PET imaging of putative microglial activation in individuals at ultra-high risk for psychosis, recently diagnosed and chronically ill with schizophrenia

Abstract

We examined putative microglial activation as a function of illness course in schizophrenia. Microglial activity was quantified using [11C](R)-(1-[2-chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide (11C-(R)-PK11195) positron emission tomography (PET) in: (i) 10 individuals at ultra-high risk (UHR) of psychosis; (ii) 18 patients recently diagnosed with schizophrenia; (iii) 15 patients chronically ill with schizophrenia; and, (iv) 27 age-matched healthy controls. Regional-binding potential (BPND) was calculated using the simplified reference-tissue model with four alternative reference inputs. The UHR, recent-onset and chronic patient groups were compared to age-matched healthy control groups to examine between-group BPND differences in 6 regions: dorsal frontal, orbital frontal, anterior cingulate, medial temporal, thalamus and insula. Correlation analysis tested for BPND associations with gray matter volume, peripheral cytokines and clinical variables. The null hypothesis of equality in BPND between patients (UHR, recent-onset and chronic) and respective healthy control groups (younger and older) was not rejected for any group comparison or region. Across all subjects, BPND was positively correlated to age in the thalamus (r=0.43, P=0.008, false discovery rate). No correlations with regional gray matter, peripheral cytokine levels or clinical symptoms were detected. We therefore found no evidence of microglial activation in groups of individuals at high risk, recently diagnosed or chronically ill with schizophrenia. While the possibility of 11C-(R)-PK11195-binding differences in certain patient subgroups remains, the patient cohorts in our study, who also displayed normal peripheral cytokine profiles, do not substantiate the assumption of microglial activation in schizophrenia as a regular and defining feature, as measured by 11C-(R)-PK11195 BPND.

TSPO expression and brain structure in the psychosis spectrum

“…We found no significant group effect on [ 18 F]FEPPA V T which is in line with five previous studies that examined TSPO expression in psychosis using second generation TSPO radioligands and V T as outcome measure 9–12, 14, 20 and also two other studies that used [ 11 C]PK11195 13, 15 . A recent study, however, reported a significantly lower TSPO expression in first-episode psychosis as compared to healthy volunteer using [ 11 C]PBR28 16 .…”

“…Upon activation, microglia increase the expression of 18kDa translocator protein (TSPO), in their mitochondria, making TSPO a target for positron emission tomography (PET) imaging studies. The majority of PET studies that investigated TSPO expression in psychosis thus far reported no significant group effect 9–15 ; one found reduced TSPO expression in first-episode psychosis patients 16 , and four reported elevated TSPO expression in schizophrenia patients or individuals at high risk for psychosis 17–20 . Three of the latter studies, however, used the first-generation radioligand for TSPO, [ 11 C]PK11195, which is known to have several limitations including low signal-to-noise ratio and brain penetration 17–19 ; while the Bloomfield and colleagues study used distribution volume ratio (instead of total volume of distribution) as outcome measure which presents important limitations for data interpretation 21 .…”

Positron Emission Tomography Studies of the Glial Cell Marker Translocator Protein in Patients With Psychosis: A Meta-analysis Using Individual Participant Data

“…Early reports using the first-generation TSPO radioligand (R)-[ 11 C]PK11195 showed higher binding in small patient groups (n = 7 and n = 10) (10,11), albeit with outcome measures that show low accuracy and reliability (i.e., binding potential estimated from rate constants) (12)(13)(14). More recent studies in larger samples using the same radioligand, but without blood sampling for full quantification, did not replicate these findings (15)(16)(17). Concerns regarding the low signal-to-noise ratio of (R)-[ 11 C]PK11195 sparked the development of a series of second-generation TSPO radioligands, showing much greater specific binding (18)(19)(20)(21).…”

PET studies of the glial cell marker TSPO in psychosis patients - a meta-analysis using individual participant data

“…binding potential estimated from rate constants) (12)(13)(14). More recent studies in larger samples using the same radioligand, but without blood sampling for full quantification, did not replicate these findings (15)(16)(17).…”