CSF homocysteine is not elevated in schizophrenia | SpringerLink

8 downloads 0 Views 106KB Size Report
Summary. Homocysteine is a neurotoxic amino acid originally found to be an independent risk factor for cardiovascular and cerebral vascular disease and more ...
DOI 10.1007/s00702-004-0269-x J Neural Transm (2005) 112: 297–302

CSF homocysteine is not elevated in schizophrenia Short Communication J. Levine1 , G. Agam1 , B. A. Sela2 , D. L. Garver3, E. F. Torrey4, and R. H. Belmaker1 1

Stanley Research Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, and 2 Institute of Pathological Chemistry, Sheba Medical Center, Tel-Hashomer, Israel 3 Department of Psychiatry and Behavioral Science, University of Louisville School of Medicine, Louisville, KY, and 4 Stanley Medical Research Institute, Bethesda, MD, USA Received September 7, 2004; accepted December 7, 2004

Summary. Homocysteine is a neurotoxic amino acid originally found to be an independent risk factor for cardiovascular and cerebral vascular disease and more recently suggested to be a risk factor for Alzheimer’s disease. Several authors have observed high plasma homocysteine levels among schizophrenia patients. We reported that such high levels characterize young male schizophrenia patients. We now studied two groups of schizophrenia patients (N ¼ 41) and controls (N ¼ 29) for CSF homocysteine levels. No difference was found for CSF homocysteine levels between schizophrenia patients and controls (p ¼ .041 for Study A and p ¼ .52 for Study B). Keywords: Cerebrospinal fluid, schizophrenia, homocysteine. Introduction Homocysteine is a neurotoxic amino acid (Gortz et al., 2004; Ho et al., 2002; Kruman et al., 2000; Lipton et al., 1997) originally found to be an independent risk factor for cardiovascular and cerebral vascular disease (Nyga˚rd et al., 1995) and more recently suggested to be a risk factor for Alzheimer’s disease (Seshadri et al., 2002). Several authors reported high plasma homocysteine levels among schizophrenia patients (Regland et al., 1995; Susser et al., 1998). Levine et al. (2002) and Appelbaum et al. (2004) reported that such high levels characterize young male schizophrenia patients. Other researchers however, could not repeat these findings (Goff et al., 2004; Virgos et al., 1999).

298

J. Levine et al.

Homocysteine is formed during methionine recycling in the cell but is rapidly extruded from the intracellular environment to extracellular compartments (Selhub, 1999). Such extracellular compartments include the plasma in the case of peripheral tissues and the CSF in the case of brain tissue. Since amino acids can not pass the intact blood brain barrier (BBB) freely (Kruse et al., 1985), it was suggested that the main source of CSF homocysteine is brain glial cells and neurons (Serot et al., 2003). Data suggesting that homocysteine is toxic to endothelium of the vascular tissue (Stuhlinger et al., 2003) may suggest that hyperhomocysteinemia may induce impairment of the BBB. Thus the statement regarding the brain as the main source of CSF homocysteine may not be true in cases of grossly increased plasma homocysteine levels. CSF homocysteine was previously reported to be elevated in a variety of disorders including Alzheimer disease (Teunissen et al., 2002). The following study measured homocysteine levels in CSF of two research groups of schizophrenia patients. Material and methods CSF homocysteine levels were measured in 40 schizophrenia and 28 healthy control subjects. The samples were obtained from two separate studies. Study A included 20 physically healthy Irish schizophrenia subjects from St Patrick Hospital, Castlerea County Roscommon and the Regional Hospital in Galway, Ireland and twenty healthy controls from the sample described in Preble and Torrey (1985). Study B included 21 physically healthy schizophrenia subjects admitted to a research inpatient service following exacerbation of psychosis and eight healthy controls as described in Garver et al. (2003). All patients in Study B were neuroleptic free for at least two months, whereas patients in Study A were all neuroleptic-treated. For Study A all subjects gave informed consent according to procedures accepted at the time (Preble and Torrey, 1985); Study B was approved by the Institutional Review Board of University of Louisville and all subjects provided written informed consent (Garver et al., 2003). The original studies (Garver et al., 2003) and Preble and Torrey (1985) included larger numbers of subjects but CSF remained available only in the subset we studied.

