Homocysteine metabolism is associated with cerebrospinal fluid levels of soluble amyloid precursor protein and amyloid beta.

Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. The objective of this study was to investigate the relationships between cerebral amyloid production and both blood and cerebrospinal fluid (CSF) markers of the homocysteine metabolism. We assessed CSF concentrations of soluble APPα, soluble APPß, and amyloid ß1-42 (Aß1-42), as well as plasma levels of homocysteine (Hcys), total vitamin B12, and folate, and CSF concentrations of homocysteine (Hcys-CSF), 5-methyltetrahydrofolate (5-MTHF), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) in 59 subjects with normal cognition. Linear regression analyses were performed to assess associations between homocysteine metabolism parameters and amyloid production. The study was approved by the Ethical Committee of the University of Bonn. After controlling for age, gender, APOEe4 status, and albumin ratio (Qalb), higher Aß1-42 CSF levels were associated with high Hcys and low vitamin B12 plasma levels as well as with high Hcys, high SAH, and low 5-MTHF CSF levels. Higher CSF concentrations of sAPPα and sAPPß were associated with high SAH levels. The results suggest that disturbed homocysteine metabolism is related to increased CSF levels of sAPP forms and Aß1-42, and may contribute to the accumulation of amyloid pathology in the brain. Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. We found associations between CSF levels of soluble APP forms and Aß1-42, and markers of the homocysteine metabolism in both plasma and CSF in adults with normal cognition. Disturbed homocysteine metabolism may represent a target for preventive and early disease-modifying interventions in Alzheimer's disease.

Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors.

OBJECTIVES: The objective of this preliminary study was to explore long-term changes in neurobehavioral parameters, brain morphology and electroencephalography of sepsis patients who received intensive care compared to non-septic intensive care unit (ICU) patients. METHODS: Two-centre follow-up study 6-24 months after discharge from hospital using published norms and existing databases of healthy controls for comparison. Patients included 25 septic and 19 non-septic ICU survivors who were recruited from two ICUs of a university and community hospital. Measurements used include brain morphology, standard electroencephalography, cognition and psychiatric health and health-related quality of life. RESULTS: Sepsis survivors showed cognitive deficits in verbal learning and memory and had a significant reduction of left hippocampal volume compared to healthy controls. Moreover, sepsis and to some extent non-septic ICU patients had more low-frequency activity in the EEG indicating unspecific brain dysfunction. No differences were found in health-related quality of life, psychological functioning or depressive symptoms, and depression could be ruled out as a confounding factor. CONCLUSIONS: This study demonstrates permanent cognitive impairment in several domains in both septic and non-septic ICU survivors and unspecific brain dysfunction. In the sepsis group, left-sided hippocampal atrophy was found compared to healthy controls. Further study is needed to clarify what contribution sepsis and other factors at the ICU make to these outcomes. Specific neuroprotective therapies are warranted to prevent persisting brain changes in ICU patients.

Homocysteine plasma levels in patients treated with antiepileptic drugs depend on folate and vitamin B12 serum levels, but not on genetic variants of homocysteine metabolism.

BACKGROUND: Antiepileptic drugs (AEDs) are commonly used in the treatment of epilepsy, psychiatric diseases and pain disorders. Several of these drugs influence blood levels of folate and vitamin B12 and, consequently, homocysteine. This may be relevant for AED effects and side effects. However, not only folate and vitamin B12, but also genetic variants modify homocysteine metabolism. Here, we aimed to determine whether there is a pharmacogenetic interaction between folate, vitamin B12 and genetic variants and homocysteine plasma level in AED-treated patients. METHODS: In this mono-center study, we measured homocysteine, folate and vitamin B12 plasma levels in a population of 498 AED-treated adult patients with epilepsy. In addition, we analyzed the genotypes of seven common genetic variants of homocysteine metabolism: methylenetetrahydrofolate reductase (MTHFR) c.677C>T and c.1298A>C, methionine synthase (MTR) c.2756A>G, dihydrofolate reductase (DHFR) c.594+59del19bp, cystathionine ß-synthase (CBS) c.844_855ins68, transcobalamin 2 (TC2) c.776C>G and methionine synthase reductase (MTRR) c.66G>A. RESULTS: On multivariate logistic regression, folate and vitamin B12 levels, but none of the genetic variants, were predictive for homocysteine levels. CONCLUSIONS: These data suggest that, in AED-treated patients, folate and vitamin B12 play important roles in the development of hyperhomocysteinemia, whereas genetic variants of homocysteine metabolism do not and thus do not contribute to the risk of developing hyperhomocysteinemia during AED treatment.

