BAY-85-8102

Translocator protein 18 kDa (TSPO) positron emission tomography (PET) imaging is used to monitor glial activation. Recent studies have proposed TSPO PET as a marker of the epileptogenic zone (EZ) in drug-resistant focal epilepsy (DRFE). This study aims to assess the contributions of TSPO imaging using [¹⁸F]DPA-714 PET and [¹⁸F]FDG PET for localizing the EZ during pre-surgical assessment of DRFE, when phase 1 pre-surgical assessment does not provide enough information.

We compared [¹⁸F]FDG and [¹⁸F]DPA-714 PET images of 23 patients who had undergone a phase 1 pre-surgical assessment, using qualitative visual analysis and quantitative analysis, at both the voxel and the regional levels. PET abnormalities (increase in binding for [¹⁸F]DPA-714 vs decrease in binding for [¹⁸F]FDG) were compared with clinical hypotheses concerning the localization of the EZ based on phase 1 pre-surgical assessment. The additional value of [¹⁸F]DPA-714 PET imaging to [¹⁸F]FDG for refining the localization of the EZ was assessed. To strengthen the visual analysis, [¹⁸F]DPA-714 PET imaging were also reviewed by two experienced clinicians blind to the EZ location.

The study included 23 patients. Visual analysis of [¹⁸F]DPA-714 PET was significantly more accurate than [¹⁸F]FDG PET to both, show anomalies (95.7% vs 56.5%, p=0.022) and provide additional information to refine the EZ localization (65.2% vs 17.4%, p=0.019). All 10 patients with normal [18F]FDG PET had anomalies when using [¹⁸F]DPA-714 PET. The additional value of [¹⁸F]DPA-714 PET appeared to be greater in patients with normal brain MRI or with neocortical EZ (especially if insula is involved). Regional analysis of [¹⁸F]DPA-714 and [¹⁸F]FDG PET provided similar results. However, using voxel-wise analysis, [¹⁸F]DPA-714 was more effective than [¹⁸F]FDG for unveiling clusters whose localization was more often consistent with the EZ hypothesis (87.0% vs 39.1%, p=0.019). Non-relevant bindings were seen in 14 of 23 patients in visual analysis, and in 9 patients out of 23 in voxel-wise analysis.

[¹⁸F]DPA-714 PET imaging provides valuable information for pre-surgical assessments of patients with DRFE. TSPO PET could become an additional tool to help to the localization of the EZ, especially in patients with negative [¹⁸F]FDG PET.

This study provide Class IV evidence on the utility of [18F]DPA-714 PET compared to [18F]FDG PET in identifying the epileptic zone in patients undergoing phase 1 pre-surgical evaluation for intractable epilepsy.

Coronavirus disease 2019 (COVID-19) patients initially develop respiratory symptoms, but they may also suffer from neurological symptoms. People with long-lasting effects after acute infections with severe respiratory syndrome coronavirus 2 (SARS-CoV-2), i.e., post-COVID syndrome or long COVID, may experience a variety of neurological manifestations. Although we do not fully understand how SARS-CoV-2 affects the brain, neuroinflammation likely plays a role.

To investigate neuroinflammatory processes longitudinally after SARS-CoV-2 infection, four experimentally SARS-CoV-2 infected rhesus macaques were monitored for 7 weeks with 18-kDa translocator protein (TSPO) positron emission tomography (PET) using [¹⁸F]DPA714, together with computed tomography (CT). The baseline scan was compared to weekly PET-CTs obtained post-infection (pi). Brain tissue was collected following euthanasia (50 days pi) to correlate the PET signal with TSPO expression, and glial and endothelial cell markers. Expression of these markers was compared to brain tissue from uninfected animals of comparable age, allowing the examination of the contribution of these cells to the neuroinflammatory response following SARS-CoV-2 infection.

TSPO PET revealed an increased tracer uptake throughout the brain of all infected animals already from the first scan obtained post-infection (day 2), which increased to approximately twofold until day 30 pi. Postmortem immunohistochemical analysis of the hippocampus and pons showed TSPO expression in cells expressing ionized calcium-binding adaptor molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), and collagen IV. In the hippocampus of SARS-CoV-2 infected animals the TSPO⁺ area and number of TSPO⁺ cells were significantly increased compared to control animals. This increase was not cell type specific, since both the number of IBA1⁺TSPO⁺ and GFAP⁺TSPO⁺ cells was increased, as well as the TSPO⁺ area within collagen IV⁺ blood vessels.

This study manifests [¹⁸F]DPA714 as a powerful radiotracer to visualize SARS-CoV-2 induced neuroinflammation. The increased uptake of [¹⁸F]DPA714 over time implies an active neuroinflammatory response following SARS-CoV-2 infection. This inflammatory signal coincides with an increased number of TSPO expressing cells, including glial and endothelial cells, suggesting neuroinflammation and vascular dysregulation. These results demonstrate the long-term neuroinflammatory response following a mild SARS-CoV-2 infection, which potentially precedes long-lasting neurological symptoms.