CSF analysis Half ml of each CSF sample was concentrated by lyophilization in a Speed-Vac to about 0.05 ml. The exact concentration factor for each sample was used to calculate the original CSF homocysteine level. CSF samples were assayed using HPLC technology with fluorescence detection following labeling of homocysteine with monobromobimane as a modification of the method reported by Araki and Sako (1987).

Results There was no significant difference in mean CSF homocysteine in Study A between schizophrenic patients (X  SD ¼ .038  .05 mm=L) and controls (.012  .04 mm=L, p ¼ .255) or in Study B (schizophrenic patients, .022  .03 mm=L vs. controls, .018  .03 mm=L). There was no mean difference in CSF homocysteine between Study A and Study B. Since Levine et al. (2002) found elevated plasma homocysteine levels in male patients only, Fig. 1 presents data for CSF homocysteine levels in male schizophrenia patients and controls.

CSF homocysteine in schizophrenia

299

Fig. 1. CSF homocysteine levels in male schizophrenia patients and controls only

Study A Two-way ANCOVA test – diagnosis and gender taken as independent variables, homocysteine taken as a dependent variable and age taken as a covariant – revealed no significant effects of diagnosis or gender and no interaction between these two independent variables on CSF homocysteine levels (df ¼ 1,35, F ¼ 0.51, p ¼ 0.47; df ¼ 1,35, F ¼ 0.42, p ¼ 0.52; df ¼ 1,35, F ¼ 0.69, p ¼ 0.41 respectively). Study B Two-way ANCOVA test – diagnosis and gender taken as independent variables, homocysteine taken as a dependent variable and age taken as a Table 1. Demographic characteristics of schizophrenia patients and controls

Study A Number Age in years: mean (range) Gender Study B Number Age in years: mean (range) Gender

Schizophrenia patients

Controls

20

20

33.5 (16–63) 11M, 9F

28.7 (21–49) 11M, 9F

21 29.1 (19–54) 15M, 6F

8 31.6 (24–62) 6M, 2F

300

J. Levine et al.

covariant – revealed no significant effect of diagnosis or gender and no interaction between these two independent variables on CSF homocysteine levels (df ¼ 1,24, F ¼ 0.47, p ¼ 0.50; df ¼ 1,24, F ¼ 0.17, p ¼ 0.69; df ¼ 1,24, F ¼ 0.44, p ¼ 0.52, respectively). Discussion No statistically significant difference was found in this study between schizophrenia patients and control subjects in two different patient populations and in different decades. No difference was also found in young male inpatients in contrast to the results of Levine et al. (2002) and Applebaum et al. (2004) in plasma. Recently Regland et al. (2004) found that a small subgroup of young psychotic male patients present extremely high CSF homocysteine levels (0.4–0.7 mm=L) compared with controls (n ¼ 25, mean  SD: 0.19  0.03 mm=L), although overall they did not find a significant mean difference between patients and controls. In study A of the present report we also found a trend for elevated homocysteine (see Fig. 1) although the overall mean was not significantly different from the controls. Neither the current study nor Regland et al. (2004) measured both plasma and CSF homocysteine levels. Such measurement would enable the comparison of peripheral and central homocysteine. Study A samples had been stored at 70 C for two decades whereas the study B samples were more recent. Average CSF homocysteine levels were very similar. Israelsson et al. (1993) reported that homocysteine concentrations remain stable for up to 10 years when kept at 20 C. Homocysteine levels in previous reports of CSF ranged between 0.007– 0.02 mm=L (Blom et al., 1993) to