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Memory impairment correlates with increased S100B serum concentrations in patients with chronic schizophrenia
Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1789–1792
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p n p b p
Memory impairment correlates with increased S100B serum concentrations in patients with chronic schizophrenia Anya Pedersen a,⁎, Markus Diedrich a, Florian Kaestner a, Katja Koelkebeck a, Patricia Ohrmann a, Gerald Ponath a, Frank Kipp b, Simone Abel a, Ansgar Siegmund a, Thomas Suslow a, Christof von Eiff b, Volker Arolt a, Matthias Rothermundt a a b
University Medical Faculty, Department of Psychiatry, 48149 Münster, Germany University Medical Faculty, Institute of Medical Microbiology, 49149 Münster, Germany
a r t i c l e
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Article history: Received 6 June 2008 Received in revised form 10 July 2008 Accepted 26 July 2008 Available online 31 July 2008 Keywords: Astrocytes Memory S100 B Schizophrenia
a b s t r a c t Astrocyte activation indicated by increased S100B is considered a potential pathogenic factor for schizophrenia. To investigate the relationship between astrocyte activation and cognitive performance, S100B serum concentration, memory performance, and psychopathology were assessed in 40 first-episode and 35 chronic schizophrenia patients upon admission and after four weeks of treatment. Chronic schizophrenia patients with high S100B were impaired concerning verbal memory performance (AVLT, Auditory Verbal Learning Test) compared to chronic and first-episode patients with low S100B levels. The findings support the hypothesis that astrocyte activation might contribute to the development of cognitive dysfunction in schizophrenia. © 2008 Elsevier Inc. All rights reserved.
1. Introduction In numerous studies, schizophrenic patients revealed deficits in a multitude of neurocognitive functions including attention and vigilance, working memory, verbal learning and memory, visual learning and memory, reasoning and problem solving, speed of processing, and social cognition (Heinrichs and Zakzanis, 1998). Although cognitive impairments associated with schizophrenia have been comprehensively examined, only a few data are available on the neurobiological correlates of these cognitive deficits. Several lines of research indicate that astrocyte dysfunction can be directly responsible for neuronal malfunction mainly via glutamateinduced Ca2+ modulation (Araque et al., 1999; Grosche et al., 1999). An indicator of astrocyte activation is the Ca2+ modulating protein S100B exerting paracrine and autocrine effects on neurons and glia. From in vivo animal experiments there is evidence that S100B modulates cognitive performance. Intraventricular S100B infusion after trau-
Abbreviations: AVLT, Auditory Verbal Learning Test; CPZ, chlorpromazine; CSF, cerebrospinal fluid; DCS, Diagnostic Test of Cerebral Dysfunction; H, high S100B serum level; L, low S100B serum level; PANSS, Positive and Negative Syndrome Scale; rhEPO, recombinant human erythropoietin; SCID, Structured Clinical Interview; T0, examination upon admission; T1, examination after four weeks of treatment; WAIS-R, Wechsler Adult Intelligence Scale—Revised. ⁎ Corresponding author. Department of Psychiatry, University of Münster, AlbertSchweitzer-Str. 11, 48149 Münster, Germany. Tel.: +49 251 8356601; fax: +49 251 8356612. E-mail address: [email protected] (A. Pedersen). 0278-5846/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2008.07.017
matic brain injury in the rat model was associated with improved cognitive recovery (Kleindienst et al., 2005). Deficits in memory and spatial learning have been reported in animals with increased (Roder et al., 1996; Whitaker-Azmitia et al., 1997; Winocur et al., 2001) or decreased S100B levels (Gromov et al., 1992; O'Dowd et al., 1997). Moreover, S100B might be involved in the regulation of hippocampal long-term potentiation, which is thought to be a physiological correlate of long-term memory (Swanson et al., 1982). Infusion of S100B into the rat hippocampus was shown to facilitate memory function for the inhibitory avoidance task but not for the open-field habituation (Mello e Souza et al., 2000). Patients with schizophrenia reveal increased S100B concentrations in CSF and serum (Lara et al., 2001; Rothermundt et al., 2001; Rothermundt et al., 2004a; Sarandol et al., 2007; Schmitt et al., 2005; Schroeter et al., 2003; Wiesmann et al., 1999). Persistently high S100B levels have repeatedly been associated with negative or deficit symptoms and slower psychopathological improvement upon treatment (Rothermundt et al., 2001, 2004b; Sarandol et al., 2007). Given the critical role of S100B for cognitive performance as established in animal experiments and the association of increased S100B levels in schizophrenia with persistent negative symptoms, it can be assumed that S100B concentration might interfere with cognition. We hypothesized that cognitive deficits might be more prevalent in schizophrenic patients with persistent high S100B concentrations. Therefore, we designed this study to investigate the impact of astrocyte activation indicated by S100B increase on memory performance in first-episode and chronic schizophrenia patients thereby
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A. Pedersen et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1789–1792
Table 1 S100B raw scores upon admission and after four weeks of treatment in schizophrenic patients First-episode schizophrenia Low S100B (n = 37) [mean ± SD] S100B upon admission (µg/L) 0.06 ± 0.02 S100B after treatment (µg/L) 0.05 ± 0.02*
Chronic schizophrenia
High S100B (n = 3) [mean ± SD]
Low S100B (n = 24) [mean ± SD]
High S100B (n = 11) [mean ± SD]
0.09 ± 0.03 0.12 ± 0.04
0.06 ± 0.02 0.05 ± 0.01*
0.09 ± 0.03 0.10 ± 0.02
Group H had high S100B levels (N 0.065 µg/L upon admission and after treatment), group L had low S100B levels. For all sub-samples scores upon and after admission were compared with paired t-tests. ⁎ p b 0.05 (paired t-tests for comparisons between S100B levels upon admission and after treatment).
further characterizing the potential role of astrocytes in the pathogenesis of schizophrenia. 2. Methods
the course of the S100B concentrations and consistent with previous studies all patients were classified according to their S100B serum concentration: Patients with S100B levels higher than the median (0.065 µg/L) upon admission and after four weeks of treatment were assigned to group H (“high S100B”), the remaining patients with low S100B concentrations upon admission or with initially elevated S100B levels normalizing during treatment, formed group L (“low S100B”). Using the mean S100B levels of healthy controls plus two standard deviations (N0.069 µg/L; see Rothermundt et al., 2001) as a cut-off score leads to identical grouping. 2.3. Neuropsychological measures Neuropsychological examination utilized standard test procedures for the assessment of memory performance: verbal learning and memory performance was measured with the Auditory Verbal Learning Test (AVLT; Heubrock, 1992), and figural memory was assessed with a Diagnostic Test of Cerebral Dysfunction (DCS; Weidlich and Lamberti, 2001). In the DCS, nine abstract figures presented as geometric pictures must be reproduced with five wooden sticks by free recall in six successive trials (sum score).
