Alexander Semmler - Academia.edu (original) (raw)

Papers by Alexander Semmler

The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques

METHODS We recruited patients with clinically and radiologically proven acute stroke admitted to ... more METHODS We recruited patients with clinically and radiologically proven acute stroke admitted to the Department of Neurology, University of Bonn, Germany. Patients with transitory ischemic attacks or lacunar ischemic stroke were excluded from the study. ...

British journal of cancer, Jan 20, 2012

Chemotherapy for primary central nervous system lymphoma (PCNSL) is based on methotrexate (MTX), ... more Chemotherapy for primary central nervous system lymphoma (PCNSL) is based on methotrexate (MTX), which interferes with both nucleic acid synthesis and methionine metabolism. We have reported previously that genetic variants with influence on methionine metabolism are associated with MTX side effects, that is, the occurrence of white matter lesions as a sign of MTX neurotoxicity. Here, we investigated whether such variants are associated with MTX efficacy in terms of overall survival in MTX-treated PCNSL patients. We analysed seven genetic variants influencing methionine metabolism in 68 PCNSL patients treated with systemic and facultative intraventricular MTX-based polychemotherapy (Bonn protocol). Median age at diagnosis was 59 years (range: 28-77), 32 patients were female. Younger age (Wald=8.9; P=0.003) and the wild-type C (CC) allele of the genotype transcobalamin c (Tc2). 776C>G (Wald=6.7; P=0.010) were associated with longer overall survival in a multivariate COX regression...

BMC research notes, 2011

The polymorphism 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C is associated with... more 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. 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. 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 prevalen...

Clinical and investigative medicine. Médecine clinique et experimentale, 2009

The role of homocysteine in the pathogenesis of arteriosclerosis and stroke is under debate. It i... more 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. 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 offsprin...

Neurology, Jan 13, 2007

Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive demyelinating disease c... more Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive demyelinating disease caused by the reactivation of JC papova virus usually in immunocompromised hosts. The disease is a chronic viral infection resulting in mortality within a year. 2 The condition characterized by white matter changes in multiple locations of the brain is caused by destruction of the oligodendrogliocytes. We report a case of AIDS associated PML presenting with progressive cerebellar symptoms, with the unusual feature of imaging abnormalities limited to the posterior fossa.

Journal of chemical neuroanatomy, 2005

During severe sepsis several immunological defence mechanisms initiate a cascade of inflammatory ... more During severe sepsis several immunological defence mechanisms initiate a cascade of inflammatory events leading to multi-organ failure including septic encephalopathy and ultimately death. To assess the reaction and participation of parenchymal brain cells during endotoxaemia, the present study evaluates micro- and astroglial activation, expression of the inducible nitric oxide synthase (iNOS) pro- and antiapoptotic protein levels Bax and Bcl-2, and apoptosis. Male Wistar rats received 10 mg/kg lipopolysaccharide (LPS) or vehicle intraperitoneally and were sacrificed for brain collection at 4, 8 or 24 h after induction of experimental sepsis. One group of animals received 10 mg/kg of the NOS inhibitor N-monomethyl-L-arginine (L-NMMA) intraperitoneally 1 day before and during the experiment. Immunohistochemical evaluation revealed a sepsis-induced, time-dependent increase in the immunoreactivity of iNOS, glial fibrillary acidic protein (GFAP) and activated microglia (ED-1), parallele...

Alcohol, 2015

Recent studies have shown that smoking and alcoholism may be associated with altered DNA methylat... more 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.

Pharmacoepidemiology and drug safety, 2011

The current study aimed at identifying and quantifying critical drug interactions in neurological... more 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. 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. In 484 patients with 2812 prescriptions, MediQ generated 8 "high danger," 518 "ave...

Frontiers in Aging Neuroscience, 2014

Hyperhomocysteinemia is a risk factor for Alzheimer&a... more 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.

