Mediterranean-Type Diet and Brain Structural Change from 73 to 79 Years in the Lothian Birth Cohort 1936.

OBJECTIVES: To test whether Mediterranean-type Diet (MeDi) at age 70 years is associated with longitudinal trajectories of total brain MRI volume over a six-year period from age 73 to 79. DESIGN: Cohort study which uses a correlational design. SETTING: Participants residing in the Lothian region of Scotland and living independently in the community. PARTICIPANTS: A relatively healthy Scottish sample drawn from the Lothian Birth Cohort 1936. MEASUREMENTS: Total brain volume measurements were available at ages 73, 76 and 79 (N ranged 332 to 563). Adherence to the MeDi was based on food frequency questionnaire data collected three years before the baseline imaging scans, and was used in growth curve models to predict the trajectory of total brain volume change. RESULTS: No association was found (p>.05) between adherence to the MeDi at age 70 and total brain volume change from 73 to 79 years in minimally-adjusted (sex) or fully adjusted models controlling for additional health confounders. CONCLUSIONS: Variation in adherence to the MeDi was not predictive of total brain atrophy over a six-year period. This suggests that previous findings of dietary associations with brain volume are not long lasting or become less important as ageing-related conditions account for greater variation in brain volume change. More frequent collection of dietary intake data is needed to clarify these findings.

Cerebral small vessel disease burden and longitudinal cognitive decline from age 73 to 82: the Lothian Birth Cohort 1936.

Slowed processing speed is considered a hallmark feature of cognitive decline in cerebral small vessel disease (SVD); however, it is unclear whether SVD's association with slowed processing might be due to its association with overall declining general cognitive ability. We quantified the total MRI-visible SVD burden of 540 members of the Lothian Birth Cohort 1936 (age: 72.6 ± 0.7 years; 47% female). Using latent growth curve modelling, we tested associations between total SVD burden at mean age 73 and changes in general cognitive ability, processing speed, verbal memory and visuospatial ability, measured at age 73, 76, 79 and 82. Covariates included age, sex, vascular risk and childhood cognitive ability. In the fully adjusted models, greater SVD burden was associated with greater declines in general cognitive ability (standardised ß: -0.201; 95% CI: [-0.36, -0.04]; pFDR = 0.022) and processing speed (-0.222; [-0.40, -0.04]; pFDR = 0.022). SVD burden accounted for between 4 and 5% of variance in declines of general cognitive ability and processing speed. After accounting for the covariance between tests of processing speed and general cognitive ability, only SVD's association with greater decline in general cognitive ability remained significant, prior to FDR correction (-0.222; [-0.39, -0.06]; p = 0.008; pFDR = 0.085). Our findings do not support the notion that SVD has a specific association with declining processing speed, independent of decline in general cognitive ability (which captures the variance shared across domains of cognitive ability). The association between SVD burden and declining general cognitive ability supports the notion of SVD as a diffuse, whole-brain disease and suggests that trials monitoring SVD-related cognitive changes should consider domain-specific changes in the context of overall, general cognitive decline.

Associations between total MRI-visible small vessel disease burden and domain-specific cognitive abilities in a community-dwelling older-age cohort.

Cerebral small vessel disease (SVD) is a leading cause of vascular cognitive impairment, however the precise nature of SVD-related cognitive deficits, and their associations with structural brain changes, remain unclear. We combined computational volumes and visually-rated MRI markers of SVD to quantify total SVD burden, using data from the Lothian Birth Cohort 1936 (n = 540; age: 72.6 ± 0.7 years). We found negative associations between total SVD burden and general cognitive ability (standardized ß: -0.363; 95%CI: [-0.49, -0.23]; p(FDR) < 0.001), processing speed (-0.371 [-0.50, -0.24]; p(FDR) < 0.001), verbal memory (-0.265; [-0.42, -0.11]; p(FDR) = 0.002), and visuospatial ability (-0.170; [-0.32, -0.02]; p(FDR) = 0.029). Only the association between SVD burden and processing speed remained after accounting for covariance with general cognitive ability (-0.325; [-0.61, -0.04]; p(FDR) = 0.029). This suggests that SVD's association with poorer processing speed is not driven by, but is independent of its association with poorer general cognitive ability. Tests of processing speed may be particularly sensitive to the cognitive impact of SVD, but all major cognitive domains should be tested to determine the full range of SVD-related cognitive characteristics.

