Publications by authors named "Alexander Semmler"

51 Publications

Intrauterine valproate exposure is associated with alterations in hippocampal cell numbers and folate metabolism in a rat model of valproate teratogenicity.

Seizure 2017 Mar 27;46:7-12. Epub 2017 Jan 27.

Helios-Klinik Hagenbrock-Ambrock, Hagen, Germany.

Purpose: Valproate is one of the most commonly used anticonvulsive drugs. Despite its significant benefits, the teratogenicity of valproate is a relevant problem in the treatment of women of childbearing age. In addition to major congenital malformations, such as neural tube defects, reduced intelligence and attention after intrauterine valproate exposure are reported. Until now the mechanisms of teratogenicity of VPA are poorly understood and concepts how to reduce valproate teratogenicity are lacking.

Methods: In a rat model of valproate teratogenicity we examined hippocampal cell structure in 4 week old animals with a stereological approach. As potential mechanisms of VPA teratogenicity we examined histone acetylation by western blotting and metabolites of the folate metabolism as well as global DNA methylation by tandem mass spectrometry in the brain and liver tissue of newborn pups (p0).

Results: We found an increase in the number of neurons in the hippocampal areas CA1/2 (p=0.018) and CA3 (p=0.022), as well as a decreased number of astrocytes in CA1/2 (p=0.004) and CA3 (p=0.003) after intrauterine VPA exposure, as a possible indication of altered cell differentiation during intrauterine VPA exposure. Valproate exposure was also associated with an increase in 5-methyl-tetrahydrofolate (THF) (p=0.002) and a decrease in 5-10-methenyl-THF in the brain of newborn pups, as well as a reduced homocysteine plasma level (p<0.001). The described changes in hippocampal cell numbers and folate metabolism were only significant after high-dose intrauterine VPA exposure indicating a dose-dependent effect. VPA exposure was not associated with changes in histone acetylation or global DNA methylation in brain tissue in newborn pups.

Conclusion: This study shows that intrauterine VPA exposure is associated with changes in hippocampal cell numbers in the CA1/2 and CA3 region and in folate metabolism.
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http://dx.doi.org/10.1016/j.seizure.2017.01.003DOI Listing
March 2017

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

J Neurochem 2016 10 30;139(2):324-332. Epub 2016 Sep 30.

Department of Psychiatry, Division of Old Age Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.

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 APPβ, and amyloid β1-42 (Aβ1-42), 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 Aβ1-42 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 sAPPβ were associated with high SAH levels. The results suggest that disturbed homocysteine metabolism is related to increased CSF levels of sAPP forms and Aβ1-42, 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 Aβ1-42, 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.
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http://dx.doi.org/10.1111/jnc.13766DOI Listing
October 2016

Alcohol abuse and cigarette smoking are associated with global DNA hypermethylation: results from the German Investigation on Neurobiology in Alcoholism (GINA).

Alcohol 2015 Mar 20;49(2):97-101. Epub 2015 Jan 20.

University of Zurich, Department of Neurology, Switzerland. Electronic address:

Recent studies have shown that smoking and alcoholism may be associated with altered DNA methylation and that alcohol consumption might induce changes in DNA methylation by altering homocysteine metabolism. In this monocenter study, we included 363 consecutive patients referred for hospitalization for alcohol detoxification treatment. Blood samples were obtained on treatment days 1, 3, and 7 for measurement of global DNA methylation in leukocytes by liquid chromatography tandem mass spectrometry. Genomic DNA was used for genotyping the following seven genetic variants of homocysteine metabolism: cystathionine beta-synthase (CBS) c.844_855ins68, dihydrofolate-reductase (DHFR) c.594 + 59del19bp, methylenetetrahydrofolate-reductase (MTHFR) c.677C > T and c.1298A > C, methyltetrahydrofolate-transferase (MTR) c.2756A > G, reduced folate carrier 1 (RFC1) c.80G > A, and transcobalamin 2 c.776C > G. Multivariate linear regression showed a positive correlation of global DNA methylation with alcohol consumption and smoking on day 1 of hospitalization. DNA methylation was not correlated with homocysteine or vitamin plasma levels, nor with the tested genetic variants of homocysteine metabolism. This suggests a direct effect of alcohol consumption and smoking on DNA methylation, which is not mediated by effects of alcohol on homocysteine metabolism.
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http://dx.doi.org/10.1016/j.alcohol.2015.01.004DOI Listing
March 2015

Genetic variants of methionine metabolism and DNA methylation.

