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.

Exploratory analysis of dietary intake and brain iron accumulation detected using magnetic resonance imaging in older individuals: the Lothian Birth Cohort 1936.

CONTEXT: Brain Iron Deposits (IDs) are associated with neurodegenerative diseases and impaired cognitive function in later life, but their cause is unknown. Animal studies have found evidence of relationships between dietary iron, calorie and cholesterol intake and brain iron accumulation. OBJECTIVES: To investigate the relationship between iron, calorie, and cholesterol intake, blood indicators of iron status, and brain IDs in humans. DESIGN, SETTING AND PARTICIPANTS: Cohort of 1063 community-dwelling older individuals born in 1936 (mean age 72.7years, SD=0.7) with dietary information, results from blood sample analyses and brain imaging data contemporaneously in old age. MEASUREMENTS: Magnetic Resonance Imaging was used to assess regional volumes of brain IDs in basal ganglia, brainstem, white matter, thalamus, and cortex/border with the corticomedullary junction, using a fully automatic assessment procedure followed by individual checking/correction where necessary. Haemoglobin, red cell count, haematocrit, mean cell volume, ferritin and transferrin were obtained from blood samples and typical daily intake of iron, calories, and cholesterol were calculated from a validated food-frequency questionnaire. RESULTS: Overall, 72.8% of the sample that had valid MRI (n=676) had brain IDs. The median total volume of IDs was 40mm3, inter-quartile range (IQR)=196. Basal ganglia IDs (median=35, IQR=159.5 mm3), were found in 70.6% of the sample. IDs in the brainstem were found in 12.9% of the sample, in the cortex in 1.9%, in the white matter in 6.1% and in the thalamus in 1.0%. The median daily intake of calories was 1808.5kcal (IQR=738.5), of cholesterol was 258.5mg (IQR=126.2) and of total iron was 11.7mg (IQR=5). Iron, calorie or cholesterol intake were not directly associated with brain IDs. However, caloric intake was associated with ferritin, an iron storage protein (p=0.01). CONCLUSION: Our results suggest that overall caloric, iron and cholesterol intake are not associated with IDs in brains of healthy older individuals but caloric intake could be associated with iron storage. Further work is required to corroborate our findings on other samples and investigate the underlying mechanisms of brain iron accumulation.

Are APOE ɛ genotype and TOMM40 poly-T repeat length associations with cognitive ageing mediated by brain white matter tract integrity?

Genetic polymorphisms in the APOE ɛ and TOMM40 '523' poly-T repeat gene loci have been associated with significantly increased risk of Alzheimer's disease. This study investigated the independent effects of these polymorphisms on human cognitive ageing, and the extent to which nominally significant associations with cognitive ageing were mediated by previously reported genetic associations with brain white matter tract integrity in this sample. Most participants in the Lothian Birth Cohort 1936 completed a reasoning-type intelligence test at age 11 years, and detailed cognitive/physical assessments and structural diffusion tensor brain magnetic resonance imaging at a mean age of 72.70 years (s.d.=0.74). Participants were genotyped for APOE ɛ2/ɛ3/ɛ4 status and TOMM40 523 poly-T repeat length. Data were available from 758-814 subjects for cognitive analysis, and 522-543 for mediation analysis with brain imaging data. APOE genotype was significantly associated with performance on several different tests of cognitive ability, including general factors of intelligence, information processing speed and memory (raw P-values all<0.05), independently of childhood IQ and vascular disease history. Formal tests of mediation showed that several significant APOE-cognitive ageing associations--particularly those related to tests of information processing speed--were partially mediated by white matter tract integrity. TOMM40 523 genotype was not associated with cognitive ageing. A range of brain phenotypes are likely to form the anatomical basis for significant associations between APOE genotype and cognitive ageing, including white matter tract microstructural integrity.

Morphologic, distributional, volumetric, and intensity characterization of periventricular hyperintensities.

