Catherine Murray

Brain white matter tract integrity as a neural foundation for general intelligence

General intelligence is a robust predictor of important life outcomes, including educational and occupational attainment, successfully managing everyday life situations, good health and longevity. Some neuronal correlates of intelligence have been discovered, mainly indicating that larger cortices in widespread parieto-frontal brain networks and efficient neuronal information processing support higher intelligence. However, there is a lack of established associations between general intelligence and any basic structural brain parameters that have a clear functional meaning. Here, we provide evidence that lower brain-wide white matter tract integrity exerts a substantial negative effect on general intelligence through reduced information-processing speed. Structural brain magnetic resonance imaging scans were acquired from 420 older adults in their early 70s. Using quantitative tractography, we measured fractional anisotropy and two white matter integrity biomarkers that are novel to the study of intelligence: longitudinal relaxation time (T1) and magnetisation transfer ratio. Substantial correlations among 12 major white matter tracts studied allowed the extraction of three general factors of biomarker-specific brain-wide white matter tract integrity. Each was independently associated with general intelligence, together explaining 10% of the variance, and their effect was completely mediated by information-processing speed. Unlike most previously established neurostructural correlates of intelligence, these findings suggest a functionally plausible model of intelligence, where structurally intact axonal fibres across the brain provide the neuroanatomical infrastructure for fast information processing within widespread brain networks, supporting general intelligence.

Brain aging, cognition in youth and old age and vascular disease in the Lothian Birth Cohort 1936: rationale, design and methodology of the imaging protocol*

Rationale As the population of the world ages, age-related cognitive decline is becoming an ever-increasing problem. However, the changes in brain structure that accompany normal aging, and the role they play in cognitive decline, remain to be fully elucidated. Aims This study aims to characterize changes in brain structure in old age, and to investigate relationships between brain aging and cognitive decline using the Lothian Birth Cohort 1936. Here, we report the rationale, design and methodology of the brain and neurovascular imaging protocol developed to study this cohort. Design An observational, longitudinal study of the Lothian Birth Cohort 1936, which comprises 1091 relatively healthy individuals now in their 70s and living in the Edinburgh area. They are surviving participants of the Scottish Mental Survey 1947, which involved a test of general intelligence taken at age 11 years. At age 70 years, the Lothian Birth Cohort 1936 undertook detailed cognitive, medical and genetic testing, and provided social, family, nutritional, quality of life and physical activity information. At mean age 73 years they underwent detailed brain MRI and neurovascular ultrasound imaging, repeat cognitive and other testing. The MRI protocol is designed to provide qualitative and quantitative measures of gray and white matter atrophy, severity and location of white matter lesions, enlarged perivascular spaces, brain mineral deposits, microbleeds and integrity of major white matter tracts. The neurovascular ultrasound imaging provides velocity, stenosis and intima–media thickness measurements of the carotid and vertebral arteries. Study This valuable imaging dataset will be used to determine which changes in brain structural parameters have the largest effects on cognitive aging. Analysis will include multimodal image analysis and multivariate techniques, such as factor analysis and structural equation modelling. Especially valuable is the ability within this sample to examine the influence that early life intelligence has on brain structural parameters in old age, and the role of genetic, vascular, educational and lifestyle factors. Outcomes Final outcomes include associations between early and late life cognition and integrity of key white matter tracts, volume of gray and white matter, myelination, brain water content, and visible abnormalities such as white matter lesions and mineral deposits; and influences of vascular risk factors, diet, environment, social metrics, education and genetics on healthy brain aging. It is intended that this information will help to inform and develop strategies for successful cognitive aging.

Neuroprotective lifestyles and the aging brain Activity, atrophy, and white matter integrity

Objectives: Increased participation in leisure and physical activities may be cognitively protective. Whether activity might protect the integrity of the brains white matter, or reduce atrophy and white matter lesion (WML) load, was examined in the Lothian Birth Cohort 1936 (n = 691), a longitudinal study of aging. Methods: Associations are presented between self-reported leisure and physical activity at age 70 years and structural brain biomarkers at 73 years. For white matter integrity, principal components analysis of 12 major tracts produced general factors for fractional anisotropy (FA) and mean diffusivity. Atrophy, gray and normal-appearing white matter (NAWM) volumes, and WML load were assessed using computational image processing methods; atrophy and WML were also assessed visually. Results: A higher level of physical activity was associated with higher FA, larger gray and NAWM volumes, less atrophy, and lower WML load. The physical activity associations with atrophy, gray matter, and WML remained significant after adjustment for covariates, including age, social class, and health status. For example, physical activity (standardized β = −0.09, nonstandardized β = −0.09, p = 0.029) and stroke (standardized β = 0.18, nonstandardized β = 0.69, p = 0.003) each had an independent effect on rated WML load. Leisure activity was associated with NAWM volume, but was nonsignificant after including covariates. Conclusions: In this large, narrow-age sample of adults in their 70s, physical activity was associated with less atrophy and WML. Its role as a potential neuroprotective factor is supported; however, the direction of causation is unclear from this observational study.

