Abstract
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.
Highlights
Atherosclerosis is an inflammatory disease 1 that is just entering the immunomodulation therapy era for personalized care 2
We developed a model of active atherosclerosis in aged non-human primate (NHP) with systemic and vascular inflammation, metabolic syndrome with cardiovascular events and neuroinflammatory consequences
We conclude that neuroinflammation is an important factor in the complex clinical picture of high-risk atherosclerosis in aging individuals, and that it can readily be reproduced in NHPs
Summary
Introduction Atherosclerosis is an inflammatory disease 1 that is just entering the immunomodulation therapy era for personalized care 2. Whereas the contribution of systemic and cardiometabolic inflammation is well recognized, localized neuroinflammation has only recently been incriminated 3. The gyrencephalic brain organization and higher white-to-gray matter ratio in humans are thought to play a major role in neuroinflammation processes 6,7. The cynomolgus macaque under atherogenic diet has been found to be invaluable in establishing the protective effect of estrogen against coronary plaque development 8. In this model, atherosclerosis develops with a lipidic blood profile and multi-site progression as in humans, and the carotid lesions reproduce the plaque morphology observed in clinical studies, as vessel geometry is very close to that found in humans 9. The innate immune system is a key player in vulnerable plaque, and this non-human primate (NHP) atherosclerosis model is the only one to display the same chemokine and cytokine armamentarium as in human atherosclerosis
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