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Neurochemical measures co-vary with personality traits: Forensic psychiatric findings replicated in a general population sample
Psychiatry Research 178 (2010) 525–530
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Psychiatry Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s
Neurochemical measures co-vary with personality traits: Forensic psychiatric findings replicated in a general population sample Thomas Nilsson a, Sara Bromander a,d,⁎, Rolf Anckarsäter c, Marianne Kristiansson d, Anders Forsman a, Kaj Blennow a, Henrik Zetterberg a, Henrik Anckarsäter a,b, Caroline Wass a a
Institute of Neuroscience and Physiology, University of Gothenburg, Sweden Institute of Clinical Sciences, Malmö, Lund University, Sweden Department of Anaesthesiology and Intensive Care, Kungälv Hospital, Sweden d Division of Forensic Psychiatry, Karolinska Institute, Sweden b c
a r t i c l e
i n f o
Article history: Received 22 December 2008 Received in revised form 18 May 2010 Accepted 21 May 2010 Keywords: Beta-trace protein (βTP) Blood–brain barrier Monoamine metabolites Dopamine Serotonin Thyroid hormones Personality
a b s t r a c t Neurobiological markers in cerebrospinal fluid (CSF) and in serum, previously found to co-vary with destructive personality traits in violent offenders, were explored in a general population sample of 21 patients undergoing knee surgery. Results on the Karolinska Scales of Personality (KSP) and the Temperament and Character Inventory (TCI) were compared with CSF/serum albumin ratios and serum concentrations of beta-trace protein (βTP) (as markers for blood–brain barrier (BBB) permeability), to CSF/ serum albumin ratios between the dopamine and serotonin metabolites homovanillic acid (HVA)/5hydroxyindoleacetic acid (HIAA) and to CSF and serum ratios between activated thyroid hormone (T3) and its precursor T4. Serum βTP concentrations correlated with CSF/serum albumin ratios (P =0.018), but not with preoperative serum creatinine concentrations. Serum βTP correlated significantly with Monotony Avoidance and Impulsiveness; CSF HVA/5-HIAA ratios with Irritability and low Cooperativeness. The βTP is a potential serum marker for the integrity of the BBB that does not necessitate lumbar puncture. Thyroid hormones did not correlate with personality traits. As reported in forensic psychiatric patients, aggressive, unempathic personality traits were thus associated with increased dopaminergic activity in relation to the serotonergic activity and impulsivity to increased BBB permeability also in a general population group. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction A high prevalence of increased cerebrospinal fluid (CSF)/serum albumin ratios, indicating increased blood–brain barrier (BBB) permeability, in its turn regarded as an unspecific indicator of central nervous system (CNS) vulnerability, has previously been found in two separate forensic psychiatric groups of violent offenders (Soderstrom et al., 2001; Anckarsäter et al., 2005). Normal age-dependent reference values for comparisons of this measure have been established among healthy volunteers (Blennow et al., 1993; Tibbling et al., 1977). Increased CSF/serum albumin ratios have also been reported in patients with CNS lesions, traumas and tumours (Rapoport, 1976), in psychiatric conditions such as psychoses (Axelsson et al., 1982; Bauer and Kornhuber, 1987) and in suicide attempters (Bayard-Burfield et al., 1996). Another possible indicator of increased BBB permeability is the serum concentrations of betatrace protein (βTP), which is synthesised in the spinal leptomeninges (Urade et al., 1993) and in the pachymeninx (Blodorn et al., 1999), ⁎ Corresponding author. Forensic Psychiatry, Lillhagsparken 3, 422 50 Hisings Backa, Sweden. Tel.: +46 768123121; fax: +46 31 559671. E-mail address: [email protected] (S. Bromander). 0165-1781/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2010.05.016
functioning as a prostaglandin synthetase (Watanabe et al., 1994) and as a carrier protein for retinoids (Tanaka et al., 1997). As the βTP is mostly synthesised in the CNS (Blodorn et al., 1999), besides minute quantities peripherally (e.g., in the male genital system, kidneys and the heart, Hoffman et al., 1997; Schell et al., 2007; White et al., 1997; Urade and Hayaishi, 2000), it may be used as an indicator of CSF leakage into peripheral fluids such as nasal secretion (Arrer et al., 2002). Thus, albumin ratios and serum βTP concentrations represent two different aspects of BBB permeability (into vs. out from the CNS). βTP levels in CSF have also been shown to change in response to different CNS pathologies, such as normal pressure hydrocephalus and bacterial meningitis (Mase et al., 2003; Tumani et al., 1998). Furthermore, experimental animal studies suggest that βTP may be protective of hypoxic ischaemic injury (Taniguchi et al 2007), and its function may also be disturbed in Alzheimer's disease (Kanekiyo et al., 2007). An increase in βTP concentration has recently been associated with the development of atherosclerosis (Miwa et al., 2008). Increased ratios between the CSF concentrations of the dopamine metabolite homovanillic acid (HVA) over the serotonin metabolite 5hydroxyindolacetic acid (5-HIAA) have correlated with psychopathic personality traits, especially the ‘disinhibited behaviours’ and ‘lack of emotionality/empathy’ dimensions, in two forensic psychiatric study
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groups (Anckarsäter et al., 2005; Soderstrom et al., 2003). Numerous studies have shown an increased propensity for destructive acting out, such as violent suicide, arson or killing a sexual partner, in subjects with decreased 5-HIAA levels (Asberg et al., 1976; Lidberg et al., 1984; Virkkunen et al., 1996), but similar studies have failed to show a corresponding link to instrumental violence or psychopathic personality traits (Castellanos et al. 1994; Coccaro et al. 1997; Gardner et al. 1990; Lidberg et al. 1985). A number of studies in forensic psychiatric offender groups have reported an association between increased serum thyroid activity, as indicated by increased ratios of the active thyroid hormone triiodothyronin (T3) over its precursor thyroxine (T4) or by decreased T4 concentrations, and criminal recidivism, aggression and psychopathic traits (Soderstrom and Forsman, 2004; Stalenheim, 2004; Stalenheim et al., 1998). Elevated T3 concentrations in serum may reflect increased conversion of T4 to T3, that is, the opposite of the pattern found in depression (Soderstrom and Forsman, 2004). Based on the above-described findings from psychiatric and forensic study populations, the present study aimed at investigating these relationships in a mentally healthy sample. CSF and serum samples were drawn before arthroplastic-knee surgery in subjects without psychiatric or neurological disorders (Anckarsäter et al., 2007a,b) and were used to analyse possible biomarkers for personality according to two self-rate questionnaires; the Temperament and Character Inventory (TCI) (Cloninger et al., 1993) and the Karolinska Scales of Personality (KSP) (Schalling, 1978; Schalling et al., 1987), aiming to assess whether: (1) increased CSF/serum albumin ratios and serum βTP concentrations correlate with impulsive personality traits. (2) increased CSF HVA/5-HIAA ratios correlate with, impulsive personality traits and low empathy/emotional reactivity. (3) T3 or T3/T4 ratios in serum and in CSF correlate with impulsive personality traits. 2. Subjects and Methods The study protocol was approved by the Ethical Review Board, University of Gothenburg. Patients scheduled for knee arthroplastic surgery at Kungälv Hospital were consecutively recruited from the anaesthesiological clinical practice doing preoperative assessments. The criteria for the selection of subjects were: (a) no use of psychotropic, anti-Parkinson, corticosteroid or anticoagulant medication; (b) practical possibility to include the patient; and (c) the ambition to include persons as healthy as possible (besides the orthopaedic problem). After oral and written information, patients who gave informed consent were included in the study and were given the personality questionnaires to fill out at home after the preoperative consultations, but before surgery. Thirty-five psychiatrically healthy patients (20 males, 15 females, aged 51–82 years, median 73 years) gave informed consent to participate in the study. Thirty-four of these 35 patients could provide CSF and serum samples to be included in the study and 26 had completed the personality questionnaires when arriving at the hospital. One patient was subsequently omitted from analyses, as she was found to have been on long-term medication with 10 mg of the serotonin reuptake inhibitor, citalopram, and four patients were excluded as they had pathological CSF/ serum albumin ratios (exceeding the normal reference value of 11.8) at inclusion and therefore not as neurologically healthy as required for the present study (details on protein findings are given in Anckarsäter et al., 2007a). The final group analyzed here consisted of 21 subjects (12 males and 9 females, aged 58–81 years, median 74 years). After a subcutaneous local anaesthesia with 10 ml 0.5% mepivacaine, a lumbar puncture was performed with an 18-gauge Portex™ epidural needle in the L3–L4 interspace, according to standard hospital procedures. After discarding the first 2–3 ml of CSF, 12 ml were sampled and gently mixed before the insertion of spinal catheters and administration of any intrathecal drugs. CSF and blood for serum and plasma analyses were centrifuged at 2000 g for 10 min and pipetted in new tubes at Kungälvs Hospital and transported to the Sahlgrenska University Hospital neurochemistry lab, Mölndal, where aliquots were stored at -80 °C until biochemical analyses were performed, according to accredited neurochemistry lab routines. Thirteen of the 21 patients included in the present analyses had a history of hypertension and five of diabetes mellitus. All subjects had been on their medications for long and stable periods. No abrupt washout was performed for the purpose of the study, besides all non-steroidal anti-inflammatory and acetyl salicyclic acid drugs, which were discontinued 1 week before surgery. No per-oral medication other than beta-blockers was given on the day of surgery. Three patients were taking lipophilic