Epigenomics 2014 ;6(6):585-91

Molecular Neuroscience Laboratory, Department of Psychiatry, Social Psychiatry & Psychotherapy, Hannover Medical School, Hannover, Germany.

Aim: Altered DNA methylation is associated with important and common pathologies such as cancer. The origin of altered DNA methylation is unknown. The methyl groups for DNA methylation are provided by methionine metabolism. This metabolism is characterized by a high interindividual variability, which is in part explained by genetic variants.

Methods: In a cohort of 313 individuals derived from a family-based study with index cases of cerebrovascular disease, we analyzed whether global methylation of leukocyte DNA was associated with age, gender, homocysteine plasma levels or functionally relevant genetic variants.

Results: We observed an association of the G-allele of the methionine synthase variant c.2756A>G (D919G) with global methylation (% methylation ± 1 SD, AA: 41.3 ± 14.9; AG: 36.4 ± 18.2; GG: 30.8 ± 16.9; F = 4.799; p = 0.009). The methionine synthase variant c.2756A>G is associated with various types of cancer.

Conclusion: Our data suggest that an impact on DNA methylation may contribute to the clinical relevance of the methionine synthase variant.
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http://dx.doi.org/10.2217/epi.14.54DOI Listing
August 2015

Reciprocal modulation of Aβ42 aggregation by copper and homocysteine.

Front Aging Neurosci 2014 8;6:237. Epub 2014 Sep 8.

Department of Neurology, University Hospital Zurich Zurich, Switzerland.

Hyperhomocysteinemia is a risk factor for Alzheimer's disease (AD). Both homocysteine (Hcy) and amyloid β (Aβ), which accumulates in the brain of AD patients, bind copper. Aim of this study was to test the hypothesis that the association of Hcy and AD results from a molecular interaction between Hcy and Aβ that is mediated by copper. We established a microtiter plate format thioflavin T aggregation assay to monitor Aβ42 fibrillization. Copper (5 μM) completely prevented Aβ42 (5 μM) fibrillization. Homocysteine in the absence of copper did not impact Aβ42 fibrillization, but physiological concentrations of Hcy (10-100 μM) attenuated the inhibitory effect of copper on Aβ42 fibril formation. These results were qualitatively confirmed by electron microscopy, which did not reveal morphological differences. To compare the toxicity of fibrillar and non-fibrillar Aβ42 exposed to copper or Hcy, rat primary cortical neurons were treated in vitro with 5 μM Aβ42 for 72 h. After incubation with 5 μM Aβ42 that had been aggregating in the absence of Hcy or copper, cell viability was reduced to 40%. Incubation with 5 μM Aβ42, in which fibril formation had been prevented or reverted by the addition of 5 μM copper, resulted in cell viability of approximately 25%. Accordingly, viability was reduced to 25% after incubation with 5 μM monomeric, i.e., non-fibrillized, Aβ42. The addition of Hcy plus copper to 5 μM Aβ42 yielded 50% viability. In conclusion, copper prevents and reverts Aβ fibril formation leading rather to formation of lower order oligomers or amorphous aggregates, and Hcy reduces these effects. Such mechanisms may explain the association of hyperhomocysteinemia and AD, leading to novel therapeutic strategies in the prevention and treatment of this disease.
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http://dx.doi.org/10.3389/fnagi.2014.00237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157544PMC
September 2014

Neurological picture. Isolated spinal neurocysticercosis.

J Neurol Neurosurg Psychiatry 2015 Feb 1;86(2):234-5. Epub 2014 Apr 1.

Department of Neurology, University Hospital Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1136/jnnp-2013-307142DOI Listing
February 2015

Methylation metabolism in sepsis and systemic inflammatory response syndrome.

Scand J Clin Lab Invest 2013 Aug 8;73(5):368-72. Epub 2013 Apr 8.

University Zurich, Department of Neurology, Zurich, Switzerland.

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.
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http://dx.doi.org/10.3109/00365513.2013.785587DOI Listing
August 2013

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.

