The hypothesis that viruses or other infectious agents may cause schizophrenia or bipolar disorder dates to the 19th century but has recently been revived. It could explain many clinical, genetic, and epidemiologic aspects of these diseases, including the winter-spring birth seasonality, regional differences, urban birth, household crowding, having an older sibling, and prenatal exposure to influenza as risk factors. It could also explain observed immunological changes such as abnormalities of lymphocytes, proteins, autoantibodies, and cytokines. However, direct studies of viral infections in individuals with these psychiatric diseases have been predominantly negative. Most studies have examined antibodies in blood or cerebrospinal fluid, and relatively few studies have been done on viral antigens, genomes, cytopathic effect on cell culture, and animal transmission experiments. Viral research on schizophrenia and bipolar disorder is thus comparable to viral research on multiple sclerosis and Parkinson9s disease: an attractive hypothesis with scattered interesting findings but no clear proof. The application of molecular biological techniques may allow the identification of novel infectious agents and the associations of these novel agents with serious mental diseases.

Viruses, schizophrenia, and bipolar disorder.

Autism spectrum disorders (ASD) are complex conditions whose pathogenesis may be attributed to gene–environment interactions. There are no definitive mechanisms explaining how environmental triggers can lead to ASD although the involvement of inflammation and immunity has been suggested. Inappropriate antigen trafficking through an impaired intestinal barrier, followed by passage of these antigens or immune-activated complexes through a permissive blood–brain barrier (BBB), can be part of the chain of events leading to these disorders. Our goal was to investigate whether an altered BBB and gut permeability is part of the pathophysiology of ASD. Postmortem cerebral cortex and cerebellum tissues from ASD, schizophrenia (SCZ), and healthy subjects (HC) and duodenal biopsies from ASD and HC were analyzed for gene and protein expression profiles. Tight junctions and other key molecules associated with the neurovascular unit integrity and function and neuroinflammation were investigated. Claudin (CLDN)-5 and -12 were increased in the ASD cortex and cerebellum. CLDN-3, tricellulin, and MMP-9 were higher in the ASD cortex. IL-8, tPA, and IBA-1 were downregulated in SCZ cortex; IL-1b was increased in the SCZ cerebellum. Differences between SCZ and ASD were observed for most of the genes analyzed in both brain areas. CLDN-5 protein was increased in ASD cortex and cerebellum, while CLDN-12 appeared reduced in both ASD and SCZ cortexes. In the intestine, 75% of the ASD samples analyzed had reduced expression of barrier-forming TJ components (CLDN-1, OCLN, TRIC), whereas 66% had increased pore-forming CLDNs (CLDN-2, -10, -15) compared to controls. In the ASD brain, there is an altered expression of genes associated with BBB integrity coupled with increased neuroinflammation and possibly impaired gut barrier integrity. While these findings seem to be specific for ASD, the possibility of more distinct SCZ subgroups should be explored with additional studies.

https://link.springer.com/content/pdf/10.1186%2Fs13229-016-0110-z.pdf

Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders.

Peripheral blood C-reactive protein (CRP) is a biomarker used clinically to measure systemic inflammation and is reproducibly increased in a subset of patients with major depressive disorder (MDD). Furthermore, increased peripheral blood CRP in MDD has been associated with altered reward circuitry and increased brain glutamate in relation with symptoms of anhedonia. Nevertheless, the relationship between peripheral CRP and other peripheral and central markers of inflammation in depressed patients has not been established. Plasma (n = 89) and CSF (n = 73) was collected from medically stable, currently unmedicated adult outpatients with MDD. Associations among plasma and CSF CRP and plasma and CSF inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor [TNF] and IL-1beta) and their soluble receptors/antagonists were examined. Relationships between plasma and CSF inflammatory markers and depressive symptoms including anhedonia and reduced motivation (RM) were also explored. Plasma CRP was correlated with multiple plasma inflammatory markers (all p  3 mg/L) and correlated with depressive symptom severity. These findings were driven by CSF TNF, which correlated with RM (r = 0.236, p = 0.045), and CSF IL-6 soluble receptor, which correlated with anhedonia (r = 0.301, p = 0.010) in the sample as a whole and particularly females. CRP appears to be a peripheral biomarker that reflects peripheral and central inflammation and seems well-suited for guiding immunotherapies targeting TNF and IL-6 in patients with MDD.

