PET Reveals Inflammatory Response in Schizophrenia, High-Risk Patients

Microglial activity—indicative of an immune response to neuroinflammation—appears to be elevated in people with schizophrenia and in subjects with subclinical symptoms who are at ultra-high risk of psychosis, according to a landmark study published online October 16 in the American Journal of Psychiatry. Moreover, the elevated microglial activity appears to be related to symptom severity.

“This study is the first to use PET methods to image the microglial cells in the living human brain,” AJP Editor Robert Freedman, M.D., told Psychiatric News. “How they became activated and what they are doing is unknown, but the presumption from their presence in the brain is that they may be attacking the nerve cells themselves.”

Researchers from several institutions in England and Italy forming the Psychiatric Imaging Group used positron emission tomography (PET) to measure in vivo microglial activity in patients with schizophrenia, high-risk individuals with pre-clinical symptoms, and healthy controls. (Microglial cells are the immune cells of the brain and are similar to immune-responsive macrophages in the blood; their presence in large numbers indicates inflammation.) The PET method employed a radioactive tracer specific for a protein (known as 18kD translocator-protein, or TSPO) that is indicative of microglial activity.

A total of 56 participants completed the study, including 14 people who met ultra-high risk criteria, as measured on the Comprehensive Assessment of the At-Risk Mental State (CAARMS), and 14 age-matched controls; an additional 14 people with schizophrenia and 14 age-matched healthy controls also participated in the trial.

The main outcome measure for the study was evidence of TSPO binding in total gray matter.

The authors found that the protein binding ratio in gray matter was elevated in ultra-high risk subjects compared with matched controls and was positively correlated with symptom severity. Patients with schizophrenia also demonstrated elevated microglial activity with respect to matched controls.

Importantly, the researchers found no relationship between depressive symptom severity and the protein binding ratio in gray matter in patients with schizophrenia or ultra-high-risk participants, suggesting the elevated microglial activity is specific to the development of psychotic-like symptoms, rather than psychiatric symptoms in general.

Also of note—at the time the paper was written, one of the participants who was at ultra-high risk of psychosis transitioned to first episode psychosis, and this participant had the highest total gray matter protein binding in the cohort.

“These findings are consistent with increasing evidence that that there is a neuroinflammatory component in the development of psychotic disorders, raising the possibility that it plays a role in its pathogenesis,” the authors stated. “Anti-inflammatory treatment may be effective in preventing the onset of the disorder [but] further studies are required to determine the clinical significance of elevated microglial activity.”

According to Freedman, both the findings from the study and the application of the PET method to image pathophysiological processes in the brain may prove transformative.

“The study found microglial cells elevated in young adults who have symptoms associated with the increased risk for schizophrenia, as well as in patients who already have schizophrenia. This paper thus may provide the first demonstration of an inflammatory process that is part of the transition into schizophrenia,” he said.

“The PET method now gives clinical researchers an invaluable tool, not before available, to monitor this transition and to search for what might be causing the inflammation,” he continued. “If anti-inflammatory interventions are attempted, then this method can assess whether the intervention has its intended effect.”

Freedman said a similar PET technique revolutionized the early detection of beta-amyloid early in the development of Alzheimer’s disease, and the technique holds the promise of similar early detection of pathophysiological processes associated with schizophrenia.

This work was funded by the Medical Research Council and King’s College London. ■