Journal of Alzheimer's Disease xx (20xx) x-xx Abstract. Hyperhomocysteinemia is associated with A... more Journal of Alzheimer's Disease xx (20xx) x-xx Abstract. 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 ArcA␤ transgenic AD mouse model. At 14 months of age, the hyperhomocysteinemia-inducing diet yielded higher plasma homocysteine levels in ArcA␤ mice compared with wild-type mice. Levels of plasma 5-methyltetrahydrofolate (5-MTHF) in 14-month-old mice on hyperhomocysteinemiainducing 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 ArcA␤ 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-␤ 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. 8 22 23 [1]. Factors like higher age, male gender, renal dys-30 function, genetic variants, high methionine uptake via 1 These authors contributed equally. protein-rich food, and deficiencies of folate, vitamin 31 B12, and vitamin B6 are linked to hyperhomocys-32 teinemia [2]. The nature of the relationship between 33 hyperhomocysteinemia and AD is controversial [3-5]. 34 Homocysteine is a toxic intermediate of methion-35 ine metabolism. It is either irreversibly metabolized 36 by the vitamin B6-dependent transsulfuration pathway 37 or is recycled to methionine by the folate-and vita-38 min B12-dependent remethylation pathway (Fig. 1). 39 Methionine can be activated to S-adenosylmethionine 40 (SAM), which serves as universal methyl-group donor, 41 e.g., for DNA, RNA, and protein methylation reactions. 42 SAM is thereby converted to S-adenosylhomocysteine 43 (SAH), which is further hydrolyzed to homocysteine 44 in a reversible reaction. Although elevated plasma 307 [6] Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland 308 PM (1998) Folate, vitamin B12, and serum total homocysteine 309 levels in confirmed Alzheimer disease. Arch Neurol 55, 1449-310 1455. 311 [7] Linnebank M, Popp J, Smulders Y, Smith D, Semm-312 ler A, Farkas M, Kulic L, Cvetanovska G, Blom H, 313 Stoffel-Wagner B, Kolsch H, Weller M, Jessen F (2010) S-314 adenosylmethionine is decreased in the cerebrospinal fluid 315 of patients with Alzheimer's disease. Neurodegener Dis 7, 316 373-378. 317 [8] Kim JM, Kim SW, Shin IS, Yang SJ, Park WY, Kim SJ, Shin 318 HY, Yoon JS (2008) Folate, vitamin b(12), and homocysteine 319 U n c o r r e c t e d A u t h o r P r o o f M. Farkas et al. / Homocysteine and Folate in AD 7 as risk factors for cognitive decline in the elderly. Psychiatry 320 Investig 5, 36-40. 321 [9] McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann 322 JI, Williams SM (2006) A controlled trial of homocysteine 323 lowering and cognitive performance. N Engl J Med 354, 2764-324 2772. 325 [10] Dangour AD, Whitehouse PJ, Rafferty K, Mitchell SA, Smith 326 L, Hawkesworth S, Vellas B (2010) B-vitamins and fatty acids 327 in the prevention and treatment of Alzheimer's disease and 328 dementia: A systematic review. J Alzheimers Dis 22, 205-329

Journal of Neuroscience, 2009

To date, long-term consequences of septic encephalopathy on cerebral metabolism, cognition, learn... more 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.

Pharmacopsychiatry, 2007

ABSTRACT The level of epigenetic DNA methylation is an important factor in the pathogenesis of va... more ABSTRACT 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.

Pharmacoepidemiology and Drug Safety, 2012

The comparative evaluation of clinical decision support software (CDSS) programs regarding their ... more 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. 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. 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. 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.

Nutrition Journal, 2010

Background: Several studies demonstrated an association of homocysteine plasma levels and the pla... more 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)(2004)(2005)(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.

Neuroscience Letters, 2010

Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease of the central nervou... more Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease of the central nervous system. We investigated the association of two missense variants of the MTHFR gene, i.e. MTHFR c.677C&amp;amp;gt;T (p.A222V) and c.1298A&amp;amp;gt;C (p.E429A), in 138 patients with clinically definite multiple sclerosis of relapsing-remitting course and 138 age- and gender-matched healthy controls. No significant differences were found in the frequency of the MTHFR c.677C&amp;amp;gt;T polymorphism between MS patients and healthy controls. However, the genotype frequencies of the missense variant MTHFR c.1298A&amp;amp;gt;C were significantly different between patients (AA/AC/CC: 0.34/0.55/0.11) and controls (0.52/0.36/0.12; Pearson&amp;amp;#39;s chi(2)=11.1; p=0.004). These results suggest that homozygosity for the A allele of MTHFR c.1298A&amp;amp;gt;C may be protective against the incidence of MS. If confirmed in an independent study sample, the underlying mechanisms should be investigated, which may lead to novel insights in biochemical factors influencing the aetiology and pathophysiology of MS.

Neuro-Oncology, 2008

Glioblastoma multiforme (GBM) is the most frequent primary brain tumor in adults. Prognosis is po... more 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 6 SE: genotype CC, 13 6 1 months; CT, 11 6 2 months; TT, 7 6 3 months; multivariate Cox regression analysis, Wald 5 8.58, p 5 0.007). In addition, the MTHFR genotype significantly influenced the overall survival of patients with a postoperative Karnofsky score .70 (CC, 12 6 2 months; CT, 11 6 1 months; TT, 10 6 4 months; Wald 5 5.89, p 5 0.015). These data suggest the MTHFR c.677C.T variant is a risk factor for survival in GBM patients.