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.

Brain iron deposits are associated with general cognitive ability and cognitive aging

A novel analysis of magnetic resonance imaging (MRI) scans based on multispectral image fusion was used to quantify iron deposits in basal ganglia and microbleeds in 143 nondemented subjects of the generally healthy Lothian Birth Cohort, who were tested for general cognitive ability (intelligence) at mean ages of 11, 70, and 72 years. Possessing more iron deposits at age 72 was significantly associated with lower general cognitive ability at age 11, 70, and 72, explaining 4% to 9% of the variance. The relationships with old age general cognitive ability remained significant after controlling for childhood cognition, suggesting that iron deposits are related to lifetime cognitive decline. Most iron deposits were in the basal ganglia, with few microbleeds. While iron deposits in the general population have so far been dismissed in the literature, our results show substantial associations with cognitive functioning. The pattern of results suggests that iron deposits are not only a biomarker of general cognitive ability in old age and age-related cognitive decline, but that they are also related to the lifelong-stable trait of intelligence.

White matter hyperintensities and normal-appearing white matter integrity in the aging brain

White matter hyperintensities (WMH) of presumed vascular origin are a common finding in brain magnetic resonance imaging of older individuals and contribute to cognitive and functional decline. It is unknown how WMH form, although white matter degeneration is characterized pathologically by demyelination, axonal loss, and rarefaction, often attributed to ischemia. Changes within normal-appearing white matter (NAWM) in subjects with WMH have also been reported but have not yet been fully characterized. Here, we describe the in vivo imaging signatures of both NAWM and WMH in a large group of community-dwelling older people of similar age using biomarkers derived from magnetic resonance imaging that collectively reflect white matter integrity, myelination, and brain water content. Fractional anisotropy (FA) and magnetization transfer ratio (MTR) were significantly lower, whereas mean diffusivity (MD) and longitudinal relaxation time (T1) were significantly higher, in WMH than NAWM (p < 0.0001), with MD providing the largest difference between NAWM and WMH. Receiver operating characteristic analysis on each biomarker showed that MD differentiated best between NAWM and WMH, identifying 94.6% of the lesions using a threshold of 0.747 × 10−9 m2s−1 (area under curve, 0.982; 95% CI, 0.975–0.989). Furthermore, the level of deterioration of NAWM was strongly associated with the severity of WMH, with MD and T1 increasing and FA and MTR decreasing in NAWM with increasing WMH score, a relationship that was sustained regardless of distance from the WMH. These multimodal imaging data indicate that WMH have reduced structural integrity compared with surrounding NAWM, and MD provides the best discriminator between the 2 tissue classes even within the mild range of WMH severity, whereas FA, MTR, and T1 only start reflecting significant changes in tissue microstructure as WMH become more severe.

Towards Understanding the Links Between Health Literacy and Physical Health

OBJECTIVE Low health literacy predicts poor health, but the underpinnings of the associations are yet to be understood. This study tested the associations between health literacy and three objective health outcomes in older people and investigated the extent to which general (not health-related) cognition and earlier life-course factors such as childhood cognitive ability, educational level and occupational class accounted for these associations. METHOD Participants were 730 community-dwelling older people (350 women; mean age 72.50 years, SD = 0.71). Physical fitness (defined by walk time, lung function, and grip strength), body mass index, and count of natural teeth were used as health outcomes. Rapid Estimate of Adult Literacy in Medicine (REALM), Shortened Test of Functional Health Literacy in Adults (S-TOFHLA), and Newest Vital Sign (NVS) were used to measure health literacy. Age 11 and concurrent general cognitive ability, educational level, and occupational social class were used as covariates. RESULTS Lower REALM, S-TOFHLA and NVS scores were associated with worse scores on all health outcomes (β = .09 to .17). However, cognitive ability in old age and childhood and educational and occupational levels accounted for the majority of these associations: After adjusting for these covariates, only physical fitness was significantly associated with REALM and S-TOFHLA (β = .06 and .11). CONCLUSIONS Low health literacy was associated with poorer health largely because it reflected general cognitive ability, educational and/or occupational levels. These variables plays some role in health beyond their association with the reading and numeracy skills captured by common health literacy measures.

