Disrupted limbic-prefrontal effective connectivity in response to fearful faces in lifetime depression.

BACKGROUND: Multiple brain imaging studies of negative emotional bias in major depressive disorder (MDD) have used images of fearful facial expressions and focused on the amygdala and the prefrontal cortex. The results have, however, been inconsistent, potentially due to small sample sizes (typically N<50). It remains unclear if any alterations are a characteristic of current depression or of past experience of depression, and whether there are MDD-related changes in effective connectivity between the two brain regions. METHODS: Activations and effective connectivity between the amygdala and dorsolateral prefrontal cortex (DLPFC) in response to fearful face stimuli were studied in a large population-based sample from Generation Scotland. Participants either had no history of MDD (N=664 in activation analyses, N=474 in connectivity analyses) or had a diagnosis of MDD during their lifetime (LMDD, N=290 in activation analyses, N=214 in connectivity analyses). The within-scanner task involved implicit facial emotion processing of neutral and fearful faces. RESULTS: Compared to controls, LMDD was associated with increased activations in left amygdala (PFWE=0.031,kE=4) and left DLPFC (PFWE=0.002,kE=33), increased mean bilateral amygdala activation (ß=0.0715,P=0.0314), and increased inhibition from left amygdala to left DLPFC, all in response to fearful faces contrasted to baseline. Results did not appear to be attributable to depressive illness severity or antidepressant medication status at scan time. LIMITATIONS: Most studied participants had past rather than current depression, average severity of ongoing depression symptoms was low, and a substantial proportion of participants were receiving medication. The study was not longitudinal and the participants were only assessed a single time. CONCLUSIONS: LMDD is associated with hyperactivity of the amygdala and DLPFC, and with stronger amygdala to DLPFC inhibitory connectivity, all in response to fearful faces, unrelated to depression severity at scan time. These results help reduce inconsistency in past literature and suggest disruption of 'bottom-up' limbic-prefrontal effective connectivity in depression.

Metabolite Signature and Differential Expression of Genes in Washington Navel Oranges (Citrus sinensis) Infected by Spiroplasma citri.

Spiroplasma citri is the pathogen that causes citrus stubborn disease (CSD). Infection of citrus with S. citri has been shown to cause leaf mottling, reduce fruit yield, and stunt tree growth. Fruit from trees exhibiting symptoms of CSD are misshapen and discolored. The symptoms of CSD are easily confused with nutrient deficiencies or symptoms of citrus greening disease. In this study, young Washington navel oranges (Citrus sinensis) were graft-inoculated with budwood originating from trees confirmed to be infected with S. citri. Leaf samples were collected monthly for 10 months for metabolomics and differential gene expression analyses. Significant differences in the concentration of metabolites and expressed genes were observed between control and S. citri-infected trees throughout the experiment. Metabolites and genes associated with important defense and stress pathways, including jasmonic acid signaling, cell wall modification, amino acid biosynthesis, and the production of antioxidant and antimicrobial secondary metabolites, were impacted by S. citri throughout the study, and even prior to symptom development. This work fills a current gap in knowledge surrounding the pathogenicity of S. citri and provides an updated mechanistic explanation for the development of CSD symptoms in S. citri-infected plants.

Spectral clustering based on structural magnetic resonance imaging and its relationship with major depressive disorder and cognitive ability.