Neurology, 2007

Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive demyelinating disease c... more Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive demyelinating disease caused by the reactivation of JC papova virus usually in immunocompromised hosts. The disease is a chronic viral infection resulting in mortality within a year. 2 The condition characterized by white matter changes in multiple locations of the brain is caused by destruction of the oligodendrogliocytes. We report a case of AIDS associated PML presenting with progressive cerebellar symptoms, with the unusual feature of imaging abnormalities limited to the posterior fossa.

Neurological Research, 2013

In order to test for mechanisms of whole brain radio therapy side effects and possible neuroprote... more 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. 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. Fourteen days after the procedure, irradiated animals showed decreased open-field activity (two-tailed t-test, sham versus 20 Gy, P&amp;amp;amp;amp;amp;amp;amp;amp;lt;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. 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.

Neurological Research, 2010

Abnormalities in the coagulation pathway are often included in the diagnostic work-up of stroke p... more Abnormalities in the coagulation pathway are often included in the diagnostic work-up of stroke patients, especially in young adults with cryptogenic stroke. Three common genetic variants within the coagulation cascade were investigated in 500 control subjects and in 167 patients with ischemic stroke defined by TOAST subclassification. Analysed variants were factor V Leiden, prothrombin 20210G--&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;A and factor XIII Val34Leu. The factor V Leiden mutation was over-represented in patients with cardioembolic stroke for trend, whereas the prothrombin 20210G--&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;A variant and the factor XIII polymorphism Val34Leu were not associated with stroke of any subtype. The three polymorphisms showed no association with stroke in subgroups of patients defined by age (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;40, 40-49, 50-59, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =60 years). This study suggests that the analysis of prothrombin 20210G--&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;A and factor XIII Val34Leu is not a useful diagnostic procedure in the work-up of ischemic stroke.

Neurodegenerative Diseases, 2010

significantly lower CSF levels of the methyl group donor SAM (193 8 31 vs. 207 8 37 nmol/l; p = 0... more significantly lower CSF levels of the methyl group donor SAM (193 8 31 vs. 207 8 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 8 2.4 vs. 9.1 8 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 8 30 vs. 207 8 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: 2 = 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.

The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques

METHODS We recruited patients with clinically and radiologically proven acute stroke admitted to ... more METHODS We recruited patients with clinically and radiologically proven acute stroke admitted to the Department of Neurology, University of Bonn, Germany. Patients with transitory ischemic attacks or lacunar ischemic stroke were excluded from the study. ...

British journal of cancer, Jan 20, 2012

Chemotherapy for primary central nervous system lymphoma (PCNSL) is based on methotrexate (MTX), ... more Chemotherapy for primary central nervous system lymphoma (PCNSL) is based on methotrexate (MTX), which interferes with both nucleic acid synthesis and methionine metabolism. We have reported previously that genetic variants with influence on methionine metabolism are associated with MTX side effects, that is, the occurrence of white matter lesions as a sign of MTX neurotoxicity. Here, we investigated whether such variants are associated with MTX efficacy in terms of overall survival in MTX-treated PCNSL patients. We analysed seven genetic variants influencing methionine metabolism in 68 PCNSL patients treated with systemic and facultative intraventricular MTX-based polychemotherapy (Bonn protocol). Median age at diagnosis was 59 years (range: 28-77), 32 patients were female. Younger age (Wald=8.9; P=0.003) and the wild-type C (CC) allele of the genotype transcobalamin c (Tc2). 776C>G (Wald=6.7; P=0.010) were associated with longer overall survival in a multivariate COX regression...

BMC research notes, 2011

The polymorphism 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C is associated with... more 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. 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. 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 prevalen...

Clinical and investigative medicine. Médecine clinique et experimentale, 2009

The role of homocysteine in the pathogenesis of arteriosclerosis and stroke is under debate. It i... more 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. 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 offsprin...

Neurology, Jan 13, 2007

Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive demyelinating disease c... more Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive demyelinating disease caused by the reactivation of JC papova virus usually in immunocompromised hosts. The disease is a chronic viral infection resulting in mortality within a year. 2 The condition characterized by white matter changes in multiple locations of the brain is caused by destruction of the oligodendrogliocytes. We report a case of AIDS associated PML presenting with progressive cerebellar symptoms, with the unusual feature of imaging abnormalities limited to the posterior fossa.

