Background: There is evidence that homocysteine contributes to various neurodegenerative disorders. Objective: To assess the values of homocysteine in patients with Creutzfeldt-Jakob disease (CJD) in both cerebrospinal fluid (CSF) and plasma. Methods: Study design: Case control study. Total homocysteine was quantified in CSF and plasma samples of CJD patients (n = 13) and healthy controls (n = 13). Results: Mean values in healthy controls: 0.15 mumol/l +/- 0.07 (CSF) and 9.10 mumol/l +/- 2.99 (plasma); mean values in CJD patients: 0.13 mumol/l +/- 0.03 (CSF) and 9.22 mumol/l +/- 1.81 (plasma). No significant differences between CJD patients and controls were observed (Mann-Whitney U, p > 0.05). Conclusions: The results indicate that the CSF and plasma of CJD patients showed no higher endogenous levels of homocysteine as compared to normal healthy controls. These findings provide no evidence for an additional role of homocysteine in the pathogenetic mechanisms underlying CJD neurodegeneration. Copyright (C) 2005 S. Karger AG, Basel

Bottiglieri T

Halliwell B

Hans A. Kretzschmar

Inga Zerr

Jens Wiltfang

Markus Otto

Otto M

Stefan Bleich

Stefan Kropp

Ubbink JB

Zerr I

English

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Creutzfeldt-Jakob Disease and Homocysteine Levels in Plasma and Cerebrospinal Fluid

Bleich, S.

Otto, Markus

Zerr, Inga

Kropp, S.

Kretzschmar, Hans A.

