Comparison of high-resolution magnetic resonance imaging and micro-computed tomography arthrography for in-vivo assessment of cartilage in non-human primate models.

BACKGROUND: Non-human primate (NHP) could be an interesting model for osteoarthritis (OA) longitudinal studies but standard medical imaging protocols are not able to acquire sufficiently high-resolution images to depict the thinner cartilage (compared to human) in an in vivo context. The aim of this study was thus to develop and validate the acquisition protocols for knee joint examination of NHP using magnetic resonance imaging (MRI) at 1.5 T and X-ray micro-computed tomography arthrography (µCTA). METHODS: The first phase of the study focused on developing dedicated in vivo HR-MRI and µCTA protocols for simultaneous acquisitions of both knee joints on NHP. For MR, a dedicated two-channel receiver array coil and acquisition sequence were developed on a 1.5 T Siemens Sonata system and tuned to respect safety issues and reasonable examination time. For µCTA, an experimental setup was devised so as to fulfill similar requirements. The two imaging protocols were used during a longitudinal study so as to confirm that repeated injections of loxaglic acid (contrast agent used for µCTA) didn't induce any bias in cartilage assessment and to compare segmentation results from the two modalities. Lateral and medial cartilage tibial plateaus were assessed using a common image processing protocol leading to a 3D estimation of the cartilage thickness. RESULTS: From HR-MRI and µCTA images, thickness distributions were extracted allowing for proper evaluation of knee cartilage thickness of the primates. Results obtained in vivo indicated that the µCTA protocol did not induce any bias in the measured cartilage parameters and moreover, segmentation results obtained from the two imaging modalities were consistent. CONCLUSIONS: MR and µCTA are valuable imaging tools for the morphological evaluation of cartilage in NHP models which in turn can be used for OA studies.

Cortical inflammation and brain signs of high-risk atherosclerosis in a non-human primate model.

Atherosclerosis is a chronic systemic inflammatory disease, inducing cardiovascular and cerebrovascular acute events. A role of neuroinflammation is suspected, but not yet investigated in the gyrencephalic brain and the related activity at blood-brain interfaces is unknown. A non-human primate model of advanced atherosclerosis was first established using longitudinal blood samples, multimodal imaging and gene analysis in aged animals. Non-human primate carotid lesions were compared with human carotid endarterectomy samples. During the whole-body imaging session, imaging of neuroinflammation and choroid plexus function was performed. Advanced plaques were present in multiple sites, premature deaths occurred and downstream lesions (myocardial fibrosis, lacunar stroke) were present in this model. Vascular lesions were similar to in humans: high plaque activity on PET and MRI imaging and systemic inflammation (high plasma C-reactive protein levels: 42 ± 14 µg/ml). We also found the same gene association (metabolic, inflammatory and anti-inflammatory markers) as in patients with similar histological features. Metabolic imaging localized abnormal brain glucose metabolism in the frontal cortex. It corresponded to cortical neuro-inflammation (PET imaging) that correlated with C-reactive protein level. Multimodal imaging also revealed pronounced choroid plexus function impairment in aging atherosclerotic non-human primates. In conclusion, multimodal whole-body inflammation exploration at the vascular level and blood-brain interfaces identified high-risk aging atherosclerosis. These results open the way for systemic and central inflammation targeting in atherosclerosis in the new era of immunotherapy.

A non-human primate model of stroke reproducing endovascular thrombectomy and allowing long-term imaging and neurological read-outs.

Stroke is a devastating disease. Endovascular mechanical thrombectomy is dramatically changing the management of acute ischemic stroke, raising new challenges regarding brain outcome and opening up new avenues for brain protection. In this context, relevant experiment models are required for testing new therapies and addressing important questions about infarct progression despite successful recanalization, reversibility of ischemic lesions, blood-brain barrier disruption and reperfusion damage. Here, we developed a minimally invasive non-human primate model of cerebral ischemia (Macaca fascicularis) based on an endovascular transient occlusion and recanalization of the middle cerebral artery (MCA). We evaluated per-occlusion and post-recanalization impairment on PET-MRI, in addition to acute and chronic neuro-functional assessment. Voxel-based analyses between per-occlusion PET-MRI and day-7 MRI showed two different patterns of lesion evolution: "symptomatic salvaged tissue" (SST) and "asymptomatic infarcted tissue" (AIT). Extended SST was present in all cases. AIT, remote from the area at risk, represented 45% of the final lesion. This model also expresses both worsening of fine motor skills and dysexecutive behavior over the chronic post-stroke period, a result in agreement with cortical-subcortical lesions. We thus fully characterized an original translational model of ischemia-reperfusion damage after stroke, with consistent ischemia time, and thrombus retrieval for effective recanalization.

Respiratory syncytial virus infection in macaques is not suppressed by intranasal sprays of pyrimidine biosynthesis inhibitors.

There is imperious need for efficient therapies against ubiquitous and life-threatening respiratory viruses, foremost among them being the human respiratory syncytial virus (hRSV). Several research groups who performed functional screens for broad-spectrum antivirals identified compounds targeting the de novo pyrimidine biosynthesis pathway. Despite their strong antiviral activity in vitro, whether such antimetabolites are effective in vivo remains highly controversial. Here, we evaluated two potent pyrimidine biosynthesis inhibitors developed in our laboratory, IPPA17-A04 and GAC50, in a model of mild hRSV-infection in cynomolgus macaques. In this model, hRSV replication is restricted to the epithelium of the upper respiratory tract, and is compatible with a topical treatment by intranasal sprays. The local administration of palivizumab, a neutralizing anti-hRSV antibody used in clinics, significantly reduced virus replication. In contrast, pyrimidine biosynthesis inhibitors did not show any inhibitory effect on hRSV growth when delivered topically as experimented in our model. Our results should help to better define the potential applications of this class of antimetabolites in the treatment of viral infections.

Evidence for an intranasal immune response to human respiratory syncytial virus infection in cynomolgus macaques.

There is no large-scale therapy available against human respiratory syncytial virus (hRSV), a major pathogen responsible for acute respiratory diseases. Macaques represent an interesting animal model to evaluate potential treatments because of their genetic, anatomical and immunological proximity with humans. However, the parameters that influence hRSV growth and control in this model are still poorly understood. We have documented in the following study the influence of age as well as repeated infections on the virological, clinical and immunological parameters of this animal model. Following intranasal inoculation, hRSV replicated in the upper respiratory tract for less than 15 days with no clinical signs regardless of age. Interestingly, we observed the induction of a local immune response at the nasal mucosa as assessed by expression profiles of inflammatory and IFN-stimulated genes. Animals also developed specific antibodies and were immune to reinfection. Thus, we showed that even in infant macaques, intranasal hRSV infection induced both local and systemic immune responses to efficiently control the virus.