Three major dimensions of human brain cortical ageing in relation to cognitive decline across the eighth decade of life.

Different brain regions can be grouped together, based on cross-sectional correlations among their cortical characteristics; this patterning has been used to make inferences about ageing processes. However, cross-sectional brain data conflate information on ageing with patterns that are present throughout life. We characterised brain cortical ageing across the eighth decade of life in a longitudinal ageing cohort, at ages ~73, ~76, and ~79 years, with a total of 1376 MRI scans. Volumetric changes among cortical regions of interest (ROIs) were more strongly correlated (average r = 0.805, SD = 0.252) than were cross-sectional volumes of the same ROIs (average r = 0.350, SD = 0.178). We identified a broad, cortex-wide, dimension of atrophy that explained 66% of the variance in longitudinal changes across the cortex. Our modelling also discovered more specific fronto-temporal and occipito-parietal dimensions that were orthogonal to the general factor and together explained an additional 20% of the variance. The general factor was associated with declines in general cognitive ability (r = 0.431, p < 0.001) and in the domains of visuospatial ability (r = 0.415, p = 0.002), processing speed (r = 0.383, p < 0.001) and memory (r = 0.372, p < 0.001). Individual differences in brain cortical atrophy with ageing are manifest across three broad dimensions of the cerebral cortex, the most general of which is linked with cognitive declines across domains. Longitudinal approaches are invaluable for distinguishing lifelong patterns of brain-behaviour associations from patterns that are specific to aging.

Psychotic-like experiences, polygenic risk scores for schizophrenia, and structural properties of the salience, default mode, and central-executive networks in healthy participants from UK Biobank.

Schizophrenia is a highly heritable disorder with considerable phenotypic heterogeneity. Hallmark psychotic symptoms can be considered as existing on a continuum from non-clinical to clinical populations. Assessing genetic risk and psychotic-like experiences (PLEs) in non-clinical populations and their associated neurobiological underpinnings can offer valuable insights into symptom-associated brain mechanisms without the potential confounds of the effects of schizophrenia and its treatment. We leveraged a large population-based cohort (UKBiobank, N = 3875) including information on PLEs (obtained from the Mental Health Questionnaire (MHQ); UKBiobank Category: 144; N auditory hallucinations = 55, N visual hallucinations = 79, N persecutory delusions = 16, N delusions of reference = 13), polygenic risk scores for schizophrenia (PRSSZ) and multi-modal brain imaging in combination with network neuroscience. Morphometric (cortical thickness, volume) and water diffusion (fractional anisotropy) properties of the regions and pathways belonging to the salience, default-mode, and central-executive networks were computed. We hypothesized that these anatomical concomitants of functional dysconnectivity would be negatively associated with PRSSZ and PLEs. PRSSZ was significantly associated with a latent measure of cortical thickness across the salience network (r = -0.069, p = 0.010) and PLEs showed a number of significant associations, both negative and positive, with properties of the salience and default mode networks (involving the insular cortex, supramarginal gyrus, and pars orbitalis, pFDR < 0.050); with the cortical thickness of the insula largely mediating the relationship between PRSSZ and auditory hallucinations. Generally, these results are consistent with the hypothesis that higher genetic liability for schizophrenia is related to subtle disruptions in brain structure and may predispose to PLEs even among healthy participants. In addition, our study suggests that networks engaged during auditory hallucinations show structural associations with PLEs in the general population.