beta-blockers. Three patients had been treated with codeine and tramadol on an asneeded basis during the time period before surgery. 2.1. Laboratory analyses Albumin concentrations were analysed by nephelometry on the Image instrument (Beckman Coulter) and βTP concentrations by nephelometry on the BNProSpec instrument (Dade Behring), using the NLatex βTP kit. Determination of the monoamine metabolites was performed by means of highperformance liquid chromatography with electrochemical detection, as described by Blennow and co-workers (1993). Thyroid hormones were determined by biochip array technique on the Evidence Investigator™ (Randox, Crumlin, United Kingdom) according to the manufacturer's instructions, using the total thyroid array for thyroid-stimulating hormone (TSH), total T3 and total T4 (Fitzgerald et al., 2005). All biological parameters were uncorrelated to age and sex. 2.2. Personality assessments Personality questionnaires were distributed to the subjects during the anaesthesiological preoperative consultation, and the completed forms were collected on admission to the hospital. Nineteen subjects had filled out the KSP, which is a 135-item self-rate questionnaire containing 15 personality scales, that is, Somatic Anxiety, Psychic Anxiety, Muscular Tension, Social Desirability, Impulsiveness, Monotony Avoidance, Detachment, Psychasthenia, Socialisation, Indirect Aggression, Verbal Aggression, Irritability, Suspicion, Guilt and Inhibition of Aggression, measuring stable temperament traits constituting vulnerability factors for different kinds of psychopathology (Schalling, 1978; Schalling et al., 1987). Twenty-one subjects had completed the TCI, which is a 238-item true-or-false questionnaire assessing four temperament dimensions, that is, Novelty Seeking, Harm Avoidance, Reward Dependence and Persistence, and three character dimensions, that is Self-Directedness, Cooperativeness and Self-Transcendence, based on Cloninger's psychobiological model of personality (Cloninger et al., 1993). No systematic differences in age, sex or general medical status were noted between responders and non-responders, the main reason for nonresponse being lack of time to fill out personality questionnaires before surgery. All personality data were transformed into T-scores (with a mean of 50 and a S.D. of± 10) derived from normal population groups, corrected for age and sex and then compared with laboratory results. To assess the representativeness of the sample, personality traits were tested against the normal mean t-score of 50 by one-sample t-tests, and, with the exception for the following KSP scales, no significant differences from the expected mean were found; Psychic Anxiety (b50, P = 0.001), Indirect Aggression (b 50, P = 0.001) and Suspicion (N50, P = 0.006). Differences between men and women for the studied personality dimensions were also tested, and strong tendencies towards higher scores in women were found for the KSP traits, Psychic Anxiety and Inhibited Aggression, but these did not reach statistical significance according to the preset significance level (P ≤ 0.01). Finally, no significant correlations were found between age and any of the KSP or the TCI dimensions. 2.3. Statistical methods All statistical analyses were performed using the Statistical Package for Social Sciences program (SPSS) 17.0 software. One sample t-test was used to analyse whether our group differed from the norm (t-score of 50) and Spearman's rho to analyse associations between variables. The sample is relatively small due to the difficulties to achieve large-enough samples of patients going through lumbar punctures. Thus, to control for the risk of type I errors, alpha was set at 1% (P b 0.01). It would be extremely difficult to assemble CSF samples from a large-enough group to have power for statistical analyses in relation to complex personality inventories after Bonferroni correction or the like. In this respect, CSF studies have to be compared with various brain-imaging studies, where such corrections are not common. In total, there are now 24 personality and biomarker correlations and with the defined alpha and two-tailed P-values, the risk that a random finding is significant in line with the preformed hypothesis (i.e., a false positive finding) is below 0.5% for each comparison.
3. Results Mean values with standard deviations for both the biological markers and the personality traits of interest are given in Table 1. 3.1. BBB integrity Serum βTP showed a trend towards correlating with the CSF/serum albumin ratios (rho=0.513, P=0.018, n=21). The serum βTP concentrations correlated positively with personality traits describing Monotony Avoidance and Impulsivity (Table 2), while the CSF/serum albumin ratios showed weaker correlations in the same direction for these traits. Both, the serum βTP concentrations and the CSF/serum albumin ratios,
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Table 1 Mean values and standard deviations (S.D.) of the biological markers and the targeted personality traits in all subjects, divided by gender, and with number (n) of patients available for analyses. Biological markers
All subjects (n = 21) mean (S.D.)
Male (n = 12) mean (S.D.)
Female (n = 9) mean (S.D.)
Serum albumin (g/l) CSF CSF albumin (mg/l) CSF albumin/serum albumin Serum ßTP (mg/l) CSF ßTP (mg/l) CSF HVA (nmol/l) CSF 5-HIAA (nmol/l) CSF HVA/5 HIAA Serum T3 (ng/ml) CSF T3 (ng/ml) Serum T4 (μg/dl) CSF T4 (μg/dl)
38.43 263.00 6.90 0.69 16.92 277.00 169.43 1.66 1.38 0.94 7.57 1.10
38.33 264.50 6.93 0.74 16.72 266.08 156.25 1.77 1.35 0.92 7.53 1.06
38.56 261.00 6.88 0.62 17.20 291.56 187.00 1.51 1.42 0.97 7.62 1.16
KSP Scales
(n = 19)
Monotony Avoidance Impulsiveness Socialization Detachment Indirect Aggression Verbal Aggression Irritability Inhibited Aggression TCI Dimensions Novelty Seeking Reward Dependence Self-Directedness Cooperativeness
(3.53) (66.97) (1.82) (0.23) (6.82) (107.58) (53.10) (0.52) (0.21) (0.13) (1.42) (0.20)
(3.50) (78.60) (1.96) (0.26) (7.57) (86.81) (55.38) (0.53) (0.23) (0.12) (0.88) (0.24)
(n = 11)
54.09 (9.72) 54.84 (10.79) 53.48 (6.20) 50.49 (7.36) 42.66 (8.79) 47.36 (6.94) 47.41 (11.97) 45.27 (13.91)
57.33 (8.11) 56.42 (10.06) 51.73 (6.42) 50.07 (7.48) 43.66 (8.51) 47.99 (7.36) 48.89 (13.54) 40.82 (13.33)
(n = 8) 49.64 (10.47) 52.66 (12.04) 55.89 (5.36) 51.07 (7.67) 43.66 (9.77) 46.49 (6.71) 44.51 (9.67) 51.38 (13.04)
(n = 21)
(n = 12)
(n = 9)
52.62 49.62 46.76 47.38
53.17 53.42 44.83 44.17
51.89 44.56 49.33 51.67
(9.21) (9.73) (12.83) (10.55)
correlated more strongly with personality traits among women than among men; among women, the serum βTP concentrations correlated with Monotony Avoidance (rho= 0.97, P b 0.001) and with Impulsiveness (rho= 0.90, P = 0.002). By standard references (women: 45–90 μmol l–1, men: 60– 105 μmol l–1), all participants, except one, had normal serum creatinine concentrations before surgery. Exclusion of the one participant with elevated serum creatinine concentration (188 μmol l–1) did not change any of the results reported.
(8.37) (10.74) (15.40) (11.44)
(3.78) (52.06) (1.73) (0.16) (6.12) (134.74) (47.15) (0.50) (0.19) (0.13) (1.98) (0.14)
(10.71) (5.27) (8.52) (7.89)
scale is designed to measure pathology as high scores rather than peculiarities associated with low scores. There was also a significant negative correlation between the HVA/5-HIAA ratios and the character dimension Cooperativeness (rho = − 0.57, P = 0.008) (Table 2), which includes subscales such as empathy, compassion and helpfulness. As there was a significant correlation between CSF concentration of HVA and time at sampling (rho = 0.51, P = 0.003), time was entered in the analyses as the co-factor and in a partial correlation analysis, controlling for time of sampling; the significant correlations remained strong (rho = −0.62, P = 0.006).
3.2. Monoaminergic metabolites 3.3. Thyroid hormones The CSF HVA/5-HIAA ratios correlated positively with Irritability (Table 2), this time strongest in men (rho = 0.70, P = 0.017). Negative correlations with Inhibited Aggression were noted, especially in women (rho = − 0.81, P = 0.016), but are difficult to interpret as this
Serum and CSF concentrations of T3 and T4 were also compared with the KSP and TCI results. On a group level, there were no significant correlations between serum or CSF thyroid hormones and
Table 2 Correlation coefficients (Spearman's rho) between personality dimensions and markers of BBB integrity and monoamine metabolism in the 19 subjects who completed KSP and the 21 who completed TCI (p-values given within brackets if b0.05). Serum β-trace protein
CSF HVA/5-HIAA ratio
KSP Scales Monotony Avoidance Impulsiveness Socialization Detachment Indirect Aggression Verbal Aggression Irritability Inhibited aggression
0.62* (p = 0.005) 0.64* (p = 0.003) -0.019 0.019 -0.05 0.11 0.14 -0.10
0.00 0.07 -0.06 0.13 0.17 0.54 (p = 0.018) 0.64* (p = 0.003) -0.49 (p = 0.039)
TCI dimensions Novelty Seeking Reward Dependence Self-Directedness Cooperativeness
-0.08 0.04 -0.16 -0.42
0.02 -0.15 -0.42 -0.57* (p = 0.008)
*Correlation significant at the 0.01 level (2-tailed).