There is increasing interest in using data-driven unsupervised methods to identify structural underpinnings of common mental illnesses, including major depressive disorder (MDD) and associated traits such as cognition. However, studies are often limited to severe clinical cases with small sample sizes and most do not include replication. Here, we examine two relatively large samples with structural magnetic resonance imaging (MRI), measures of lifetime MDD and cognitive variables: Generation Scotland (GS subsample, N = 980) and UK Biobank (UKB, N = 8,900), for discovery and replication, using an exploratory approach. Regional measures of FreeSurfer derived cortical thickness (CT), cortical surface area (CSA), cortical volume (CV) and subcortical volume (subCV) were input into a clustering process, controlling for common covariates. The main analysis steps involved constructing participant K-nearest neighbour graphs and graph partitioning with Markov stability to determine optimal clustering of participants. Resultant clusters were (1) checked whether they were replicated in an independent cohort and (2) tested for associations with depression status and cognitive measures. Participants separated into two clusters based on structural brain measurements in GS subsample, with large Cohen's d effect sizes between clusters in higher order cortical regions, commonly associated with executive function and decision making. Clustering was replicated in the UKB sample, with high correlations of cluster effect sizes for CT, CSA, CV and subCV between cohorts across regions. The identified clusters were not significantly different with respect to MDD case-control status in either cohort (GS subsample: pFDR = .2239-.6585; UKB: pFDR = .2003-.7690). Significant differences in general cognitive ability were, however, found between the clusters for both datasets, for CSA, CV and subCV (GS subsample: d = 0.2529-.3490, pFDR  < .005; UKB: d = 0.0868-0.1070, pFDR  < .005). Our results suggest that there are replicable natural groupings of participants based on cortical and subcortical brain measures, which may be related to differences in cognitive performance, but not to the MDD case-control status.

Blunted medial prefrontal cortico-limbic reward-related effective connectivity and depression.

Major depressive disorder is a leading cause of disability and significant mortality, yet mechanistic understanding remains limited. Over the past decade evidence has accumulated from case-control studies that depressive illness is associated with blunted reward activation in the basal ganglia and other regions such as the medial prefrontal cortex. However it is unclear whether this finding can be replicated in a large number of subjects. The functional anatomy of the medial prefrontal cortex and basal ganglia has been extensively studied and the former has excitatory glutamatergic projections to the latter. Reduced effect of glutamatergic projections from the prefrontal cortex to the nucleus accumbens has been argued to underlie motivational disorders such as depression, and many prominent theories of major depressive disorder propose a role for abnormal cortico-limbic connectivity. However, it is unclear whether there is abnormal reward-linked effective connectivity between the medial prefrontal cortex and basal ganglia related to depression. While resting state connectivity abnormalities have been frequently reported in depression, it has not been possible to directly link these findings to reward-learning studies. Here, we tested two main hypotheses. First, mood symptoms are associated with blunted striatal reward prediction error signals in a large community-based sample of recovered and currently ill patients, similar to reports from a number of studies. Second, event-related directed medial prefrontal cortex to basal ganglia effective connectivity is abnormally increased or decreased related to the severity of mood symptoms. Using a Research Domain Criteria approach, data were acquired from a large community-based sample of subjects who participated in a probabilistic reward learning task during event-related functional MRI. Computational modelling of behaviour, model-free and model-based functional MRI, and effective connectivity dynamic causal modelling analyses were used to test hypotheses. Increased depressive symptom severity was related to decreased reward signals in areas which included the nucleus accumbens in 475 participants. Decreased reward-related effective connectivity from the medial prefrontal cortex to striatum was associated with increased depressive symptom severity in 165 participants. Decreased striatal activity may have been due to decreased cortical to striatal connectivity consistent with glutamatergic and cortical-limbic related theories of depression and resulted in reduced direct pathway basal ganglia output. Further study of basal ganglia pathophysiology is required to better understand these abnormalities in patients with depressive symptoms and syndromes.

Aspirin moderates the association between cardiovascular risk, brain white matter hyperintensity total lesion volume and processing speed in normal ageing.