Clin Chem Lab Med 2013 Mar;51(3):665-9

Department of Neurology, University of Zurich, Switzerland.

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 β-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.
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http://dx.doi.org/10.1515/cclm-2012-0580DOI Listing
March 2013

An efficient method for fractionated whole rodent brain radiation.

Neurol Res 2013 May 10;35(4):355-9. Epub 2013 Jan 10.

Department of Neurology, University Zurich, Switzerland.

Objective: In order to test for mechanisms of whole brain radio therapy side effects and possible neuroprotective measures, a rodent model is desirable. In many models, a high single dose of 8-20 Gray (Gy) of whole brain irradiation is used. These experimental radiation protocols do not closely reflect the clinical situation, where the cumulative dosage is applied in smaller fractions. We describe an efficient method to perform repetitive, fractionated whole brain radio therapy to the rat brain.

Methods: Fifteen-week-old rats were irradiated with a dose of 5 or 10 Gy on four consecutive days, resulting in a cumulative dose in opposing fields of 20 Gy (n = 15) and 40 Gy (n = 17), respectively. Sham-irradiated rats (n = 14) received the same procedure but without application of cranial irradiation. Four collimators with a diameter of 3 cm each were used to place four rats and an ionization chamber simultaneously in the dose field for monitoring.

Results: Fourteen days after the procedure, irradiated animals showed decreased open-field activity (two-tailed t-test, sham versus 20 Gy, P<0.001; sham versus 40 Gy, P = 0.002), but no cognitive deficit as indicated by latencies in the Morris water maze test. Six weeks after the irradiation, no group showed alterations of histopathology such as vascular changes, demyelination, or white matter necrosis.

Discussion: The proposed model represents an efficient and safe method to perform fractioned high-dose irradiation of the rodent brain. Speculatively, it is possible to increase the cumulative dosage and dose per fraction used in this model to achieve a higher degree of radiation-induced toxicity.
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http://dx.doi.org/10.1179/1743132812Y.0000000143DOI Listing
May 2013

Plasma homocysteine levels increase following stress in older but not younger men.

Psychoneuroendocrinology 2013 Aug 9;38(8):1381-7. Epub 2013 Jan 9.

Department of Clinical Psychology and Psychotherapy, University of Zurich, Zurich, Switzerland.

Background: The incidence and prevalence of cardiovascular disease (CVD) increases with age. Some evidence suggests that mental stress may increase plasma homocysteine (Hcy), an amino acid relating to CVD. However, none of these studies assessed age effects on Hcy stress reactivity, nor did they control for age. The objective of this study was (a) to investigate whether Hcy reactivity to psychosocial stress differs between younger and middle-aged to older men and (b) to study whether psychosocial stress induces Hcy increases independent of age.

Methods: Twenty eight younger (20-30 years) and 22 middle-aged to older (47-65 years) apparently healthy men underwent an acute standardized psychosocial stress task combining public speaking and mental arithmetic in front of an audience. Blood samples for Hcy measurements were obtained immediately before and after, as well as 10 and 20min after stress. Moreover, salivary cortisol was repeatedly measured to test the effectiveness of the stress task in triggering a neuroendocrine stress response.

Results: Hcy reactivity to stress differed between age groups (F(1.4, 60.7)=5.41, p=.014). While the older group displayed an increase in the Hcy response to stress (F(2.5, 39.8)=3.86, p=.022), Hcy levels in the younger group did not change (p=.27). Psychosocial stress per se did not change Hcy levels independent of age (p=.53).

Conclusions: Our findings suggest that psychosocial stress does not evoke an Hcy response per se, but only in interaction with age pointing to a mechanism by which mental stress may increase CVD risk in older individuals.
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http://dx.doi.org/10.1016/j.psyneuen.2012.12.003DOI Listing
August 2013

A possible genetic link between MTHFR genotype and smoking behavior.

PLoS One 2012 28;7(12):e53322. Epub 2012 Dec 28.

Department of Neurology, University Hospital Bonn, Bonn, Germany.

Background: Hyperhomocysteinemia is an independent risk factor for stroke and other vascular events. The variant methylenetetrahydrofolate reductase (MTHFR) C677T is associated with elevated homocysteine levels, cardiovascular disease and stroke, which supports a causal relationship between hyperhomocysteinemia and vascular disease. However, MTHFR variants have also been reported to be associated with smoking behavior, which could be an important confounder.

