Cerebral blood flow and glucose metabolism in ischemic stroke : multimodal imaging investigations in a clinically relevant rat model

Abstract: Ischemic stroke is one of the leading causes of death worldwide. Ischemic stroke is also a major cause of long-term disability with vast socioeconomic results for patients, their relatives and health services. Over the last decades, experimental research has resulted in significant progress of our understanding of mechanisms leading to brain injury after ischemic stroke. However, so far, translational research targeting these mechanisms has failed. This failure has resulted in a general consensus that a more integrative approach is needed to account for not only neurobiology under ischemia, but also the ischemic impact on the neurovascular interface. Accordingly, new tools for simultaneously imaging and perturbing this interface needs to be established. The aims of the present work were firstly to develop an ischemic stroke model in rats that more closely mimics human stroke. Secondly, our goal was to incorporate the model with perfusion- and metabolic imaging using high-field magnetic resonance imaging (HF-MRI) and positron emission tomography (PET). Finally we wanted to apply the model in a treatment study targeting the neurovascular interface, and use HF-MRI and PET to assess treatment outcome. We translated endovascular techniques from bedside to bench in the interest of realizing a new rat model for focal cerebral ischemia, in which a microwire is navigated under X-ray fluoroscopy to an occluding position in the middle cerebral artery (MCA). Furthermore, we were able to use the endovascular technique to facilitate intra-arterial microcatheter access to the cerebrovascular system in the rat accommodating injections with varying degree of selectivity. Next, we established protocols for HF-MRI and PET to obtain imaging of pathophysiological events following acute and subacute ischemic stroke. Finally we applied the aforementioned techniques in a treatment study targeting vascular endothelial growth factor B (VEGF-B) in ischemic stroke. We found that the translation of clinical endovascular techniques to the experimental setting opened up several possibilities to access and perturb the neurovascular interface. In comparison with earlier models for focal stroke in the rat, the model for ischemic stroke presented in Paper I produces an injury and pathophysiology more resembling human stroke. Furthermore, the model showed to be highly compatible with small animal imaging systems with the possibility to occlude the MCA and to inject substances directly to the cerebrovascular supply before, during and after imaging (Paper II). The model also makes it possible to control blood flow during scanning with various modalities. HF-MRI and [2-18F]- 2-Fluoro-2-deoxy-D-glucose PET investigations of acute ischemia in Paper III provided evidence for hypermetabolism of glucose occurring in parallel with diffusion restriction of brain water, suggesting an extension of the current paradigm of the mechanisms behind infarct-related diffusion restriction of water. In Paper IV, we found that VEGF-B antagonism result in a reduction of stroke volume, indicating a mechanism of action of VEGF-B in ischemic stroke warranting further treatment studies targeting VEGF-B in ischemic stroke.