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any of the personality measures. Correlations in subgroups by gender were, therefore, not assessed. Finally, all analyses presented in the article were re-made after excluding the three patients treated with lipophilic beta-blockers, which did not change the direction or magnitude of the main findings (serum βTP correlated with Monotony Avoidance rho = 0.59, P = 0.017 and with Impulsivity rho = 0.61, P = 0.013, CSF HVA/5HIAA ratios correlated with Irritability rho = 0.66, P = 0.005 and with Cooperativeness rho = −0.58, P = 0.012). 4. Discussion Overall, the main findings in this general population study group are that increased dopaminergic neurotransmission, in relation to serotonergic neurotransmission, is associated with increased Irritability and inversely correlated with Inhibited Aggression and Cooperativeness, or in other words, with aspects of acceptance of others, compassion and ability to co-operate. Furthermore, the findings support that an increased BBB permeability, as assessed by the serum concentrations of the βTP, may be associated with impulsive personality traits, including Monotony Avoidance and Impulsiveness, that is, the need for novelty, inability to tolerate boredom and thoughtless acting out on the spur of the moment, and with temperamental dispositions in the form of being outgoing, bold and confident as well as uninhibited, nonchalant and carefree. However, these associations need to be studied further, preferably in well-ascertained, general-population-based study groups. Increased albumin ratios have previously been demonstrated in violent offenders and were hypothesised to correlate with impulsive and destructive personality traits (Anckarsäter et al., 2005; Soderstrom et al., 2001). In the present study, albumin ratios correlated positively with personality traits thought to confer susceptibility for mental health problems, even if these correlations did not reach statistical significance. Neither were there any significant correlations between thyroid hormone concentrations and personality traits. Lack of such a significant association may be due to limitations of the present study population (as discussed below), or to the lack of such a relationship in non-psychiatric populations. Since to the best of our knowledge, this is the first study made to investigate the relationship between serum βTP concentrations and personality dimensions and temperament, these findings need to be evaluated in larger general population studies and in studies of psychiatric populations. Using serum βTP concentrations to assess BBB permeability may be a means of assessing leakage out of CSF as the concentration of βTP in the CSF is considerably higher than that in serum (Arrer et al., 2002; Bachmann et al., 2002). In the present study, the CSF concentration of βTP was found to be 24 times higher than that in serum (see Table 1). As summarised in Abbott et al. (2006), there are several different transport mechanisms over the BBB, and albumin and βTP are probably transported by two functionally different mechanisms (transcytosis and diffusion). However, since serum βTP is also a marker for renal dysfunction (Hoffman et al., 1997), this would only be feasible in subjects in whom normal kidney function has been ascertained by other methods. The HVA/5-HIAA ratios were hypothesised to be associated with disinhibited behaviours and low empathy/emotional reactivity. The present findings seem to confirm a relationship between increased ratios between the metabolites of dopamine over serotonin in the CSF and psychopathy-related personality traits, such as Irritability and a decrease in Cooperativeness, as previously found in independent groups of violent offenders. Cloninger et al. (1993) defined Cooperativeness as a conceptual system of cognitive guidance of behaviour in relation to other people. The character dimensions, according to this personality theory, have actually shown biological correlations to the same extent as the temperaments, which were initially thought to underlie character development and to form the
main biological substrate for personality development. There is currently a lack of studies investigating the HVA/5-HIAA ratios in association with personality in healthy subjects, although a number of studies have found correlations between the Self-Transcendence dimension and serotonin functioning using brain imaging methods or molecular genetics (Borg et al., 2003; Nilsson et al., 2007). Most studies have focussed on monoamine metabolites in psychiatric or criminal populations and associations between, for example, low 5HIAA levels, suicide, depression and aggression, which is one of the most consistently replicated findings of biological psychiatry (Stanley et al., 2000; Hou et al., 2006; Lidberg et al., 1984). Such findings along with the present results warrant further research on the functional role of the monoamine systems in the development of destructive – or pro-social – personality traits. Re-examination of older studies presenting data on the individual metabolites only is called for, as is the use of new methods to assess activity in the brain systems and their underlying chemical apparatus, such as genetic variants. 4.1. Limitations The present study investigating the relationship between BBB permeability, peripheral and central biomarkers and personality in patients undergoing non-neurological surgery, has several limitations. A limitation of all research on CSF is that, it is not fully possible to evaluate the exact relationship between the levels of substance studied at the site of synthesis in the brain and the lumbar area, where the samples are drawn (Reiber et al., 2001). The sample consisted of 21 non-neurologic, non-psychiatric patients undergoing knee arthroplastic surgery, a procedure that is mostly carried out in an older population. Thus, the present population was not a general population age-wise, had a high incidence of hypertension and diabetes mellitus, used several different medicines (although not on the day of surgery) and contained a relatively small number of subjects. Measures of subjective pain were not assessed in the present investigation; however, the effects of prevailing pain on the behavioural measures are an interesting aspect. To the best of our knowledge, there are no studies on the effects of chronic pain on outcome of the TCI, but Conrad et al. (2007) have investigated personality profiles and personality disorders in chronic pain patients using the TCI. Since chronic pain patients differ from the study population used in our study in several respects, including the definition of pain, conclusions regarding the present study population based on that previous study should thus be made with caution. The results from the Conrad et al. (2007) showed that chronic pain patients, compared with pain-free patients, scored higher on the Harm Avoidance temperament dimension and lower on the SelfDirectedness and Cooperativeness character dimensions. The correlations between biomarkers and personality measures were all based on data collected before the surgical procedure was initiated, and thus the effects of surgical medication were excluded. Little is known, however, about diurnal variations in CSF proteins and hormones in humans. However, there was a significant positive correlation between sampling time and CSF HVA concentrations and serum albumin levels. In addition, there was a negative correlation between sampling time and serum βTP level. 4.2. Conclusion Despite the limitations, the present study reveals interesting, significant correlations that, together with previous scientific support for the association between these biomarkers and personality dimensions in forensic psychiatric populations, call for further investigation. To verify the validity of the present findings, a study with high power and a representative sample consisting of healthy, younger volunteers is to be desired. In such an ideal study, serum and CSF sampling should be continuously
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made over 24 h to investigate the diurnal fluctuations in the considered biomarkers, as no such studies have yet been undertaken. In addition, one group of healthy volunteers would be subjected to a psychological stressor during the continuous CSF sampling, and both groups would have dimensions of personality and character assessed. This far, continuous CSF sampling has been conducted in healthy volunteers over a maximum of 6 h, at a rate of 0.1 ml min–1 (Geracioti et al., 1998), assessing the individual variations in 5-HIAA and HVA. Such an ideal study would provide knowledge about diurnal fluctuations of hormones and monoaminergic metabolites as well as insight into the response of these markers to stress. Furthermore, associations between such biomarkers and personality and character dimensions would be made clear and less influenced by confounders such as age and medical treatments due to age-related disorders. Psychopathic traits are problematic to define as they consist of heterogeneous behavioural patterns, interpersonal attitudes and emotional reactions. Scaling down personality traits to measurable units, as attempted by the personality scales used in this study, may be a crude way of defining very complex phenomena. It is, however, a step towards increased understanding of the neurobiological systems governing both normal and pathological behaviour. As such, the present study replicated some of the findings from forensic psychiatric population studies, confirming a relationship between personality traits related to psychopathology and neurochemical markers, in a general population-based sample. Acknowledgements The study was sponsored by The Swedish Research Council and ALF funding.
References Abbott, N.J., Ronnback, L., Hansson, E., 2006. Astrocyte-endothelial interactions at the blood-brain barrier. Nature Reviews Neuroscience 7, 41–53. Anckarsäter, H., Forsman, A., Blennow, K., 2005. Increased CSF/serum albumin ratio: a recurrent finding in violent offenders. Acta Neurologica Scandinavica 112, 48–50. Anckarsäter, R., Vasic, N., Jideus, L., Kristiansson, M., Zetterberg, H., Blennow, K., Anckarsäter, H., 2007a. Cerebrospinal fluid protein reactions during non-neurological surgery. Acta Neurologica Scandinavica 115, 254–259. Anckarsäter, R., Zetterberg, H., Blennow, K., Anckarsäter, H., 2007b. Association between thyroid hormone levels and monoaminergic neurotransmission during surgery. Psychoneuroendocrinology 32, 1138–1143. Arrer, E., Meco, C., Oberascher, G., Piotrowski, W., Albegger, K., Patsch, W., 2002. beta-Trace protein as a marker for cerebrospinal fluid rhinorrhea. Clinical Chemistry 48, 939–941. Asberg, M., Traskman, L., Thoren, P., 1976. 5-HIAA in the cerebrospinal fluid. A biochemical suicide predictor? Archives of General Psychiatry 33, 1193–1197. Axelsson, R., Martensson, E., Alling, C., 1982. Impairment of the blood-brain barrier as an aetiological factor in paranoid psychosis. British Journal of Psychiatry 141, 273–281. Bachmann, G., Petereit, H., Djenabi, U., Michel, O., 2002. Predictive values of beta-trace protein (prostaglandin D synthase) by use of laser-nephelometry assay for the identification of cerebrospinal fluid. Neurosurgery 50, 571–576 discussion 576-7. Bauer, K., Kornhuber, J., 1987. Blood-cerebrospinal fluid barrier in schizophrenic patients. European Archives of Psychiatry and Neurological Science 236, 257–259. Bayard-Burfield, L., Alling, C., Blennow, K., Jonsson, S., Traskman-Bendz, L., 1996. Impairment of the blood-CSF barrier in suicide attempters. European Neuropsychopharmacology 6, 195–199. Blennow, K., Wallin, A., Gottfries, C.G., Karlsson, I., Mansson, J.E., Skoog, I., Wikkelso, C., Svennerholm, L., 1993. Cerebrospinal fluid monoamine metabolites in 114 healthy individuals 18-88 years of age. European Neuropsychopharmacology 3, 55–61. Blodorn, B., Bruck, W., Tumani, H., Michel, U., Rieckmann, P., Althans, N., Mader, M., 1999. Expression of the beta-trace protein in human pachymeninx as revealed by in situ hybridization and immunocytochemistry. Journal of Neuroscience Research 57, 730–734. Borg, J., Andree, B., Soderstrom, H., Farde, L., 2003. The serotonin system and spiritual experiences. American Journal of Psychiatry 160, 1965–1969. Castellanos, F.X., Elia, J., Kruesi, M.J., Gulotta, C.S., Mefford, I.N., Potter, W.Z., Ritchie, G.F., Rapoport, J.L., 1994. Cerebrospinal fluid monoamine metabolites in boys with attention-deficit hyperactivity disorder. Psychiatry Research 52, 305–316. Cloninger, C.R., Svrakic, D.M., Przybeck, T.R., 1993. A psychobiological model of temperament and character. Archives of General Psychiatry 50, 975–990. Coccaro, E.F., Kavoussi, R.J., Cooper, T.B., Hauger, R.L., 1997. Central serotonin activity and aggression: inverse relationship with prolactin response to d-fenfluramine, but not CSF 5-HIAA concentration, in human subjects. American Journal of Psychiatry 154, 1430–1435.