Journal of chemical neuroanatomy, 2005

During severe sepsis several immunological defence mechanisms initiate a cascade of inflammatory ... more During severe sepsis several immunological defence mechanisms initiate a cascade of inflammatory events leading to multi-organ failure including septic encephalopathy and ultimately death. To assess the reaction and participation of parenchymal brain cells during endotoxaemia, the present study evaluates micro- and astroglial activation, expression of the inducible nitric oxide synthase (iNOS) pro- and antiapoptotic protein levels Bax and Bcl-2, and apoptosis. Male Wistar rats received 10 mg/kg lipopolysaccharide (LPS) or vehicle intraperitoneally and were sacrificed for brain collection at 4, 8 or 24 h after induction of experimental sepsis. One group of animals received 10 mg/kg of the NOS inhibitor N-monomethyl-L-arginine (L-NMMA) intraperitoneally 1 day before and during the experiment. Immunohistochemical evaluation revealed a sepsis-induced, time-dependent increase in the immunoreactivity of iNOS, glial fibrillary acidic protein (GFAP) and activated microglia (ED-1), parallele...

Alcohol, 2015

Recent studies have shown that smoking and alcoholism may be associated with altered DNA methylat... more 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.

Pharmacoepidemiology and drug safety, 2011

The current study aimed at identifying and quantifying critical drug interactions in neurological... more 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. 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. In 484 patients with 2812 prescriptions, MediQ generated 8 "high danger," 518 "ave...

Frontiers in Aging Neuroscience, 2014

Hyperhomocysteinemia is a risk factor for Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;a... more Hyperhomocysteinemia is a risk factor for Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;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.

Journal of Alzheimer's Disease xx (20xx) x-xx Abstract. Hyperhomocysteinemia is associated with A... more Journal of Alzheimer's Disease xx (20xx) x-xx Abstract. 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 ArcA␤ transgenic AD mouse model. At 14 months of age, the hyperhomocysteinemia-inducing diet yielded higher plasma homocysteine levels in ArcA␤ mice compared with wild-type mice. Levels of plasma 5-methyltetrahydrofolate (5-MTHF) in 14-month-old mice on hyperhomocysteinemiainducing 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 ArcA␤ 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-␤ 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. 8 22 23 [1]. Factors like higher age, male gender, renal dys-30 function, genetic variants, high methionine uptake via 1 These authors contributed equally. protein-rich food, and deficiencies of folate, vitamin 31 B12, and vitamin B6 are linked to hyperhomocys-32 teinemia [2]. The nature of the relationship between 33 hyperhomocysteinemia and AD is controversial [3-5]. 34 Homocysteine is a toxic intermediate of methion-35 ine metabolism. It is either irreversibly metabolized 36 by the vitamin B6-dependent transsulfuration pathway 37 or is recycled to methionine by the folate-and vita-38 min B12-dependent remethylation pathway (Fig. 1). 39 Methionine can be activated to S-adenosylmethionine 40 (SAM), which serves as universal methyl-group donor, 41 e.g., for DNA, RNA, and protein methylation reactions. 42 SAM is thereby converted to S-adenosylhomocysteine 43 (SAH), which is further hydrolyzed to homocysteine 44 in a reversible reaction. Although elevated plasma 307 [6] Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland 308 PM (1998) Folate, vitamin B12, and serum total homocysteine 309 levels in confirmed Alzheimer disease. Arch Neurol 55, 1449-310 1455. 311 [7] Linnebank M, Popp J, Smulders Y, Smith D, Semm-312 ler A, Farkas M, Kulic L, Cvetanovska G, Blom H, 313 Stoffel-Wagner B, Kolsch H, Weller M, Jessen F (2010) S-314 adenosylmethionine is decreased in the cerebrospinal fluid 315 of patients with Alzheimer's disease. Neurodegener Dis 7, 316 373-378. 317 [8] Kim JM, Kim SW, Shin IS, Yang SJ, Park WY, Kim SJ, Shin 318 HY, Yoon JS (2008) Folate, vitamin b(12), and homocysteine 319 U n c o r r e c t e d A u t h o r P r o o f M. Farkas et al. / Homocysteine and Folate in AD 7 as risk factors for cognitive decline in the elderly. Psychiatry 320 Investig 5, 36-40. 321 [9] McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann 322 JI, Williams SM (2006) A controlled trial of homocysteine 323 lowering and cognitive performance. N Engl J Med 354, 2764-324 2772. 325 [10] Dangour AD, Whitehouse PJ, Rafferty K, Mitchell SA, Smith 326 L, Hawkesworth S, Vellas B (2010) B-vitamins and fatty acids 327 in the prevention and treatment of Alzheimer's disease and 328 dementia: A systematic review. J Alzheimers Dis 22, 205-329

Journal of Neuroscience, 2009

To date, long-term consequences of septic encephalopathy on cerebral metabolism, cognition, learn... more 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.

