Neuroinflammation in psychiatric disorders: PET imaging and promising new targets

Abstract

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.

Figure 1:. Stratification of patients using TSPO imaging for putative anti-inflammatory treatments

To stratify patients during the development of candidate antidepressants that modulate neuroinflammation, the methods that can be applied are either PET imaging to establish TSPO distribution volume in regions participating in mood regulation, such as the PFC or ACC, or low-cost surrogate serum markers. The graph represents the frequency of cases for different levels of TSPO binding. In contrast to cases with low TSPO binding (green), cases with high TSPO binding (red) are more likely to have gliosis and would be anticipated to have greater reduction in symptoms after anti-inflammatory medication, as shown in a recent open trial of celecoxib. Examples of surrogate serum markers could include ln(prostaglandin E2/CRP) and ln(TNFα/CRP), which were shown to be predictive of TSPO V_T in the PFC and ACC in individuals experiencing MDEs. ACC=anterior cingulate cortex. MDE=major depressive episode. PFC=prefrontal cortex. TSPO=18 kDa translocator protein. V_T distribution volume.

Figure 2:. Standardised differences in total V_T between patients with psychosis and healthy controls

TSPO V_T values of all individual patients with psychosis and healthy controls. A linear mixed-effects model, with varying intercepts and slopes for all included studies with genotype as covariate, yielded effect sizes of −0·41 (p=0·0022) for the frontal cortex, −0·38 (p=0·048) for the temporal cortex, and −0·53 (p=0·0001) for the hippocampus. The data have been standardised within genotype and study, with a mean of 0 and SD of 1, to allow for visualisation of compiled data obtained with different radioligands. Controls=healthy controls. Patients=patients with psychosis. TSPO=18 kDa translocator protein. V_T=distribution volume.

Figure 3:. Constitutive expression of COX-1 in healthy human brain

Parametric total V_T images of [¹¹C]PS13, a selective radioligand for COX-1, in healthy humans. MRI scans are from a representative participant, and PET images are averaged from 20 scans in ten participants. The third row depicts fusion images created from MRI and PET. Arrows represent notable [¹¹C]PS13 binding in the pericentral cortex, occipital cortex, and hippocampus. Reproduced from Kim et al. COX-1=cyclooxygenase-1. V_T= distribution volume.

Figure 4:. Inflammation-induced upregulation of COX-2

[¹¹C]MC1 PET images showing COX-2 binding in a monkey brain with lipopolysaccharide-induced neuroinflammation (A), and in hands of patients with rheumatoid arthritis and healthy controls (B). Parametric V_T images are shown before lipopolysaccharide injection (top row), on day 1 after a repeated lipopolysaccharide injection (middle row), and after blockade by cold MC1 (1 mg/kg intravenously; bottom row). Orthogonal crosshairs show the injected putamen. [¹⁸C]MC1 uptake was markedly increased near the injection site after lipopolysaccharide injection. Cold MC1 blocked radioligand binding to COX-2 to a lower extent near the injection site than in the remainder of brain. Because this dose of MC1 achieved almost complete blockade (ie, 75%), the residual uptake closely reflected V_ND. Thus, V_ND in the area of the lesion was reduced to less than that of normal brain, which was caused by a delayed haemorrhage between the repeated lipopolysaccharide injections. (B) Increased [¹¹C]MC1 uptake in the bilateral hand joints (marked by arrows) reflected increased COX-2 binding in a patient with rheumatoid arthritis compared with a healthy control. The increased uptake in the patient was partially blocked (ie, the uptake was not reduced to that in controls) by celecoxib (400 mg orally, administered 2 h before the blocked scan). Adapted from Shrestha et al. COX-2=cyclooxygenase-2. LPS=lipopolysaccharide. V_ND=non-displaceable distribution volume. V_T=distribution volume.

Figure 5:. CSF1R PET images in a baboon

Parametric V_T images of [¹¹C]CPPC PET in baboon in baseline, lipopolysaccharide, and lipopolysaccharide-plus-block experiments. The lipopolysaccharide dose was 0·05 mg/kg (intravenously), given 4 h before radiotracer injection. Lipopolysaccharide treatment increased V_T of [¹¹C]CPPC, whereas lipopolysaccharide-plus-block treatment reduced V_T to baseline levels. Adapted from Horti et al. CSF1R= colony stimulating factor 1 receptor. LPS=lipopolysaccharide. V_T=distribution volume.