Glutamate-mediated blood-brain barrier opening. implications for neuroprotection and drug delivery

The blood-brain barrier is a highly selective anatomical and functional interface allowing a unique environment for neuro-glia networks. Blood-brain barrier dysfunction is common in most brain disorders and is associated with disease course and delayed complications. However, the mechanisms underlying blood-brain barrier opening are poorly understood. Here we demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeability in vivo Using intravital microscopy, we show that recurrent seizures and the associated excessive glutamate release lead to increased vascular permeability in the rat cerebral cortex, through activation of NMDA receptors. NMDA receptor antagonists reduce barrier permeability in the peri-ischemic brain, whereas neuronal activation using high-intensity magnetic stimulation increases barrier permeability and facilitates drug delivery. Finally, we conducted a double-blind clinical trial in patients with malignant glial tumors, using contrast-enhanced magnetic resonance imaging to quantitatively assess blood-brain barrier permeability. We demonstrate the safety of stimulation that efficiently increased blood-brain barrier permeability in 10 of 15 patients with malignant glial tumors. We suggest a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders. SIGNIFICANCE STATEMENT: In this study, we reveal a new mechanism that governs blood-brain barrier (BBB) function in the rat cerebral cortex, and, by using the discovered mechanism, we demonstrate bidirectional control over brain endothelial permeability. Obviously, the clinical potential of manipulating BBB permeability for neuroprotection and drug delivery is immense, as we show in preclinical and proof-of-concept clinical studies. This study addresses an unmet need to induce transient BBB opening for drug delivery in patients with malignant brain tumors and effectively facilitate BBB closure in neurological disorders

Role of Cerebrovascular Abnormality in Neurodegenerative Disease and Subcortical Ischemic Disease: CT Perfusion and PET Imaging

Clinical studies indicate that about 30% ~ 50% of patients have cognitive impairment after the first or recurrent stroke. Ischemic injury, particularly subcortical lesions, caused by stroke has been demonstrated to further exacerbate cognitive impairment of Alzheimer’s disease (AD) and vascular dementia. However, the mechanisms whereby cerebrovascular abnormalities contribute to neurodegeneration at early stage of disease and eventually to cognitive decline remain unclear. CT perfusion and positron emission tomography (PET) were used to investigate early mechanisms in a rat comorbid model of cerebral ischemia (CI) and β-amyloid (Aβ, a pathological hallmark of AD) toxicity, and in patients with small subcortical ischemic lesions. Chapter 2 investigates the early hemodynamic disturbances within the first month after transient CI insult in the presence of Aβ toxicity in the comorbid rat model. CT perfusion revealed significantly lower cerebral blood flow (CBF) and blood volume (CBV) at acute phase due to the transient ischemia, and increased CBF and CBV in the ipsilateral striatum of CI+Aβ and CI groups at the first week post ischemia. These results suggest that CI is the primary driving factor of cerebrovascular abnormalities at early stage, and prolonged hyperperfusion and hypervolemia may imply reperfusion-related injury and downstream inflammation. Chapter 3 further addresses these questions with CT Perfusion-PET imaging. Chapter 3 describes the temporal profiles of blood-brain barrier (BBB) disruption and neuroinflammation over 3 months after CI with and without concurrent Aβ toxicity in the comorbid rat model. CT perfusion showed significantly higher BBB permeability surface product (BBB-PS) in the ipsilateral striatum of CI+Aβ group at day 7, month 2 and 3, as compared to CI and sham group. PET imaging revealed the highest level of neuroinflammation as reflected by the significantly increased 18F-FEPPA uptake due to microglial activation in the striatal lesion of CI+Aβ group at day 7 and 14. The temporal features of these cererbrovascular and cellular changes may serve as early imaging biomarkers for development of cognitive impairment in high-risk patients post ischemic insult. Chapter 4 investigates the temporal changes in BBB-PS and cerebral perfusion using CT perfusion over the first 3 months after small lacunar/subcortical stroke in patients. This longitudinal investigation suggests the chronic BBB leakage detected by CT perfusion may contribute to cognitive impairment and associated pathology in lacunar/subcortical stroke. Overall, the imaging results presented in this thesis have demonstrated that BBB-PS, CBF, CBV and activated microglia can be used as imaging biomarkers for delineating the early pathogenic pattern and underlying contribution of cerebral ischemia to the disease development in the animal comorbid model and subcortical stroke patients

Magnetic resonance imaging of brain angiogenesis after stroke

Stroke is a major cause of mortality and long-term disability worldwide. The initial changes in local perfusion and tissue status underlying loss of brain function are increasingly investigated with noninvasive imaging methods. In addition, there is a growing interest in imaging of processes that contribute to post-stroke recovery. In this review, we discuss the application of magnetic resonance imaging (MRI) to assess the formation of new vessels by angiogenesis, which is hypothesized to participate in brain plasticity and functional recovery after stroke. The excellent soft tissue contrast, high spatial and temporal resolution, and versatility render MRI particularly suitable to monitor the dynamic processes involved in vascular remodeling after stroke. Here we review recent advances in the field of MR imaging that are aimed at assessment of tissue perfusion and microvascular characteristics, including cerebral blood flow and volume, vascular density, size and integrity. The potential of MRI to noninvasively monitor the evolution of post-ischemic angiogenic processes is demonstrated from a variety of in vivo studies in experimental stroke models. Finally, we discuss some pitfalls and limitations that may critically affect the accuracy and interpretation of MRI-based measures of (neo)vascularization after stroke

Impaired Cerebral Perfusion in Multiple Sclerosis: Relevance of Endothelial Factors.

Magnetic resonance imaging techniques measuring in vivo brain perfusion and integrity of the blood-brain barrier have developed rapidly in the past decade, resulting in a wide range of available methods. This review first discusses their principles, possible pitfalls, and potential for quantification and outlines clinical application in neurological disorders. Then, we focus on the endothelial cells of the blood-brain barrier, pointing out their contribution in regulating vascular tone by production of vasoactive substances. Finally, the role of these substances in brain hypoperfusion in multiple sclerosis is discussed