2.1. Subjects 2.4. Data analysis Ninety-four schizophrenic inpatients diagnosed with a Structured Clinical Interview for DSM-IV (SCID) participated in the study. Patients with any history of other psychiatric disorders, neurological disorders, brain damage, serious head injury, tardive dyskinesia, alcohol or illegal drug abuse were excluded from the study. After written informed consent was acquired, serum samples were taken upon admission (T0) and after four weeks of treatment (T1). Clinical symptoms were rated by an experienced and trained clinician with the Positive and Negative Syndrome Scale (PANSS) at both time points; neuropsychological measures were performed only at T1. From the initial pool of recruited patients, 40 first-episode and 35 chronic schizophrenic patients completed the study, three patients were excluded for diagnostic reasons, and sixteen patients dropped out before reinvestigation. The mean ages of the first-episode and chronic patients were 24.9 years (SD = 5.7; 28 males and 12 females) and 32.6 (SD = 7.9; 22 males and 13 females), respectively. All patients received antipsychotic drugs (T0: quetiapine 33, amisulpride 16, risperidone 15, clozapine 14, olanzapine 7, haloperidol 4, perazine 2, ziprasidone 1, flupenthixol 1, zuclopenthixol 1, 19 patients received a combination of drugs, mean chlorpromazine (CPZ) equivalent dose ± SD, 568.7 ± 392.3 mg/day; T1: quetiapine 39, risperidone 17, clozapine 13, amisulpride 16, olanzapine 5, perazine 3, ziprasidone 2, flupenthixol 1, 21 patients received a combination of drugs, mean CPZ equivalent dose 519.1 ± 286.1 mg/day). The two groups did not differ in sex (χ2 = 0.429, df = 1, p = 0.625), years of education (t = 0.069, df = 73, p = 0.945), intellectual performance (vocabulary test of the WAIS-R, Wechsler Adult Intelligence Scale—Revised; t = − 0.544, df = 73, p = 0.588) or CPZ equivalent dose (T0: t = 0.352, df = 73, p = 0.726; T1: t = 1.295, df = 73, p = 0.199), but as expected age (t = −4.891, df = 73, p b 0.01) and duration of illness (t = −8.177, df = 73, p b 0.001) were significantly higher in patients with chronic schizophrenia. All participants were native speakers of German. The study protocol was approved by the local ethics committee according to the Declaration of Helsinki of 1964, and written informed consent was obtained from all participants prior to their enrolment in the study.
The categorical data were analyzed using Pearson's χ2-tests. Differences in continuous variables were evaluated by Student's ttest. Correlations were determined using the Pearson Correlation Coefficient. Significance was assumed for p b 0.05 (two-tailed). All statistical analyses were performed by SPSS 15.0 (SPSS 15.0 for Windows, SPSS Inc., Chicago, IL, USA). 3. Results Table 1 shows the mean S100B levels upon admission and after treatment. For the total sample the differences in S100B concentration between admission (T0) and after treatment (T1) did not reach statistic significance (t = 1.891, df = 74, p = 0.063; paired t-test). However, in the low S100B groups there was a significant decline in S100B level between T0 and T1 (first-episode patients, group L: t = 2.126, df = 36, p = 0.040; chronic patients, group L: t = 2.609, df = 23, p = 0.016; paired t-test). Furthermore, the proportion of patients with high S100B levels (group H: 31.4%) was significantly larger in chronic patients than in first-episode patients (group H: 7.5%; χ2 = 7.30, df = 2, p = 0.007).
2.2. S100B measurements in serum Blood samples were centrifuged within 2 h, aliquoted, and frozen at −80 °C until analysis. S100B concentrations were determined by applying the LIAISON Sangtec-100-assay (AB Sangtec Medical, Bromma, Sweden), a quantitative automated luminometric immunoassay, according to the manufacturers' instructions. To investigate
Fig. 1. Verbal memory (AVLT) and figural memory (DCS) of patients with chronic schizophrenia group according to S100B levels. Group H had high S100B levels (N0.065 µg/L upon admission and after treatment), group L had low S100B levels. Error bars indicate standard errors. ⁎p b 0.05.
A. Pedersen et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1789–1792 Table 2 Psychopathological and neuropsychological measures Variable
First-episode schizophrenia (n = 40) [mean ± SD]
Chronic schizophrenia (n = 35) [mean ± SD]
Statistics
df
p
Intellectual performance (WAIS-R vocabulary) AVLT sum AVLT recall AVLT recognition DCS PANSS total score upon admission Positive symptoms Negative symptoms General psychopathology PANSS total score after 4 weeks of treatment Positive symptoms Negative symptoms General psychopathology
21.8 ± 5.0
22.5 ± 6.4
t = −0.544
73
NS
51.6 ± 9.7 10.0 ± 3.0 11.8 ± 3.6 23.0 ± 8.4 67.7 ± 14.2#
48.3 ± 10.3 9.1 ± 3.8 11.0 ± 4.1 25.5 ± 9.0 61.6 ± 13.7#
t = 1.401 t = 1.081 t = 0.834 t = −1.242 t = 2.044
73 73 73 73 73
NS NS NS NS 0.045
14.1 ± 4.3 17.6 ± 5.4 36.0 ± 8.1# 58.9 ± 14.9***
12.3 ± 4.9 17.0 ± 5.8 31.5 ± 6.6# 55.8 ± 12.9*
t = 1.688 t = 0.485 t = 2.608 t = 0.949
73 73 73 73
NS NS 0.011 NS
12.0 ± 4.3#, *** 16.3 ± 6.2* 30.7 ± 7.1***
10.1 ± 2.8#, ** 16.1 ± 6.1 29.8 ± 6.6
t = 2.125 t = 0.112 t = 0.584
73 73 73
0.037 NS NS
#
p b 0.05 (t-tests for comparisons between the two groups). *p b 0.05; **p b 0.01; ***p b 0.001 (paired t-tests for comparisons between PANSS scores upon admission and after treatment). Abbreviations: WAIS-R, Wechsler Adult Intelligence Scale—Revised; AVLT, Auditory Verbal Learning Test; DCS, Diagnostic Test of Cerebral Dysfunction; PANSS, Positive and Negative Symptom Scale.