Methodology/principal Findings: We analyzed the MTHFR variants C677T and A1298C in two independent samples of 525 and 535 individuals, respectively. 21% of the non-smokers, but only 12% of the smokers were homozygous carriers of both MTHFR wildtype alleles, i.e. 677CC and 1298AA (Chi² = 15.8; p<0.001; binary regression). Plasma homocysteine levels were higher in smokers (13.9±4.1 µmol/L) than in non-smokers (12.6±4.0 µmol/L; F = 11.4; p = 0.001; ANOVA). Smoking MTHFR 677TT individuals had the highest plasma homocysteine levels (16.2±5.2 µmol/L), non-smoking 677CC individuals had the lowest (12.2±13.6 µmol/L).

Conclusions/significance: In our study samples, MTHFR variants and smoking behaviour were associated with homocysteine plasma levels. In addition, the MTHFR variants were associated with smoking behaviour. Such an association may be a relevant confounder between MTHFR variants, homocysteine plasma levels and vascular diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0053322PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532068PMC
July 2013

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

J Neurol Neurosurg Psychiatry 2013 Jan 7;84(1):62-9. Epub 2012 Nov 7.

Department of Neurology, University of Bonn, Bonn, Germany.

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.
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http://dx.doi.org/10.1136/jnnp-2012-302883DOI Listing
January 2013

Hyperhomocysteinemia in Alzheimer's disease: the hen and the egg?

J Alzheimers Dis 2013 ;33(4):1097-104

Department of Neurology, University Hospital Zurich, Zurich, Switzerland.

Hyperhomocysteinemia is associated with Alzheimer's disease (AD). The causality of this association is controversial. In this study we tested the effect of a hyperhomocysteinemia-inducing diet in the ArcAβ transgenic AD mouse model. At 14 months of age, the hyperhomocysteinemia-inducing diet yielded higher plasma homocysteine levels in ArcAβ mice compared with wild-type mice. Levels of plasma 5-methyltetrahydrofolate (5-MTHF) in 14-month-old mice on hyperhomocysteinemia-inducing diet were lower in the transgenic than in the wild-type mice. The folate derivate 5-MTHF serves as cofactor in homocysteine metabolism. Oxidative stress, which occurs in the course of disease in the ArcAβ mice, consumes 5-MTHF. Thus, the transgenic mice may plausibly be more vulnerable to 5-MTHF-depleting effects of hyperhomocysteinemia and more vulnerable to hyperhomocysteinemia-inducing diet. This argues that AD pathology predisposes to hyperhomocysteinemia, i.e., as a facultative consequence of AD. However, we also observed that dietary-induced folate reduction and homocysteine increase was associated with an increase of plasma (young animals) and brain (older animals) amyloid-β concentrations. This suggests that the hyperhomocysteinemia-inducing diet worsened pathology in the transgenic mice. In conclusion, this data may argue that folate reduction and hyperhomocysteinemia may contribute to neurodegeneration and may also be triggered by neurodegenerative processes, i.e., represent both a cause and a consequence of neurodegeneration. Such a vicious cycle may be breakable by dietary or supplementation strategies increasing the availability of 5-MTHF.
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http://dx.doi.org/10.3233/JAD-2012-121378DOI Listing
October 2013

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

Clin Chem Lab Med 2012 Mar 24;50(9):1641-7. Epub 2012 Mar 24.

Department of Clinical Chemistry, Metabolic Laboratory, VU University Medical Center, Amsterdam, The Netherlands.

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.
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http://dx.doi.org/10.1515/cclm-2012-0056DOI Listing
March 2012

Long-term neuromuscular sequelae of critical illness.

J Neurol 2013 Jan 21;260(1):151-7. Epub 2012 Jul 21.

Department of Neurology, University of Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland.

