Central nervous system autoimmunity and infectious exposures in the early phases of psychosis

Student thesis: Doctoral ThesisDoctor of Clinical Psychology


Introduction: Neuronal surface autoantibodies (NSAbs) such as those targeting the NMDA receptor (NMDAR) were originally described in association with autoimmune encephalopathies which initially present with psychosis, usually alongside multiple neurological features. NSAbs might also contribute to the onset of illness in a subgroup of patients with psychotic disorders, and while they are evident in a proportion of patients at the first episode of psychosis, different antibody testing methods appear to give rise to different estimates of seroprevalence in psychiatric patient groups and in healthy controls. Furthermore, it is not known if NSAbs are present prior to illness onset, whether they occur as a sequel to infection and whether they associate with presenting symptomatology or with clinical outcomes. 
Methods: Sera from a) a cohort of 254 subjects at clinical high risk (CHR) for psychosis; b) a cohort of 398 first episode psychosis (FEP) patients and c) 116 healthy volunteers were tested for neuronal autoantibodies targeting multiple antigens, using a combination of fixed and live cell-based assays (CBAs), immunohistochemistry using fixed brain slices and immunocytochemistry using live cultured hippocampal neurons. Antibodies to common infectious pathogens were also measured in the CHR cohort. I compared the prevalence of these antibodies between groups, and examined their relationship to psychopathology, cognitive function, inflammatory markers and MRI measures. Antibody detection techniques were compared to establish if different methods detected different seroprevalence rates in cases and controls. 
Results: Seroprevalence of NSAbs did not differ between cases and controls, regardless of the assay used. Nevertheless, within the CHR sample, NMDAR antibody seropositive subjects had more severe affective and catatonic symptoms and poorer cognitive function than seronegative subjects. Interactions between the presence of NSAbs and the level of S100B, a marker of blood brain barrier (BBB) integrity, were found such that in patients with high BBB permeability, seropositivity for NSAbs was associated with more severe psychopathology across multiple domains and with larger volume of limbic structures. NSAbs did not predict transition to psychosis over two years in CHR subjects. In FEP subjects, NMDAR antibodies associated with shorter duration of psychosis and, unexpectedly, a better response to antipsychotic treatment. Live CBA consistently detected greater NSAb seropositivity rates than fixed CBA and appeared to detect antibodies which had more clinically relevant associations. GABAA receptor antibodies showed no useful clinical associations in these psychiatric cohorts. 
Toxoplasma exposure in CHR subjects was associated with more severe negative symptoms and poorer functional outcomes. Epstein-Barr Virus was associated with reduced risk of being at CHR for psychosis, reduced rates of transition to psychosis and better functional outcomes. NMDAR autoantibody seropositivity was associated with measures of exposure to Toxoplasma and influenza. 
Conclusion: Serum neuronal autoantibodies – and NMDAR antibodies in particular – are detectable at appreciable rates in early psychosis and appear to be associated with psychopathological, cognitive, and neuroanatomical abnormalities, particularly before the onset of frank psychosis. The pattern of findings in CHR subjects is qualitatively similar to that in autoimmune encephalitis, consistent with the notion than in a minority of patients with psychosis, the onset of illness may be related to autoantibodies to CNS antigens, and that they may have a useful biomarker role. Exposure to infectious pathogens is associated with clinical status and outcome in individuals at CHR for psychosis, and may in some cases be a trigger for autoimmunity in these individuals. These studies raise the exciting possibility of future targeted therapeutic or even preventative interventions focusing on either autoimmunity, infection or both at the earliest phases of psychotic illness.
Date of Award1 May 2019
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorPhilip McGuire (Supervisor), Anthony David (Supervisor) & James Stone (Supervisor)

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