First-episode and chronic schizophrenia patients with low S100B did not differ significantly on any of the neuropsychological measures (Fig. 1). However, patients with chronic schizophrenia and high S100B concentrations revealed significantly poorer verbal memory performance than patients with first-episode schizophrenia (AVLT sum: t = 2.408; df = 46; p = 0.020). Chronic schizophrenic patients displaying low S100B levels revealed significantly better AVLT performance than those with high S100B levels (sum: t = 2.198; df = 33; p = 0.035; recognition: t = 2.048; df = 33; p = 0.049). There were no significant group differences regarding figural memory. Because of the small sample size (n = 3) first-episode patients with high S100B were not included in the analysis. Table 2 shows the mean neuropsychological performance scores of first-episode vs. chronic patients. After treatment first-episode patients revealed improved PANSS scores (all sub-scales), whereas patients with chronic schizophrenia showed no improvement regarding PANSS negative symptoms and general psychopathology (Table 2). No significant correlations were revealed between S100B concentrations and PANSS total scores in first-episode (T0: r = −0.161, p = 0.322, n.s.; T1: r = −0.177, p = 0.275, n.s.) and chronic patients (T0: r = −0.058, p = 0.739, n.s.; T1: r = −0.022, p = 0.900, n.s.). Moreover, there were no significant correlations between S100B levels and PANSS positive scores (all p's N 0.144, n.s.), PANSS negative scores (all p's N 0.297, n.s.), and PANSS general scores (all p's N 0.158, n.s.). 4. Discussion The present study demonstrates significant differences in cognitive performance related to S100B in patients with schizophrenia. In chronic schizophrenic patients with high S100B serum concentrations, verbal memory was significantly impaired compared to chronic patients with low S100B concentrations and first-episode patients. These results are in line with findings by Ehrenreich et al. (2007), who reported a significant improvement of cognitive performance and decline in serum S100B in chronic schizophrenic patients treated with recombinant human erythropoietin (rhEPO). The authors suggest that rhEPO either reduces the intracerebral S100B production or “seals” the blood-brain barrier and thereby prevents S100B from crossing into the circulation.
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In our study, the impact of S100B on neuropsychological parameters was limited to patients with chronic schizophrenia. This result is in accordance with earlier findings that S100B concentrations are associated with persistent negative symptoms (Rothermundt et al., 2001, 2004b; Schmitt et al., 2005). It appears that persistently increased S100B concentrations indicate or are involved in an ongoing pathological process resulting in chronic course of disease with cognitive impairment. Patients with chronic schizophrenia who experience a normalization of S100B levels obviously develop less cognitive decline. This is in concordance with the hypothesis that in schizophrenia astrocyte activation indicated by S100B increase might be a counteraction of the brain to fight a so far unknown pathological process. A normalization of S100B would then indicate a stop of this process. The finding of Schmitt et al. (2005) lacking a significant correlation between S100B and various cognitive parameters in elderly, chronic schizophrenic patients might be influenced by much longer disease course and antipsychotic pharmacological treatment in their sample. It remains to be clarified whether the underlying pathological process is reversible or at a certain stage reaches a point of no return. Increased serum levels of S100B have been related to a passive release due to astrocyte destruction or an active release by secretion. Thus, increase of peripheral levels of S100B could be a sign of astrocytic injury and/or of astrocytic response to neuronal injury. Hanson and Gottesman (2005) hypothesize disruptions in astroglial mediated coupling of cerebral blood flow to neuronal metabolic needs to cause a neurointegrative defect, which leads to psychotic psychopathology as the vascular-glial-neuron triad is progressively damaged over time by repeated inflammatory episodes. In a clinical study, however, increased S100B concentrations were detected in schizophrenic patients without signs of glial or neuronal degeneration thus interpreted as S100B secretion (Steiner et al., 2006). Even though S100B is predominantly expressed in astrocytes it has to be taken into consideration that S100B is also present in other brain cells such as oligodendrocytes, microglial or even neuronal cells (for review: Steiner et al., 2007a,b). There is evidence that oligodendrocytes independently produce S100B (Steiner et al., 2008). Therefore, it appears that these cells could in addition to astrocytes contribute to elevated S100B serum concentrations even without destruction. An altered metabolism of e.g. oligodendrocytes might very well lead to cognitive impairment. The hypothesis that glial–neuronal interactions might be relevant for the pathogenesis of schizophrenia is also supported by research focusing on neurotransmission. Apart from the dopamine hypothesis an involvement of glutamatergic and GABAergic pathways is discussed especially regarding the development of cognitive deficits and negative symptoms. Astrocytes are important in controlling the glutamate homeostasis (for review: Kondziella et al., 2007). They also play a major role in the regulation of kynurenine metabolism which is directly connected to the glutamatergic system (for review: Muller and Schwarz 2006). When interpreting the present results, several issues need to be addressed. First, the origin of serum S100B is not exclusively cerebral. Nonetheless, S100B serum measures have been proven to reliably reflect S100B concentration in the cerebrospinal fluid in healthy subjects (Nygaard et al., 1997) and in patients with various neurological diseases (Reiber, 2001) as well as in patients with schizophrenia (Rothermundt et al., 2004a). In addition, elevated S100B serum levels were associated with increased myo-inositol concentration in the brain as measured by MRspectroscopy (Rothermundt et al., 2007) further supporting that glia cells serve as a source of increased S100B in schizophrenia. Second, raised S100B indicating astrocyte activation is not likely to be specific for schizophrenia. In affective disorders, for instance, a correlation between S100B concentration and pathologic evoked potential patterns has been reported (Dietrich et al., 2004; Hetzel et al., 2005). Third, most