529
Conrad, R., Schilling, G., Bausch, C., Nadstawek, J., Wartenberg, H.C., Wegener, I., Geiser, F., Imbierowicz, K., Liedtke, R., 2007. Temperament and character personality profiles and personality disorders in chronic pain patients. Pain 133, 197–209. Fitzgerald, S.P., Lamont, J.V., McConnell, R.I., Benchikh el, O., 2005. Development of a high-throughput automated analyzer using biochip array technology. Clinical Chemistry 51, 1165–1176. Gardner, D.L., Lucas, P.B., Cowdry, R.W., 1990. CSF metabolites in borderline personality disorder compared with normal controls. Biological Psychiatry 28, 247–254. Geracioti Jr., T.D., Keck Jr., P.E., Ekhator, N.N., West, S.A., Baker, D.G., Hill, K.K., Bruce, A.B., Wortman, M.D., 1998. Continuous covariability of dopamine and serotonin metabolites in human cerebrospinal fluid. Biological Psychiatry 44, 228–233. Hoffmann, A., Nimtz, M., Conradt, H.S., 1997. Molecular characterization of beta-trace protein in human serum and urine: a potential diagnostic marker for renal diseases. Glycobiology 7, 499–506. Hou, C., Jia, F., Liu, Y., Li, L., 2006. CSF serotonin, 5-hydroxyindolacetic acid and neuropeptide Y levels in severe major depressive disorder. Brain Research 1095, 154–158. Kanekiyo, T., Ban, T., Aritake, K., Huang, Z.L., Qu, W.M., Okazaki, I., Mohri, I., Murayama, S., Ozono, K., Taniike, M., Goto, Y., Urade, Y., 2007. Lipocalin-type prostaglandin D synthase/beta-trace is a major amyloid beta-chaperone in human cerebrospinal fluid. Proceedings of the National Academy of Sciences of the United States of America 104, 6412–6417. Lidberg, L., Asberg, M., Sundqvist-Stensman, U.B., 1984. 5-Hydroxyindoleacetic acid levels in attempted suicides who have killed their children. Lancet 2, 928. Lidberg, L., Tuck, J.R., Asberg, M., Scalia-Tomba, G.P., Bertilsson, L., 1985. Homicide, suicide and CSF 5-HIAA. Acta Psychiatrica Scandinavica 71, 230–236. Mase, M., Yamada, K., Shimazu, N., Seiki, K., Oda, H., Nakau, H., Inui, T., Li, W., Eguchi, N., Urade, Y., 2003. Lipocalin-type prostaglandin D synthase (beta-trace) in cerebrospinal fluid: a useful marker for the diagnosis of normal pressure hydrocephalus. Neuroscience Research 47, 455–459. Miwa, Y., Oda, H., Shiina, Y., Shikata, K., Tsushima, M., Nakano, S., Maruyama, T., Kyotani, S., Eguchi, N., Urade, Y., Takahashi-Yanaga, F., Morimoto, S., Sasaguri, T., 2008. Association of serum lipocalin-type prostaglandin D synthase levels with subclinical atherosclerosis in untreated asymptomatic subjects. Hypertension Research 31, 1931–1939. Nilsson, K.W., Damberg, M., Ohrvik, J., Leppert, J., Lindstrom, L., Anckarsäter, H., Oreland, L., 2007. Genes encoding for AP-2beta and the Serotonin Transporter are associated with the Personality Character Spiritual Acceptance. Neuroscience Letters 411, 233–237. Rapoport, S., 1976. Pathological alterations in the blood-brain barrier. In: Rapoport, S. (Ed.), Blood-brain Barrier in Physiology and Medicine. Raven Press, New York, pp. 131–133. Reiber, H., 2001. Dynamics of brain-derived proteins in cerebrospinal fluid. Clinica Chimica Acta 310, 173–186. Schalling, D., 1978. Psychopathy-related personality variables and the psychophysiology of socialization. In: Hare, R.D., Schalling, D. (Eds.), Psychopathic Behavior. Approaches to Research. John Wiley & Sons, Chichester, UK. Schalling, D., Asberg, M., Edman, G., Oreland, L., 1987. Markers for vulnerability to psychopathology: temperament traits associated with platelet MAO activity. Acta Psychiatrica Scandinavica 76, 172–182. Schell, C., Frungieri, M.B., Albrecht, M., Gonzalez-Calvar, S.I., Kohn, F.M., Calandra, R.S., Mayerhofer, A., 2007. A prostaglandin D2 system in the human testis. Fertility and Sterility 88, 233–236. Soderstrom, H., Forsman, A., 2004. Elevated triiodothyronine in psychopathy - possible physiological mechanisms. Journal of Neural Transmission 111, 739–744. Soderstrom, H., Blennow, K., Manhem, A., Forsman, A., 2001. CSF studies in violent offenders. II. Blood-brain barrier dysfunction without concurrent inflammation or structure degeneration. Journal of Neural Transmission 108, 879–886. Soderstrom, H., Blennow, K., Sjodin, A.K., Forsman, A., 2003. New evidence for an association between the CSF HVA:5-HIAA ratio and psychopathic traits. Journal of Neurology, Neurosurgery, and Psychiatry 74, 918–921. Stalenheim, E.G., 2004. Long-term validity of biological markers of psychopathy and criminal recidivism: follow-up 6-8 years after forensic psychiatric investigation. Psychiatry Research 121, 281–291. Stalenheim, E.G., von Knorring, L., Wide, L., 1998. Serum levels of thyroid hormones as biological markers in a Swedish forensic psychiatric population. Biological Psychiatry 43, 755–761. Stanley, B., Molcho, A., Stanley, M., Winchel, R., Gameroff, M.J., Parsons, B., Mann, J.J., 2000. Association of aggressive behavior with altered serotonergic function in patients who are not suicidal. American Journal of Psychiatry 157, 609–614. Tanaka, T., Urade, Y., Kimura, H., Eguchi, N., Nishikawa, A., Hayaishi, O., 1997. Lipocalintype prostaglandin D synthase (beta-trace) is a newly recognized type of retinoid transporter. Journal of Biological Chemistry 272, 15789–15795. Taniguchi, H., Mohri, I., Okabe-Arahori, H., Aritake, K., Wada, K., Kanekiyo, T., Narumiya, S., Nakayama, M., Ozono, K., Urade, Y., Taniike, M., 2007. Prostaglandin D2 protects neonatal mouse brain from hypoxic ischemic injury. Journal of Neuroscience 27, 4303–4312. Tibbling, G., Link, H., Ohman, S., 1977. Principles of albumin and IgG analyses in neurological disorders. I. Establishment of reference values. Scandinavian Journal of Clinical and Laboratory Investigation 37, 385–390. Tumani, H., Reiber, H., Nau, R., Prange, H.W., Kauffmann, K., Mader, M., Felgenhauer, K., 1998. Beta-trace protein concentration in cerebrospinal fluid is decreased in patients with bacterial meningitis. Neuroscience Letters 242, 5–8. Urade, Y., Hayaishi, O., 2000. Biochemical, structural, genetic, physiological, and pathophysiological features of lipocalin-type prostaglandin D synthase. Biochimica et Biophysica Acta 1482, 259–271.
530
T. Nilsson et al. / Psychiatry Research 178 (2010) 525–530
Urade, Y., Kitahama, K., Ohishi, H., Kaneko, T., Mizuno, N., Hayaishi, O., 1993. Dominant expression of mRNA for prostaglandin D synthase in leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. Proceedings of the National Academy of Sciences of the United States of America 90, 9070–9074. Virkkunen, M., Eggert, M., Rawlings, R., Linnoila, M., 1996. A prospective follow-up study of alcoholic violent offenders and fire setters. Archives of General Psychiatry 53, 523–529.
Watanabe, K., Urade, Y., Mader, M., Murphy, C., Hayaishi, O., 1994. Identification of betatrace as prostaglandin D synthase. Biochemical and Biophysical Research Communications 203, 1110–1116. White, D.M., Takeda, T., DeGroot, L.J., Stefansson, K., Arnason, B.G., 1997. Beta-trace gene expression is regulated by a core promoter and a distal thyroid hormone response element. Journal of Biological Chemistry 272, 14387–14393.