OBJECTIVES: Cardiovascular risk is associated with cognitive decline and this effect is attributed to brain pathology, including white matter hyperintensity (WMH) burden. Low-dose aspirin is frequently recommended for reducing vascular events. We investigated the effect of taking aspirin on the association between cardiovascular risk, WMH burden and cognitive function. STUDY DESIGN: The study sample was drawn from 318 dementia-free adults aged 67-71 years. Brain magnetic resonance imaging (MRI) scans were acquired from 239 participants. MAIN OUTCOME MEASURES: WMH total lesion volumes (TLV) were extracted using the automated lesion segmentation algorithm. We measured cardiovascular risk by calculating ASSIGN score. Cognitive ability was measured using a test of processing speed. We developed structural equation models to test our hypothesis. RESULTS: Sixty-eight participants (47.1 % male, mean age = 68.8 years) reported that they took aspirin. The demographic measures did not differ significantly by aspirin use. Among aspirin users, there was a strong negative association between WMH TLV and cognition (ß = -0.43, p-value < 0.001), while in non-users of aspirin the only significant predictor of poorer cognition was cardiovascular risk (ß = -0.17, p-value = 0.001). CONCLUSIONS: Aspirin use moderates the negative effect of WMH burden on cognition. Considering WMH burden in addition to cardiovascular risk could improve the prediction of cognitive decline in older adults with aspirin use.

Evaluation of California-Grown Blood and Cara Cara Oranges Through Consumer Testing, Descriptive Analysis, and Targeted Chemical Profiling.

The acceptability of Moro, Tarocco, Cara Cara, Shahani, Bream Tarocco, Boukhobza, and Sanguinelli oranges from both commercial and research orchards was tested with adult (n = 152) and child (n = 72) consumers. Qualitative focus groups were also conducted to understand consumer familiarity and thoughts about the fruit. Sensory descriptive and chemical analyses were carried out to identify drivers of liking. Overall, consumers preferred the lighter colored varieties consisting of Tarocco, Cara Cara, and Boukhobza. One cluster of adults (n = 80) showed preferences towards sweet and fruity flavors and away from sourness and citric acid. The second adult cluster (n = 72) was tolerant of the sour fruit but did not like fruit high in bitterness and flavonoid content. The largest child cluster (n = 42) showed preferences for samples higher in orange and tropical flavors (Cara Cara, Tarocco, and Boukhobza varieties). The appearance of the Cara Cara was strongly liked by the consumer population in both quantitative and qualitative settings. Hunter scale a color values strongly correlated to the higher berry/dried fruit flavors, and concentrations of naringenin. Focus group participants noted that they were relatively unfamiliar with blood oranges. Growers and producers may want to invest in the lighter colored varieties, such as Cara Cara, Tarocco, Boukhobza and Shahani, as these were liked by a majority of consumers and were low in less desirable sensory characteristics, such as bitterness and sourness. PRACTICAL APPLICATION: Through consumer tests, sensory evaluation, and chemical analyses, this research uncovered which sensory properties may drive consumer acceptance of blood and Cara Cara oranges, and informed potential production and marketing strategies for increasing their consumption. This information should benefit the citrus industry as a whole and may enhance the use of specialty oranges by the food, beverage, and food service industries.

Cohort profile for the STratifying Resilience and Depression Longitudinally (STRADL) study: A depression-focused investigation of Generation Scotland, using detailed clinical, cognitive, and neuroimaging assessments.

STratifying Resilience and Depression Longitudinally (STRADL) is a population-based study built on the Generation Scotland: Scottish Family Health Study (GS:SFHS) resource. The aim of STRADL is to subtype major depressive disorder (MDD) on the basis of its aetiology, using detailed clinical, cognitive, and brain imaging assessments. The GS:SFHS provides an important opportunity to study complex gene-environment interactions, incorporating linkage to existing datasets and inclusion of early-life variables for two longitudinal birth cohorts. Specifically, data collection in STRADL included: socio-economic and lifestyle variables; physical measures; questionnaire data that assesses resilience, early-life adversity, personality, psychological health, and lifetime history of mood disorder; laboratory samples; cognitive tests; and brain magnetic resonance imaging. Some of the questionnaire and cognitive data were first assessed at the GS:SFHS baseline assessment between 2006-2011, thus providing longitudinal measures of depression and resilience. Similarly, routine NHS data and early-life variables are linked to STRADL data, further providing opportunities for longitudinal analysis. Recruitment has been completed and we consented and tested 1,188 participants.