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patients received medication throughout the study which might influence neurocognitive performance and S100B concentration. However, this fact does not affect the comparability between groups. Finally, only verbal and visual memory performance was examined in our study. Reproducing the impact of S100B during treatment on other neurocognitive domains remains to be studied preferably in a larger number of patients with high S100B concentrations. 5. Conclusions In conclusion our findings support the hypothesis that astrocytic activation may play an important role in the pathogenesis of schizophrenia, possibly influencing the development of chronic deficits. Acknowledgements We would like to express our appreciation to the patients and control subjects who participated in the present experiment. Astra Zeneca Pharmaceuticals partially supported this investigator initiated trial (study number: D1449L00019). References Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 1999;22:208–15. Dietrich DE, Hauser U, Peters M, Zhang Y, Wiesmann M, Hasselmann M, et al. S100B serum levels correlate with target evaluation processing in remitted major depression. Neurosci Lett 2004;354:69–73. Ehrenreich H, Hinze-Selch D, Stawicki S, Aust C, Knolle-Veentjer S, Wilms S, et al. Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol Psychiatry 2007;12:206–20. Gromov LA, Syrovatskaya LP, Ovinova GV. Functional role of the neurospecific S-100 protein in the processes of memory. Neurosci Behav Physiol 1992;22:25–39. Grosche J, Matyash V, Moeller T, Verkhratsky A, Reichenbach A, Kettenmann H. Microdomains for neuron–glia interaction: parallel fiber signaling to Bergmann glial cells. Nat Neurosci 1999;2:139–43. Hanson DR, Gottesman II. Theories of schizophrenia: a genetic-inflammatory-vascular synthesis. BMC Med Gene 2005;6:7. Heinrichs RW, Zakzanis KK. Neurocognitive deficit in schizophrenia: a quantitative review of evidence. Neuropsychology 1998;12:426–45. Hetzel G, Moeller O, Evers S, Erfurth A, Ponath G, Arolt V, et al. The astroglial protein S100B and visually-evoked event-related potentials before and after antidepressant treatment. Psychopharmacology 2005;178:161–6. Heubrock D. The Auditory-Verbal Learning Test (AVLT) in clinical and experimental neuropsychology: administration, evaluation, and research findings. Z Differ Diagn Psychol 1992;13:161–74. Kleindienst A, McGinn MJ, Harvey HB, Colello RJ, Hamm RJ, Bullock MR. Enhanced hippocampal neurogenesis by intraventricular S100B infusion is associated with improved cognitive recovery after traumatic brain injury. J Neurotrauma 2005;22: 645–55. Kondziella D, Brenner E, Eyjolfsson EM, Sonnewald U. How do glial–neuronal interactions fit into current neurotransmitter hypotheses of schizophrenia? Neurochem Int 2007;50:291–301. Lara DR, Gama CS, Belmonte-de-Abreu P, Portela LVC, Gonçalves CA, Fonseca M, et al. Increased serum S100B protein in schizophrenia: a study in medication-free patients. J Psychiatr Res 2001;35:11–4. Mello e Souza T, Rohden A, Meinhardt M, Goncalves CA, Quillfeldt JA. S100B infusion into the rat hippocampus facilitates memory for the inhibitory avoidance task but not for the open-field habituation. Physiol Behav 2000;71:29–33.
Muller N, Schwarz M. Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission. Neurotox Res 2006;10:131–48. Nygaard O, Langbakk B, Romner B. Age- and sex-related changes of S-100 protein concentrations in cerebrospinal fluid and serum in patients with no previous history of neurological disorder. Clin Chem 1997;43:541–3. O'Dowd BS, Zhao WQ, Ng KM, Robinson SR. Chicks injected with antisera to either S100α or S-100β protein develop amnesia for a passive avoidance task. Neurobiol Learn Mem 1997;67:197–206. Reiber H. Dynamics of brain-derived proteins in cerebrospinal fluid. Clin Chim Acta 2001;310:173–86. Roder JK, Roder JC, Gerlai R. Conspecific exploration in the T-maze: abnormalities in S100βtransgenic mice. Physiol Behav 1996;60:31–6. Rothermundt M, Missler U, Arolt V, Peters M, Leadbeater J, Wiesmann M, et al. Increased S100B blood levels in unmedicated and treated schizophrenic patients are correlated with negative symptomatology. Mol Psychiatry 2001;6:445–9. Rothermundt M, Falkai P, Ponath G, Abel S, Bürkle H, Diedrich M, et al. Glial cell dysfunction in schizophrenia indicated by increased S100B in the CSF. Mol Psychiatry 2004a;9:897–9. Rothermundt M, Ponath G, Glaser T, Hetzel G, Arolt V. S100B serum levels and longterm improvement of negative symptoms in patients with schizophrenia. Neuropsychopharmacology 2004b;29:1004–11. Rothermundt M, Ohrmann P, Abel S, Siegmund A, Pedersen A, Ponath G, et al. Glial cell activation in a subgroup of patients with schizophrenia indicated by increased S100B serum concentrations and elevated myo-inositol. Prog Neuro-psychopharmacol Biol Psychiatry 2007;31:361–4. Sarandol A, Kirli S, Akkaya C, Aysun A, Demirci M, Sarandol E. Oxidative–antioxidative systems and their relation with serum S100B levels in patients with schizophrenia: effects of short term antipsychotic treatment. Prog Neuro-psychopharmacol Biol Psychiatry 