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Psychiatry Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s
Neurochemical measures co-vary with personality traits: Forensic psychiatric findings replicated in a general population sample Thomas Nilsson a, Sara Bromander a,d,⁎, Rolf Anckarsäter c, Marianne Kristiansson d, Anders Forsman a, Kaj Blennow a, Henrik Zetterberg a, Henrik Anckarsäter a,b, Caroline Wass a a
Institute of Neuroscience and Physiology, University of Gothenburg, Sweden Institute of Clinical Sciences, Malmö, Lund University, Sweden Department of Anaesthesiology and Intensive Care, Kungälv Hospital, Sweden d Division of Forensic Psychiatry, Karolinska Institute, Sweden b c
a r t i c l e
i n f o
Article history: Received 22 December 2008 Received in revised form 18 May 2010 Accepted 21 May 2010 Keywords: Beta-trace protein (βTP) Blood–brain barrier Monoamine metabolites Dopamine Serotonin Thyroid hormones Personality
a b s t r a c t Neurobiological markers in cerebrospinal fluid (CSF) and in serum, previously found to co-vary with destructive personality traits in violent offenders, were explored in a general population sample of 21 patients undergoing knee surgery. Results on the Karolinska Scales of Personality (KSP) and the Temperament and Character Inventory (TCI) were compared with CSF/serum albumin ratios and serum concentrations of beta-trace protein (βTP) (as markers for blood–brain barrier (BBB) permeability), to CSF/ serum albumin ratios between the dopamine and serotonin metabolites homovanillic acid (HVA)/5hydroxyindoleacetic acid (HIAA) and to CSF and serum ratios between activated thyroid hormone (T3) and its precursor T4. Serum βTP concentrations correlated with CSF/serum albumin ratios (P =0.018), but not with preoperative serum creatinine concentrations. Serum βTP correlated significantly with Monotony Avoidance and Impulsiveness; CSF HVA/5-HIAA ratios with Irritability and low Cooperativeness. The βTP is a potential serum marker for the integrity of the BBB that does not necessitate lumbar puncture. Thyroid hormones did not correlate with personality traits. As reported in forensic psychiatric patients, aggressive, unempathic personality traits were thus associated with increased dopaminergic activity in relation to the serotonergic activity and impulsivity to increased BBB permeability also in a general population group. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction A high prevalence of increased cerebrospinal fluid (CSF)/serum albumin ratios, indicating increased blood–brain barrier (BBB) permeability, in its turn regarded as an unspecific indicator of central nervous system (CNS) vulnerability, has previously been found in two separate forensic psychiatric groups of violent offenders (Soderstrom et al., 2001; Anckarsäter et al., 2005). Normal age-dependent reference values for comparisons of this measure have been established among healthy volunteers (Blennow et al., 1993; Tibbling et al., 1977). Increased CSF/serum albumin ratios have also been reported in patients with CNS lesions, traumas and tumours (Rapoport, 1976), in psychiatric conditions such as psychoses (Axelsson et al., 1982; Bauer and Kornhuber, 1987) and in suicide attempters (Bayard-Burfield et al., 1996). Another possible indicator of increased BBB permeability is the serum concentrations of betatrace protein (βTP), which is synthesised in the spinal leptomeninges (Urade et al., 1993) and in the pachymeninx (Blodorn et al., 1999), ⁎ Corresponding author. Forensic Psychiatry, Lillhagsparken 3, 422 50 Hisings Backa, Sweden. Tel.: +46 768123121; fax: +46 31 559671. E-mail address: [email protected] (S. Bromander). 0165-1781/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2010.05.016
functioning as a prostaglandin synthetase (Watanabe et al., 1994) and as a carrier protein for retinoids (Tanaka et al., 1997). As the βTP is mostly synthesised in the CNS (Blodorn et al., 1999), besides minute quantities peripherally (e.g., in the male genital system, kidneys and the heart, Hoffman et al., 1997; Schell et al., 2007; White et al., 1997; Urade and Hayaishi, 2000), it may be used as an indicator of CSF leakage into peripheral fluids such as nasal secretion (Arrer et al., 2002). Thus, albumin ratios and serum βTP concentrations represent two different aspects of BBB permeability (into vs. out from the CNS). βTP levels in CSF have also been shown to change in response to different CNS pathologies, such as normal pressure hydrocephalus and bacterial meningitis (Mase et al., 2003; Tumani et al., 1998). Furthermore, experimental animal studies suggest that βTP may be protective of hypoxic ischaemic injury (Taniguchi et al 2007), and its function may also be disturbed in Alzheimer's disease (Kanekiyo et al., 2007). An increase in βTP concentration has recently been associated with the development of atherosclerosis (Miwa et al., 2008). Increased ratios between the CSF concentrations of the dopamine metabolite homovanillic acid (HVA) over the serotonin metabolite 5hydroxyindolacetic acid (5-HIAA) have correlated with psychopathic personality traits, especially the ‘disinhibited behaviours’ and ‘lack of emotionality/empathy’ dimensions, in two forensic psychiatric study
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groups (Anckarsäter et al., 2005; Soderstrom et al., 2003). Numerous studies have shown an increased propensity for destructive acting out, such as violent suicide, arson or killing a sexual partner, in subjects with decreased 5-HIAA levels (Asberg et al., 1976; Lidberg et al., 1984; Virkkunen et al., 1996), but similar studies have failed to show a corresponding link to instrumental violence or psychopathic personality traits (Castellanos et al. 1994; Coccaro et al. 1997; Gardner et al. 1990; Lidberg et al. 1985). A number of studies in forensic psychiatric offender groups have reported an association between increased serum thyroid activity, as indicated by increased ratios of the active thyroid hormone triiodothyronin (T3) over its precursor thyroxine (T4) or by decreased T4 concentrations, and criminal recidivism, aggression and psychopathic traits (Soderstrom and Forsman, 2004; Stalenheim, 2004; Stalenheim et al., 1998). Elevated T3 concentrations in serum may reflect increased conversion of T4 to T3, that is, the opposite of the pattern found in depression (Soderstrom and Forsman, 2004). Based on the above-described findings from psychiatric and forensic study populations, the present study aimed at investigating these relationships in a mentally healthy sample. CSF and serum samples were drawn before arthroplastic-knee surgery in subjects without psychiatric or neurological disorders (Anckarsäter et al., 2007a,b) and were used to analyse possible biomarkers for personality according to two self-rate questionnaires; the Temperament and Character Inventory (TCI) (Cloninger et al., 1993) and the Karolinska Scales of Personality (KSP) (Schalling, 1978; Schalling et al., 1987), aiming to assess whether: (1) increased CSF/serum albumin ratios and serum βTP concentrations correlate with impulsive personality traits. (2) increased CSF HVA/5-HIAA ratios correlate with, impulsive personality traits and low empathy/emotional reactivity. (3) T3 or T3/T4 ratios in serum and in CSF correlate with impulsive personality traits. 2. Subjects and Methods The study protocol was approved by the Ethical Review Board, University of Gothenburg. Patients scheduled for knee arthroplastic surgery at Kungälv Hospital were consecutively recruited from the anaesthesiological clinical practice doing preoperative assessments. The criteria for the selection of subjects were: (a) no use of psychotropic, anti-Parkinson, corticosteroid or anticoagulant medication; (b) practical possibility to include the patient; and (c) the ambition to include persons as healthy as possible (besides the orthopaedic problem). After oral and written information, patients who gave informed consent were included in the study and were given the personality questionnaires to fill out at home after the preoperative consultations, but before surgery. Thirty-five psychiatrically healthy patients (20 males, 15 females, aged 51–82 years, median 73 years) gave informed consent to participate in the study. Thirty-four of these 35 patients could provide CSF and serum samples to be included in the study and 26 had completed the personality questionnaires when arriving at the hospital. One patient was subsequently omitted from analyses, as she was found to have been on long-term medication with 10 mg of the serotonin reuptake inhibitor, citalopram, and four patients were excluded as they had pathological CSF/ serum albumin ratios (exceeding the normal reference value of 11.8) at inclusion and therefore not as neurologically healthy as required for the present study (details on protein findings are given in Anckarsäter et al., 2007a). The final group analyzed here consisted of 21 subjects (12 males and 9 females, aged 58–81 years, median 74 years). After a subcutaneous local anaesthesia with 10 ml 0.5% mepivacaine, a lumbar puncture was performed with an 18-gauge Portex™ epidural needle in the L3–L4 interspace, according to standard hospital procedures. After discarding the first 2–3 ml of CSF, 12 ml were sampled and gently mixed before the insertion of spinal catheters and administration of any intrathecal drugs. CSF and blood for serum and plasma analyses were centrifuged at 2000 g for 10 min and pipetted in new tubes at Kungälvs Hospital and transported to the Sahlgrenska University Hospital neurochemistry lab, Mölndal, where aliquots were stored at -80 °C until biochemical analyses were performed, according to accredited neurochemistry lab routines. Thirteen of the 21 patients included in the present analyses had a history of hypertension and five of diabetes mellitus. All subjects had been on their medications for long and stable periods. No abrupt washout was performed for the purpose of the study, besides all non-steroidal anti-inflammatory and acetyl salicyclic acid drugs, which were discontinued 1 week before surgery. No per-oral medication other than beta-blockers was given on the day of surgery. Three patients were taking lipophilic
