Neuroimmune activation is associated with neurological outcome in anoxic and traumatic coma

Abstract

The pathophysiological underpinnings of critically disrupted brain connectomes resulting in coma are poorly understood. Inflammation is potentially an important but still undervalued factor. Here, we present a first-in-human prospective study using the 18-kDa translocator protein (TSPO) radioligand 18F-DPA714 for PET imaging to allow in vivo neuroimmune activation quantification in patients with coma (n = 17) following either anoxia or traumatic brain injuries in comparison with age- and sex-matched controls. Our findings yielded novel evidence of an early inflammatory component predominantly located within key cortical and subcortical brain structures that are putatively implicated in consciousness emergence and maintenance after severe brain injury (i.e. mesocircuit and frontoparietal networks). We observed that traumatic and anoxic patients with coma have distinct neuroimmune activation profiles, both in terms of intensity and spatial distribution. Finally, we demonstrated that both the total amount and specific distribution of PET-measurable neuroinflammation within the brain mesocircuit were associated with the patient's recovery potential. We suggest that our results can be developed for use both as a new neuroprognostication tool and as a promising biometric to guide future clinical trials targeting glial activity very early after severe brain injury.

Trial registration: ClinicalTrials.gov 03482115.

Keywords: TSPO PET scan; brain anoxia; disorders of consciousness; mesocircuit; neuroimmune activation; prognosis; traumatic brain injury.

Figure 1

Study flow chart. TSPO: a third generation translocator protein (18 kDa) radioligand for PET imaging (¹⁸F-DPA714).

Figure 2

Individual neuroimmune activation. Translocator protein (18 kDa; TSPO) PET scan data depicted as co-registration with the subject’s native T1-weighted MRI. Six anoxic and 11 traumatic coma patients are shown. Brain images from one control subject are represented. Controls subjects and anoxic patient’s individual scans are depicted using canonical alignment to anterior and posterior commissure (ACPC). In a few cases, traumatic patients brain levels were displaced (±20 mm from ACPC) to better illustrate brain concussions and focal TSPO binding.

Figure 3

In vivo neuroimmune activation profiles according to primary brain injury mechanisms. (A). ¹⁸F-DPA-714 binding potential, group analysis. (B) Whole-brain comparisons between comatose patient groups according to primary brain injury mechanism (z-scores). (C) Hypothesis-driven comparisons between comatose patient groups according to primary brain injury mechanism (volume of interest, VOI). *Corrected P-value < 0.05. ACC = anterior cingulate cortex; mPFC = medial prefrontal cortex; PCC = posterior cingulate cortex.

Figure 4

Relationship between neuroimmune activation in vivo and coma patient’s neurological outcome. (A). Whole-brain ¹⁸F-DPA-714 binding potential difference between patients with a favourable versus unfavourable neurological outcome at 3 months after coma onset. (B). Volume of interest ¹⁸F-DPA-714 binding potential difference between patients with a favourable versus unfavourable neurological outcome at 3 months after coma onset. (C) Estimation of patient Coma Recovery Scale-Revised (CRS-R) outcomes after 90 days using whole-brain voxel-wise cross-validated partial least squares (PLS) model [variable importance in projection (VIP) map]. The x-axis corresponds to observed outcomes and the y-axis to estimated outcomes. (D). Parametric map of VIP scores from the PLS regression. High values indicate an important contribution of the voxels to the model. ACC = anterior cingulate cortex; FO = favourable outcome; mPFC = medial prefrontal cortex; PCC = posterior cingulate cortex; UO = unfavourable outcome.