2007;31:1164–9. Schmitt A, Bertsch T, Henning U, Tost H, Klimke A, Hennet FA, et al. Increased serum 100B in elderly, chronic schizophrenic patients: negative correlation with deficit symptoms. Schizophr Res 2005;80:305–13. Schroeter ML, Abdul-Khaliq H, Fruhauf S, et al. Serum S100B is increased during early treatment with antipsychotics and in deficit schizophrenia. Schizophr Res 2003;62:231–6. Steiner J, Bielau H, Bernstein HG, Bogerts B, Wunderlich MT. Increased cerebrospinal fluid and serum levels of S00B in first-onset schizophrenia are not related to a degenerative release of glial fibrillar acidic protein, myelin basic protein and neurone-specific enolase from glia or neurones. J Neurol Neurosurg Psychiatry 2006;77:1284–7. Steiner J, Bernstein HG, Bielau H, Berndt A, Brisch R, Mawrin C, et al. Evidence for a wide extra-astrocytic distribution of S100B in human brain. BMC Neurosci 2007a;8:2. Steiner J, Bernstein HG, Bielau H, Farkas N, Winter J, Dobrowolny H, et al. S100Bimmunopositive glia is elevated in paranoid as compared to residual schizophrenia: a morphometric study. J Psychiatr Res 2007b Nov 12 Electronic publication ahead of print. Steiner J, Bernstein HG, Bogerts B, Gos T, Richter-Landsberg C, Wunderlich MT, et al. S100B is expressed in, and released from, OLN-93 oligodendrocytes: influence of serum and glucose deprivation. Neuroscience 2008 Apr 8 [Electronic publication ahead of print]. Swanson LW, Teyler TJ, Thompson RF. Hippocampal long-term potentiation: mechanisms and implications for memory. Neurosci Res Prog Bull 1982;20:613–769. Weidlich S, Lamberti G. DCS. Diagnosticum für Cerebralschädigung. Bern: Huber; 2001. Whitaker-Azmitia PM, Wingate M, Borella A, Gerlai R, Roder J, Azmitia EC. Transgenic mice overexpressing the neurotrophic factor S-100β show neuronal cytoskeletal and behavioural signs of altered aging processes: implications for Alzheimer's disease and Down's syndrome. Brain Res 1997;776:51–60. Wiesmann M, Wandinger KP, Missler U, Eckhoff D, Rothermundt M, Arolt V, et al. Elevated plasma levels of S-100b protein in schizophrenic patients. Biol Psychiatry 1999;45:1508–11. Winocur G, Roder J, Lobaugh N. Learning and memory in S100-β transgenic mice: an analysis of impaired and preserved function. Neurobiol Learn Mem 2001;75: 230–43.
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p n p b p
Memory impairment correlates with increased S100B serum concentrations in patients with chronic schizophrenia Anya Pedersen a,⁎, Markus Diedrich a, Florian Kaestner a, Katja Koelkebeck a, Patricia Ohrmann a, Gerald Ponath a, Frank Kipp b, Simone Abel a, Ansgar Siegmund a, Thomas Suslow a, Christof von Eiff b, Volker Arolt a, Matthias Rothermundt a a b
University Medical Faculty, Department of Psychiatry, 48149 Münster, Germany University Medical Faculty, Institute of Medical Microbiology, 49149 Münster, Germany
a r t i c l e
i n f o
Article history: Received 6 June 2008 Received in revised form 10 July 2008 Accepted 26 July 2008 Available online 31 July 2008 Keywords: Astrocytes Memory S100 B Schizophrenia
a b s t r a c t Astrocyte activation indicated by increased S100B is considered a potential pathogenic factor for schizophrenia. To investigate the relationship between astrocyte activation and cognitive performance, S100B serum concentration, memory performance, and psychopathology were assessed in 40 first-episode and 35 chronic schizophrenia patients upon admission and after four weeks of treatment. Chronic schizophrenia patients with high S100B were impaired concerning verbal memory performance (AVLT, Auditory Verbal Learning Test) compared to chronic and first-episode patients with low S100B levels. The findings support the hypothesis that astrocyte activation might contribute to the development of cognitive dysfunction in schizophrenia. © 2008 Elsevier Inc. All rights reserved.
1. Introduction In numerous studies, schizophrenic patients revealed deficits in a multitude of neurocognitive functions including attention and vigilance, working memory, verbal learning and memory, visual learning and memory, reasoning and problem solving, speed of processing, and social cognition (Heinrichs and Zakzanis, 1998). Although cognitive impairments associated with schizophrenia have been comprehensively examined, only a few data are available on the neurobiological correlates of these cognitive deficits. Several lines of research indicate that astrocyte dysfunction can be directly responsible for neuronal malfunction mainly via glutamateinduced Ca2+ modulation (Araque et al., 1999; Grosche et al., 1999). An indicator of astrocyte activation is the Ca2+ modulating protein S100B exerting paracrine and autocrine effects on neurons and glia. From in vivo animal experiments there is evidence that S100B modulates cognitive performance. Intraventricular S100B infusion after trau-
Abbreviations: AVLT, Auditory Verbal Learning Test; CPZ, chlorpromazine; CSF, cerebrospinal fluid; DCS, Diagnostic Test of Cerebral Dysfunction; H, high S100B serum level; L, low S100B serum level; PANSS, Positive and Negative Syndrome Scale; rhEPO, recombinant human erythropoietin; SCID, Structured Clinical Interview; T0, examination upon admission; T1, examination after four weeks of treatment; WAIS-R, Wechsler Adult Intelligence Scale—Revised. ⁎ Corresponding author. Department of Psychiatry, University of Münster, AlbertSchweitzer-Str. 11, 48149 Münster, Germany. Tel.: +49 251 8356601; fax: +49 251 8356612. E-mail address: [email protected] (A. Pedersen). 0278-5846/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2008.07.017