Polygenic risk score for schizophrenia and structural brain connectivity in older age: A longitudinal connectome and tractography study.

Higher polygenic risk score for schizophrenia (szPGRS) has been associated with lower cognitive function and might be a predictor of decline in brain structure in apparently healthy populations. Age-related declines in structural brain connectivity-measured using white matter diffusion MRI -are evident from cross-sectional data. Yet, it remains unclear how graph theoretical metrics of the structural connectome change over time, and whether szPGRS is associated with differences in ageing-related changes in human brain connectivity. Here, we studied a large, relatively healthy, same-year-of-birth, older age cohort over a period of 3 years (age ∼ 73 years, N = 731; age ∼76 years, N = 488). From their brain scans we derived tract-averaged fractional anisotropy (FA) and mean diffusivity (MD), and network topology properties. We investigated the cross-sectional and longitudinal associations between these structural brain variables and szPGRS. Higher szPGRS showed significant associations with longitudinal increases in MD in the splenium (ß = 0.132, pFDR = 0.040), arcuate (ß = 0.291, pFDR = 0.040), anterior thalamic radiations (ß = 0.215, pFDR = 0.040) and cingulum (ß = 0.165, pFDR = 0.040). Significant declines over time were observed in graph theory metrics for FA-weighted networks, such as mean edge weight (ß = -0.039, pFDR = 0.048) and strength (ß = -0.027, pFDR = 0.048). No significant associations were found between szPGRS and graph theory metrics. These results are consistent with the hypothesis that szPGRS confers risk for ageing-related degradation of some aspects of structural connectivity.

Cognitive function, disease burden and the structural connectome in systemic lupus erythematosus.

Objective To investigate brain structural connectivity in relation to cognitive abilities and systemic damage in systemic lupus erythematosus (SLE). Methods Structural and diffusion MRI data were acquired from 47 patients with SLE. Brains were segmented into 85 cortical and subcortical regions and combined with whole brain tractography to generate structural connectomes using graph theory. Global cognitive abilities were assessed using a composite variable g, derived from the first principal component of three common clinical screening tests of neurological function. SLE damage ( LD) was measured using a composite of a validated SLE damage score and disease duration. Relationships between network connectivity metrics, cognitive ability and systemic damage were investigated. Hub nodes were identified. Multiple linear regression, adjusting for covariates, was employed to model the outcomes g and LD as a function of network metrics. Results The network measures of density (standardised ß = 0.266, p = 0.025) and strength (standardised ß = 0.317, p = 0.022) were independently related to cognitive abilities. Strength (standardised ß = -0.330, p = 0.048), mean shortest path length (standardised ß = 0.401, p = 0.020), global efficiency (standardised ß = -0.355, p = 0.041) and clustering coefficient (standardised ß = -0.378, p = 0.030) were independently related to systemic damage. Network metrics were not related to current disease activity. Conclusion Better cognitive abilities and more SLE damage are related to brain topological network properties in this sample of SLE patients, even those without neuropsychiatric involvement and after correcting for important covariates. These data show that connectomics might be useful for understanding and monitoring cognitive function and white matter damage in SLE.

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.

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.

Association of polygenic risk for major psychiatric illness with subcortical volumes and white matter integrity in UK Biobank.

Major depressive disorder (MDD), schizophrenia (SCZ) and bipolar disorder (BP) are common, disabling and heritable psychiatric diseases with a complex overlapping polygenic architecture. Individuals with these disorders, as well as their unaffected relatives, show widespread structural differences in corticostriatal and limbic networks. Structural variation in many of these brain regions is also heritable and polygenic but whether their genetic architecture overlaps with that of major psychiatric disorders is unknown. We sought to address this issue by examining the impact of polygenic risk of MDD, SCZ, and BP on subcortical brain volumes and white matter (WM) microstructure in a large single sample of neuroimaging data; the UK Biobank Imaging study. The first release of UK Biobank imaging data comprised participants with overlapping genetic data and subcortical volumes (N = 978) and WM measures (N = 816). The calculation of polygenic risk scores was based on genome-wide association study results generated by the Psychiatric Genomics Consortium. Our findings indicated no statistically significant associations between either subcortical volumes or WM microstructure, and polygenic risk for MDD, SCZ or BP. These findings suggest that subcortical brain volumes and WM microstructure may not be closely linked to the genetic mechanisms of major psychiatric disorders.