In this observational study, we analyzed the long-term neuromuscular deficits of survivors of critical illness. Intensive care unit-acquired muscular weakness (ICU-AW) is a very common complication of critical illness. Critical illness polyneuropathy (CIP) and critical illness myopathy (CIM) are two main contributors to ICU-AW. ICU-AW is associated with an increased mortality and leads to rehabilitation problems. However, the long-term outcome of ICU-AW and factors influencing it are not well known. We analyzed the medical records of 490 survivors of critical illness, aged 18-75 years and located in the area of the study center. Intensive care unit (ICU) survivors with comorbidities that might influence neuromuscular follow-up examinations, muscle strength, or results of nerve conduction studies, such as renal or hepatic insufficiency, diabetes mellitus, or vitamin deficiency were excluded. A total of 51 patients were finally included in the study. Six to 24 months after discharge from the ICU, we measured the Medical Research Council (MRC) sum score, the Overall Disability Sum score (ODSS), and also performed nerve conduction studies and EMG. For all ICU survivors, the median MRC sum score was 60 (range 47-60) and the median ODSS score was 0 (range 0-8). CIP was diagnosed in 21 patients (41 %). No patient was diagnosed with CIM. Patients with diagnosis of CIP showed a higher median ODSS scores 1 (range 0-8) versus 0 (range 0-5); p < 0.001 and lower median MRC sum scores 56 (range 47-60) versus 60 (range 58-60); p < 0.001. The three main outcome variables MRC sum score, ODSS score and diagnosis of CIP were not related to age, gender, or diagnosis of sepsis. The MRC sum score (r = -0.33; p = 0.02) and the ODSS score (r = 0.31; p = 0.029) were correlated with the APACHE score. There was a trend for an increased APACHE score in patients with diagnosis of CIP 19 (range 6-33) versus 16.5 (range 6-28); p = 0.065. Patients with the diagnosis of CIP had more days of ICU treatment 11 days (range 2-74) versus 4 days (range 1-61); p = 0.015, and had more days of ventilator support 8 days (range 1-59) versus 2 days (range 1-46); p = 0.006. The MRC sum score and the ODSS score were correlated with the days of ICU treatment and with the days of ventilator support. The neuromuscular long-term consequences of critical illness were not severe in our study population. As patients with concomitant diseases and old patients were excluded from this study the result of an overall favorable prognosis of ICU-acquired weakness may not be true for other patient's case-mix. Risk factors for the development of long-term critical illness neuropathy are duration of ICU treatment, duration of ventilator support, and a high APACHE score, but not diagnosis of sepsis. Although ICU-AW can be serious complication of ICU treatment, this should not influence therapeutic decisions, given its favorable long-term prognosis, at least in relatively young patients with no concomitant diseases.
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http://dx.doi.org/10.1007/s00415-012-6605-4DOI Listing
January 2013

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

Alcohol Alcohol 2012 Sep-Oct;47(5):497-500. Epub 2012 May 29.

Department of Addiction and Psychotherapy, LVR-Clinic Bonn, Bonn, Germany.

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.
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http://dx.doi.org/10.1093/alcalc/ags058DOI Listing
December 2012

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

Pharmacoepidemiol Drug Saf 2012 Aug 20;21(8):872-80. Epub 2012 Apr 20.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland.

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.
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http://dx.doi.org/10.1002/pds.3279DOI Listing
August 2012

Antiepileptic drugs and vitamin B6 plasma levels in adult patients.

Epilepsy Res 2012 Aug 30;101(1-2):182-4. Epub 2012 Mar 30.

Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, Zurich, Switzerland.

Treatment with several antiepileptic drugs (AED) is associated with lower serum concentrations of folate or vitamin B12. This prospective monocenter study analyzed vitamin B6 blood levels in 400 serial patients with epilepsy, AED-treated (n=385), untreated (n=15) and healthy controls (n=233). The mean plasma vitamin B6 levels of the AED-treated (12.1±10.1; p=0.093) and the untreated patients (15.6±12.4; p=0.664) were not significantly different from the controls (13.9±15.2). These observations do not support the hypothesis that vitamin B6 blood levels are influenced by AED treatment.
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http://dx.doi.org/10.1016/j.eplepsyres.2012.03.002DOI Listing
August 2012

The ratio of S-adenosylmethione and S-adenosyl-homocysteine is increased in the brains of newborn rats in a model of valproic acid teratogenicity.

Toxicology 2012 Mar 11;293(1-3):132-133. Epub 2012 Jan 11.