matic brain injury in the rat model was associated with improved cognitive recovery (Kleindienst et al., 2005). Deficits in memory and spatial learning have been reported in animals with increased (Roder et al., 1996; Whitaker-Azmitia et al., 1997; Winocur et al., 2001) or decreased S100B levels (Gromov et al., 1992; O'Dowd et al., 1997). Moreover, S100B might be involved in the regulation of hippocampal long-term potentiation, which is thought to be a physiological correlate of long-term memory (Swanson et al., 1982). Infusion of S100B into the rat hippocampus was shown to facilitate memory function for the inhibitory avoidance task but not for the open-field habituation (Mello e Souza et al., 2000). Patients with schizophrenia reveal increased S100B concentrations in CSF and serum (Lara et al., 2001; Rothermundt et al., 2001; Rothermundt et al., 2004a; Sarandol et al., 2007; Schmitt et al., 2005; Schroeter et al., 2003; Wiesmann et al., 1999). Persistently high S100B levels have repeatedly been associated with negative or deficit symptoms and slower psychopathological improvement upon treatment (Rothermundt et al., 2001, 2004b; Sarandol et al., 2007). Given the critical role of S100B for cognitive performance as established in animal experiments and the association of increased S100B levels in schizophrenia with persistent negative symptoms, it can be assumed that S100B concentration might interfere with cognition. We hypothesized that cognitive deficits might be more prevalent in schizophrenic patients with persistent high S100B concentrations. Therefore, we designed this study to investigate the impact of astrocyte activation indicated by S100B increase on memory performance in first-episode and chronic schizophrenia patients thereby
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Table 1 S100B raw scores upon admission and after four weeks of treatment in schizophrenic patients First-episode schizophrenia Low S100B (n = 37) [mean ± SD] S100B upon admission (µg/L) 0.06 ± 0.02 S100B after treatment (µg/L) 0.05 ± 0.02*
Chronic schizophrenia
High S100B (n = 3) [mean ± SD]
Low S100B (n = 24) [mean ± SD]
High S100B (n = 11) [mean ± SD]
0.09 ± 0.03 0.12 ± 0.04
0.06 ± 0.02 0.05 ± 0.01*
0.09 ± 0.03 0.10 ± 0.02
Group H had high S100B levels (N 0.065 µg/L upon admission and after treatment), group L had low S100B levels. For all sub-samples scores upon and after admission were compared with paired t-tests. ⁎ p b 0.05 (paired t-tests for comparisons between S100B levels upon admission and after treatment).
further characterizing the potential role of astrocytes in the pathogenesis of schizophrenia. 2. Methods
the course of the S100B concentrations and consistent with previous studies all patients were classified according to their S100B serum concentration: Patients with S100B levels higher than the median (0.065 µg/L) upon admission and after four weeks of treatment were assigned to group H (“high S100B”), the remaining patients with low S100B concentrations upon admission or with initially elevated S100B levels normalizing during treatment, formed group L (“low S100B”). Using the mean S100B levels of healthy controls plus two standard deviations (N0.069 µg/L; see Rothermundt et al., 2001) as a cut-off score leads to identical grouping. 2.3. Neuropsychological measures Neuropsychological examination utilized standard test procedures for the assessment of memory performance: verbal learning and memory performance was measured with the Auditory Verbal Learning Test (AVLT; Heubrock, 1992), and figural memory was assessed with a Diagnostic Test of Cerebral Dysfunction (DCS; Weidlich and Lamberti, 2001). In the DCS, nine abstract figures presented as geometric pictures must be reproduced with five wooden sticks by free recall in six successive trials (sum score).
2.1. Subjects 2.4. Data analysis Ninety-four schizophrenic inpatients diagnosed with a Structured Clinical Interview for DSM-IV (SCID) participated in the study. Patients with any history of other psychiatric disorders, neurological disorders, brain damage, serious head injury, tardive dyskinesia, alcohol or illegal drug abuse were excluded from the study. After written informed consent was acquired, serum samples were taken upon admission (T0) and after four weeks of treatment (T1). Clinical symptoms were rated by an experienced and trained clinician with the Positive and Negative Syndrome Scale (PANSS) at both time points; neuropsychological measures were performed only at T1. From the initial pool of recruited patients, 40 first-episode and 35 chronic schizophrenic patients completed the study, three patients were excluded for diagnostic reasons, and sixteen patients dropped out before reinvestigation. The mean ages of the first-episode and chronic patients were 24.9 years (SD = 5.7; 28 males and 12 females) and 32.6 (SD = 7.9; 22 males and 13 females), respectively. All patients received antipsychotic drugs (T0: quetiapine 33, amisulpride 16, risperidone 15, clozapine 14, olanzapine 7, haloperidol 4, perazine 2, ziprasidone 1, flupenthixol 1, zuclopenthixol 1, 19 patients received a combination of drugs, mean chlorpromazine (CPZ) equivalent dose ± SD, 568.7 ± 392.3 mg/day; T1: quetiapine 39, risperidone 17, clozapine 13, amisulpride 16, olanzapine 5, perazine 3, ziprasidone 2, flupenthixol 1, 21 patients received a combination of drugs, mean CPZ equivalent dose 519.1 ± 286.1 mg/day). The two groups did not differ in sex (χ2 = 0.429, df = 1, p = 0.625), years of education (t = 0.069, df = 73, p = 0.945), intellectual performance (vocabulary test of the WAIS-R, Wechsler Adult Intelligence Scale—Revised; t = − 0.544, df = 73, p = 0.588) or CPZ equivalent dose (T0: t = 0.352, df = 73, p = 0.726; T1: t = 1.295, df = 73, p = 0.199), but as expected age (t = −4.891, df = 73, p b 0.01) and duration of illness (t = −8.177, df = 73, p b 0.001) were significantly higher in patients with chronic schizophrenia. All participants were native speakers of German. The study protocol was approved by the local ethics committee according to the Declaration of Helsinki of 1964, and written informed consent was obtained from all participants prior to their enrolment in the study.
