No effect of folic acid and methionine supplementation on D4Z4 methylation in patients with facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is associated with a contraction of the D4Z4 allele on chromosome 4qter. There is also marked DNA hypomethylation of the D4Z4 allele. The DNA hypomethylation may have a central role in the pathogenesis of FSHD. Supplemental folic acid can boost DNA methylation. We evaluated the effect of oral folic acid and methionine supplementation on the methylation level of 4qter D4Z4 alleles in peripheral-blood lymphocytes of nine patients affected with FSHD and six healthy controls. Methylation levels did not change, while recommended serum-folate concentrations were reached.     

Television viewing,C-reactive protein,and depressive symptoms in older adults

There is emerging evidence for a link between sedentary behavior and mental health, although the mechanisms remain unknown. We tested if an underlying inflammatory process explains the association between sedentary behavior and depressive symptoms. We conducted a two year follow-up of 4964 (aged 64.5 ± 8.9 years) men and women from the English Longitudinal Study of Ageing, a cohort of community dwelling older adults. Self-reported TV viewing time was assessed at baseline as a marker of leisure time sedentary behavior. The eight-item Centre of Epidemiological Studies Depression (CES-D) scale was administered to measure depressive symptoms at follow-up. At baseline, TV time was associated with C-reactive protein (CRP), adjusted geometric mean CRP values were 2.94 mg/L (<2 h/d TV); 3.04 mg/L (2–4 h/d TV); 3.29 mg/L (4–6 h/d TV); 3.23 mg/L (>6 h/d TV). We observed both a direct association of TV time on CES-D score at follow-up (B = 0.08, 95% CI, 0.05, 0.10) and indirect effects (B = 0.07, 95% CI, 0.05, 0.08). The indirect effects were largely explained through lack of physical activity, smoking, and alcohol, but not by CRP or body mass index.     

Effects of folic acid supplementation on inflammatory and thrombogenic markers in chronic smokers. A randomised controlled trial

INTRODUCTION: Cigarette smoking may induce pro-inflammatory and pro-thrombotic changes. It is not known whether these abnormalities are caused at least partly by increased homocysteine levels. We investigated whether lowering homocysteine by folic acid supplementation might reduce the plasma concentration of inflammatory and thrombogenic markers in chronic smokers. MATERIAL AND METHODS: Twenty-four healthy cigarette smokers (age 37.8+/-2.5 years, mean+/-SEM) were randomly assigned to 4 weeks of folic acid 5 mg/day or placebo. The following parameters were measured before and after treatment: (1) markers of inflammation (C-reactive protein, CRP, and white cell count, WCC); (2) blood coagulation screen (Activated Partial Thromboplastin time Ratio, APTR, and International Normalized Ratio, INR); (3) pro-thrombotic markers (fibrinogen, factor VIII coagulant activity, VIII:C, von Willebrand factor, vWF, and D-dimer). RESULTS: Folic acid induced a significant reduction in homocysteine (10.8+/-0.6 vs. 8.2+/-0.5 micromol/l, p<0.001), plasma fibrinogen (3.15+/-0.14 vs. 2.87+/-0.14 g/l, p<0.05), and D-dimer (102+/-44 vs. 80+/-26 microg/l, p<0.05) concentrations. By contrast, no significant changes were observed in CRP (2.2+/-0.7 vs. 1.7+/-0.7 mg/l), WCC (7.2+/-0.5 vs. 6.8+/-0.5 10(9) cells/l), APTR (0.91+/-0.02 vs. 0.93+/-0.02), INR (0.92+/-0.01 vs. 0.91+/-0.01), vWF (103+/-8 vs. 102+/-9 U/dl), and VIII:C (120+/-8 vs. 107+/-8 U/dl) levels. Changes in folic acid plasma concentrations were significantly and negatively correlated with changes in fibrinogen (r=-0.48, p=0.01) but not with changes in D-dimer (r=-0.15, p=0.5) levels. Changes in plasma homocysteine concentrations did not correlate with changes in either fibrinogen or D-dimer. No significant changes in homocysteine, inflammatory and thrombogenic markers were observed in the placebo group. CONCLUSIONS: Short-term folic acid supplementation had no significant effects on inflammatory markers but induced a significant reduction in plasma fibrinogen and D-dimer concentrations in healthy chronic smokers. Thus, folic acid might have an anti-thrombotic effect in this high-risk group independent of the homocysteine lowering effect.     