Methylation metabolism in sepsis and systemic inflammatory response syndrome.

We have recently shown that sepsis leads to alterations of methylation metabolism in a rodent model. In this study we analyzed methylation metabolism and DNA methylation in human sepsis. Patients treated in one of the Intensive Care Units (ICU) at the University Hospital Bonn diagnosed with sepsis or systemic inflammatory response syndrome (n = 12) and patients who were treated due to traumatic brain injury, or stroke without clinical or laboratory signs of sepsis or major inflammation (n = 22) were included. Blood samples were taken two times a week, until ICU treatment was discontinued. Deproteinized plasma was used for simultaneous determination of the ubiquitous methyl-group donor S-adenosylmethionine (SAM) and its demethylated residue, S-adenosylhomocysteine (SAH), by using stable isotope dilution tandem mass spectrometry. Homocysteine (Hcys), hydrolyzation product of SAH, was determined by fully automated particle-enhanced immunonephelometry, and global DNA-methylation was measured by liquid chromatography tandem mass spectrometry. SAM (p < 0.001) and SAH (p < 0.001) plasma levels were higher in septic patients suggesting an increased cellular release of SAM and SAH in septic patients. The SAM/SAH ratio was decreased in septic patients (p = 0.002). There were no differences in homocysteine plasma levels (p = 0.32) or global leukocyte DNA methylation between septic and non-septic patients (p = 0.21) suggesting that sepsis-induced changes in methylation metabolism do not affect homocysteine plasma levels or the availability of SAM-derived methyl groups for DNA methylation. Sepsis and systemic inflammatory response syndrome induce considerable changes of methylation metabolism without apparent functional consequences on homocysteine plasma levels or DNA methylation. Further studies may explore the clinical relevance of the observed changes.

Antiepileptic drugs interact with folate and vitamin B12 serum levels.

OBJECTIVE: Antiepileptic drugs (AEDs) are important for the treatment of epilepsy, psychiatric diseases, and pain syndromes. Small studies have suggested that AED treatment reduces serum levels of folate and vitamin B12. METHODS: This prospective monocenter study aimed at testing the hypothesis that AED treatment is associated with folate and vitamin B12 serum levels in a large population. A total of 2730 AED-treated and 170 untreated patients with epilepsy and 200 healthy individuals were enrolled. RESULTS: Treatment with carbamazepine, gabapentin, oxcarbazepine, phenytoin, primidone, or valproate was associated with lower mean serum folate levels or with a higher frequency of folate levels below the reference range in comparison with the entire group of patients, untreated patients, or controls. Treatment with phenobarbital, pregabalin, primidone, or topiramate was associated with lower vitamin B12 levels compared with the entire group of patients. Vitamin B12 serum levels were higher in patients treated with valproate compared with the entire group of patients, untreated patients, and healthy controls. Folate or vitamin B12 levels below the reference range were associated with higher mean corpuscular volume (MCV) and higher homocysteine plasma levels. Vitamin substitution for 3 months in 141 patients with folate or vitamin B12 levels below the reference range yielded normal vitamin levels in 95% of the supplemented patients and reduced MCV and homocysteine plasma levels. INTERPRETATION: Treatment with most of the commonly used AEDs is associated with reduced folate or vitamin B12 serum levels and is a risk factor for hyperhomocysteinemia. Oral substitution is effective to restore vitamin, MCV, and homocysteine levels.

Determinants of the essential one-carbon metabolism metabolites, homocysteine, S-adenosylmethionine, S-adenosylhomocysteine and folate, in cerebrospinal fluid.