Wiltfang, Jens

Open Access LMU

Short CommunicationGerontology 2005;51:142–144DOI: 10.1159/000082200Creutzfeldt-Jakob Disease andHomocysteine Levels in Plasma andCerebrospinal FluidStefan Bleicha Markus Ottob Inga Zerrb Stefan KroppcHans A. Kretzschmard Jens WiltfangaaDepartment of Psychiatry and Psychotherapy, Friedrich-Alexander-University, Erlangen-Nuremberg,bDepartment of Neurology, Georg-August-University Göttingen, cDepartment of Psychiatry and Psychotherapy,Medical School University, Hannover, and dInstitute of Neuropathology, Ludwig-Maximilians-University,Munich, GermanyReceived: June 16, 2004Accepted: August 23, 2004Prof. Dr. Jens WiltfangFriedrich-Alexander-University of Erlangen-NurembergDepartment of Psychiatry and Psychotherapy, Schwabachanlage 6–10DE–91054 Erlangen (Germany), Tel. +49 9131 853 4597Fax +49 9131 853 4105, E-Mail jens.wiltfang@psych.imed.uni-erlangen.deABCFax + 41 61 306 12 34E-Mail karger@karger.chwww.karger.com© 2005 S. Karger AG, Basel0304–324X/05/0512–0142$22.00/0Accessible online at:www.karger.com/gerKey WordsCreutzfeldt-Jakob disease W Cerebrospinal fluid WHomocysteine W Neurotoxicity W NeurodegenerationAbstractBackground: There is evidence that homocysteine con-tributes to various neurodegenerative disorders. Objec-tive: To assess the values of homocysteine in patientswith Creutzfeldt-Jakob disease (CJD) in both cerebrospi-nal fluid (CSF) and plasma. Methods: Study design: Casecontrol study. Total homocysteine was quantified in CSFand plasma samples of CJD patients (n = 13) and healthycontrols (n = 13). Results: Mean values in healthy con-trols: 0.15 Ìmol/l B 0.07 (CSF) and 9.10 Ìmol/l B 2.99(plasma); mean values in CJD patients: 0.13 Ìmol/l B0.03 (CSF) and 9.22 Ìmol/l B 1.81 (plasma). No signifi-cant differences between CJD patients and controls wereobserved (Mann-Whitney U, p 1 0.05). Conclusions: Theresults indicate that the CSF and plasma of CJD patientsshowed no higher endogenous levels of homocysteineas compared to normal healthy controls. These findingsprovide no evidence for an additional role of homocys-teine in the pathogenetic mechanisms underlying CJDneurodegeneration.Copyright © 2005 S. Karger AG, BaselIntroductionElevated plasma homocysteine concentrations arelinked to neuropsychiatric disorders such as alcoholismand alcohol-related brain atrophy [3], Alzheimer‘s disease(AD), and cognitive impairment [8]. Furthermore, in-creased plasma homocysteine levels are an independentrisk factor for the development of AD [8]. Homocysteineis a neurotoxic excitatory amino acid, which plays a rolein a shared biochemical cascade involving overstimula-tion of N-methyl-D-aspartate (NMDA) receptors, oxida-tive stress, activation of caspases, DNA damage, andmitochondrial dysfunction. These mechanisms are be-lieved to be important in the pathogenesis of neurotoxici-ty and excitotoxicity [3, 6].Prion diseases or spongiform encephalopathies are agroup of fatal neurodegenerative disorders includingCreutzfeldt-Jakob disease (CJD). Since the chemical com-position of human cerebrospinal fluid (CSF) is consideredto reflect brain metabolism, we investigated homocys-teine levels in the CSF of CJD patients and healthy con-trols. Additionally, plasma samples were examined fortotal homocysteine levels. It was the aim of the presentpilot study to assess the possible involvement of homocys-teine in the pathogenesis of CJD.Creutzfeldt-Jakob Disease andHomocysteine LevelsGerontology 2005;51:142–144 143MethodsThe present case control study was approved by the local EthicsCommittee. Diagnosis of CJD and laboratory investigations wereperformed as previously described [1, 7, 10]. 13 CJD patients wereexamined clinically by a member of the German CJD SurveillanceStudy Group and each patient underwent a detailed neurologicexamination. The mean age of CJD patients was 65.8 years (range53.8–83.5 years). All patients of this group have succumbed to theirdisease, and the diagnosis CJD was confirmed neuropathologicallyusing immunohistochemistry for the prion protein in all cases. 14-3-3protein was detected according to various methods [7, 10, 11] in all13 CJD patients. The controls consisted of 13 healthy subjects withnormal cognition and without a diagnosis of any psychiatric or neu-rologic disease. After complete description of the study to the sub-jects, written informed consent was obtained. Controls were matchedto cases by age and gender.Screening for non-genetic factors possibly associated with ele-vated homocysteine levels such as lifestyle (alcohol abuse, nutritionalstatus, medication), endocrinological conditions and other diseases(i.e. diabetes mellitus, cardiovascular diseases), laboratory methodsand measurements (vitamins B12, B6 and folate) were performed onthe basis of a previous study [2]. All patients and controls were classi-fied as normally nourished (data not shown). Under these conditions,a plasma homocysteine reference interval of 4.9–11.7 Ìmol/l wasdefined as normal according to Ubbink et al. [9]. Normal ranges forCSF homocysteine are not known.Total homocysteine in plasma and cerebrospinal fluid (CSF) wasmeasured by an enzyme-linked immunosorbent assay (Axis® Homo-cysteine EIA, Germany/Norway, IBL-No. AX 513 01). Statisticalanalysis: The significance of differences between groups was evaluat-ed by the non-parametric Mann-Whitney U test. Results are present-ed as the central tendency (mean) B SD. p ! 