No effect of C-reactive protein on early atherosclerosis in LDLR-/- / human C-reactive protein transgenic mice

The association between increased concentrations of C-reactive protein (CRP) and future cardiovascular events is well established. However, it is currently unclear whether this clinical observation represents an epiphenomenon or whether the pentraxin may actively promote the development of atherosclerosis. Experimental studies with knockout mice with a defect in apolipoprotein E (ApoE(-/-)) have been used to investigate the role of CRP in atherogenesis, but the results obtained have been contradictory so far. Since knockout mice with a defect in low density lipoprotein receptor (LDLR(-/-)) may represent a better model of atherogenesis compared to ApoE(-/-) animals, we undertook experiments to investigate the atherogenic potential of CRP using LDLR(-/-) knockout mice. We crossbred CRP transgenic animals expressing the human CRP pentraxin (huCRP) to LDLR(-/-) mice, fed the resulting double mutants a pro-atherogenic Western type diet (WTD) for four, eight or 12 weeks, respectively, and quantitated atherosclerotic lesion development. Significant differences of lesion size or lesion composition could not be detected between the huCRP-positive LDLR(-/-) mice and the huCRP-negative LDLR(-/-) controls corroborating the contention that CRP does not play a pathogenetic role in early murine atherogenesis.     

Spontaneous abortion and the prophylactic effect of folic acid supplementation in epileptic women undergoing antiepileptic therapy

Background   Antiepileptic drugs (AEDs) like phenytoin (PHE), carbamazepine (CBZ), barbiturates and valproic acid (VPA) interfere with folic acid absorption and metabolism, which in turn can be the cause of adverse pregnancy outcome. Objective   To study the prophylactic effect of folic acid supplementation with regard to spontaneous abortion and preterm delivery (fetal demise after week 20 of gestational age) in pregnant women receiving AED therapy, as well as benefits of most common dosage and preconceptional commencement. Methods   Prospective examination of 104 patients, registered in EURAP from 1999–2004 at a single center and a retrospective analysis of data from our epilepsy databank completed with medical records and patients interviews of the Department of Neurology of Innsbruck University Hospital from 1971 to 1999. Results   388 pregnancies in 244 patients were analyzed. Pregnancies with folic acid supplementation showed significant reduction of spontaneous abortion. With regard to monotherapies, in the group of women taking VPA, supplementation of folic acid had significant benefit. Other examined monotherapies (CBZ, PHE, and PB) known to interfere with folic acid showed no significant results. Conclusions   This study confirms the prophylactic effect of folic acid supplementation on spontaneous abortion. For AED therapy, folic acid supplementation should be part of the therapy of every pregnant epileptic woman, especially for those treated with VPA.     

C-reactive protein is related to memory and medial temporal brain volume in older adults

Recent research suggests a central role for inflammatory mechanisms in cognitive decline that may occur prior to evidence of neurodegeneration. Limited information exists, however, regarding the relationship between low-grade inflammation and cognitive function in healthy older adults. This study examined the relation between inflammation, verbal memory consolidation, and medial temporal lobe volumes in a cohort of older community-dwelling subjects. Subjects included 141 functionally intact, community-dwelling older adults with detectable (n = 76) and undetectable (n = 65) levels of C-reactive protein. A verbal episodic memory measure was administered to all subjects, and measures of delayed recall and recognition memory were assessed. A semiautomated parcellation program was used to analyze structural MRI scans. On the episodic memory task, analysis of covariance revealed a significant CRP group by memory recall interaction, such that participants with detectable levels of CRP evidenced worse performance after a delay compared to those with undetectable levels of CRP. Individuals with detectable CRP also demonstrated lower performance on a measure of recognition memory. Imaging data demonstrated smaller left medial temporal lobe volumes in the detectable CRP group as compared with the undetectable CRP group. These findings underscore a potential role for inflammation in cognitive aging as a modifiable risk factor.     

