Magnetic Resonance Imaging of Mouse Cerebral Cavernomas Reveal Differential Lesion Progression and Variable Permeability to Gadolinium.

BACKGROUND: Cerebral cavernous malformations, also known as cavernous angiomas, are blood vessel abnormalities comprised of clusters of grossly enlarged and hemorrhage-prone capillaries. The prevalence in the general population, including asymptomatic cases, is estimated to be 0.5%. Some patients develop severe symptoms, including seizures and focal neurological deficits, whereas others remain asymptomatic. The causes of this remarkable presentation heterogeneity within a primarily monogenic disease remain poorly understood. METHODS: We established a chronic mouse model of cerebral cavernous malformations, induced by postnatal ablation of Krit1 with Pdgfb-CreERT2, and examined lesion progression in these mice with T2-weighted 7T magnetic resonance imaging (MRI). We also established a modified protocol for dynamic contrast-enhanced MRI and produced quantitative maps of gadolinium tracer gadobenate dimeglumine. After terminal imaging, brain slices were stained with antibodies against microglia, astrocytes, and endothelial cells. RESULTS: These mice develop cerebral cavernous malformations lesions gradually over 4 to 5 months of age throughout the brain. Precise volumetric analysis of individual lesions revealed nonmonotonous behavior, with some lesions temporarily growing smaller. However, the cumulative lesional volume invariably increased over time and after about 2 months followed a power trend. Using dynamic contrast-enhanced MRI, we produced quantitative maps of gadolinium in the lesions, indicating a high degree of heterogeneity in lesional permeability. MRI properties of the lesions were correlated with cellular markers for endothelial cells, astrocytes, and microglia. Multivariate comparisons of MRI properties of the lesions with cellular markers for endothelial and glial cells revealed that increased cell density surrounding lesions correlates with stability, whereas denser vasculature within and surrounding the lesions may correlate with high permeability. CONCLUSIONS: Our results lay a foundation for better understanding individual lesion properties and provide a comprehensive preclinical platform for testing new drug and gene therapies for controlling cerebral cavernous malformations.

Recent Advances in the Use of Focused Ultrasound for Magnetic Resonance Image-Guided Therapeutic Nanoparticle Delivery to the Central Nervous System.

Targeting systemically-administered drugs and genes to specific regions of the central nervous system (CNS) remains a challenge. With applications extending into numerous disorders and cancers, there is an obvious need for approaches that facilitate the delivery of therapeutics across the impervious blood-brain barrier (BBB). Focused ultrasound (FUS) is an emerging treatment method that leverages acoustic energy to oscillate simultaneously administered contrast agent microbubbles. This FUS-mediated technique temporarily disrupts the BBB, allowing ordinarily impenetrable agents to diffuse and/or convect into the CNS. Under magnetic resonance image guidance, FUS and microbubbles enable regional targeting-limiting the large, and potentially toxic, dosage that is often characteristic of systemically-administered therapies. Subsequent to delivery across the BBB, therapeutics face yet another challenge: penetrating the electrostatically-charged, mesh-like brain parenchyma. Non-bioadhesive, encapsulated nanoparticles can help overcome this additional barrier to promote widespread treatment in selected target areas. Furthermore, nanoparticles offer significant advantages over conventional systemically-administered therapeutics. Surface modifications of nanoparticles can be engineered to enhance targeted cellular uptake, and nanoparticle formulations can be tailored to control many pharmacokinetic properties such as rate of drug liberation, distribution, and excretion. For instance, nanoparticles loaded with gene plasmids foster relatively stable transfection, thus obviating the need for multiple, successive treatments. As the formulations and applications of these nanoparticles can vary greatly, this review article provides an overview of FUS coupled with polymeric or lipid-based nanoparticles currently utilized for drug delivery, diagnosis, and assessment of function in the CNS.