BACKGROUND: Disturbances in the levels of one-carbon (1C) metabolism metabolites have been associated with a wide variety of neuropsychiatric diseases. Cerebrospinal fluid (CSF) levels of homocysteine (Hcy) and the other 1C metabolites, nor their interrelatedness and putative determinants, have been studied extensively in a healthy population. METHODS: Plasma and CSF samples from 100 individuals free from neuropsychiatric diseases were analyzed (55 male, 45 female; age 50±17 years). In blood, we measured plasma Hcy, serum folate and serum vitamin B12. In CSF, we measured total Hcy, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and 5-methyltetrahydrofolate (5-methylTHF). Highly selective analytical methods like liquid chromatography combined with either mass spectrometry or fluorescence detection were used. RESULTS: CSF Hcy was inversely correlated with CSF 5-methylTHF and positively with plasma Hcy, independent of serum folate status. CSF SAH correlated with age, lower CSF 5-methylTHF and higher CSF Hcy. CSF 5-methylTHF showed independent negative correlations with age and positive correlations with serum folate. CSF SAM did not correlate with any of the 1C metabolites. CONCLUSIONS: Aging is characterized by a reduction in CSF 5-methylTHF levels and increased CSF levels of the potentially neurotoxic transmethylation inhibitor SAH. CSF 5-methylTHF, which is itself determined in part by systemic folate status, is a powerful independent determinant of CSF levels of Hcy and SAH.

Comparative evaluation of the drug interaction screening programs MediQ and ID PHARMA CHECK in neurological inpatients.

PURPOSE: The comparative evaluation of clinical decision support software (CDSS) programs regarding their sensitivity and positive predictive value for the identification of clinically relevant drug interactions. METHODS: In this research, we used a cross-sectional study that identified potential drug interactions using the CDSS MediQ and the ID PHARMA CHECK in 484 neurological inpatients. Interactions were reclassified according to the Zurich Interaction System, a multidimensional classification that incorporates the Operational Classification of Drug Interactions. RESULTS: In 484 patients with 2812 prescriptions, MediQ and ID PHARMA CHECK generated a total of 1759 and 1082 alerts, respectively. MediQ identified 658 unique potentially interacting combinations, 8 classified as "high danger," 164 as "average danger," and 486 as "low danger." ID PHARMA CHECK detected 336 combinations assigned to one or several of 12 risk and management categories. Altogether, both CDSS issued alerts relating to 808 unique potentially interacting combinations. According to the Zurich Interaction System, 6 of these were contraindicated, 25 were provisionally contraindicated, 190 carried a conditional risk, and 587 had a minimal risk of adverse events. The positive predictive value for alerts having at least a conditional risk was 0.24 for MediQ and 0.48 for ID PHARMA CHECK. CONCLUSIONS: CDSS showed major differences in the identification and grading of interactions, and many interactions were only identified by one of the two CDSS. For both programs, only a small proportion of all identified interactions appeared clinically relevant, and the selected display of alerts that imply management changes is a key issue in the further development and local setup of such programs.

Alterations of homocysteine serum levels during alcohol withdrawal are influenced by folate and riboflavin: results from the German Investigation on Neurobiology in Alcoholism (GINA).

AIMS: Various studies have shown that plasma homocysteine (HCY) serum levels are elevated in actively drinking alcohol-dependent patients a during alcohol withdrawal, while rapidly declining during abstinence. Hyperhomocysteinemia has been associated not only with blood alcohol concentration (BAC), but also with deficiency of different B-vitamins, particularly folate, pyridoxine and cobalamin. METHODS: Our study included 168 inpatients (110 men, 58 women) after admission for detoxification treatment. BAC, folate, cobalamin, pyridoxine, thiamine and riboflavin were obtained on admission (Day 1). HCY was assessed on Days 1, 7 and 11. RESULTS: HCY levels significantly declined during withdrawal. General linear models and linear regression analysis showed an influence of BAC, folate and riboflavin on the HCY levels on admission as well as on HCY changes occurring during alcohol withdrawal. No significant influence was found for thiamine, cobalamin and pyridoxine. CONCLUSIONS: These findings show that not only BAC and plasma folate levels, but also plasma levels of riboflavin influence HCY plasma levels in alcohol-dependent patients.