beta-blockers. Three patients had been treated with codeine and tramadol on an asneeded basis during the time period before surgery. 2.1. Laboratory analyses Albumin concentrations were analysed by nephelometry on the Image instrument (Beckman Coulter) and βTP concentrations by nephelometry on the BNProSpec instrument (Dade Behring), using the NLatex βTP kit. Determination of the monoamine metabolites was performed by means of highperformance liquid chromatography with electrochemical detection, as described by Blennow and co-workers (1993). Thyroid hormones were determined by biochip array technique on the Evidence Investigator™ (Randox, Crumlin, United Kingdom) according to the manufacturer's instructions, using the total thyroid array for thyroid-stimulating hormone (TSH), total T3 and total T4 (Fitzgerald et al., 2005). All biological parameters were uncorrelated to age and sex. 2.2. Personality assessments Personality questionnaires were distributed to the subjects during the anaesthesiological preoperative consultation, and the completed forms were collected on admission to the hospital. Nineteen subjects had filled out the KSP, which is a 135-item self-rate questionnaire containing 15 personality scales, that is, Somatic Anxiety, Psychic Anxiety, Muscular Tension, Social Desirability, Impulsiveness, Monotony Avoidance, Detachment, Psychasthenia, Socialisation, Indirect Aggression, Verbal Aggression, Irritability, Suspicion, Guilt and Inhibition of Aggression, measuring stable temperament traits constituting vulnerability factors for different kinds of psychopathology (Schalling, 1978; Schalling et al., 1987). Twenty-one subjects had completed the TCI, which is a 238-item true-or-false questionnaire assessing four temperament dimensions, that is, Novelty Seeking, Harm Avoidance, Reward Dependence and Persistence, and three character dimensions, that is Self-Directedness, Cooperativeness and Self-Transcendence, based on Cloninger's psychobiological model of personality (Cloninger et al., 1993). No systematic differences in age, sex or general medical status were noted between responders and non-responders, the main reason for nonresponse being lack of time to fill out personality questionnaires before surgery. All personality data were transformed into T-scores (with a mean of 50 and a S.D. of± 10) derived from normal population groups, corrected for age and sex and then compared with laboratory results. To assess the representativeness of the sample, personality traits were tested against the normal mean t-score of 50 by one-sample t-tests, and, with the exception for the following KSP scales, no significant differences from the expected mean were found; Psychic Anxiety (b50, P = 0.001), Indirect Aggression (b 50, P = 0.001) and Suspicion (N50, P = 0.006). Differences between men and women for the studied personality dimensions were also tested, and strong tendencies towards higher scores in women were found for the KSP traits, Psychic Anxiety and Inhibited Aggression, but these did not reach statistical significance according to the preset significance level (P ≤ 0.01). Finally, no significant correlations were found between age and any of the KSP or the TCI dimensions. 2.3. Statistical methods All statistical analyses were performed using the Statistical Package for Social Sciences program (SPSS) 17.0 software. One sample t-test was used to analyse whether our group differed from the norm (t-score of 50) and Spearman's rho to analyse associations between variables. The sample is relatively small due to the difficulties to achieve large-enough samples of patients going through lumbar punctures. Thus, to control for the risk of type I errors, alpha was set at 1% (P b 0.01). It would be extremely difficult to assemble CSF samples from a large-enough group to have power for statistical analyses in relation to complex personality inventories after Bonferroni correction or the like. In this respect, CSF studies have to be compared with various brain-imaging studies, where such corrections are not common. In total, there are now 24 personality and biomarker correlations and with the defined alpha and two-tailed P-values, the risk that a random finding is significant in line with the preformed hypothesis (i.e., a false positive finding) is below 0.5% for each comparison.
3. Results Mean values with standard deviations for both the biological markers and the personality traits of interest are given in Table 1. 3.1. BBB integrity Serum βTP showed a trend towards correlating with the CSF/serum albumin ratios (rho=0.513, P=0.018, n=21). The serum βTP concentrations correlated positively with personality traits describing Monotony Avoidance and Impulsivity (Table 2), while the CSF/serum albumin ratios showed weaker correlations in the same direction for these traits. Both, the serum βTP concentrations and the CSF/serum albumin ratios,
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Table 1 Mean values and standard deviations (S.D.) of the biological markers and the targeted personality traits in all subjects, divided by gender, and with number (n) of patients available for analyses. Biological markers
All subjects (n = 21) mean (S.D.)
Male (n = 12) mean (S.D.)
Female (n = 9) mean (S.D.)
Serum albumin (g/l) CSF CSF albumin (mg/l) CSF albumin/serum albumin Serum ßTP (mg/l) CSF ßTP (mg/l) CSF HVA (nmol/l) CSF 5-HIAA (nmol/l) CSF HVA/5 HIAA Serum T3 (ng/ml) CSF T3 (ng/ml) Serum T4 (μg/dl) CSF T4 (μg/dl)
38.43 263.00 6.90 0.69 16.92 277.00 169.43 1.66 1.38 0.94 7.57 1.10
38.33 264.50 6.93 0.74 16.72 266.08 156.25 1.77 1.35 0.92 7.53 1.06
38.56 261.00 6.88 0.62 17.20 291.56 187.00 1.51 1.42 0.97 7.62 1.16
KSP Scales
(n = 19)
Monotony Avoidance Impulsiveness Socialization Detachment Indirect Aggression Verbal Aggression Irritability Inhibited Aggression TCI Dimensions Novelty Seeking Reward Dependence Self-Directedness Cooperativeness
(3.53) (66.97) (1.82) (0.23) (6.82) (107.58) (53.10) (0.52) (0.21) (0.13) (1.42) (0.20)
(3.50) (78.60) (1.96) (0.26) (7.57) (86.81) (55.38) (0.53) (0.23) (0.12) (0.88) (0.24)
(n = 11)
54.09 (9.72) 54.84 (10.79) 53.48 (6.20) 50.49 (7.36) 42.66 (8.79) 47.36 (6.94) 47.41 (11.97) 45.27 (13.91)
57.33 (8.11) 56.42 (10.06) 51.73 (6.42) 50.07 (7.48) 43.66 (8.51) 47.99 (7.36) 48.89 (13.54) 40.82 (13.33)
(n = 8) 49.64 (10.47) 52.66 (12.04) 55.89 (5.36) 51.07 (7.67) 43.66 (9.77) 46.49 (6.71) 44.51 (9.67) 51.38 (13.04)
(n = 21)
(n = 12)
(n = 9)
52.62 49.62 46.76 47.38
53.17 53.42 44.83 44.17
51.89 44.56 49.33 51.67
(9.21) (9.73) (12.83) (10.55)
correlated more strongly with personality traits among women than among men; among women, the serum βTP concentrations correlated with Monotony Avoidance (rho= 0.97, P b 0.001) and with Impulsiveness (rho= 0.90, P = 0.002). By standard references (women: 45–90 μmol l–1, men: 60– 105 μmol l–1), all participants, except one, had normal serum creatinine concentrations before surgery. Exclusion of the one participant with elevated serum creatinine concentration (188 μmol l–1) did not change any of the results reported.
(8.37) (10.74) (15.40) (11.44)
(3.78) (52.06) (1.73) (0.16) (6.12) (134.74) (47.15) (0.50) (0.19) (0.13) (1.98) (0.14)
(10.71) (5.27) (8.52) (7.89)
scale is designed to measure pathology as high scores rather than peculiarities associated with low scores. There was also a significant negative correlation between the HVA/5-HIAA ratios and the character dimension Cooperativeness (rho = − 0.57, P = 0.008) (Table 2), which includes subscales such as empathy, compassion and helpfulness. As there was a significant correlation between CSF concentration of HVA and time at sampling (rho = 0.51, P = 0.003), time was entered in the analyses as the co-factor and in a partial correlation analysis, controlling for time of sampling; the significant correlations remained strong (rho = −0.62, P = 0.006).
3.2. Monoaminergic metabolites 3.3. Thyroid hormones The CSF HVA/5-HIAA ratios correlated positively with Irritability (Table 2), this time strongest in men (rho = 0.70, P = 0.017). Negative correlations with Inhibited Aggression were noted, especially in women (rho = − 0.81, P = 0.016), but are difficult to interpret as this
Serum and CSF concentrations of T3 and T4 were also compared with the KSP and TCI results. On a group level, there were no significant correlations between serum or CSF thyroid hormones and
Table 2 Correlation coefficients (Spearman's rho) between personality dimensions and markers of BBB integrity and monoamine metabolism in the 19 subjects who completed KSP and the 21 who completed TCI (p-values given within brackets if b0.05). Serum β-trace protein
CSF HVA/5-HIAA ratio
KSP Scales Monotony Avoidance Impulsiveness Socialization Detachment Indirect Aggression Verbal Aggression Irritability Inhibited aggression
0.62* (p = 0.005) 0.64* (p = 0.003) -0.019 0.019 -0.05 0.11 0.14 -0.10
0.00 0.07 -0.06 0.13 0.17 0.54 (p = 0.018) 0.64* (p = 0.003) -0.49 (p = 0.039)
TCI dimensions Novelty Seeking Reward Dependence Self-Directedness Cooperativeness
-0.08 0.04 -0.16 -0.42
0.02 -0.15 -0.42 -0.57* (p = 0.008)
*Correlation significant at the 0.01 level (2-tailed).