Pharmacopsychiatry, 2007

ABSTRACT The level of epigenetic DNA methylation is an important factor in the pathogenesis of va... more ABSTRACT 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&#39;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.

Pharmacoepidemiology and Drug Safety, 2012

The comparative evaluation of clinical decision support software (CDSS) programs regarding their ... more 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. 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. 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;high danger,&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; 164 as &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;average danger,&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; and 486 as &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;low danger.&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; 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. 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.

Nutrition Journal, 2010

Background: Several studies demonstrated an association of homocysteine plasma levels and the pla... more 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)(2004)(2005)(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.

Neuroscience Letters, 2010

Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease of the central nervou... more Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease of the central nervous system. We investigated the association of two missense variants of the MTHFR gene, i.e. MTHFR c.677C&amp;amp;gt;T (p.A222V) and c.1298A&amp;amp;gt;C (p.E429A), in 138 patients with clinically definite multiple sclerosis of relapsing-remitting course and 138 age- and gender-matched healthy controls. No significant differences were found in the frequency of the MTHFR c.677C&amp;amp;gt;T polymorphism between MS patients and healthy controls. However, the genotype frequencies of the missense variant MTHFR c.1298A&amp;amp;gt;C were significantly different between patients (AA/AC/CC: 0.34/0.55/0.11) and controls (0.52/0.36/0.12; Pearson&amp;amp;#39;s chi(2)=11.1; p=0.004). These results suggest that homozygosity for the A allele of MTHFR c.1298A&amp;amp;gt;C may be protective against the incidence of MS. If confirmed in an independent study sample, the underlying mechanisms should be investigated, which may lead to novel insights in biochemical factors influencing the aetiology and pathophysiology of MS.

Neuro-Oncology, 2008

Glioblastoma multiforme (GBM) is the most frequent primary brain tumor in adults. Prognosis is po... more 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 6 SE: genotype CC, 13 6 1 months; CT, 11 6 2 months; TT, 7 6 3 months; multivariate Cox regression analysis, Wald 5 8.58, p 5 0.007). In addition, the MTHFR genotype significantly influenced the overall survival of patients with a postoperative Karnofsky score .70 (CC, 12 6 2 months; CT, 11 6 1 months; TT, 10 6 4 months; Wald 5 5.89, p 5 0.015). These data suggest the MTHFR c.677C.T variant is a risk factor for survival in GBM patients.

Neurology, 2007

Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive demyelinating disease c... more Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive demyelinating disease caused by the reactivation of JC papova virus usually in immunocompromised hosts. The disease is a chronic viral infection resulting in mortality within a year. 2 The condition characterized by white matter changes in multiple locations of the brain is caused by destruction of the oligodendrogliocytes. We report a case of AIDS associated PML presenting with progressive cerebellar symptoms, with the unusual feature of imaging abnormalities limited to the posterior fossa.

Neurological Research, 2013

In order to test for mechanisms of whole brain radio therapy side effects and possible neuroprote... more 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. 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. Fourteen days after the procedure, irradiated animals showed decreased open-field activity (two-tailed t-test, sham versus 20 Gy, P&amp;amp;amp;amp;amp;amp;amp;amp;lt;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. 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.

Neurological Research, 2010

Abnormalities in the coagulation pathway are often included in the diagnostic work-up of stroke p... more Abnormalities in the coagulation pathway are often included in the diagnostic work-up of stroke patients, especially in young adults with cryptogenic stroke. Three common genetic variants within the coagulation cascade were investigated in 500 control subjects and in 167 patients with ischemic stroke defined by TOAST subclassification. Analysed variants were factor V Leiden, prothrombin 20210G--&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;A and factor XIII Val34Leu. The factor V Leiden mutation was over-represented in patients with cardioembolic stroke for trend, whereas the prothrombin 20210G--&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;A variant and the factor XIII polymorphism Val34Leu were not associated with stroke of any subtype. The three polymorphisms showed no association with stroke in subgroups of patients defined by age (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;40, 40-49, 50-59, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =60 years). This study suggests that the analysis of prothrombin 20210G--&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;A and factor XIII Val34Leu is not a useful diagnostic procedure in the work-up of ischemic stroke.

Neurodegenerative Diseases, 2010

significantly lower CSF levels of the methyl group donor SAM (193 8 31 vs. 207 8 37 nmol/l; p = 0... more significantly lower CSF levels of the methyl group donor SAM (193 8 31 vs. 207 8 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 8 2.4 vs. 9.1 8 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 8 30 vs. 207 8 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: 2 = 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.