The thermolabile variant of 5,10-methylenetetrahydrofolate reductase is a possible risk factor for amyotrophic lateral sclerosis.

Hyperhomocysteinemia is a risk factor for neurodegeneration, and binding of copper by homocysteine is a putative underlying mechanism. As mutations of the copper-dependent superoxide dismutase are observed in familial ALS, we tested whether genetic variants with influence on homocysteine metabolism are associated with ALS. We compared the frequency of seven variants of genes involved in homocysteine metabolism in 162 patients with sporadic ALS and 162 controls who did not significantly differ in age (t = 1.27, p = 0.205) and gender (χ(2) = 2.48, p = 0.115) using binary regression analysis. Results showed that the variant MTHFR c.677C>T was significantly associated with ALS, i.e. the T-allele was more frequent among patients. Explorative regression analysis revealed that MTHFR c.677C>T was not associated with spinal ALS, but with bulbar onset: CC/CT/TT in patients 0.33/0.51/0.16 versus 0.50/0.44/0.06 in controls; Wald = 5.73, p = 0.017. In addition, DHFR c.594+59del19bp was not associated with spinal, but with bulbar onset: del,del/del,ins/ins,ins in patients 0.16/0.67/0.18 versus 0.11/0.52/0.37 in controls; Wald = 5.02, p = 0.025. The other variants did not show significant associations. In summary, the variants MTHFR c.677C>T and DHFR c.594+59del19bp are involved in homocysteine metabolism. Homocysteine is neurotoxic and binds copper. Thus, the individual variability of homocysteine metabolism, e.g. due to genetic variants, may contribute to the vulnerability of ALS.

Evaluation of drug interactions and dosing in 484 neurological inpatients using clinical decision support software and an extended operational interaction classification system (Zurich Interaction System).

PURPOSE: The current study aimed at identifying and quantifying critical drug interactions in neurological inpatients using clinical decision support software (CDSS). Reclassification of interactions with a focus on clinical management aimed to support the development of CDSS with higher efficacy to reduce overalerting and improve medication safety in clinical practice. METHODS: We conducted a cross-sectional study in consecutive patients admitted to the neurology ward of a tertiary care hospital. We developed a customized interface for mass analysis with the CDSS MediQ, which we used for automated retrospective identification of drug interactions during the first day of hospitalization. Interactions were reclassified according to the Zurich Interaction System (ZHIAS), which incorporates the Operational Classification of Drug Interactions (ORCA). Dose adjustments for renal impairment were also evaluated. RESULTS: In 484 patients with 2812 prescriptions, MediQ generated 8 "high danger," 518 "average danger," and 1233 "low danger" interaction alerts. According to ZHIAS, 6 alerts involved contraindicated and 33 alerts involved provisionally contraindicated combinations, and 327 alerts involved a conditional and 1393 alerts involved a minimal risk of adverse outcomes. Thirty-five patients (6.2%) had at least one combination that was at least provisionally contraindicated. ZHIAS also provides categorical information on expected adverse outcomes and management recommendations, which are presented in detail. We identified 13 prescriptions without recommended dose adjustment for impaired renal function. CONCLUSIONS: MediQ detected a large number of drug interactions with variable clinical relevance in neurological inpatients. ZHIAS supports the selection of those interactions that require active management, and the effects of its implementation into CDSS on medication safety should be evaluated in future prospective studies.

NOS2 gene deficiency protects from sepsis-induced long-term cognitive deficits.

To date, long-term consequences of septic encephalopathy on cerebral metabolism, cognition, learning, and memory capabilities and factors involved are poorly understood. In this study, we used a murine sepsis model to demonstrate that bacterial lipopolysaccharide (LPS) causes long-term cognitive deficits in mice. Two months after LPS treatment, wild-type mice committed more working and reference memory errors than controls. The behavioral impairment was independent of the cerebral glucose uptake as evidenced by (18)F-Fluordeoxyglucose small animal positron emission tomography. In contrast, mice deficient for the inducible nitric oxide synthase gene (NOS2-/-) did not show any cognitive changes when challenged with LPS. Immunohistochemical analysis demonstrated that LPS did not lead to neuronal cell death but caused sustained microglial activation in wild-type as compared to NOS2-/- mice. Expression analysis showed that LPS-treated NOS2-/- mice had lower brain mRNA levels for proinflammatory factors compared with wild-type mice. Expression analysis demonstrated distinct changes in the content of synaptic proteins in wild-type mice, which were not observed in the NOS2-/- mice. Together, this data set outlines the importance of the NOS2 activation for long-term cerebral changes after severe sepsis.

