[11C]PBR28 MR–PET imaging reveals lower regional brain expression of translocator protein (TSPO) in young adult males with autism spectrum disorder

Abstract

Mechanisms of neuroimmune and mitochondrial dysfunction have been repeatedly implicated in autism spectrum disorder (ASD). To examine these mechanisms in ASD individuals, we measured the in vivo expression of the 18 kDa translocator protein (TSPO), an activated glial marker expressed on mitochondrial membranes. Participants underwent scanning on a simultaneous magnetic resonance-positron emission tomography (MR-PET) scanner with the second-generation TSPO radiotracer [ 11 C]PBR28. By comparing TSPO in 15 young adult males with ASD with 18 age-and sex-matched controls, we showed that individuals with ASD exhibited lower regional TSPO expression in several brain regions, including the bilateral insular cortex, bilateral precuneus/posterior cingulate cortex, and bilateral temporal, angular, and supramarginal gyri, which have previously been implicated in autism in functional MR imaging studies. No brain region exhibited higher regional TSPO expression in the ASD group compared with the control group. A subset of participants underwent a second MR-PET scan after a median interscan interval of 3.6 months, and we determined that TSPO expression over this period of time was stable and replicable. Furthermore, voxelwise analysis confirmed lower regional TSPO expression in ASD at this later time point. Lower TSPO expression in ASD could reflect abnormalities in neuroimmune processes or mitochondrial dysfunction.

[ 11 C]PK11195-PET Brain Imaging of the Mitochondrial Translocator Protein in Mitochondrial Disease

“… 16 - 18 Although this is probably valid for CNS disorders where the primary disease process is related to inflammation, TSPO abundance and radiotracer binding are likely to be differentially affected in many other noninflammatory conditions. 19 In particular, a decrease in radiotracer binding, as previously observed in autism spectrum disorder, 20 schizophrenia, 31 or inactive multiple sclerosis lesions, 32 is more difficult to reconcile with microglial activity or inflammation. Given its localization to mitochondria in all cell types of the CNS, 15 it is conceivable that TSPO abundance in the brain is affected by pathologic changes associated with mitochondrial disease.…”

“…[ 11 C]PK11195 positron emission tomography (PET) imaging of TSPO has mainly been used as a marker of neuro-inflammation and microglial activation, based on strong radiotracer accumulation in ischemic and inflammatory brain lesions [16][17][18] . However, it is increasingly appreciated that TSPO ligand binding as a measurement of microglial activation is an oversimplification, and altered TSPO abundance is likely affected by many other diseasespecific processes 19,20 . Given its localization to mitochondria [13][14][15] , we sought to explore the utility of [ 11 C]PK11195 PET imaging of TSPO as an in vivo biomarker of mitochondrial pathology in the brain, with a view to monitoring progression of mitochondrial disease.…”

“… 16 - 18 However, it is increasingly appreciated that TSPO ligand binding as a measurement of microglial activation is an oversimplification, and altered TSPO abundance is likely affected by many other disease-specific processes. 19 , 20 Given its localization to mitochondria, 13 - 15 we sought to explore the utility of [ 11 C]PK11195 PET imaging of TSPO as an in vivo biomarker of mitochondrial pathology in the brain, with a view to monitoring progression of mitochondrial disease.…”

A simultaneous [11C]raclopride positron emission tomography and functional magnetic resonance imaging investigation of striatal dopamine binding in autism

“…This study was also restricted to participants with higher cognitive abilities and may not represent the broader ASD population. In this regard, we have established PET-MR protocols for adults with ASD with lower intellectual functioning 80 and recently completed a PET-MR study that included individuals with ASD with full-scale IQs ranging from 47 to 112 81 . Finally, two results should be interpreted with caution until replicated: (1) a cluster in the right caudate nucleus showed increased phasic DA release to rewards in the ASD group, a finding that was unexpected and in the opposite direction of other striatal PET clusters; and (2) the relations between phasic DA release in the left and right putamen, and performance on the theory-of-mind measure were only significant at an uncorrected threshold.…”

A Simultaneous [11C]Raclopride Positron Emission Tomography and Functional Magnetic Resonance Imaging Investigation of Striatal Dopamine Binding in Autism

“…This study was also restricted to participants with higher cognitive abilities and may not represent the broader ASD population. In this regard, we have established PET-MR protocols for adults with ASD with lower intellectual functioning [84] and recently completed a PET-MR study that included individuals with ASD with full-scale IQs ranging from 47 to 112 [85]. Finally, two results should be interpreted with caution until replicated: 1) a cluster in the right caudate nucleus showed increased phasic DA release to rewards in the ASD group, a finding that was unexpected and in the opposite direction of other striatal PET clusters; and 2) the relation between phasic DA release in the left putamen and performance on the theory-of-mind measure was only significant at an uncorrected threshold.…”