Fatigue and cognitive function in systemic lupus erythematosus: associations with white matter microstructural damage. A diffusion tensor MRI study and meta-analysis.

Objective The objective of this study was to investigate fatigue and cognitive impairments in systemic lupus erythematous (SLE) in relation to diffuse white matter microstructural brain damage. Methods Diffusion tensor MRI, used to generate biomarkers of brain white matter microstructural integrity, was obtained in patients with SLE and age-matched controls. Fatigue and cognitive function were assessed and related to SLE activity, clinical data and plasma biomarkers of inflammation and endothelial dysfunction. Results Fifty-one patients with SLE (mean age 48.8 ± 14.3 years) were included. Mean diffusivity (MD) was significantly higher in all white matter fibre tracts in SLE patients versus age-matched healthy controls ( p < 0.0001). Fatigue in SLE was higher than a normal reference range ( p < 0.0001) and associated with lower MD ( ß = -0.61, p = 0.02), depression ( ß = 0.17, p = 0.001), anxiety ( ß = 0.13, p = 0.006) and higher body mass index ( ß = 0.10, p = 0.004) in adjusted analyses. Poorer cognitive function was associated with longer SLE disease duration ( p = 0.003) and higher MD ( p = 0.03) and, in adjusted analysis, higher levels of IL-6 ( ß = -0.15, p = 0.02) but not with MD. Meta-analysis (10 studies, n = 261, including the present study) confirmed that patients with SLE have higher MD than controls. Conclusion Patients with SLE have more microstructural brain white matter damage for age than the general population, but this does not explain increased fatigue or lower cognition in SLE. The association between raised IL-6 and worse current cognitive function in SLE should be explored in larger datasets.

Social responsiveness to inanimate entities: Altered white matter in a 'social synaesthesia'.

Judgments about personalities and social traits can be made by relatively brief exposure to animate living things. Here we show that unusual architecture in the microstructure of the human brain is related to atypical mental projections of personality and social structure onto things that are neither living nor animate. Our participants experience automatic, life-long and consistent crossmodal associations between language sequences (e.g., letters, numbers and days) and complex personifications (e.g., A is a businessman; 7 a good-natured woman). Participants with this 'Ordinal Linguistic Personification' (Simner and Hubbard, 2006) which we describe here as a form of social synaesthesia, showed lower fractional anisotropy (FA) values in five clusters at whole-brain significance, compared with non-synaesthetes (in the pre-postcentral gyrus/dorsal corticospinal tract, left superior corona radiata, and the genu, body and left side of the corpus callosum). We found no regions of the brain with increased FA in synaesthetes. A number of these regions with reduced FA play a role in social responsiveness, and our study is the first to show that unusual differences in white matter microstructure in these regions is associated with compelling feelings of social cohesion and personality towards non-animate entities. We show too that altered patterns of connectivity known to typify synaesthesia are not limited to variants involving a 'merging of the senses', but also extend to what might be thought of as a cogno-social variant of synaesthesia, linking language and personality attributes in this surprising way.

Epigenomic profiling of preterm infants reveals DNA methylation differences at sites associated with neural function.