Acetylsalicylic acid is compounding to antiplatelet effect of C-reactive protein

The contribution of inflammatory process to the modulation of platelet response to acetylsalicylic acid (ASA) remains obscure. In our study, we examined the in vitro effect of C-reactive protein (CRP) on the ASA-mediated inhibition of collagen-stimulated platelet reactivity. Influence of CRP on platelet responsiveness to ASA was analysed using classical turbidimetric aggregation and flow cytometry. When acting alone, both C-reactive protein and ASA inhibited collagen-dependent platelet aggregation and reduced the expressions of two platelet surface membrane activation markers: P-selectin and activated GPIIbIIIa complex. Compared to the effects observed for ASA alone, the simultaneous action of both agents lead to further reductions in platelet aggregation (by 56.7+/-1.0% vs. 14.9+/-0.6%, p<0.0001) and lowered the expressions of platelet surface membrane P-selectin (by 72.1+/-5.3% vs. 65.0+/-6.0%, p<0.01) and activated GPIIbIIIa (by 67.0+/-5.6% vs. 47.7+/-8.3%, p<0.01). In general, our findings showed for the first time the augmenting effect of native C-reactive protein in the antiplatelet action of acetylsalicylic acid. Thus, we conclude that the effectiveness of aspirin therapy may strongly depend upon the presence of native CRP in circulation.     

Self-reported experiences of everyday discrimination are associated with elevated C-reactive protein levels in older African-American adults

Self-reported experiences of “everyday” discrimination have been linked to indices of cardiovascular disease and overall mortality and findings have been particularly pronounced for African-American populations. However, the biological mechanisms underlying these associations remain unclear. C-reactive protein (CRP), a marker of inflammation, is a known correlate of cardiovascular and other health outcomes and has also been linked to several psychosocial processes. To our knowledge, no studies have examined the association between experiences of discrimination and CRP. We examined the cross-sectional association between self-reported experiences of discrimination and CRP in a sample of 296 older African-American adults (70% female, mean age = 73.1). Experiences of discrimination were assessed with the 9-item everyday discrimination scale and CRP was assayed from blood samples. In linear regression models adjusted for age, sex and education, experiences of discrimination were associated with higher levels of CRP (B = .10, p = .03). This association remained significant after additional adjustments for depressive symptoms (B = .10, p = .04), smoking, and chronic health conditions (heart disease, diabetes, hypertension) that might influence inflammation (B = .11, p = .02). However, results were attenuated when body mass index (BMI) was added to the model (B = .09, p = .07). In conclusion, self-reported experiences of everyday discrimination are associated with higher levels of CRP in older African-American adults, although this association is not completely independent of BMI.     

Neurobiological markers of exercise-related brain plasticity in older adults

The current study examined how a randomized one-year aerobic exercise program for healthy older adults would affect serum levels of brain-derived neurotrophic factor (BDNF), insulin-like growth factor type 1 (IGF-1), and vascular endothelial growth factor (VEGF) – putative markers of exercise-induced benefits on brain function. The study also examined whether (a) change in the concentration of these growth factors was associated with alterations in functional connectivity following exercise, and (b) the extent to which pre-intervention growth factor levels were associated with training-related changes in functional connectivity. In 65 participants (mean age = 66.4), we found that although there were no group-level changes in growth factors as a function of the intervention, increased temporal lobe connectivity between the bilateral parahippocampus and the bilateral middle temporal gyrus was associated with increased BDNF, IGF-1, and VEGF for an aerobic walking group but not for a non-aerobic control group, and greater pre-intervention VEGF was associated with greater training-related increases in this functional connection. Results are consistent with animal models of exercise and the brain, but are the first to show in humans that exercise-induced increases in temporal lobe functional connectivity are associated with changes in growth factors and may be augmented by greater baseline VEGF.     

Homocysteine metabolism and effects of folic acid supplementation in patients affected with spina bifida

Folic acid supplementation around conception decreases the risk of having offspring with a neural tube defect. However, the aetiology is often still unknown. This study investigated whether spina bifida patients have lower blood folate and higher fasting and post-methionine-load plasma total homocysteine (tHcy) concentrations than control patients. Moreover, the effects of supplementation with 500 microg folic acid/d on folate and tHcy concentrations were determined. Spina bifida patients (n = 12) and disabled control patients (n = 15) received 4 weeks of placebo treatment followed by 4 weeks of intervention with 500 microg folic acid/d. Blood was collected at the start and after 4 and 8 weeks. A methionine-loading test was performed at the start and the end of the study. At baseline, no significant differences occurred between spina bifida and control patients. Folic acid supplementation significantly increased plasma and red blood cell folate concentrations in both groups. Folic acid decreased fasting tHcy concentrations in control patients by 1.6+/-0.5 micromol/l (p<0.01) and in spina bifida patients by 2.2 +/- 1.3 micromol/l (p = 0.10). This study does not show a derangement in homocysteine metabolism in spina bifida compared to control patients. Moreover, folic acid supplementation seems at least as effective in spina bifida patients as in controls.     

