Cerebrospinal fluid biomarkers in twins with schizophrenia and bipolar disorder

Previously identified cerebrospinal fluid (CSF) biomarkers were studied in 37 twins with schizophrenia or bipolar disorder to determine their genetic and environmental properties. Further, comorbidities and sibling risks were investigated in patients with schizophrenia (n=22,781), bipolar disorder (n=30,761) and depression (n=172,479) in relation to multiple sclerosis (MS) (n=16,467) in a nationwide cohort.

In Study I, CSF was analyzed using scanning electron microscopy in twins with schizophrenia and bipolar disorder to identify microscopic structures that had previously been established in patients with schizophrenia and bipolar disorder. Microscopic structures were found not only in the patients but also in the non-affected twin siblings to a higher degree than in healthy controls. The results indicate that genetic and shared environmental mechanisms might be involved in the development of CSF structures.

Study II was a case series in which microparticles were studied in the CSF of healthy controls and in patients with schizophrenia. Microparticles may be indicative of stressinduced cell activation. In the patients with schizophrenia microparticles that originated from leukocyte and endothelial cells were accumulated in higher levels as compared with the healthy controls.

In Study III, immune and amyloid biomarkers previously associated with psychotic disorders were analyzed in the CSF of twins. Soluble cluster of differentiation 14 (sCD14), a protein expressed by microglia in the central nervous system, was found to highly correlate within monozygotic twins. In the co-twin control analysis higher levels were observed in patients with schizophrenia and bipolar disorder compared with the nonaffected co-twins. sCD14 was also associated with negative psychotic symptoms and schizotypal and paranoid personality traits. The results strengthen previous findings of microglia activation in psychotic disorders.

In Study IV, tryptophan metabolites and cytokines were analyzed in twins with schizophrenia and bipolar disorder. None of the substances correlated within the monozygotic twin pairs, which indicates the influence of environmental factors. Kynurenic and quinolinic acid were shown to be associated with schizotypal personality traits, strengthening previous results of an association between the tryptophan metabolites and psychosis.

In Study V, comorbidity between the neuroinflammatory disorder MS and schizophrenia, bipolar disorder and depression was analyzed in a nationwide cohort. Consistent with previous studies an increased MS risk was noted in patients with bipolar disorder and depression. An increased MS risk was also found in males with a diagnosis of bipolar disorder and previous manic episodes. Decreased MS risk was seen in patients with schizophrenia. No change in MS risk was detected in the siblings to patients with schizophrenia, bipolar disorder and depression. Possible inflammatory mechanisms may account for the comorbidity between affective disorders and MS, whereas the protective effect of schizophrenia on MS risk remains to be further investigated.

Biomarker analysis in CSF using twin methodology revealed some promising findings for future biomarker studies. However, larger twin cohorts are desirable for conclusive confirmation. The potential mechanisms underlying the associations between MS and psychiatric disorders require further study.

List of scientific papers

I. VIKTORIA JOHANSSON, Rolf Nybom, Lennart Wetterberg, Christina M Hultman, Tyrone D Cannon, Anette G Johansson, Carl-Johan Ekman, Mikael Landén. Microscopic particles in two fractions of fresh cerebrospinal fluid in twins with schizophrenia or bipolar disorder and in healthy controls. PLoS One, 2012. 7(9): p. e45994.
https://doi.org/10.1371/journal.pone.0045994

II. Fariborz Mobarrez, Rolf Nybom, VIKTORIA JOHANSSON, Christina M Hultman, Håkan Wallén, Mikael Landén, Lennart Wetterberg. Microparticles and microscopic structures in three fractions of fresh cerebrospinal fluid in schizophrenia: Case report of twins. Schizophr Res, 2013. 143(1): p. 192-7.
https://doi.org/10.1016/j.schres.2012.10.030

III. VIKTORIA JOHANSSON, Joel Jakobsson, Becky Fortgang, Tyrone D Cannon, Lennart Wetterberg, Christina Hultman, Mikael Landén. Cerebrospinal fluid microglia and amyloid biomarkers in twins concordant or discordant for psychotic disorders. [Manuscript]

IV. Magdalena Kegel, VIKTORIA JOHANSSON, Lennart Wetterberg, Maria Bhat, Lilly Schwieler, Tyrone D Cannon, Ina Schuppe-Koistinen, Göran Engberg, Mikael Landén, Christina M. Hultman, Sophie Erhardt. Association between kynurenic acid and schizotypal personality traits in twin pairs with psychiatric morbidity. [Manuscript]

V. VIKTORIA JOHANSSON, Cecilia Lundholm, Jan Hillert, Tomas Masterman, Paul Lichtenstein, Mikael Landén, Christina M Hultman. Multiple sclerosis and psychiatric disorders: comorbidity and sibling risk in a nationwide Swedish cohort. Mult Scler, 2014. 20(14): p. 1881-91.
https://doi.org/10.1177/1352458514540970