The Neurobiology of Personal Control During Reward Learning and Its Relationship to Mood.

BACKGROUND: The majority of reward learning neuroimaging studies have not focused on the motivational aspects of behavior, such as the inherent value placed on choice itself. The experience and affective value of personal control may have particular relevance for psychiatric disorders, including depression. METHODS: We adapted a functional magnetic resonance imaging reward task that probed the value placed on exerting control over one's decisions, termed choice value, in 122 healthy participants. We examined activation associated with choice value; personally chosen versus passively received rewards; and reinforcement learning metrics, such as prediction error. Relationships were tested between measures of motivational orientation (categorized as autonomy, control, and impersonal) and subclinical depressive symptoms. RESULTS: Anticipating personal choice activated left insula, cingulate, right inferior frontal cortex, and ventral striatum (pfamilywise error-corrected < .05). Ventral striatal activations to choice were diminished in participants with subclinical depressive symptoms. Personally chosen rewards were associated with greater activation of the insula and inferior frontal gyrus, cingulate cortex, hippocampus, thalamus, and substantia nigra compared with rewards that were passively received. In participants who felt they had little control over their own behavior (impersonal orientation), prediction error signals in nucleus accumbens were stronger during passive trials. CONCLUSIONS: Previous findings regarding personal choice have been verified and advanced through the use of both reinforcement learning models and correlations with psychopathology. Personal choice has an impact on the extended reward network, potentially allowing these clinically important areas to be addressed in ways more relevant to personality styles, self-esteem, and symptoms such as motivational anhedonia.

The association between polypharmacy and late life deficits in cognitive, physical and emotional capability: a cohort study.

Background Polypharmacy is a growing health concern for older adults and is associated with poorer clinical outcome. Objective This study aim is to investigate the association between polypharmacy and impairment in cognitive, physical and emotional capability controlling for the confounding effect of co-morbidities. Setting The Aberdeen 1936 Birth Cohort from 1999 to 2004. Method Recruited were 498 dementia free participants around 64 years old and recruited into wave one. Linear regression and structural equation models were used. Models were adjusted for the effect of age, gender, childhood IQ, education and Body Mass Index. A triad of impairment was defined as a composite measure of impairment in cognitive, physical and emotional function. Main outcome measure The relationships between polypharmacy, co-morbidity and triad of impairment. Results The prevalence of polypharmacy was 12.3% in this relatively healthy sample. Polypharmacy was significantly associated with increased impairment in cognitive, physical and emotional ability (ß = 3.6, p = 0.003) after controlling for the effect of comorbidities and other confounding variables. As expected, higher childhood IQ and educational achievement had protective effects against impairment while higher comorbidity score and Body Mass Index were associated with increased impairment in this population. Conclusions The independent association of polypharmacy and reduced cognitive, physical and emotional capability makes this a promising target for predicting and potentially reducing the risk of impairment and associated healthcare costs in older adults. Longitudinal studies are required to investigate the underlying mechanisms for the observed relationships further.

Increased diastolic blood pressure is associated with MRI biomarkers of dementia-related brain pathology in normative ageing.

