A team of researchers that includes NARSAD 2012 Young Investigator Grantee, Christian Hammer, Ph.D., of Germany’s Max Planck Institute of Experimental Medicine, set out to investigate the prevalence and relevance of antibodies against the NMDA receptor (NMDAR) in psychiatric patients, particularly those with schizophrenia, associated with an illness described in 2007 as “anti-NMDAR encephalitis.” This disease is known to cause symptoms such as psychosis, epilepsy or cognitive decline.

Dr. Hammer and his colleagues show for the first time that NMDAR autoantibodies can be found in the blood of more than 10 percent of the population. They studied a sample of nearly 3,000 individuals, including patients with neuropsychiatric illness (schizophrenia, affective disorders and Parkinson’s disease) and healthy “controls.” Earlier studies involved generally fairly small numbers of patients. With this larger sample, the researchers were able to investigate the fundamental question of why these antibodies are sometimes linked to neuropsychiatric illness and sometimes are present in the blood of healthy individuals who stay healthy.

In a series of experiments using animal models, the researchers discovered that a dysfunction in the blood-brain barrier triggered the symptoms that can be caused by these antibodies. The blood-brain barrier in a healthy organism filters out pathogenic agents and toxins in the blood stream before they can enter the brain. In this case, the researchers found evidence that a disruption of this natural protective barrier in the animals with symptoms had enabled the NMDAR autoantibodies circulating in the blood to enter the brain. In humans, they found that people with a history of birth complications or neurotrauma, both of which affect the blood-brain barrier integrity, had more severe neurological symptoms, if antibodies also were present.

The researchers also investigated what causes these NMDA autoantibodies to be generated in the blood in the first place. They found a link with past influenza A or B infections and also, through a genome-wide association study, identified a genetic risk factor related to NMDAR biology.

This work highlights the importance of the integrity of the blood-brain barrier and how a disruption in the barrier can increase susceptibility to neuropsychiatric illness. Dr. Hammer says that the NARSAD Young Investigator Grant “was of major importance for the establishment of a large database, allowing the convergence of genetic, serological, and phenotypical data, which paved the way for the present study.”

Read the research paper abstract.