Neuroinflammation in psychiatric disorders: PET imaging and promising new targets

Summary

Neuroinflammation is a multifaceted physiological and pathophysiological response of the brain to injury and disease. Given imaging findings of 18 kDa translocator protein (TSPO) and the development of radioligands for other inflammatory targets, PET imaging of neuroinflammation is at a particularly promising stage. This Review critically evaluates PET imaging results of inflammation in psychiatric disorders, including major depressive disorder, schizophrenia and psychosis disorders, substance use, and obsessive-compulsive disorder. We also consider promising new targets that can be measured in the brain, such as monoamine oxidase B, cyclooxygenase-1 and cyclooxygenase-2, colony stimulating factor 1 receptor, and the purinergic P2X7 receptor. Thus far, the most compelling TSPO imaging results have arguably been found in major depressive disorder, for which consistent increases have been observed, and in schizophrenia and psychosis, for which patients show reduced TSPO levels. This pattern highlights the importance of validating brain biomarkers of neuroinflammation for each condition separately before moving on to patient stratification and treatment monitoring trials.

Introduction

PET imaging of neuroinflammation was applied first in neurological disorders and later in psychiatric disorders. In this context, neurological disorders, in which inflammation is an established pathological contributor, are ideal positive controls for assessing whether a new biomarker probe works in the human brain. For example, testing 18 kDa translocator protein (TSPO) as a biomarker of neuroinflammation in neurological disorders yielded promising results for Alzheimer's disease, which justified the extension of this probe to psychiatric disorders. Nevertheless, such an extension is associated with many hurdles.

Psychiatric disorders (eg, major depressive disorder and schizophrenia) are more heterogeneous than most neurological illnesses; that is, biological measurements of pathologies sampled from patients with specific diagnoses never completely separate from those of healthy controls and, because symptoms overlap across diagnoses, phenotypes are often shared. Moreover, large variability exists in the course of illness, in response to treatments, and, quite importantly, in the heterogeneous group of associated genetic polymorphisms. These factors probably explain why, to date, no biomarker has been found to fully separate individual patients with specific psychiatric diagnoses from healthy controls. In order to detect a significant difference in the mean of a phenotype measure—in this case, neuroinflammation—in moderately sized samples, the phenotype should be substantially different and reasonably common in the entire population with the disease. One advantage for such markers of more moderate effect sizes is that the prevalence of associated pathology is sufficient for these markers to stratify patients—in this case, as having high or low neuroinflammation—for subsequent studies or treatments. For instance, elevated TSPO binding has been observed in six of seven studies of unmedicated patients with major depressive disorder. By implication, anti-inflammatory treatments in patients with this disorder should preferentially improve symptoms in those patients with PET measures of inflammation at baseline. As will be described in this Review, a study found that elevated TSPO in unmedicated patients with major depressive disorder predicted response to celecoxib, a non-steroidal anti-inflammatory drug and selective inhibitor of cyclooxygenase (COX)-2.¹

Regardless of the advantages or disadvantages of TSPO as a biomarker, additional biomarkers of neuroinflammation are needed to reflect the wide range of proinflammatory and anti-inflammatory responses that occur in the brain. This Review will critically evaluate PET imaging results of inflammation in psychiatric disorders, including major depressive disorder, schizophrenia and psychosis, and obsessive-compulsive disorder, as well as in studies of substance use. These illnesses were chosen because they are common major diseases in which quantitative studies have been completed with reasonably high-quality radioligands. The Review will also assess several promising novel PET radioligands of neuroinflammation, including those for COX-1, COX-2, monoamine oxidase B (MAO-B), colony stimulating factor 1 receptor (CSF1R), and the purinergic P2X7 receptor (P2X7R; table 1).