Background: hypertension is a risk for brain ageing, but the mechanisms underlying this effect remain unclear. Magnetic resonance imaging (MRI) detected biomarkers of brain ageing include white matter hyperintensities (WMHs), a marker of cerebrovascular disease, and hippocampal volume, a marker of Alzheimer's disease pathology. Objective: to examine relationships between blood pressure (BP) components and brain pathology in older adults. Subjects: two hundred and twenty-seven members of the Aberdeen 1936 Birth Cohort between ages 64 and 68 years. Methods: BP was assessed biennially between 64 and 68 years and brain MRI performed at 68 years. The risk factors of interest were diastolic and systolic BP and their visit-to-visit variability. Outcomes were WMH abundance and hippocampal volume. Regression models, controlling for confounding factors, examined their relationships. Results: higher diastolic BP predicted increased WMH (ß = 0.13, P = 0.044) and smaller hippocampi (ß = -0.25, P = 0.006). In contrast, increased systolic BP predicted larger hippocampi (ß = 0.22, P = 0.013). Variability of diastolic BP predicted lower hippocampal volume (ß = -0.15, P = 0.033). These relationships were independent of confounding life-course risk factors. Anti-hypertensive medication did not modify these relationships, but was independently associated with increased WMH (ß = 0.17, P = 0.011). Conclusion: increased diastolic BP is associated with biomarkers of both cerebrovascular and Alzheimer's diseases, whereas the role of systolic BP is less clear, with evidence for a protective effect on hippocampal volume. These differing relationships emphasise the importance of considering individual BP components with regard to brain ageing and pathology. Interventions targeting diastolic hypertension and its chronic variability may provide new strategies able to slow the accumulation of these harmful pathologies.

Klotho, APOEε4, cognitive ability, brain size, atrophy, and survival: a study in the Aberdeen Birth Cohort of 1936.

A single copy of klotho allele KL-VS is associated with longevity, better health, increased cognition, and bigger regional brain volume. However, its longitudinal effects on cognition and brain volumes, both global and regional, in late life are unclear. In this study we show that, relative to noncarriers, KL-VS heterozygotes had (1) shorter survival; (2) smaller white matter volumes; (3) slower cognitive decline; and (4) greater right frontal lobe volumes. The KL-VS heterozygote survival and white matter volume disadvantages were unexpected. A possible explanation for these results in the context of the literature is a potential interaction between the environment and/or age of the participants, leading to a heterozygote disadvantage. The longitudinal cognitive trajectories indicate that heterozygotes would have an advantage in very late life. Collectively these results suggest that the genotype-survival advantage of the KL-VS allele is age-dependent and possibly mediated through differential cognition and brain volume.

A comparison of measurement methods of hippocampal atrophy rate for predicting Alzheimer's dementia in the Aberdeen Birth Cohort of 1936.

INTRODUCTION: Various methods are available to measure hippocampal atrophy rate. We compared methods to predict Alzheimer's dementia. METHODS: Participants with brain imaging at ages 69 and 73 years were identified from a previous study. Simple manual measures and computationally automated volumetry were performed. Receiver operating characteristics assessed the predictive ability of each method at baseline and on logit regression analysis of two serial scans. RESULTS: Ten of 149 participants developed Alzheimer's dementia and had lower baseline volumes (3647 vs. 4194 mm3P = .002), rates of volume loss (-126 vs. -36 mm3/y; P = .001), and rates of loss in hippocampal fraction (-8.55 vs. -2.35 x 10-5/y; P = .001). Baseline volume with a rate of change gave the highest area under the curve value of 0.96. DISCUSSION: Automated volumetry measuring hippocampal size at age 69 years and subsequent rate of change predicts Alzheimer's dementia development.

Late-life deficits in cognitive, physical and emotional functions, childhood intelligence and occupational profile: a life-course examination of the Aberdeen 1936 Birth Cohort (ABC1936).

OBJECTIVES: the 'triad of impairment' phenomenon describes the co-occurrence of age-related cognitive, emotional and physical functioning deficits. We investigated how occupational profile and childhood intelligence contribute to the triad of impairment in late life. METHODS: we analysed data of a subsample of the Aberdeen Birth Cohort of 1936 (n = 346). Data were collected on participants' childhood intelligence, late-life cognitive ability, physical functioning, depressive symptoms and main lifetime occupation. We summarised the various occupational and impairment measures into two latent variables, 'occupational profile' and the 'triad of impairment'. We used a series of data reduction approaches and structural equation models (SEMs) of increasing complexity to test both the validity of the models and to understand causal relationships between the life-course risks for the triad of impairment. RESULTS: occupational profile had a significant effect on the triad of impairment independent of childhood intelligence. Childhood intelligence was the predominant influence on the triad of impairment and exerted its effect directly and indirectly via its influence on occupation. The direct effect of childhood intelligence exceeded the independent influence of the occupational profile on impairment by a factor of 1.7-1.8 and was greater by a factor of ∼4 from the indirect pathway (via occupation). CONCLUSIONS: childhood intelligence was the predominant influence on the triad of impairment in late life, independently of the occupational profile. Efforts to reduce impairment in older adults should be informed by a life-course approach with special attention to the early-life environment.