0.05 (two-tailed) wasconsidered to indicate statistical significance.ResultsAs shown in figure 1, CSF as well as plasma homocys-teine levels did not differ significantly between CJDpatients (n = 13) and controls (n = 13). Central tendencies(CT or ‘mean’ B SD in Ìmol/l) in controls: 0.15 B 0.07(CSF) and 9.10 B 2.99 (plasma); CT values in CJDpatients: 0.13 B 0.03 (CSF) and 9.22 B 1.81 (plasma).Thus, no significant differences between CJD patientsand controls in respect to homocysteine concentrations insamples of CSF (Z = –0.46, p = 0.65) and plasma (Z =–0.33, p = 0.76) were found. Furthermore, in both groupshomocysteine concentrations were within the referenceinterval (4.9–11.7 Ìmol/l).Fig. 1. Cerebrospinal fluid and plasma homocysteine levels inpatients with CJD and controls.DiscussionTo our knowledge, this is the first study evaluatinghomocysteine levels in patients suffering from (sporadic)CJD. However, we did not detect any significant differ-ences of homocysteine levels in CSF or plasma. A numberof reviews detail acute or chronic pathophysiology inwhich free radicals and homocysteine express their toxici-ty in neurodegenerative disorders [5]. Taking into accountthat there is no evidence of oxidative stress in CJDpatients [1] the results of the present study are in line withthese previous observations. However, determining ho-mocysteine levels in an earlier stage of CJD patientsmight deliver other results. Despite the identification ofhyperhomocysteinemia as an independent risk factor forneurodegenerative disorders such as AD [8], little isknown about the presence of homocysteine in the CSF.However, similar results were found in a recent study of18 healthy adults with CSF homocysteine concentrationsbetween 0.015 and 0.140 Ìmol/l [4].Furthermore, it must be taken into account that anintracellular accumulation of homocysteine leads to hy-perhomocysteinemia. Thus, the neurotoxicity of homo-cysteine is not only caused by an elevated extracellularhomocysteine concentration, but especially by the toxiceffects that can be triggered by the intracellular hyperho-mocysteinemia and can affect the intracellular compart-ments [3].144 Gerontology 2005;51:142–144 Bleich/Otto/Zerr/Kropp/Kretzschmar/WiltfangSince we could not disclose an intracellular accumula-tion of homocysteine, further studies are needed whichshould be directed to CJD brain tissue. However, at thismoment we conclude that homocysteine possibly does notplay a pathophysiological role in CJD and may not serveas a biological marker of CJD but may be useful in thedifferential diagnosis of other neurodegenerative disor-ders, in particular AD.AcknowledgementsThis study was supported by a grant from the Federal Ministry ofHealth to H.A.K. and to S.P. (BMG Az325-4473-05/3). We are grate-ful to all colleagues from other clinics for their cooperation, whichhas enabled us to conduct the study in this way. We are especiallyobliged to Maya Schneider-Dominco and Monika Bodemer for tech-nical assistance. This work is dedicated to our excellent colleagueProf. Dr. Sigrid Poser (MD), who died unexpectedly in July 2004.References1 Bleich S, Kropp S, Degner D, Zerr I, Pilz J,Gleiter CH, Otto M, Ruther E, KretzschmarHA, Wiltfang J, Kornhuber J, Poser S: Creutz-feldt-Jakob disease and oxidative stress. ActaNeurol Scand 2000;101:332–334.2 Bleich S, Jünemann A, von Ahsen N, Lausen B,Ritter K, Beck G, Naumann GO, Kornhuber J:Homocysteine and risk of open-angle glauco-ma. J Neural Transm 2002;109:1499–1504.3 Bleich S, Bandelow B, Javaheripour K, MüllerA, Degner D, Wilhelm J, Havemann-ReineckeU, Sperling W, Rüther E, Kornhuber J: Hyper-homocysteinemia as a new risk factor for brainshrinkage in patients with alcoholism. Neuro-sci Lett 2003;335:179–182.4 Bottiglieri T: Folate, vitamin B12 and neuropsy-chiatric disorders. Nutr Rev 1996;54:382–390.5 Halliwell B, Gutteridge JMC: Oxygen toxicity,oxygen radicals, transition metals and disease(review article). Biochem J 1984:219:1–14.6 Lipton SA, Kim WK, Choi YB, Kumar S,D’Emilia DM, Rayudu PV, Arnelle DR, Stam-ler JS: Neurotoxicity associated with dual ac-tions of homocysteine at the N-methyl-D-as-partate receptor. Proc Natl Acad Sci USA1997;94:5923–5928.7 Otto M, Wiltfang J, Cepek L, Neumann M,Mollenhauer B, Steinacker P, Ciesielczyk B,Schulz-Schaeffer W, Kretzschmar HA, Poser S:Tau protein and 14-3-3 protein in the differ-ential diagnosis of Creutzfeldt-Jakob disease.Neurology 2002;58:192–197.8 Seshadri S, Beiser A, Selhub J, Jacques PF,Rosenberg IH, D’Agostino RB, Wilson PW,Wolf PA: Plasma homocysteine as a risk factorfor dementia and Alzheimer’s disease. N Engl JMed 2002;346:476–483.9 Ubbink JB, Becker PJ, Vermaak WJ, DelportR: Results of B-vitamin supplementation studyused in a prediction model to define a referencerange for plasma homocysteine. Clin Chem1995;41:1033–1037.10 Zerr I, Bodemer M, Weber T: The 14-3-3 brainprotein and transmissible spongiform encepha-lopathy. N Engl J Med 1997;336:874.11 Zerr I, Pocchiari M, Collins S, Brandel JP, dePedro Cuesta J, Knight RS, Bernheimer H,Cardone F, Delasnerie-Laupretre N, CuadradoCorrales N, Ladogana A, Bodemer M, FletcherA, Awan T, Ruiz Bremon A, Budka H, La-planche JL, Will RG, Poser S: Analysis of EEGand CSF 14-3-3 proteins as aids to the diagno-sis of Creutzfeldt-Jakob disease. Neurology2000;55:811–815.

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Creutzfeldt-Jakob disease and oxidative stress.

Delport R: Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine.

Folate, vitamin B12 and neuropsychiatric disorders. Nutr Rev

Gutteridge JMC: Oxygen toxicity, oxygen radicals, transition metals and disease (review article).

Homocysteine and risk of open-angle glaucoma.

Hyperhomocysteinemia as a new risk factor for brain shrinkage in patients with alcoholism.

PA: Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease.

S: Analysis of EEG and CSF 14-3-3 proteins as aids to the diagnosis of Creutzfeldt-Jakob disease.

Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt-Jakob disease.

The 14-3-3 brain protein and transmissible spongiform encephalopathy.

Creutzfeldt-Jakob disease and homocysteine levels in plasma and cerebrospinal fluid

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Creutzfeldt-Jakob disease and homocysteine levels in plasma and cerebrospinal fluid

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