The categorical data were analyzed using Pearson's χ2-tests. Differences in continuous variables were evaluated by Student's ttest. Correlations were determined using the Pearson Correlation Coefficient. Significance was assumed for p b 0.05 (two-tailed). All statistical analyses were performed by SPSS 15.0 (SPSS 15.0 for Windows, SPSS Inc., Chicago, IL, USA). 3. Results Table 1 shows the mean S100B levels upon admission and after treatment. For the total sample the differences in S100B concentration between admission (T0) and after treatment (T1) did not reach statistic significance (t = 1.891, df = 74, p = 0.063; paired t-test). However, in the low S100B groups there was a significant decline in S100B level between T0 and T1 (first-episode patients, group L: t = 2.126, df = 36, p = 0.040; chronic patients, group L: t = 2.609, df = 23, p = 0.016; paired t-test). Furthermore, the proportion of patients with high S100B levels (group H: 31.4%) was significantly larger in chronic patients than in first-episode patients (group H: 7.5%; χ2 = 7.30, df = 2, p = 0.007).
2.2. S100B measurements in serum Blood samples were centrifuged within 2 h, aliquoted, and frozen at −80 °C until analysis. S100B concentrations were determined by applying the LIAISON Sangtec-100-assay (AB Sangtec Medical, Bromma, Sweden), a quantitative automated luminometric immunoassay, according to the manufacturers' instructions. To investigate
Fig. 1. Verbal memory (AVLT) and figural memory (DCS) of patients with chronic schizophrenia group according to S100B levels. Group H had high S100B levels (N0.065 µg/L upon admission and after treatment), group L had low S100B levels. Error bars indicate standard errors. ⁎p b 0.05.
A. Pedersen et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1789–1792 Table 2 Psychopathological and neuropsychological measures Variable
First-episode schizophrenia (n = 40) [mean ± SD]
Chronic schizophrenia (n = 35) [mean ± SD]
Statistics
df
p
Intellectual performance (WAIS-R vocabulary) AVLT sum AVLT recall AVLT recognition DCS PANSS total score upon admission Positive symptoms Negative symptoms General psychopathology PANSS total score after 4 weeks of treatment Positive symptoms Negative symptoms General psychopathology
21.8 ± 5.0
22.5 ± 6.4
t = −0.544
73
NS
51.6 ± 9.7 10.0 ± 3.0 11.8 ± 3.6 23.0 ± 8.4 67.7 ± 14.2#
48.3 ± 10.3 9.1 ± 3.8 11.0 ± 4.1 25.5 ± 9.0 61.6 ± 13.7#
t = 1.401 t = 1.081 t = 0.834 t = −1.242 t = 2.044
73 73 73 73 73
NS NS NS NS 0.045
14.1 ± 4.3 17.6 ± 5.4 36.0 ± 8.1# 58.9 ± 14.9***
12.3 ± 4.9 17.0 ± 5.8 31.5 ± 6.6# 55.8 ± 12.9*
t = 1.688 t = 0.485 t = 2.608 t = 0.949
73 73 73 73
NS NS 0.011 NS
12.0 ± 4.3#, *** 16.3 ± 6.2* 30.7 ± 7.1***
10.1 ± 2.8#, ** 16.1 ± 6.1 29.8 ± 6.6
t = 2.125 t = 0.112 t = 0.584
73 73 73
0.037 NS NS
#
p b 0.05 (t-tests for comparisons between the two groups). *p b 0.05; **p b 0.01; ***p b 0.001 (paired t-tests for comparisons between PANSS scores upon admission and after treatment). Abbreviations: WAIS-R, Wechsler Adult Intelligence Scale—Revised; AVLT, Auditory Verbal Learning Test; DCS, Diagnostic Test of Cerebral Dysfunction; PANSS, Positive and Negative Symptom Scale.
First-episode and chronic schizophrenia patients with low S100B did not differ significantly on any of the neuropsychological measures (Fig. 1). However, patients with chronic schizophrenia and high S100B concentrations revealed significantly poorer verbal memory performance than patients with first-episode schizophrenia (AVLT sum: t = 2.408; df = 46; p = 0.020). Chronic schizophrenic patients displaying low S100B levels revealed significantly better AVLT performance than those with high S100B levels (sum: t = 2.198; df = 33; p = 0.035; recognition: t = 2.048; df = 33; p = 0.049). There were no significant group differences regarding figural memory. Because of the small sample size (n = 3) first-episode patients with high S100B were not included in the analysis. Table 2 shows the mean neuropsychological performance scores of first-episode vs. chronic patients. After treatment first-episode patients revealed improved PANSS scores (all sub-scales), whereas patients with chronic schizophrenia showed no improvement regarding PANSS negative symptoms and general psychopathology (Table 2). No significant correlations were revealed between S100B concentrations and PANSS total scores in first-episode (T0: r = −0.161, p = 0.322, n.s.; T1: r = −0.177, p = 0.275, n.s.) and chronic patients (T0: r = −0.058, p = 0.739, n.s.; T1: r = −0.022, p = 0.900, n.s.). Moreover, there were no significant correlations between S100B levels and PANSS positive scores (all p's N 0.144, n.s.), PANSS negative scores (all p's N 0.297, n.s.), and PANSS general scores (all p's N 0.158, n.s.). 4. Discussion The present study demonstrates significant differences in cognitive performance related to S100B in patients with schizophrenia. In chronic schizophrenic patients with high S100B serum concentrations, verbal memory was significantly impaired compared to chronic patients with low S100B concentrations and first-episode patients. These results are in line with findings by Ehrenreich et al. (2007), who reported a significant improvement of cognitive performance and decline in serum S100B in chronic schizophrenic patients treated with recombinant human erythropoietin (rhEPO). The authors suggest that rhEPO either reduces the intracerebral S100B production or “seals” the blood-brain barrier and thereby prevents S100B from crossing into the circulation.