BACKGROUND AND PURPOSE: White matter hyperintensities are characteristic of old age and identifiable on FLAIR and T2-weighted MR imaging. They are typically separated into periventricular or deep categories. It is unclear whether the innermost segment of periventricular white matter hyperintensities is truly abnormal or is imaging artifacts. MATERIALS AND METHODS: We used FLAIR MR imaging from 665 community-dwelling subjects 72-73 years of age without dementia. Periventricular white matter hyperintensities were visually allocated into 4 categories: 1) thin white line; 2) thick rim; 3) penetrating toward or confluent with deep white matter hyperintensities; and 4) diffuse ill-defined, labeled as "subtle extended periventricular white matter hyperintensities." We measured the maximum intensity and width of the periventricular white matter hyperintensities, mapped all white matter hyperintensities in 3D, and investigated associations between each category and hypertension, stroke, diabetes, hypercholesterolemia, cardiovascular disease, and total white matter hyperintensity volume. RESULTS: The intensity patterns and morphologic features were different for each periventricular white matter hyperintensity category. Both the widths (r = 0.61, P < .001) and intensities (r = 0.51, P < .001) correlated with total white matter hyperintensity volume and with each other (r = 0.55, P < .001) for all categories with the exception of subtle extended periventricular white matter hyperintensities, largely characterized by evidence of erratic, ill-defined, and fragmented pale white matter hyperintensities (width: r = 0.02, P = .11; intensity: r = 0.02, P = .84). The prevalence of hypertension, hypercholesterolemia, and neuroradiologic evidence of stroke increased from periventricular white matter hyperintensity categories 1 to 3. The mean periventricular white matter hyperintensity width was significantly larger in subjects with hypertension (mean difference = 0.5 mm, P = .029) or evidence of stroke (mean difference = 1 mm, P < .001). 3D mapping revealed that periventricular white matter hyperintensities were discontinuous with deep white matter hyperintensities in all categories, except only in particular regions in brains with category 3. CONCLUSIONS: Periventricular white matter hyperintensity intensity levels, distribution, and association with risk factors and disease suggest that in old age, these are true tissue abnormalities and therefore should not be dismissed as artifacts. Dichotomizing periventricular and deep white matter hyperintensities by continuity from the ventricle edge toward the deep white matter is possible.

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.

Influence of thickening of the inner skull table on intracranial volume measurement in older people.

INTRODUCTION: It is generally assumed that intracranial volume (ICV) remains constant after peaking in early adulthood. Thus ICV is used as a 'proxy' for original brain size when trying to estimate brain atrophy in older people in neuroimaging studies. However, physiological changes in the skull, such as thickening of the frontal inner table, are relatively common in older age and will reduce ICV. The potential influence that inner table skull thickening may have on ICV measurement in old age has yet to be investigated. METHODS: We selected 60 (31 males, 29 females) representative older adults aged 71.1-74.3years from a community-dwelling ageing cohort, the Lothian Birth Cohort 1936. A semi-automatically derived current ICV measurement obtained from high resolution T1-weighted volume scans was compared to the estimated original ICV by excluding inner skull table thickening using expert manual image processing. RESULTS: Inner table skull thickening reduced ICV from an estimated original 1480.0ml to a current 1409.1ml, a median decrease of 7.3% (Z=-6.334; p<0.001), and this reduction was more prominent in women than men (median decrease 114.6 vs. 101.9ml respectively). This led to potential significant underestimations of brain atrophy in this sample by 5.3% (p<0.001) and obscured potential gender differences. CONCLUSIONS: The effects of skull thickening are important to consider when conducting research in ageing, as they can obscure gender differences and result in underestimation of brain atrophy. Research into reliable methods of determining the estimated original ICV is required for research into brain ageing.

Neuroticism, depressive symptoms and white-matter integrity in the Lothian Birth Cohort 1936.

BACKGROUND: Clinical depression is associated with reductions in white-matter integrity in several long tracts of the brain. The extent to which these findings are localized or related to depressive symptoms or personality traits linked to disease risk remains unclear. Method Members of the Lothian Birth Cohort 1936 (LBC936) were assessed in two waves at mean ages of 70 and 73 years. At wave 1, they underwent assessments of depressive symptoms and the personality traits of neuroticism and extraversion. Brain diffusion magnetic resonance imaging (MRI) data were obtained at the second wave and mood assessments were repeated. We tested whether depressive symptoms were related to reduced white-matter tract fractional anisotropy (FA), a measure of integrity, and then examined whether high neuroticism or low extraversion mediated this relationship. RESULTS: Six hundred and sixty-eight participants provided useable data. Bilateral uncinate fasciculus FA was significantly negatively associated with depressive symptoms at both waves (standardized ß=0.12-0.16). Higher neuroticism and lower extraversion were also significantly associated with lower uncinate FA bilaterally (standardized ß=0.09-0.15) and significantly mediated the relationship between FA and depressive symptoms. CONCLUSIONS: Trait liability to depression and depressive symptoms are associated with reduced structural connectivity in tracts connecting the prefrontal cortex with the amygdala and anterior temporal cortex. These effects suggest that frontotemporal disconnection is linked to the etiology of depression, in part through personality trait differences.

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.