Nutritional B vitamin deficiency alters the expression of key proteins associated with vascular smooth muscle cell proliferation and migration in the aorta of atherosclerotic apolipoprotein E null mice.

Low B vitamin status is linked with human vascular disease. We employed a proteomic and biochemical approach to determine whether nutritional folate deficiency and/or hyperhomocysteinemia altered metabolic processes linked with atherosclerosis in ApoE null mice. Animals were fed either a control fat (C; 4 % w/w lard) or a high-fat [HF; 21 % w/w lard and cholesterol (0/15 % w/w)] diet with different B vitamin compositions for 16 weeks. Aorta tissue was prepared and global protein expression, B vitamin, homocysteine and lipoprotein status measured. Changes in the expression of aorta proteins were detected in response to multiple B vitamin deficiency combined with a high-fat diet (P < 0.05) and were strongly linked with lipoprotein concentrations measured directly in the aorta adventitia (P < 0.001). Pathway analysis revealed treatment effects in the aorta-related primarily to cytoskeletal organisation, smooth muscle cell adhesion and invasiveness (e.g., fibrinogen, moesin, transgelin, vimentin). Combined B vitamin deficiency induced striking quantitative changes in the expression of aorta proteins in atherosclerotic ApoE null mice. Deregulated expression of these proteins is associated with human atherosclerosis. Cellular pathways altered by B vitamin status included cytoskeletal organisation, cell differentiation and migration, oxidative stress and chronic inflammation. These findings provide new insight into the molecular mechanisms through which B vitamin deficiency may accelerate atherosclerosis.

Early life socioeconomic circumstance and late life brain hyperintensities--a population based cohort study.

CONTEXT: There have been many reports confirming the association between lower childhood socioeconomic circumstance and cardiovascular disease but evidence for links with cerebrovascular disease is contradictory. Hyperintensities on brain magnetic resonance imaging are associated with vascular risk factors, cognitive decline, dementia and death. However, the relationship between childhood socioeconomic circumstance and these lesions is unclear. OBJECTIVE: To test the hypothesis that childhood socioeconomic circumstance is associated with late life hyperintensity burden and that neither adult socioeconomic circumstance nor change in socioeconomic circumstance during life influence this effect. DESIGN: Cohort study. SETTING: Community. PARTICIPANTS: 227 community dwelling members of the 1936 Aberdeen Birth Cohort aged 68 years, who were free from dementia. MAIN OUTCOME MEASURES: Relationship between early life socioeconomic circumstance (paternal occupation) and abundance of late life brain hyperintensities. RESULTS: We find significant negative correlations between childhood socioeconomic circumstance and white matter hyperintensities (ρ = -0.18, P<0.01), and periventricular hyperintensities (ρ = -0.15, P<0.05), between educational attainment and white matter hyperintensities (ρ = -0.15, P<0.05) and periventricular hyperintensities (ρ = -0.17, P<0.05), and between childhood intelligence and periventricular hyperintensities (ρ = -0.14, P<0.05). The relationship is strongest for childhood socioeconomic circumstance and regional white matter hyperintensities, where there is a step change in increased burden from paternal occupation grades equivalent to a shift from "white collar" to "blue collar" paternal occupation. Significant correlations were also found between hypertension and hyperintensity burden in all brain regions (ρ = 0.15-0.24, P<0.05). In models that include hypertension, the magnitude of the effect of childhood socioeconomic circumstance is similar to and independent from that of hypertension. CONCLUSIONS: Childhood socioeconomic circumstance predicts the burden of brain white matter hyperintensities aged 68 years. The mechanism underlying this effect is unknown, but may act through fetal and/or early life programming of cerebrovascular disease. Future work to understand this vulnerability will inform strategies to reduce dementia and stroke.