Effects of dietary folic acid supplementation on cerebrovascular endothelial dysfunction in rats with induced hyperhomocysteinemia

The gram-negative bacteria-derived endotoxin lipopolysaccharide (LPS) is known to play an important role in immune and neurological manifestations during bacterial infections. In mammals, peripheral or brain administration of LPS induces anorexia and is thought to exert its effects through activation of pro-inflammatory cytokines. In this study, we investigated the effects of peripheral (intraperitoneal, IP) and central (intracerebroventricular, ICV) injections of LPS on food intake of goldfish. Fish treated IP with 10, 25, 50, 100 or 250 ng/g LPS or ICV with 1, 10 and 100 ng/g LPS showed a significant dose-dependent decrease in food intake, compared to the saline-treated fish. We also examined the brain mRNA expression of several hypothalamic appetite-related neuropeptides in response to the administration of LPS. IP injections of LPS (100 ng/g) induced a decrease in NPY expression and an increase in CCK, CRF and CART expression. These results indicate that LPS is a potent anorexigenic factor in goldfish and that this endotoxin induces a reduction in appetite, at least in part, by influencing gene expression of appetite-related neuropeptides.     

Lifestyle factors and the course of depression in older adults: A NESDO study

Objectives

To investigate whether lifestyle indicators including physical exercise, sleep duration, alcohol use, body mass index, smoking status, and a composite lifestyle index are associated with the depression course in older adults.

Methods

Data of 283 older adults were used from the Netherlands Study of Depression in Older Persons. Depressive disorders at baseline were assessed with the Composite International Diagnostic Interview. The depression course at 2‐year follow‐up was assessed with the Inventory of Depressive Symptoms (IDS, score 0–84) every 6 months; physical exercise with the International Physical Activity Questionnaire; alcohol use with the Alcohol Use Disorders Identification Test; body mass index by anthropometry; and sleep duration and smoking status by interview questions. A composite lifestyle index was calculated by summing scores assigned to each lifestyle factor, with a higher score indicating healthier behavior.

Results

Of all participants, 61.1% had chronic depression (all IDS scores 14–84), 20.1% had intermittent depression (1 IDS score ≤ 14), and 18.7% remitted depression (last 2 IDS scores ≤14). None of the investigated lifestyle indicators, nor the composite lifestyle index was associated with depression course, after adjustment for covariates.

Conclusions

Lifestyle factors do not predict the course of depression at 2‐year follow‐up in older adults.     

The longitudinal course of cognition in older adults with bipolar disorder

Objectives:  Epidemiological studies suggest that elders with bipolar disorder (BD) may be at increased risk for dementia compared to the general population. We sought to investigate whether older adults with BD would present with more cognitive dysfunction than expected for their age and education, and whether they would experience a more rapid cognitive decline over three-year prospective follow-up.
Methods:  Thirty-three subjects age ≥ 50, mean (SD) age 69.7 (7.9) years, with BD I (n = 28) and II (n = 5) had neuropsychological examination at baseline and longitudinally over three years. All subjects were administered the Dementia Rating Scale (DRS) when euthymic. Thirty-six mentally healthy comparators ('controls'), equated on age and education, were selected from ongoing studies in our research center examining the longitudinal relationship between late-life mood disorders and cognitive function.
Results:  Compared to mentally healthy comparators, subjects with BD performed significantly worse on the DRS at baseline [mean (SD) 135.2 (4.7); n = 33 versus 139.5 (3.3); n = 36], and over follow-up [131.9 (7.7); n = 14 versus 139.1 (3.4); n = 22]. There was a group-by-time interaction between the subjects with BD and the controls [group × time: F (1,64) = 5.07, p = 0.028].
Conclusions:  In our study, older adults with BD had more cognitive dysfunction and more rapid cognitive decline than expected given their age and education. Cognitive dysfunction and accelerated cognitive decline may lead to decreased independence, with increased reliance on family and community supports, and potential placement in assisted-living facilities.     