Plasma folate levels are associated with the lipoprotein profile: a retrospective database analysis.

BACKGROUND: Several studies demonstrated an association of homocysteine plasma levels and the plasma lipoprotein profile. This cross-sectional pilot study aimed at analyzing whether blood levels of the two important cofactors of homocysteine metabolism, folate and vitamin B12, coincide with the lipoprotein profile. METHODS: In a retrospective single center approach, we analyzed the laboratory database (2003-2006) of the University Hospital Bonn, Germany, including 1743 individuals, in whom vitamin B12, folate and at least one lipoprotein parameter had been determined by linear multilogistic regression. RESULTS: Higher folate serum levels were associated with lower serum levels of low density lipoprotein cholesterol (LDL-C; Beta = -0.164; p < 0.001), higher levels of high density lipoprotein cholesterol (HDL-C; Beta = 0.094; p = 0.021 for trend) and a lower LDL-C-C/HDL-C-ratio (Beta = -0.210; p < 0.001). Using ANOVA, we additionally compared the individuals of the highest with those of the lowest quartile of folate. Individuals of the highest folate quartile had higher levels of HDL-C (1.42 +/- 0.44 mmol/l vs. 1.26 +/- 0.47 mmol/l; p = 0.005), lower levels of LDL-C (3.21 +/- 1.04 mmol/l vs. 3.67 +/- 1.10 mmol/l; p = 0.001) and a lower LDL-C/HDL-C- ratio (2.47 +/- 1.18 vs. 3.77 +/- 5.29; p = 0.002). Vitamin B12 was not associated with the lipoprotein profile. CONCLUSION: In our study sample, high folate levels were associated with a favorable lipoprotein profile. A reconfirmation of these results in a different study population with a well defined status of health, diet and medication is warranted.

The G allele of transcobalamin 2 c.776C→G is associated with an unfavorable lipoprotein profile.

BACKGROUND/AIM: Recent studies have suggested a relation of homocysteine with lipid metabolism. The aim of this study was to analyze a possible genetic basis for such a relation in 504 individuals including 135 consecutive Caucasian patients diagnosed with cerebrovascular disease as well as the patients' healthy spouses (n = 100) and offspring (n = 269). METHODS: We analyzed the association of plasma levels of lipoprotein(a), total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides with plasma homocysteine levels and with the following 7 variants of homocysteine metabolism: dihydrofolate reductase c.594 + 59del19bp, cystathionine ß-synthase c.844_855ins68, methionine synthase c.2756A→G, methylenetetrahydrofolate reductase c.677C→T and c.1298A→C, reduced folate carrier 1 c.80G→A, and transcobalamin 2 (Tc2) c.776C→G. RESULTS: Linear regression analysis showed an association of Tc2 c.776C→G with LDL (p = 0.010), HDL (p = 0.009), and TG (p = 0.007), with the G allele of Tc2 c.776C→G associated with an unfavorable blood lipid profile. Moreover, the G allele of Tc2 c.776C→G was associated with higher homocysteine plasma levels in the subgroup of patients (p = 0.013, 1-way ANOVA). CONCLUSION: These data support the hypothesis that alterations in homocysteine metabolism and an unfavorable blood lipoprotein profile may have a common genetic basis. Such conditions may be relevant for studies investigating independent risk factors for vascular disease.

S-adenosylmethionine is decreased in the cerebrospinal fluid of patients with Alzheimer's disease.