Depressive symptoms in late life and cerebrovascular disease: the importance of intelligence and lesion location.

BACKGROUND: The influence of white matter lesions on depressive symptoms in healthy ageing populations remains unclear. In this study, we examined the relationship between depressive symptoms and magnetic resonance imaging (MRI) detected cerebrovascular disease in a normal population living independently in the community, and measured the influence of location of brain abnormalities, fluid intelligence, living alone, and sex. METHODS: Prospective cohort: 497 community dwelling individuals all born in 1936, who took part in the Scottish Mental Survey of 1947, were followed up in 2000 and at biannual intervals in a longitudinal study of health and cognitive aging. Two hundred forty-four volunteered for brain MRI in 2004-2006. Suitable data were available in 219/244, of whom 115 were men. Brain hyperintensities in lobar white matter, basal ganglia , periventricular, and infratentorial regions were measured using Scheltens' scale. Depressed mood was assessed using the Hospital Anxiety and Depression Scale (HADS) on three biannual intervals. Relationships between Scheltens' scores, HADS-D scores, fluid intelligence, living alone, and sex were assessed using general linear modeling. RESULTS: The main predictor of depressive symptom scores was poorer fluid intelligence (partial η(2) =0.023-0.028, P < .05). Ischemic change in the brainstem (partial η(2) = 0.026, P ≤.05) and basal ganglia (partial η(2) =0.018, P ≤ .05) also predicted HADS-D scores. There was no relationship with sex or living alone. CONCLUSIONS: Hyperintensities in the brainstem and basal ganglia are associated with depressive symptoms. Higher fluid intelligence is associated with lower depressive symptoms in this normal, ageing population.

Nutritional B vitamin deficiency disrupts lipid metabolism causing accumulation of proatherogenic lipoproteins in the aorta adventitia of ApoE null mice.

SCOPE: Cardiovascular disease is the major cause of death in the world. Low dietary folate, elevated homocysteine, and high circulating cholesterol are risk factors. METHODS AND RESULTS: We investigated whether folate and/or B vitamin deficiency would change lipoprotein and fatty acid metabolism and lipid accumulation in the aorta adventitia of ApoE null mice. Mice (n = 10 per group) were fed a control (C; 4%) or high saturated fat (HF; 21%), and high cholesterol (0.15%) diet for 16 weeks. Folate (F-) or folate, B6 and B12 deficiency (F-B-) were imposed on these diets. Feeding a HF diet increased plasma and liver total cholesterol and HDL cholesterol (two- to threefold; p < 0.05). Total cholesterol increased (twofold; p < 0.05) in aorta adventitial lipid in response to HF. Feeding a diet depleted of folate and B vitamins (F-B-) significantly increased cholesterol accumulation in both liver and aorta adventitial lipid (approximately 50-70%; p < 0.05). Moreover, the proportions of fatty acids in hepatic and adventitial lipid was significantly changed by B vitamin depletion, measured as an increase in saturated fatty acids (approximately 15%) and a decrease (approximately 11%) in monounsaturated fatty acids (p < 0.05). CONCLUSION: B vitamin deficiency perturbs lipid metabolism in ApoE null mice, causing accumulation of proatherogenic cholesterol and fatty acids in the aorta adventitia.

The balance between cognitive reserve and brain imaging biomarkers of cerebrovascular and Alzheimer's diseases.

