Cerebrospinal fluid microglia and neurodegenerative markers in twins concordant and discordant for psychotic disorders

Viktoria Johansson,Christina M Hultman,Joel Jakobsson,Henrik Zetterberg,Rebecca G Fortgang,Tyrone D Cannon,Mikael Landén,Kaj Blennow,Lennart Wetterberg

doi:10.1007/s00406-016-0759-5

Abstract

Schizophrenia and bipolar disorder are debilitating psychiatric disorders with partially shared symptomatology including psychotic symptoms and cognitive impairment. Aberrant levels of microglia and neurodegenerative cerebrospinal fluid (CSF) markers have previously been found in schizophrenia and bipolar disorder. We aimed to analyze familial and environmental influences on these CSF markers and their relation to psychiatric symptoms and cognitive ability. CSF was collected from 17 complete twin pairs, nine monozygotic and eight dizygotic, and from one twin sibling. Two pairs were concordant for schizophrenia, and 11 pairs discordant for schizophrenia, schizoaffective disorder or bipolar disorder, and four pairs were not affected by psychotic disorders. Markers of microglia activation [monocyte chemoattractant protein-1 (MCP-1), chitinase 3-like protein 1 (YKL-40), and soluble cluster of differentiation 14 (sCD14)], markers of β-amyloid metabolism (AβX-38, AβX-40, AβX-42 and Aβ1-42), soluble amyloid precursor proteins (sAPP-α and sAPP-β), total tau (T-tau), phosphorylated tau (P-tau), and CSF/serum albumin ratio were measured in CSF using immunoassays. Heritability of the CSF markers was estimated, and associations to psychiatric and cognitive measurements were analyzed. Heritability estimates of the microglia markers were moderate, whereas several neurodegenerative markers showed high heritability. In contrast, AβX-42, Aβ1-42, P-tau and CSF/serum albumin ratio were influenced by dominant genetic variation. Higher sCD14 levels were found in twins with schizophrenia or bipolar disorder compared to their not affected co-twins, and higher sCD14-levels were associated with psychotic symptoms. The study provides support for a significant role of sCD14 in psychotic disorders and a possible role of microglia activation in psychosis.

Highlights

Bipolar disorder and schizophrenia are serious psychotic disorders associated with severe symptomatology and functional impairment
Eleven of the pairs were discordant for schizophrenia, schizoaffective disorder, or bipolar disorder
The additive genetic effects on the microglia markers soluble form of Cluster of differentiation 14 protein (CD14) (sCD14) and YKL-40 were moderate, while MCP-1 was entirely driven by environmental effects

Summary

Introduction

Bipolar disorder and schizophrenia are serious psychotic disorders associated with severe symptomatology and functional impairment. In the 1990s, it was proposed that chronically activated macrophages produce compounds such as proinflammatory cytokines, which predisposes the brain for developing schizophrenia and mood disorders [13, 15, 16]. This hypothesis has produced a number of studies on inflammatory mechanisms in psychiatric disorders. Recent studies found that the soluble form of CD14 (sCD14) was higher in plasma from patients with schizophrenia [18] and bipolar disorder compared with controls [19]. Another study using blood-derived monocytes from patients with bipolar disorder and controls found higher expression of inflammatory related genes in patients compared with controls [20]

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