Regional brain distribution of translocator protein using [11C]DPA-713 PET in individuals infected with HIV

Abstract

Imaging the brain distribution of translocator protein (TSPO), a putative biomarker for glial cell activation and neuroinflammation, may inform management of individuals infected with HIV by uncovering regional abnormalities related to neurocognitive deficits and enable non-invasive therapeutic monitoring. Using the second-generation TSPO-targeted radiotracer, [11C]DPA-713, we conducted a positron emission tomography (PET) study to compare the brains of 12 healthy human subjects to those of 23 individuals with HIV who were effectively treated with combination antiretroviral therapy (cART). Compared to PET data from age-matched healthy control subjects, [11C]DPA-713 PET of individuals infected with HIV demonstrated significantly higher volume-of-distribution (VT) ratios in white matter, cingulate cortex, and supramarginal gyrus, relative to overall gray matter VT, suggesting localized glial cell activation in susceptible regions. Regional TSPO abnormalities were evident within a sub-cohort of neuro-asymptomatic HIV subjects, and an increase in the VT ratio within frontal cortex was specifically linked to individuals affected with HIV-associated dementia. These findings were enabled by employing a gray matter normalization approach for PET data quantification, which improved test–retest reproducibility, intra-class correlation within the healthy control cohort, and sensitivity of uncovering abnormal regional findings.

Neuroimaging of HIV-associated neurocognitive disorders (HAND)

“…Cross-sectional comparisons, in theory, cannot be done except within the same binding affinity group. Despite these limitations, one study used a second generation TSPO ligand ( 11 C-DPA713) to compare HIV+/cART+ individuals and HIV− controls [94]. Adapting a new method of data analysis based on assessing the volume-of-distribution ratios relative to overall gray matter, HIV+ patients were noted to have higher binding in specific brain regions that may reflect localized rather than diffuse glial cell activation.…”

“…Adapting a new method of data analysis based on assessing the volume-of-distribution ratios relative to overall gray matter, HIV+ patients were noted to have higher binding in specific brain regions that may reflect localized rather than diffuse glial cell activation. A novel gray matter normalization approach was employed that improves test-retest reproducibility and may uncover abnormal regional findings not seen using traditional methods [94]. However, additional studies are needed to validate this method for other TSPO ligands.…”

Neuroimaging of translocator protein in patients with systemic lupus erythematosus: a pilot study using [11C]DPA-713 positron emission tomography

“…It was administered over a 20 – 30 min period on a standard PC or laptop computer as we have previously reported 26, 27 . All subjects in both the SLE and control groups were also assessed for TSPO (rs6971) genotype as previously described 22 .…”

“…A number of second-generation TSPO radiotracers, such as [ 11 C]DPA-713 (DPA), [ 11 C]PBR28, and [ 18 F]FEPPA, have been developed and have shown improved brain delivery and increased specificity for TSPO 6, 19–21 , which may, in turn, facilitate the study of various neurological diseases. For example, using [ 11 C]DPA-713 PET, we found that increased frontal cortex TSPO binding was specifically linked to HIV-associated dementia 22 , while neuro-asymptomatic individuals infected with HIV demonstrated increases in other brain regions. In a recent study using [ 11 C]PBR28, it was shown that neuroinflammation, indicated by increased [ 11 C]PBR28 binding to TSPO in several brain regions (e.g., prefrontal cortex and hippocampus), occurs after conversion of mild cognitive impairment to Alzheimer’s disease and worsens with disease progression 18 .…”

“…Although a common single nucleotide polymorphism (SNP) in the TSPO gene (rs6971) has demonstrated deterministic effects on brain uptake of second generation TSPO PET radioligands 23 , including DPA, these effects can be controlled during data analysis, as shown by 18 and 22 . The involvement of TSPO in the development of cutaneous pathology in a mouse model of SLE was previously studied 24 , but to our knowledge no study of patients with SLE using TSPO-targeted brain PET has been reported.…”