BACKGROUND: Increased plasma homocysteine levels have been described as an independent risk factor for Alzheimer's disease (AD), but the underlying pathophysiology is unclear. OBJECTIVE: This single-center, cross-sectional, correlational study analyzed homocysteine metabolism in 60 AD patients and 60 control subjects. METHODS: Fasting plasma levels of vitamin B12, folate and homocysteine as well as cerebrospinal fluid (CSF) levels of folate derivates, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and homocysteine were measured. In addition, the apolipoprotein E (APOE) genotype was determined. RESULTS: As expected, the APOE4 allele was significantly overrepresented in AD patients compared with controls (p < 0.001). Homocysteine plasma levels in the highest quartile were more frequent in the AD patients than in the controls (p = 0.008). In addition, AD patients had significantly lower CSF levels of the methyl group donor SAM (193 ± 31 vs. 207 ± 37 nmol/l; p = 0.032). Accordingly, the SAM/SAH ratio, which represents the methylation capacity, was significantly lower in the CSF of the AD patients (7.6 ± 2.4 vs. 9.1 ± 2.8; p = 0.003). Further, explorative analysis of all subjects showed that CSF SAM levels were lower in carriers of the APOE4 allele compared with noncarriers (189 ± 30 vs. 207 ± 36 nmol/l; p = 0.010). Of the individuals with CSF SAM levels in the lowest quartile, 63% carried the APOE4 allele compared with 17% of the individuals with CSF SAM levels in the highest quartile (Pearson: χ² = 9.9; p = 0.002; odds ratio 0.126, 95% confidence interval 0.32-0.49). CONCLUSION: These data suggest that AD is associated with lower CSF SAM levels and that this is at least partly due to an association of the APOE4 allele with reduced SAM levels in the CSF.

Association of genetic variants of methionine metabolism with methotrexate-induced CNS white matter changes in patients with primary CNS lymphoma.

Methotrexate (MTX) is an important anticancer drug and the most efficient chemotherapy component in primary CNS lymphoma (PCNSL). A typical side effect of intravenous high-dose MTX is the occurrence of confluent CNS white matter changes (WMC). Because MTX directly interferes with methionine metabolism, we analyzed the impact of genetic variants of methionine metabolism on the occurrence of WMC as a model of MTX toxicity. In a retrospective analysis of 68 PCNSL patients treated with MTX-based polychemotherapy with (n = 42) or without (n = 26) intraventricular treatment, 10 genetic variants influencing methionine metabolism were analyzed. Pearson's chi(2) test and multinominal regression analysis were used to define the relevance of these genetic variants for the occurrence of WMC. In this patient sample, the occurrence of WMC was significantly predicted by the TT genotype of methylenetetrahydrofolate reductase c.677C>T (chi(2) = 8.67; p = 0.013; df = 2), the AA genotype of methylenetetrahydrofolate reductase c.1298A>C (chi(2) = 13.5; p = 0.001; df = 2), and the GG genotype of transcobalamin 2 c.776C>G (chi(2) = 19.73; p < 0.001), in addition to male gender (chi(2) = 11.95; p = 0.001). These data strengthen the hypothesis that MTX effects are influenced by methionine metabolism, which may offer new strategies to improve MTX-based therapies.

The effect of MTHFR c.677C>T on plasma homocysteine levels depends on health, age and smoking.

PURPOSE: The role of homocysteine in the pathogenesis of arteriosclerosis and stroke is under debate. It is important to determine the interplay of factors that influence homocysteine plasma levels, such as age, gender, smoking and the genetic background. The T-allele of the common variant methylenetetrahydrofolate reductase (MTHFR) c.677C > T is the most prevalent known genetic cause of elevated plasma homocysteine levels, but the association of this allele with vascular disease has been controversial. The aim of the present study was to examine whether the influence of MTHFR c.677C > T on homocysteine levels depends on individual factors. METHODS: From an ongoing study on atherosclerosis, we analyzed 523 Caucasian individuals, including patients with cerebrovascular disease (n=141), their healthy spouses (n=106) and the offspring (n=276). ANOVA and regression analyses were employed to separately analyze the effect of MTHFR c.677C > T on homocysteine levels in patients, spouses and offspring as well as in subgroups defined by age, gender and smoking. RESULTS: MTHFR c.677C > T was associated with homocysteine plasma levels in the study sample (P < 0.001), but not in the patients with cerebrovascular disease, if analyzed separately. Analyses of subgroups divided by the age of 55 years revealed that the MTHFR c.677 C > T genotype was associated with homocysteine plasma levels in the younger (P < 0.001), but not in the older individuals. In addition, if individuals with at least less than ten cigarette package years were analyzed separately, MTHFR c.677C > T was associated with plasma homocysteine levels only in the group with the lower cigarette consumption (P=0.002). CONCLUSION: In our study, the association of the MTHFR c.677C > T genotype with plasma homocysteine levels was weakened by other factors that impact homocysteine levels. The effect of MTHFR c.677C > T on plasma homocysteine levels may, thus, be of major importance for healthy, young, non-smoking persons. Such specifications may explain the controversial results of epidemiological studies on the relevance of MTHFR c.677C > T.

