of ASD and ADHD conducted by the Psychiatric Genetics Consortium. Risk scores were created in three independent cohorts: Generation Scotland Scottish Family Health Study (GS:SFHS) (n=9863), the Lothian Birth Cohorts 1936 and 1921 (n=1522), and the Brisbane Adolescent Twin Sample (BATS) (n=921). We report that polygenic risk for ASD is positively correlated with general cognitive ability (beta=0.07, P=6 × 10(-7), r(2)=0.003), logical memory and verbal intelligence in GS:SFHS. This was replicated in BATS as a positive association with full-scale intelligent quotient (IQ) (beta=0.07, P=0.03, r(2)=0.005). We did not find consistent evidence that polygenic risk for ADHD was associated with cognitive function; however, a negative correlation with IQ at age 11 years (beta=-0.08, Z=-3.3, P=0.001) was observed in the Lothian Birth Cohorts. These findings are in individuals from the general population, suggesting that the relationship between genetic risk for ASD and intelligence is partly independent of clinical state. These data suggest that common genetic variation relevant for ASD influences general cognitive ability.

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.

APOE E4 status predicts age-related cognitive decline in the ninth decade: longitudinal follow-up of the Lothian Birth Cohort 1921.

Carriers of the APOE E4 allele have an increased risk of developing Alzheimer's disease. However, it is less clear whether APOE E4 status may also be involved in non-pathological cognitive ageing. The present study investigated the associations between APOE genotypes and cognitive change over 8 years in older community-dwelling individuals. APOE genotype was determined in 501 participants of the Lothian Birth Cohort 1921, whose intelligence had been measured in childhood in the Scottish Mental Survey 1932. A polymorphic variant of TOMM40 (rs10524523) was included to differentiate between the effects of the APOE E3 and E4 allelic variants. Cognitive performance on the domains of verbal memory, abstract reasoning and verbal fluency was assessed at mean age 79 years (n=501), and again at mean ages of 83 (n=284) and 87 (n=187). Using linear mixed models adjusted for demographic variables, vascular risk factors and IQ at age 11 years, possession of the APOE E4 allele was associated with a higher relative rate of cognitive decline over the subsequent 8 years for verbal memory and abstract reasoning. Individuals with the long allelic variant of TOMM40, which is linked to APOE E4, showed similar results. Verbal fluency was not affected by APOE E4 status. APOE E2 status was not associated with change in cognitive performance over 8 years. In non-demented older individuals, possession of the APOE E4 allele predicted a higher rate of cognitive decline on tests of verbal memory and abstract reasoning between 79 and 87 years. Thus, possession of the APOE E4 allele may not only predispose to Alzheimer's disease, but also appears to be a risk factor for non-pathological decline in verbal memory and abstract reasoning in the ninth decade of life.

Dietary Iodine Exposure and Brain Structures and Cognition in Older People. Exploratory Analysis in the Lothian Birth Cohort 1936.

BACKGROUND: Iodine deficiency is one of the three key micronutrient deficiencies highlighted as major public health issues by the World Health Organisation. Iodine deficiency is known to cause brain structural alterations likely to affect cognition. However, it is not known whether or how different (lifelong) levels of exposure to dietary iodine influences brain health and cognitive functions. METHODS: From 1091 participants initially enrolled in The Lothian Birth Cohort Study 1936, we obtained whole diet data from 882. Three years later, from 866 participants (mean age 72 yrs, SD±0.8), we obtained cognitive information and ventricular, hippocampal and normal and abnormal tissue volumes from brain structural magnetic resonance imaging scans (n=700). We studied the brain structure and cognitive abilities of iodine-rich food avoiders/low consumers versus those with a high intake in iodine-rich foods (namely dairy and fish). RESULTS: We identified individuals (n=189) with contrasting diets, i) belonging to the lowest quintiles for dairy and fish consumption, ii) milk avoiders, iii) belonging to the middle quintiles for dairy and fish consumption, and iv) belonging to the middle quintiles for dairy and fish consumption. Iodine intake was secured mostly though the diet (n=10 supplement users) and was sufficient for most (75.1%, median 193 µg/day). In individuals from these groups, brain lateral ventricular volume was positively associated with fat, energy and protein intake. The associations between iodine intake and brain ventricular volume and between consumption of fish products (including fish cakes and fish-containing pasties) and white matter hyperintensities (p=0.03) the latest being compounded by sodium, proteins and saturated fats, disappeared after type 1 error correction. CONCLUSION: In this large Scottish older cohort, the proportion of individuals reporting extreme (low vs. high)/medium iodine consumption is small. In these individuals, low iodine-rich food intake was associated with increased brain volume shrinkage, raising an important hypothesis worth being explored for designing appropriate guidelines.