DNA methylation (DNAm) plays a determining role in neural cell fate and provides a molecular link between early-life stress and neuropsychiatric disease. Preterm birth is a profound environmental stressor that is closely associated with alterations in connectivity of neural systems and long-term neuropsychiatric impairment. The aims of this study were to examine the relationship between preterm birth and DNAm, and to investigate factors that contribute to variance in DNAm. DNA was collected from preterm infants (birth<33 weeks gestation) and healthy controls (birth>37 weeks), and a genome-wide analysis of DNAm was performed; diffusion magnetic resonance imaging (dMRI) data were acquired from the preterm group. The major fasciculi were segmented, and fractional anisotropy, mean diffusivity and tract shape were calculated. Principal components (PC) analysis was used to investigate the contribution of MRI features and clinical variables to variance in DNAm. Differential methylation was found within 25 gene bodies and 58 promoters of protein-coding genes in preterm infants compared with controls; 10 of these have neural functions. Differences detected in the array were validated with pyrosequencing. Ninety-five percent of the variance in DNAm in preterm infants was explained by 23 PCs; corticospinal tract shape associated with 6th PC, and gender and early nutritional exposure associated with the 7th PC. Preterm birth is associated with alterations in the methylome at sites that influence neural development and function. Differential methylation analysis has identified several promising candidate genes for understanding the genetic/epigenetic basis of preterm brain injury.

Cigarette smoking and thinning of the brain's cortex.

Cigarette smoking is associated with cognitive decline and dementia, but the extent of the association between smoking and structural brain changes remains unclear. Importantly, it is unknown whether smoking-related brain changes are reversible after smoking cessation. We analyzed data on 504 subjects with recall of lifetime smoking data and a structural brain magnetic resonance imaging at age 73 years from which measures of cortical thickness were extracted. Multiple regression analyses were performed controlling for gender and exact age at scanning. To determine dose-response relationships, the association between smoking pack-years and cortical thickness was tested and then repeated, while controlling for a comprehensive list of covariates including, among others, cognitive ability before starting smoking. Further, we tested associations between cortical thickness and number of years since last cigarette, while controlling for lifetime smoking. There was a diffuse dose-dependent negative association between smoking and cortical thickness. Some negative dose-dependent cortical associations persisted after controlling for all covariates. Accounting for total amount of lifetime smoking, the cortex of subjects who stopped smoking seems to have partially recovered for each year without smoking. However, it took ~25 years for complete cortical recovery in affected areas for those at the mean pack-years value in this sample. As the cortex thins with normal aging, our data suggest that smoking is associated with diffuse accelerated cortical thinning, a biomarker of cognitive decline in adults. Although partial recovery appears possible, it can be a long process.

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.

Effects of acute glucocorticoid blockade on metabolic dysfunction in patients with Type 2 diabetes with and without fatty liver.

To investigate the potential of therapies which reduce glucocorticoid action in patients with Type 2 diabetes we performed a randomized, double-blinded, placebo-controlled crossover study of acute glucocorticoid blockade, using the glucocorticoid receptor antagonist RU38486 (mifepristone) and cortisol biosynthesis inhibitor (metyrapone), in 14 men with Type 2 diabetes. Stable isotope dilution methodologies were used to measure the rates of appearance of glucose, glycerol, and free fatty acids (FFAs), including during a low-dose (10 mU·m⁻² ·min⁻¹) hyperinsulinemic clamp, and subgroup analysis was conducted in patients with high or low liver fat content measured by magnetic resonance spectroscopy (n = 7/group). Glucocorticoid blockade lowered fasting glucose and insulin levels and improved insulin sensitivity of FFA and glycerol turnover and hepatic glucose production. Among this population with Type 2 diabetes high liver fat was associated with hyperinsulinemia, higher fasting glucose levels, peripheral and hepatic insulin resistance, and impaired suppression of FFA oxidation and FFA and glycerol turnover during hyperinsulinemia. Glucocorticoid blockade had similar effects in those with and without high liver fat. Longer term treatments targeting glucocorticoid action may be useful in Type 2 diabetes with and without fatty liver.

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.

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.

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.