What does plasma CRP tell us about peripheral and central inflammation in depression

The causes of most neurological disorders are not fully understood. Inflammation and blood-brain barrier dysfunction appear to play major roles in the pathology of these diseases. Inflammatory insults that occur during brain development may have widespread effects later in life for a spectrum of neurological disorders. In this review, a new hypothesis suggesting a mechanistic link between inflammation and blood-brain barrier function (integrity), which is universally important in both neurodevelopmental and neurodegenerative diseases, is proposed. The role of inflammation and the blood-brain barrier will be discussed in cerebral palsy, schizophrenia, Parkinson's disease, Alzheimer's disease and multiple sclerosis, conditions where both inflammation and blood-brain barrier dysfunction occur either during initiation and/or progression of the disease. We suggest that breakdown of normal blood-brain barrier function resulting in a short-lasting influx of blood-born molecules, in particular plasma proteins, may cause local damage, such as reduction of brain white matter observed in some newborn babies, but may also be the mechanism behind some neurodegenerative diseases related to underlying brain damage and long-term changes in barrier properties.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2990.2008.01005.x

Review: Role of developmental inflammation and blood-brain barrier dysfunction in neurodevelopmental and neurodegenerative diseases.

The focus of schizophrenia research has been turning from studies of structural and functional brain abnormalities to an increasing emphasis on possible etiologic factors. One etiologic hypothesis is that schizophrenia is the result of an infection (especially by a virus) or of an autoimmune reaction (perhaps following an infection) against central nervous system (CNS) tissue. Indirect evidence supporting this hypothesis includes possible geographic variance in the prevalence of schizophrenia, a season-of-birth effect, and observed associations between schizophrenia and prenatal exposure to viral epidemics. Several studies of cell-based and humoral immunity, as well as studies of cytokines, have indicated abnormalities in the immune function of schizophrenia patients, but many of these findings have not been replicated consistently. In addition, most observed alterations in immune function have been modest in degree and nonspecific. Attempts to identify a specific infectious agent or an antibody directed against CNS tissue have not produced a consistently replicable finding. In summary, no research evidence to date irrefutably indicates an infectious or autoimmune etiologic process in schizophrenia. It is probably unreasonable, however, to view schizophrenia as having a single cause. It is much more likely to be a heterogeneous disorder resulting from interactions between multiple factors, including the person's genetic endowment and various environmental influences. Infectious agents or CNS autoantibodies may well be among these environmental variables. A major current emphasis is on studying potential interactions between exposure to an infection or an autoimmune response and key early phases of brain development. A corresponding priority in the research agenda will be the development of animal models of CNS development that might elucidate the pathogenic mechanisms of such an interaction.

/pdf/infection-and-autoimmunity-as-etiologic-factors-in-57fe01ujlm.pdf

Infection and Autoimmunity as Etiologic Factors in Schizophrenia: A Review and Reappraisal

The ratio of albumin in cerebrospinal fluid (CSF) to serum may serve as an index of the integrity of the blood-CSF barrier, with increases in this ratio indicating increased permeability. The ratio of immunoglobulin G (IgG) in CSF to serum (divided by the albumin ratio to correct for variance in blood-CSF permeability) represents an index of the endogenous production of IgG in the central nervous system (CNS), with increases reflecting a possible infectious and/or autoimmune process stimulating central IgG synthesis. We analyzed simultaneously collected CSF and serum samples from 46 schizophrenic subjects, 8 of whom were studied both on and off neuroleptic treatment, and samples from 20 normal controls. The data indicated increases in CSF/ serum albumin ratios or CSF/serum IgG indices in 22% and 20%, respectively, of the schizophrenic patients. Only 3 patients showed elevations in both indices. Comparison of values on and off neuroleptics indicated no significant effect of neuroleptics on these indices.

D. G. Kirch

Papers

Blood-CSF barrier permeability and central nervous system immunoglobulin G in schizophrenia