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any of the personality measures. Correlations in subgroups by gender were, therefore, not assessed. Finally, all analyses presented in the article were re-made after excluding the three patients treated with lipophilic beta-blockers, which did not change the direction or magnitude of the main findings (serum βTP correlated with Monotony Avoidance rho = 0.59, P = 0.017 and with Impulsivity rho = 0.61, P = 0.013, CSF HVA/5HIAA ratios correlated with Irritability rho = 0.66, P = 0.005 and with Cooperativeness rho = −0.58, P = 0.012). 4. Discussion Overall, the main findings in this general population study group are that increased dopaminergic neurotransmission, in relation to serotonergic neurotransmission, is associated with increased Irritability and inversely correlated with Inhibited Aggression and Cooperativeness, or in other words, with aspects of acceptance of others, compassion and ability to co-operate. Furthermore, the findings support that an increased BBB permeability, as assessed by the serum concentrations of the βTP, may be associated with impulsive personality traits, including Monotony Avoidance and Impulsiveness, that is, the need for novelty, inability to tolerate boredom and thoughtless acting out on the spur of the moment, and with temperamental dispositions in the form of being outgoing, bold and confident as well as uninhibited, nonchalant and carefree. However, these associations need to be studied further, preferably in well-ascertained, general-population-based study groups. Increased albumin ratios have previously been demonstrated in violent offenders and were hypothesised to correlate with impulsive and destructive personality traits (Anckarsäter et al., 2005; Soderstrom et al., 2001). In the present study, albumin ratios correlated positively with personality traits thought to confer susceptibility for mental health problems, even if these correlations did not reach statistical significance. Neither were there any significant correlations between thyroid hormone concentrations and personality traits. Lack of such a significant association may be due to limitations of the present study population (as discussed below), or to the lack of such a relationship in non-psychiatric populations. Since to the best of our knowledge, this is the first study made to investigate the relationship between serum βTP concentrations and personality dimensions and temperament, these findings need to be evaluated in larger general population studies and in studies of psychiatric populations. Using serum βTP concentrations to assess BBB permeability may be a means of assessing leakage out of CSF as the concentration of βTP in the CSF is considerably higher than that in serum (Arrer et al., 2002; Bachmann et al., 2002). In the present study, the CSF concentration of βTP was found to be 24 times higher than that in serum (see Table 1). As summarised in Abbott et al. (2006), there are several different transport mechanisms over the BBB, and albumin and βTP are probably transported by two functionally different mechanisms (transcytosis and diffusion). However, since serum βTP is also a marker for renal dysfunction (Hoffman et al., 1997), this would only be feasible in subjects in whom normal kidney function has been ascertained by other methods. The HVA/5-HIAA ratios were hypothesised to be associated with disinhibited behaviours and low empathy/emotional reactivity. The present findings seem to confirm a relationship between increased ratios between the metabolites of dopamine over serotonin in the CSF and psychopathy-related personality traits, such as Irritability and a decrease in Cooperativeness, as previously found in independent groups of violent offenders. Cloninger et al. (1993) defined Cooperativeness as a conceptual system of cognitive guidance of behaviour in relation to other people. The character dimensions, according to this personality theory, have actually shown biological correlations to the same extent as the temperaments, which were initially thought to underlie character development and to form the
main biological substrate for personality development. There is currently a lack of studies investigating the HVA/5-HIAA ratios in association with personality in healthy subjects, although a number of studies have found correlations between the Self-Transcendence dimension and serotonin functioning using brain imaging methods or molecular genetics (Borg et al., 2003; Nilsson et al., 2007). Most studies have focussed on monoamine metabolites in psychiatric or criminal populations and associations between, for example, low 5HIAA levels, suicide, depression and aggression, which is one of the most consistently replicated findings of biological psychiatry (Stanley et al., 2000; Hou et al., 2006; Lidberg et al., 1984). Such findings along with the present results warrant further research on the functional role of the monoamine systems in the development of destructive – or pro-social – personality traits. Re-examination of older studies presenting data on the individual metabolites only is called for, as is the use of new methods to assess activity in the brain systems and their underlying chemical apparatus, such as genetic variants. 4.1. Limitations The present study investigating the relationship between BBB permeability, peripheral and central biomarkers and personality in patients undergoing non-neurological surgery, has several limitations. A limitation of all research on CSF is that, it is not fully possible to evaluate the exact relationship between the levels of substance studied at the site of synthesis in the brain and the lumbar area, where the samples are drawn (Reiber et al., 2001). The sample consisted of 21 non-neurologic, non-psychiatric patients undergoing knee arthroplastic surgery, a procedure that is mostly carried out in an older population. Thus, the present population was not a general population age-wise, had a high incidence of hypertension and diabetes mellitus, used several different medicines (although not on the day of surgery) and contained a relatively small number of subjects. Measures of subjective pain were not assessed in the present investigation; however, the effects of prevailing pain on the behavioural measures are an interesting aspect. To the best of our knowledge, there are no studies on the effects of chronic pain on outcome of the TCI, but Conrad et al. (2007) have investigated personality profiles and personality disorders in chronic pain patients using the TCI. Since chronic pain patients differ from the study population used in our study in several respects, including the definition of pain, conclusions regarding the present study population based on that previous study should thus be made with caution. The results from the Conrad et al. (2007) showed that chronic pain patients, compared with pain-free patients, scored higher on the Harm Avoidance temperament dimension and lower on the SelfDirectedness and Cooperativeness character dimensions. The correlations between biomarkers and personality measures were all based on data collected before the surgical procedure was initiated, and thus the effects of surgical medication were excluded. Little is known, however, about diurnal variations in CSF proteins and hormones in humans. However, there was a significant positive correlation between sampling time and CSF HVA concentrations and serum albumin levels. In addition, there was a negative correlation between sampling time and serum βTP level. 4.2. Conclusion Despite the limitations, the present study reveals interesting, significant correlations that, together with previous scientific support for the association between these biomarkers and personality dimensions in forensic psychiatric populations, call for further investigation. To verify the validity of the present findings, a study with high power and a representative sample consisting of healthy, younger volunteers is to be desired. In such an ideal study, serum and CSF sampling should be continuously
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made over 24 h to investigate the diurnal fluctuations in the considered biomarkers, as no such studies have yet been undertaken. In addition, one group of healthy volunteers would be subjected to a psychological stressor during the continuous CSF sampling, and both groups would have dimensions of personality and character assessed. This far, continuous CSF sampling has been conducted in healthy volunteers over a maximum of 6 h, at a rate of 0.1 ml min–1 (Geracioti et al., 1998), assessing the individual variations in 5-HIAA and HVA. Such an ideal study would provide knowledge about diurnal fluctuations of hormones and monoaminergic metabolites as well as insight into the response of these markers to stress. Furthermore, associations between such biomarkers and personality and character dimensions would be made clear and less influenced by confounders such as age and medical treatments due to age-related disorders. Psychopathic traits are problematic to define as they consist of heterogeneous behavioural patterns, interpersonal attitudes and emotional reactions. Scaling down personality traits to measurable units, as attempted by the personality scales used in this study, may be a crude way of defining very complex phenomena. It is, however, a step towards increased understanding of the neurobiological systems governing both normal and pathological behaviour. As such, the present study replicated some of the findings from forensic psychiatric population studies, confirming a relationship between personality traits related to psychopathology and neurochemical markers, in a general population-based sample. Acknowledgements The study was sponsored by The Swedish Research Council and ALF funding.
References Abbott, N.J., Ronnback, L., Hansson, E., 2006. Astrocyte-endothelial interactions at the blood-brain barrier. Nature Reviews Neuroscience 7, 41–53. Anckarsäter, H., Forsman, A., Blennow, K., 2005. Increased CSF/serum albumin ratio: a recurrent finding in violent offenders. Acta Neurologica Scandinavica 112, 48–50. Anckarsäter, R., Vasic, N., Jideus, L., Kristiansson, M., Zetterberg, H., Blennow, K., Anckarsäter, H., 2007a. Cerebrospinal fluid protein reactions during non-neurological surgery. Acta Neurologica Scandinavica 115, 254–259. Anckarsäter, R., Zetterberg, H., Blennow, K., Anckarsäter, H., 2007b. Association between thyroid hormone levels and monoaminergic neurotransmission during surgery. Psychoneuroendocrinology 32, 1138–1143. Arrer, E., Meco, C., Oberascher, G., Piotrowski, W., Albegger, K., Patsch, W., 2002. beta-Trace protein as a marker for cerebrospinal fluid rhinorrhea. Clinical Chemistry 48, 939–941. Asberg, M., Traskman, L., Thoren, P., 1976. 5-HIAA in the cerebrospinal fluid. A biochemical suicide predictor? Archives of General Psychiatry 33, 1193–1197. Axelsson, R., Martensson, E., Alling, C., 1982. Impairment of the blood-brain barrier as an aetiological factor in paranoid psychosis. British Journal of Psychiatry 141, 273–281. Bachmann, G., Petereit, H., Djenabi, U., Michel, O., 2002. Predictive values of beta-trace protein (prostaglandin D synthase) by use of laser-nephelometry assay for the identification of cerebrospinal fluid. Neurosurgery 50, 571–576 discussion 576-7. Bauer, K., Kornhuber, J., 1987. Blood-cerebrospinal fluid barrier in schizophrenic patients. European Archives of Psychiatry and Neurological Science 236, 257–259. Bayard-Burfield, L., Alling, C., Blennow, K., Jonsson, S., Traskman-Bendz, L., 1996. Impairment of the blood-CSF barrier in suicide attempters. European Neuropsychopharmacology 6, 195–199. Blennow, K., Wallin, A., Gottfries, C.G., Karlsson, I., Mansson, J.E., Skoog, I., Wikkelso, C., Svennerholm, L., 1993. Cerebrospinal fluid monoamine metabolites in 114 healthy individuals 18-88 years of age. European Neuropsychopharmacology 3, 55–61. Blodorn, B., Bruck, W., Tumani, H., Michel, U., Rieckmann, P., Althans, N., Mader, M., 1999. Expression of the beta-trace protein in human pachymeninx as revealed by in situ hybridization and immunocytochemistry. Journal of Neuroscience Research 57, 730–734. Borg, J., Andree, B., Soderstrom, H., Farde, L., 2003. The serotonin system and spiritual experiences. American Journal of Psychiatry 160, 1965–1969. Castellanos, F.X., Elia, J., Kruesi, M.J., Gulotta, C.S., Mefford, I.N., Potter, W.Z., Ritchie, G.F., Rapoport, J.L., 1994. Cerebrospinal fluid monoamine metabolites in boys with attention-deficit hyperactivity disorder. Psychiatry Research 52, 305–316. Cloninger, C.R., Svrakic, D.M., Przybeck, T.R., 1993. A psychobiological model of temperament and character. Archives of General Psychiatry 50, 975–990. Coccaro, E.F., Kavoussi, R.J., Cooper, T.B., Hauger, R.L., 1997. Central serotonin activity and aggression: inverse relationship with prolactin response to d-fenfluramine, but not CSF 5-HIAA concentration, in human subjects. American Journal of Psychiatry 154, 1430–1435.