The effect of exercise and nettle supplementation on oxidative stress markers in the rat brain

Chronic swimming training and phytotherapeutic supplementation are assumed to alleviate oxidative damage, and support cell survival in the brain. The effect of forced, chronic swimming training, and enriched lab chow containing 1% (w/w) dried nettle (Urtica dioica) leaf were investigated for oxidative stress, inflammation and neurotrophic markers in Wistar rat brains. The rats were divided into groups subjected to swimming training (6 weeks) or to nettle supplementation (8 weeks) or to a combination of these two treatments. The level of oxidative stress was measured by electron spin resonance (EPR), and by the concentration of carbonylated proteins. Nettle supplementation resulted in a decreased concentration of free radicals in both cerebellum and frontal lobe. Swimming, however, did not influence significantly the oxidative damage nor was it reflected in the carbonyl content. The protein content of nerve growth factor (NGF), and brain-derived neurotrophic factors (BDNF) was evaluated by E-Max ImmunoAssay in the cerebellum. No changes occurred either with exercise or nettle diet treatments. On the other hand, nuclear factor kappa B (NF-kappaB) binding activity to DNA increased with the combined effect of swimming training and nettle diet, while the activator protein1 (AP-1) DNA binding activity showed a more profound elevation in the nettle treated animals. The amount of c-Jun decreased by swimming training. In conclusion, the results suggest that both exercise and nettle influenced physiological brain functions. Nettle supplementation reduces the free radical concentration and increases the DNA binding of AP-1 in the brain. Nettle was found to be an effective antioxidant and possible antiapoptotic supplement promoting cell survival in the brain. Exercise, as a downregulator of c-Jun and in combined group as an upregulator of NF-kappaB, may play also a role in antiapoptotic processes, which is important after brain injury.     

Sex differences in the relationship between obesity,C-reactive protein,physical activity,depression, sleep quality and fatigue in older adults

Fatigue is a serious health concern in the elderly. Sex differences exist in adiposity, systemic inflammation, physical activity/fitness and fatigue; however, the relations among these variables remain inadequately characterized impeding the development of fatigue prevention strategies. Measures of adiposity, C-reactive protein, physical activity, aerobic fitness, fatigue, sleep quality and depression were obtained from 127 community-dwelling older adults. Although similar in age (70 y) and BMI (28.0 kg/m²) women (n = 80) reported 63% greater fatigue than men (p = 0.04). Adiposity (r = 0.44), CRP (r = 0.29), physical activity (r = ?0.26) and fitness (r = ?0.41) were related to fatigue in women (all p < 0.05), but not in men. Depression was also related to fatigue in women (r = 0.37), and was the only variable related to fatigue in men (r = 0.42). In women, fatigue was independently explained (all p < 0.05) by CRP (6.6%), depression (6.3%), physical activity (5.8%), and adiposity (3.9%); however, in men, only depression explained variance in fatigue (12.0%). CRP was 40% higher and adiposity 12% higher in women reporting fatigue compared to those with no fatigue; no such differences existed in men. Obese women perceived a greater degree of fatigue than non-obese women, but this was not the case in men. Women report more fatigue than men which was independently associated with inflammation, depression, physical activity and adiposity, whereas in men the only independent predictor was depression. Strategies to prevent fatigue may differ in older women and men, especially with regard to inflammation, physical activity and adiposity.     

C-reactive protein, but not homocysteine, is related to cognitive dysfunction in older adults with cardiovascular disease.

Cardiovascular disease (CVD) is a risk factor for cognitive impairment and dementia. Recent studies implicate homocysteine (HCY) and C-reactive protein (CRP) in this increased risk, as both are associated with cognitive dysfunction in demented and non-demented patients. However, it remains unclear whether they confer added risk in older adults with CVD. A total of 126 older CVD patients underwent blood and neuropsychological evaluation as part of a prospective examination of the neurocognitive consequences of CVD. A subset of these participants (n=37) also underwent neuroimaging to quantify the degree of white matter disease. After adjusting for demographic and medical factors, no significant relationship emerged between HCY and cognitive performance. In contrast, CRP showed significant independent relationships to test performance, including global cognitive performance, attention/psychomotor function, executive function, memory, and visuospatial abilities. Neither HCY nor CRP was related to extent of white matter disease or whole brain volume on magnetic resonance imaging. Further study is needed to identify mechanisms by which inflammatory processes impact on cognitive function and to determine whether reducing circulating levels of inflammatory markers results in improved cognition.