University Hospital Zurich, Department of Neurology, Frauenklinikstrasse 26, 8091 Zurich, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.tox.2012.01.001DOI Listing
March 2012

Haplotype analysis of the 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C (E429A) polymorphism.

BMC Res Notes 2011 Oct 24;4:439. Epub 2011 Oct 24.

Department of Neurology, University Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland.

Background: The polymorphism 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C is associated with various diseases. 45 DNA samples homozygous for the A allele and 40 DNA probes homozygous for the C allele were taken from healthy German subjects of white Caucasian origin to analyze the haplotype of the two MTHFR c.1298A>C alleles. Samples were genotyped for the polymorphism MTHFR c.677C>T and for the silent polymorphisms MTHFR c.129C>T, IVS2 533 G>A, c.1068C>T and IVS10 262C>G.

Findings: Haplotype construction revealed that the C-allele of MTHFR c.1298A>C was more frequently observed in cis with c.129T, IVS2 533A, c.677C, c.1068T, and IVS10 262 G than expected from normal distribution. Estimation of the most recent common ancestor with the DMLE + 2.3 program resulted in an estimated age of approximately 36,660 years of the MTHFR c.1298C allele.

Conclusion: Given that the era from 30,000 to 40,000 years ago is characterised by the spread of modern humans in Europe and that the prevalence of the MTHFR c.1298C allele is significantly higher in Central Europe in comparison to African populations, a selective advantage of MTHFR c.1298C could be assumed, e. g. by adaption to changes in the nutritional environment. The known founder ancestry of the T allele of MTHFR c.677C>T allele, together with the present data suggests that the MTHFR mutant alleles c.677T and 1298C arose from two independent ancestral alleles, that both confer a selective advantage.
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http://dx.doi.org/10.1186/1756-0500-4-439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3212962PMC
October 2011

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).

Pharmacoepidemiol Drug Saf 2011 Sep 20;20(9):930-8. Epub 2011 Jul 20.

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland.

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.
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http://dx.doi.org/10.1002/pds.2197DOI Listing
September 2011

Antiepileptic drugs interact with folate and vitamin B12 serum levels.

Ann Neurol 2011 Feb 19;69(2):352-9. Epub 2011 Jan 19.

Department of Neurology, University Hospital Zurich, Switzerland.

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.
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http://dx.doi.org/10.1002/ana.22229DOI Listing
February 2011

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

Amyotroph Lateral Scler 2011 Mar 6;12(2):136-9. Epub 2010 Dec 6.

Department of Neurology, University of Ulm, Germany.

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.
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http://dx.doi.org/10.3109/17482968.2010.536985DOI Listing
March 2011

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

Ann Nutr Metab 2010 14;57(2):112-5. Epub 2010 Oct 14.

Department of Neurology, University of Zürich, Frauenklinikstrasse 26, Zürich, Switzerland.

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 β-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.
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http://dx.doi.org/10.1159/000320418DOI Listing
March 2011

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

Nutr J 2010 Jul 28;9:31. Epub 2010 Jul 28.

University Zurich, Department of Neurology, Switzerland.

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.
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http://dx.doi.org/10.1186/1475-2891-9-31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2916887PMC
July 2010

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

Neurodegener Dis 2010 3;7(6):373-8. Epub 2010 Jun 3.

Department of Neurology, University Hospital Zurich, Zurich, Switzerland.

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.
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http://dx.doi.org/10.1159/000309657DOI Listing
February 2011

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

Clin Invest Med 2009 Dec 1;32(6):E310. Epub 2009 Dec 1.

University Zurich, Department Neurology, 8091 Zurich, Switzerland.

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.
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http://dx.doi.org/10.25011/cim.v32i6.10667DOI Listing
December 2009

Plasma homocysteine levels after acute stroke and in the convalescent phase.

Can J Neurol Sci 2009 Nov;36(6):789-90

Department of Neurology, University of Bonn, Bonn, Germany.

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http://dx.doi.org/10.1017/s0317167100008477DOI Listing
November 2009

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

J Neurosci 2009 Nov;29(45):14177-84

Department of Neurology, University of Bonn, 53127 Bonn, Germany.

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.
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http://dx.doi.org/10.1523/JNEUROSCI.3238-09.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6665081PMC
November 2009