The online professional master of science in food safety degree program at Michigan State University: an innovative graduate education in food safety.

A market-research study conducted in 2000 indicated a need for a degree program in food safety that would cover all aspects of the food system, from production to consumption. Despite this, such a program was not enthusiastically supported by employers, who feared losing their valued employees while they were enrolled in traditional on-campus graduate programs. A terminal professional degree was successfully created, offered, and modified over the succeeding five years. The innovative, non-traditional online program was developed to include a core curriculum and leadership training, with elective courses providing flexibility in specific areas of student interest or need. The resulting Professional Master of Science in Food Safety degree program provides a transdisciplinary approach for the protection of an increasingly complex food system and the improvement of public health. Enrollment in the program steadily increased in the first three years of delivery, with particular interest from industry and government employees. The curriculum provides a platform of subject material from which certificate programs, short-courses, seminars, workshops, and executive training programs may be delivered, not only to veterinarians but also to related food and health specialists. The program has fulfilled a need for adult learners to continue as working professionals in the workforce. The benefit to the employer and to society is an individual with enhanced knowledge and networking and leadership skills.

Childhood mental ability and dementia.

OBJECTIVE: To examine links between childhood mental ability and dementia using data from a 1932 survey of the mental ability of the 1921 Scottish birth cohort. METHOD: Patients with dementia from the 1921 Scottish birth cohort were located in 1) a national survey of early-onset dementia (1974-1988), 2) local mental health services, and 3) a survey of 264 of 519 surviving Aberdeen residents who took the 1932 test. Control subjects were identified in the 1932 Scottish Mental Survey. RESULTS: Mean 1932 ability score for the Scottish 1921 cohort did not differ from early-onset dementia. Early-onset dementia was not associated with lower childhood mental ability when compared with matched control subjects. In Aberdeen, mental ability scores were significantly lower in children who eventually developed late-onset dementia when compared with other Aberdeen children tested in 1932. This difference was also detected between cases and tested subjects (controls) alive in 1994. CONCLUSIONS: Late-onset dementia is associated with lower mental ability scores in childhood. Early-onset dementia mental ability scores did not differ from locally matched control subjects or from late-onset dementia. Mechanisms that account for the link between lower mental ability and late-onset dementia are probably not relevant to early-onset dementia.

Behavioural disabilities in psychogeriatric patients and residents of old people's homes.

A comparison was made of the behavioural disabilities of two groups of elderly institutionalised people, one in psychogeriatric hospital wards and the other in residential homes. The results indicated that despite considerable overlap, there is evidence of significantly greater disability in the hospital population, particularly as regards incontinence, confusion, communication difficulties, and need for supervision. Comparison with previous data suggests that there is an increasing number of elderly people with such problems in the care of social services departments. This trend, if supported and continued, is likely to reduce further the distinction between old people in hospital and those in social services homes, with important implications for future planning of the care and management of the elderly.

A survey version of the Clifton Assessment Procedures for the Elderly (CAPE).

A shortened version of the Clifton Assessment Procedures for the Elderly (CAPE) based on two of the subscales is described and evaluated in relation to the full scales and a measure of composite disability based on the factor analysis of the results of 400 subjects. Its reliability and apparent validity make the new CAPE Survey Score a useful measure for assessment of the dependency levels of the elderly.

MTHFR polymorphisms and cognitive ageing in the ninth decade: the Lothian Birth Cohort 1921.