Childhood cognitive ability accounts for associations between cognitive ability and brain cortical thickness in old age

Associations between brain cortical tissue volume and cognitive function in old age are frequently interpreted as suggesting that preservation of cortical tissue is the foundation of successful cognitive aging. However, this association could also, in part, reflect a lifelong association between cognitive ability and cortical tissue. We analyzed data on 588 subjects from the Lothian Birth Cohort 1936 who had intelligence quotient (IQ) scores from the same cognitive test available at both 11 and 70 years of age as well as high-resolution brain magnetic resonance imaging data obtained at approximately 73 years of age. Cortical thickness was estimated at 81 924 sampling points across the cortex for each subject using an automated pipeline. Multiple regression was used to assess associations between cortical thickness and the IQ measures at 11 and 70 years. Childhood IQ accounted for more than two-third of the association between IQ at 70 years and cortical thickness measured at age 73 years. This warns against ascribing a causal interpretation to the association between cognitive ability and cortical tissue in old age based on assumptions about, and exclusive reference to, the aging process and any associated disease. Without early-life measures of cognitive ability, it would have been tempting to conclude that preservation of cortical thickness in old age is a foundation for successful cognitive aging when, instead, it is a lifelong association. This being said, results should not be construed as meaning that all studies on aging require direct measures of childhood IQ, but as suggesting that proxy measures of prior cognitive function can be useful to take into consideration.

Estimated maximal and current brain volume predict cognitive ability in old age

Brain tissue deterioration is a significant contributor to lower cognitive ability in later life; however, few studies have appropriate data to establish how much influence prior brain volume and prior cognitive performance have on this association. We investigated the associations between structural brain imaging biomarkers, including an estimate of maximal brain volume, and detailed measures of cognitive ability at age 73 years in a large (N = 620), generally healthy, community-dwelling population. Cognitive ability data were available from age 11 years. We found positive associations (r) between general cognitive ability and estimated brain volume in youth (male, 0.28; females, 0.12), and in measured brain volume in later life (males, 0.27; females, 0.26). Our findings show that cognitive ability in youth is a strong predictor of estimated prior and measured current brain volume in old age but that these effects were the same for both white and gray matter. As 1 of the largest studies of associations between brain volume and cognitive ability with normal aging, this work contributes to the wider understanding of how some early-life factors influence cognitive aging.

Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936

Apolipoprotein E (APOE) ε genotype has previously been significantly associated with cognitive, brain imaging, and Alzheimers disease-related phenotypes (e.g., age of onset). In the TOMM40 gene, the rs10524523 (“523”) variable length poly-T repeat polymorphism has more recently been associated with similar ph/enotypes, although the allelic directions of these associations have varied between initial reports. Using diffusion magnetic resonance imaging tractography, the present study aimed to investigate whether there are independent effects of apolipoprotein E (APOE) and TOMM40 genotypes on human brain white matter integrity in a community-dwelling sample of older adults, the Lothian Birth Cohort 1936 (mean age = 72.70 years, standard deviation = 0.74, N approximately = 640–650; for most analyses). Some nominally significant effects were observed (i.e., covariate-adjusted differences between genotype groups at p < 0.05). For APOE, deleterious effects of ε4 “risk” allele presence (vs. absence) were found in the right ventral cingulum and left inferior longitudinal fasciculus. To test for biologically independent effects of the TOMM40 523 repeat, participants were stratified into APOE genotype subgroups, so that any significant effects could not be attributed to APOE variation. In participants with the APOE ε3/ε4 genotype, effects of TOMM40 523 status were found in the left uncinate fasciculus, left rostral cingulum, left ventral cingulum, and a general factor of white matter integrity. In all 4 of these tractography measures, carriers of the TOMM40 523 “short” allele showed lower white matter integrity when compared with carriers of the “long” and “very-long” alleles. Most of these effects survived correction for childhood intelligence test scores and vascular disease history, though only the effect of TOMM40 523 on the left ventral cingulum integrity survived correction for false discovery rate. The effects of APOE in this older population are more specific and restricted compared with those reported in previous studies, and the effects of TOMM40 on white matter integrity appear to be novel, although replication is required in large independent samples.