The methylenetetrahydrofolate reductase (MTHFR) variant c.677C>T (A222V) influences overall survival of patients with glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most frequent primary brain tumor in adults. Prognosis is poor. Using a series of 214 GBM patients, we observed an effect of the variant 5,10-methylenetetrahydrofolate reductase (MTHFR) c.677C>T on overall survival. This effect was strongest in patients younger than 60 years at diagnosis (overall survival, median +/- SE: genotype CC, 13 +/- 1 months; CT, 11 +/- 2 months; TT, 7 +/- 3 months; multivariate Cox regression analysis, Wald = 8.58, p = 0.007). In addition, the MTHFR genotype significantly influenced the overall survival of patients with a postoperative Karnofsky score >70 (CC, 12 +/- 2 months; CT, 11 +/- 1 months; TT, 10 +/- 4 months; Wald = 5.89, p = 0.015). These data suggest the MTHFR c.677C>T variant is a risk factor for survival in GBM patients.

Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism.

BACKGROUND: Septic encephalopathy is a severe brain dysfunction caused by systemic inflammation in the absence of direct brain infection. Changes in cerebral blood flow, release of inflammatory molecules and metabolic alterations contribute to neuronal dysfunction and cell death. METHODS: To investigate the relation of electrophysiological, metabolic and morphological changes caused by SE, we simultaneously assessed systemic circulation, regional cerebral blood flow and cortical electroencephalography in rats exposed to bacterial lipopolysaccharide. Additionally, cerebral glucose uptake, astro- and microglial activation as well as changes of inflammatory gene transcription were examined by small animal PET using [18F]FDG, immunohistochemistry, and real time PCR. RESULTS: While the systemic hemodynamic did not change significantly, regional cerebral blood flow was decreased in the cortex paralleled by a decrease of alpha activity of the electroencephalography. Cerebral glucose uptake was reduced in all analyzed neocortical areas, but preserved in the caudate nucleus, the hippocampus and the thalamus. Sepsis enhanced the transcription of several pro- and anti-inflammatory cytokines and chemokines including tumor necrosis factor alpha, interleukin-1 beta, transforming growth factor beta, and monocot chemoattractant protein 1 in the cerebrum. Regional analysis of different brain regions revealed an increase in ED1-positive microglia in the cortex, while total and neuronal cell counts decreased in the cortex and the hippocampus. CONCLUSION: Together, the present study highlights the complexity of sepsis induced early impairment of neuronal metabolism and activity. Since our model uses techniques that determine parameters relevant to the clinical setting, it might be a useful tool to develop brain specific therapeutic strategies for human septic encephalopathy.

Global DNA methylation is influenced by smoking behaviour.

The level of epigenetic DNA methylation is an important factor in the pathogenesis of various human diseases. As smoking may influence DNA methylation, we investigated the effect of smoking habits on global DNA methylation in 298 genomic DNA samples (73 fathers, 69 mothers and 156 offspring). We did not find a direct effect of smoking on global DNA methylation. However, there was an association of the offspring's DNA methylation with paternal DNA methylation that was strongest if both had never smoked (R2corr=0.41, Beta=0.68, p=0.02) and completely vanished if the offspring smoked or had ever smoked. These findings suggest an association between smoking behaviour and global DNA methylation, which may be of importance for a wide range of diseases.