Low blood levels of B vitamins have been implicated in age-associated cognitive impairment. The present study investigated the association between genetic variation in folate metabolism and age-related cognitive decline in the ninth decade of life. Both the 677C>T (rs1801133) polymorphism and the scarcely studied 1298A>C (rs1801131) polymorphism of the MTHFR gene were assessed in relation to cognitive change over 8 years in older community-dwelling individuals. MTHFR genotype was determined in 476 participants of the Lothian Birth Cohort 1921, whose intelligence was measured in childhood in the Scottish Mental Survey of 1932. Cognitive performance on the domains of verbal memory, reasoning and verbal fluency was assessed at mean age of 79 (n = 476) and again at mean ages of 83 (n = 275) and 87 (n = 180). Using linear mixed models, the MTHFR 677C>T and 1298A>C variants were not associated with the rate of cognitive change between 79 and 87 years, neither in the total sample, nor in a subsample of individuals with erythrocyte folate levels below the median. APOE E4 allele carrier status did not interact with MTHFR genotype in affecting change in cognitive performance over 8 years. No significant combined effect of the two polymorphisms was found. In conclusion, MTHFR 677C>T and 1298A>C polymorphisms were not associated with individual change in cognitive functioning in the ninth decade of life. Although polymorphisms in the MTHFR gene may cause disturbances in folate metabolism, they do not appear to be accompanied by changes in cognitive functioning in old age.

White matter integrity and cognition in childhood and old age.

OBJECTIVE: To test the hypothesis that white matter integrity, as measured by diffusion tensor and magnetization transfer MRI is significantly associated with cognitive ability measured in youth and old age. METHODS: Forty, nondemented, surviving participants of the Scottish Mental Survey of 1932 underwent brain MRI and a battery of psychometric tests covering major cognitive domains and tests of information processing efficiency. IQ scores were available from age 11. Mean diffusivity, fractional anisotropy (FA), and magnetization transfer ratio (MTR) were measured in frontal and parieto-occipital white matter and centrum semiovale. RESULTS: Centrum semiovale FA correlated (r = 0.36 to 0.56; p < 0.02) with contemporaneous (age 83) scores on psychometric tests of nonverbal reasoning, working memory, executive function, and information processing efficiency. Centrum semiovale FA also correlated with IQ at age 11 (r = 0.37; p = 0.02). Controlling for IQ at age 11 and information processing at age 83 attenuated the association between centrum semiovale FA and general cognitive ability by approximately 85%. MTR, largely, did not show significant correlations with cognitive test scores. CONCLUSIONS: These data support the information processing efficiency hypothesis of cognitive aging and suggest one foundation for individual differences in processing efficiency. They also suggest that studies of imaging and cognition in the elderly should take into account prior mental ability rather than assuming that any associations between imaging parameters and cognitive test scores are the result of age-related changes.

The two-year predictive validity of the Clifton Assessment Schedule and the Shortened Stockton Geriatric Rating Scale.

Assessment of cognitive and behavioural disability on 100 elderly psychiatric admissions was carried out by means of the Clifton Assessment Schedule and the Shortened Stockton Geriatric Rating Scale. The results provided useful predictive indices, confirming the relationship between cognitive impairment and unfavourable outcome at two-year follow up.

The Stockton Geriatric Rating Scale: a shortened version with British normative data.

This paper presents information on a shortened form of the Stockton Geriatric Rating Scale, which is shown to be as effective as the original version in discriminating among the elderly. The results for 400 people in the care of hospital or social services provide provisional normative data for the use of the scale, which should be of value in assessing the behavioural competence of the elderly on an individual and group basis.

The effect of location on the elderly mentally infirm: relationship to mortality and behavioural deterioration.

An investigation was carried out into the effects of location on the elderly mentally infirm. While location had no bearing on subsequent mortality there was some evidence to suggest that some aspects of behavioural deterioration were influenced by the type of location and in those cases residential home placement seemed to produce the least deterioration over and 18-month period when the effects of mental and behavioural competent were taken into account. The implications of these findings for the provision of long-term care for the elderly are discussed.

A brief psychogeriatric assessment schedule. Validation against psychiatric diagnosis and discharge from hospital.

This paper represents part of an investigation designed to establish the validity of the Clifton Assessment Scale (a brief psychogeriatric assessment procedure) and the Stockton Geriatric Rating Schedule. One hundred consecutive admissions over the age of 60 were assessed soon after admission to the acute wards of a psychiatric hospital. The results indicated a close relationship between the scores and psychiatric diagnosis. Outcome was differentiated in terms of discharge home or of transfer to psychogeriatric and to other non-psychogeriatric wards, and significant differences were obtained between groups. The assessment procedure had predicitive validity comparable with other reported procedures, with the advantages of brevity and test acceptability for an elderly population.