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In our study, the impact of S100B on neuropsychological parameters was limited to patients with chronic schizophrenia. This result is in accordance with earlier findings that S100B concentrations are associated with persistent negative symptoms (Rothermundt et al., 2001, 2004b; Schmitt et al., 2005). It appears that persistently increased S100B concentrations indicate or are involved in an ongoing pathological process resulting in chronic course of disease with cognitive impairment. Patients with chronic schizophrenia who experience a normalization of S100B levels obviously develop less cognitive decline. This is in concordance with the hypothesis that in schizophrenia astrocyte activation indicated by S100B increase might be a counteraction of the brain to fight a so far unknown pathological process. A normalization of S100B would then indicate a stop of this process. The finding of Schmitt et al. (2005) lacking a significant correlation between S100B and various cognitive parameters in elderly, chronic schizophrenic patients might be influenced by much longer disease course and antipsychotic pharmacological treatment in their sample. It remains to be clarified whether the underlying pathological process is reversible or at a certain stage reaches a point of no return. Increased serum levels of S100B have been related to a passive release due to astrocyte destruction or an active release by secretion. Thus, increase of peripheral levels of S100B could be a sign of astrocytic injury and/or of astrocytic response to neuronal injury. Hanson and Gottesman (2005) hypothesize disruptions in astroglial mediated coupling of cerebral blood flow to neuronal metabolic needs to cause a neurointegrative defect, which leads to psychotic psychopathology as the vascular-glial-neuron triad is progressively damaged over time by repeated inflammatory episodes. In a clinical study, however, increased S100B concentrations were detected in schizophrenic patients without signs of glial or neuronal degeneration thus interpreted as S100B secretion (Steiner et al., 2006). Even though S100B is predominantly expressed in astrocytes it has to be taken into consideration that S100B is also present in other brain cells such as oligodendrocytes, microglial or even neuronal cells (for review: Steiner et al., 2007a,b). There is evidence that oligodendrocytes independently produce S100B (Steiner et al., 2008). Therefore, it appears that these cells could in addition to astrocytes contribute to elevated S100B serum concentrations even without destruction. An altered metabolism of e.g. oligodendrocytes might very well lead to cognitive impairment. The hypothesis that glial–neuronal interactions might be relevant for the pathogenesis of schizophrenia is also supported by research focusing on neurotransmission. Apart from the dopamine hypothesis an involvement of glutamatergic and GABAergic pathways is discussed especially regarding the development of cognitive deficits and negative symptoms. Astrocytes are important in controlling the glutamate homeostasis (for review: Kondziella et al., 2007). They also play a major role in the regulation of kynurenine metabolism which is directly connected to the glutamatergic system (for review: Muller and Schwarz 2006). When interpreting the present results, several issues need to be addressed. First, the origin of serum S100B is not exclusively cerebral. Nonetheless, S100B serum measures have been proven to reliably reflect S100B concentration in the cerebrospinal fluid in healthy subjects (Nygaard et al., 1997) and in patients with various neurological diseases (Reiber, 2001) as well as in patients with schizophrenia (Rothermundt et al., 2004a). In addition, elevated S100B serum levels were associated with increased myo-inositol concentration in the brain as measured by MRspectroscopy (Rothermundt et al., 2007) further supporting that glia cells serve as a source of increased S100B in schizophrenia. Second, raised S100B indicating astrocyte activation is not likely to be specific for schizophrenia. In affective disorders, for instance, a correlation between S100B concentration and pathologic evoked potential patterns has been reported (Dietrich et al., 2004; Hetzel et al., 2005). Third, most
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patients received medication throughout the study which might influence neurocognitive performance and S100B concentration. However, this fact does not affect the comparability between groups. Finally, only verbal and visual memory performance was examined in our study. Reproducing the impact of S100B during treatment on other neurocognitive domains remains to be studied preferably in a larger number of patients with high S100B concentrations. 5. Conclusions In conclusion our findings support the hypothesis that astrocytic activation may play an important role in the pathogenesis of schizophrenia, possibly influencing the development of chronic deficits. Acknowledgements We would like to express our appreciation to the patients and control subjects who participated in the present experiment. Astra Zeneca Pharmaceuticals partially supported this investigator initiated trial (study number: D1449L00019). References Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 1999;22:208–15. Dietrich DE, Hauser U, Peters M, Zhang Y, Wiesmann M, Hasselmann M, et al. S100B serum levels correlate with target evaluation processing in remitted major depression. Neurosci Lett 2004;354:69–73. Ehrenreich H, Hinze-Selch D, Stawicki S, Aust C, Knolle-Veentjer S, Wilms S, et al. Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol Psychiatry 2007;12:206–20. Gromov LA, Syrovatskaya LP, Ovinova GV. Functional role of the neurospecific S-100 protein in the processes of memory. Neurosci Behav Physiol 1992;22:25–39. Grosche J, Matyash V, Moeller T, Verkhratsky A, Reichenbach A, Kettenmann H. Microdomains for neuron–glia interaction: parallel fiber signaling to Bergmann glial cells. Nat Neurosci 1999;2:139–43. Hanson DR, Gottesman II. Theories of schizophrenia: a genetic-inflammatory-vascular synthesis. BMC Med Gene 2005;6:7. Heinrichs RW, Zakzanis KK. Neurocognitive deficit in schizophrenia: a quantitative review of evidence. Neuropsychology 1998;12:426–45. Hetzel G, Moeller O, Evers S, Erfurth A, Ponath G, Arolt V, et al. The astroglial protein S100B and visually-evoked event-related potentials before and after antidepressant treatment. Psychopharmacology 2005;178:161–6. Heubrock D. The Auditory-Verbal Learning Test (AVLT) in clinical and experimental neuropsychology: administration, evaluation, and research findings. Z Differ Diagn Psychol 1992;13:161–74. Kleindienst A, McGinn MJ, Harvey HB, Colello RJ, Hamm RJ, Bullock MR. Enhanced hippocampal neurogenesis by intraventricular S100B infusion is associated with improved cognitive recovery after traumatic brain injury. J Neurotrauma 2005;22: 645–55. Kondziella D, Brenner E, Eyjolfsson EM, Sonnewald U. How do glial–neuronal interactions fit into current neurotransmitter hypotheses of schizophrenia? Neurochem Int 2007;50:291–301. Lara DR, Gama CS, Belmonte-de-Abreu P, Portela LVC, Gonçalves CA, Fonseca M, et al. Increased serum S100B protein in schizophrenia: a study in medication-free patients. J Psychiatr Res 2001;35:11–4. Mello e Souza T, Rohden A, Meinhardt M, Goncalves CA, Quillfeldt JA. S100B infusion into the rat hippocampus facilitates memory for the inhibitory avoidance task but not for the open-field habituation. Physiol Behav 2000;71:29–33.
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