529
Conrad, R., Schilling, G., Bausch, C., Nadstawek, J., Wartenberg, H.C., Wegener, I., Geiser, F., Imbierowicz, K., Liedtke, R., 2007. Temperament and character personality profiles and personality disorders in chronic pain patients. Pain 133, 197–209. Fitzgerald, S.P., Lamont, J.V., McConnell, R.I., Benchikh el, O., 2005. Development of a high-throughput automated analyzer using biochip array technology. Clinical Chemistry 51, 1165–1176. Gardner, D.L., Lucas, P.B., Cowdry, R.W., 1990. CSF metabolites in borderline personality disorder compared with normal controls. Biological Psychiatry 28, 247–254. Geracioti Jr., T.D., Keck Jr., P.E., Ekhator, N.N., West, S.A., Baker, D.G., Hill, K.K., Bruce, A.B., Wortman, M.D., 1998. Continuous covariability of dopamine and serotonin metabolites in human cerebrospinal fluid. Biological Psychiatry 44, 228–233. Hoffmann, A., Nimtz, M., Conradt, H.S., 1997. Molecular characterization of beta-trace protein in human serum and urine: a potential diagnostic marker for renal diseases. Glycobiology 7, 499–506. Hou, C., Jia, F., Liu, Y., Li, L., 2006. CSF serotonin, 5-hydroxyindolacetic acid and neuropeptide Y levels in severe major depressive disorder. Brain Research 1095, 154–158. Kanekiyo, T., Ban, T., Aritake, K., Huang, Z.L., Qu, W.M., Okazaki, I., Mohri, I., Murayama, S., Ozono, K., Taniike, M., Goto, Y., Urade, Y., 2007. Lipocalin-type prostaglandin D synthase/beta-trace is a major amyloid beta-chaperone in human cerebrospinal fluid. Proceedings of the National Academy of Sciences of the United States of America 104, 6412–6417. Lidberg, L., Asberg, M., Sundqvist-Stensman, U.B., 1984. 5-Hydroxyindoleacetic acid levels in attempted suicides who have killed their children. Lancet 2, 928. Lidberg, L., Tuck, J.R., Asberg, M., Scalia-Tomba, G.P., Bertilsson, L., 1985. Homicide, suicide and CSF 5-HIAA. Acta Psychiatrica Scandinavica 71, 230–236. Mase, M., Yamada, K., Shimazu, N., Seiki, K., Oda, H., Nakau, H., Inui, T., Li, W., Eguchi, N., Urade, Y., 2003. Lipocalin-type prostaglandin D synthase (beta-trace) in cerebrospinal fluid: a useful marker for the diagnosis of normal pressure hydrocephalus. Neuroscience Research 47, 455–459. Miwa, Y., Oda, H., Shiina, Y., Shikata, K., Tsushima, M., Nakano, S., Maruyama, T., Kyotani, S., Eguchi, N., Urade, Y., Takahashi-Yanaga, F., Morimoto, S., Sasaguri, T., 2008. Association of serum lipocalin-type prostaglandin D synthase levels with subclinical atherosclerosis in untreated asymptomatic subjects. Hypertension Research 31, 1931–1939. Nilsson, K.W., Damberg, M., Ohrvik, J., Leppert, J., Lindstrom, L., Anckarsäter, H., Oreland, L., 2007. Genes encoding for AP-2beta and the Serotonin Transporter are associated with the Personality Character Spiritual Acceptance. Neuroscience Letters 411, 233–237. Rapoport, S., 1976. Pathological alterations in the blood-brain barrier. In: Rapoport, S. (Ed.), Blood-brain Barrier in Physiology and Medicine. Raven Press, New York, pp. 131–133. Reiber, H., 2001. Dynamics of brain-derived proteins in cerebrospinal fluid. Clinica Chimica Acta 310, 173–186. Schalling, D., 1978. Psychopathy-related personality variables and the psychophysiology of socialization. In: Hare, R.D., Schalling, D. (Eds.), Psychopathic Behavior. Approaches to Research. John Wiley & Sons, Chichester, UK. Schalling, D., Asberg, M., Edman, G., Oreland, L., 1987. Markers for vulnerability to psychopathology: temperament traits associated with platelet MAO activity. Acta Psychiatrica Scandinavica 76, 172–182. Schell, C., Frungieri, M.B., Albrecht, M., Gonzalez-Calvar, S.I., Kohn, F.M., Calandra, R.S., Mayerhofer, A., 2007. A prostaglandin D2 system in the human testis. Fertility and Sterility 88, 233–236. Soderstrom, H., Forsman, A., 2004. Elevated triiodothyronine in psychopathy - possible physiological mechanisms. Journal of Neural Transmission 111, 739–744. Soderstrom, H., Blennow, K., Manhem, A., Forsman, A., 2001. CSF studies in violent offenders. II. Blood-brain barrier dysfunction without concurrent inflammation or structure degeneration. Journal of Neural Transmission 108, 879–886. Soderstrom, H., Blennow, K., Sjodin, A.K., Forsman, A., 2003. New evidence for an association between the CSF HVA:5-HIAA ratio and psychopathic traits. Journal of Neurology, Neurosurgery, and Psychiatry 74, 918–921. Stalenheim, E.G., 2004. Long-term validity of biological markers of psychopathy and criminal recidivism: follow-up 6-8 years after forensic psychiatric investigation. Psychiatry Research 121, 281–291. Stalenheim, E.G., von Knorring, L., Wide, L., 1998. Serum levels of thyroid hormones as biological markers in a Swedish forensic psychiatric population. Biological Psychiatry 43, 755–761. Stanley, B., Molcho, A., Stanley, M., Winchel, R., Gameroff, M.J., Parsons, B., Mann, J.J., 2000. Association of aggressive behavior with altered serotonergic function in patients who are not suicidal. American Journal of Psychiatry 157, 609–614. Tanaka, T., Urade, Y., Kimura, H., Eguchi, N., Nishikawa, A., Hayaishi, O., 1997. Lipocalintype prostaglandin D synthase (beta-trace) is a newly recognized type of retinoid transporter. Journal of Biological Chemistry 272, 15789–15795. Taniguchi, H., Mohri, I., Okabe-Arahori, H., Aritake, K., Wada, K., Kanekiyo, T., Narumiya, S., Nakayama, M., Ozono, K., Urade, Y., Taniike, M., 2007. Prostaglandin D2 protects neonatal mouse brain from hypoxic ischemic injury. Journal of Neuroscience 27, 4303–4312. Tibbling, G., Link, H., Ohman, S., 1977. Principles of albumin and IgG analyses in neurological disorders. I. Establishment of reference values. Scandinavian Journal of Clinical and Laboratory Investigation 37, 385–390. Tumani, H., Reiber, H., Nau, R., Prange, H.W., Kauffmann, K., Mader, M., Felgenhauer, K., 1998. Beta-trace protein concentration in cerebrospinal fluid is decreased in patients with bacterial meningitis. Neuroscience Letters 242, 5–8. Urade, Y., Hayaishi, O., 2000. Biochemical, structural, genetic, physiological, and pathophysiological features of lipocalin-type prostaglandin D synthase. Biochimica et Biophysica Acta 1482, 259–271.
530
T. Nilsson et al. / Psychiatry Research 178 (2010) 525–530
Urade, Y., Kitahama, K., Ohishi, H., Kaneko, T., Mizuno, N., Hayaishi, O., 1993. Dominant expression of mRNA for prostaglandin D synthase in leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. Proceedings of the National Academy of Sciences of the United States of America 90, 9070–9074. Virkkunen, M., Eggert, M., Rawlings, R., Linnoila, M., 1996. A prospective follow-up study of alcoholic violent offenders and fire setters. Archives of General Psychiatry 53, 523–529.
Watanabe, K., Urade, Y., Mader, M., Murphy, C., Hayaishi, O., 1994. Identification of betatrace as prostaglandin D synthase. Biochemical and Biophysical Research Communications 203, 1110–1116. White, D.M., Takeda, T., DeGroot, L.J., Stefansson, K., Arnason, B.G., 1997. Beta-trace gene expression is regulated by a core promoter and a distal thyroid hormone response element. Journal of Biological Chemistry 272, 14387–14393.