The cognitive reserve hypothesis explains the disparity between clinical and pathological phenotypes and why, in two individuals with the same extent of neuropathology, one may be demented while the other remains cognitively intact. We examined the balance between brain magnetic resonance imaging measures of the two most common pathologies associated with brain ageing, cerebrovascular disease and Alzheimer's disease, and parameters of cerebral reserve in well-characterized participants born in 1936, for whom childhood intelligence is known. Brain magnetic resonance imaging was carried out at 1.5T using fluid attenuation inversion recovery and T(1)-weighted volumetric sequences in 249 participants. Cerebrovascular disease was quantified by measuring brain white matter hyperintensities on fluid attenuation inversion recovery images using Scheltens' scale and Alzheimer's disease was measured from volumetric data using FreeSurfer to extract whole brain volume and hippocampal volumes in turn. The effect of these measures of brain burden on life-long cognitive ageing from the age of 11 to 68 years was compared with the effect of educational attainment and occupational grade using structural equation modelling. Complete brain burden and reserve data were available in 224 participants. We found that educational attainment, but not occupation, has a measurable and positive effect, with a standardized regression weight of +0.23, on late life cognitive ability in people without cognitive impairment aged 68 years, allowing for the influence of childhood intelligence and the two most common subclinical brain pathological burdens in the ageing brain. In addition, we demonstrate that the magnitude of the contribution of education is greater than the negative impact of either neuropathological burden alone, with standardized regression weights of -0.14 for white matter hyperintensities and -0.20 for hippocampal atrophy. This study illustrates how education counteracts the deleterious effects of cerebrovascular disease and Alzheimer's disease and highlights the importance of quantifying cognitive reserve in dementia research.

Maternal diets deficient in folic acid and related methyl donors modify mechanisms associated with lipid metabolism in the fetal liver of the rat.

Previously we have examined the effects of diets deficient in folic acid ( - F) or folate deficient with low methionine and choline ( - F LM LC) on the relative abundance of soluble proteins in the liver of the pregnant rat. In the present study we report the corresponding changes in the fetal liver at day 21 of gestation. The abundance of eighteen proteins increased when dams were fed the - F diet. When dams were fed the - F LM LC diet, thirty-three proteins increased and eight decreased. Many of the differentially abundant proteins in the fetal liver could be classified into the same functional groups as those previously identified in the maternal liver, namely protein synthesis, metabolism, lipid metabolism and proteins associated with the cytoskeleton and endoplasmic reticulum. The pattern was consistent with reduced cell proliferation in the - F LM LC group but not in the - F group. Metabolic enzymes associated with lipid metabolism changed in both the - F and - F LM LC groups. The mRNA for carnitine palmitoyl transferase were up-regulated and CD36 (fatty acid translocase) down-regulated in the - F group, suggesting increased mitochondrial oxidation of fatty acids as an indirect response to altered maternal lipid metabolism. In the - F LM LC group the mRNA for acetyl CoA carboxylase was down-regulated, suggesting reduced fatty acid synthesis. The mRNA for transcriptional regulators including PPARalpha and sterol response element-binding protein-1c were unchanged. These results suggest that an adequate supply of folic acid and the related methyl donors may benefit fetal development directly by improving lipid metabolism in fetal as well as maternal tissues.

Gene and protein expression profiles in the foetal liver of the pregnant rat fed a low protein diet.

Foetal growth is particularly sensitive to the protein content of the mother's diet. Microarray data from the foetal liver of pregnant rats fed normal (HP) or reduced protein diets (LP) were compared by gene set enrichment analysis. Soluble proteins from a second portion of the liver were analysed by two-dimensional gel electrophoresis. Genes associated with progesterone, insulin-like growth factor-1 and vascular endothelial growth factor were upregulated in HP compared to LP, in addition to genes associated with cell differentiation and signalling from the extracellular matrix. In contrast, cytokine signalling was downregulated. Proteomics showed that proteins associated with amino acid metabolism, mitochondrial function and cell motility were differentially abundant in the HP compared to the LP groups. These growth factor and extracellular matrix signalling pathways linked to cell motility may be important mediators of the changes in liver structure that occur in utero and persist into adult life.