Perivascular spaces - MRI marker of inflammatory activity in the brain?

The Virchow-Robin spaces (VRS), perivascular compartments surrounding small blood vessels as they penetrate the brain parenchyma, are increasingly recognized for their role in leucocyte trafficking as well as for their potential to modulate immune responses. In the present study, we investigated VRS numbers and volumes in different brain regions in 45 multiple sclerosis patients and 30 healthy controls of similar age and gender distribution, applying three different MRI sequence modalities (T(2)-weighted, T(1)-weighted and FLAIR). VRS were detected in comparable numbers in both multiple sclerosis patients and healthy individuals, indicating that perivascular compartments present on MRI are not a unique feature of multiple sclerosis. However, multiple sclerosis patients had significantly larger VRS volumes than healthy controls (P = 0.004). This finding was not explained by a significantly lower brain parenchymal fraction (BPF), resulting from a higher degree of atrophy, in the patient cohort. In a multiple linear regression analysis, age had a significant influence on VRS volumes in the control group but not in multiple sclerosis patients (P = 0.023 and P = 0.263, respectively). A subsequent prospective longitudinal substudy with monthly follow-up MRI over a period of up to 12 months in 18 patients revealed a significant increase in VRS volumes and counts accompanying the occurrence of contrast-enhancing lesions (CEL). At time points when blood-brain barrier (BBB) breakdown was indicated by the appearance of CEL, total VRS volumes and counts were significantly higher compared with preceding time points without CEL (P = 0.011 and P = 0.041, respectively), whereas a decrease thereafter was not statistically significant. Thus, our data points to an association of VRS with CEL as a sign for inflammation rather than with factors such as age, observed in healthy controls, and therefore suggests a role of VRS in inflammatory processes of the brain

Mouse model mimics multiple sclerosis in the clinico-radiological paradox

The value of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, in deriving novel diagnostic and therapeutic input has been subject to recent debate. This study is the first to report a disseminated distribution of plaques including cranial nerves, prior to or at early stages of disease in murine adoptive transfer EAE, irrespective of the development of clinical symptoms. We induced EAE by adoptive proteolipid protein-specific T-cell transfer in 26 female SJL/J mice, and applied high-field-strength magnetic resonance imaging (MRI) scans longitudinally, assessing bloodbrain barrier (BBB) disruption by gadopentate dimeglumine enhancement. We visualized inflammatory nerve injury by gadofluorine M accumulation, and phagocytic cells in inflamed tissue by very small anionic iron oxide particles (VSOP-C184). MRI was correlated with immunohistological sections. In this study, we discovered very early BBB breakdown of white and grey brain matter in 25 mice; one mouse developed exclusively spinal cord inflammation. Widely disseminated contrast-enhancing lesions preceded the onset of disease in 10 animals. Such lesions were present despite the absence of any clinical disease formation in four mice, and coincided with the first detectable symptoms in others. Cranial nerves, predominantly the optic and trigeminal nerves, showed signal intensity changes in nuclei and fascicles of 14 mice. At all sites of MRI lesions we detected cellular infiltrates on corresponding histological sections. The discrepancy between the disease burden visualized by MRI and the extent of disability indeed mimics the human clinico-radiological paradox. MRI should therefore be implemented into evaluational in vivo routines of future therapeutic EAE studies

Targeting activated microglia in Alzheimer's pathology by intraventricular delivery of a phagocytosable MRI contrast agent in APP23 transgenic mice

The role of phagocytosing immune cells in Alzheimer's pathology can be studied experimentally in APP23 transgenic mice. This present study intended to label phagocytosing immune cells in the plaque periphery of APP23 mice in vivo by intraventricular injection of VSOP-C184, a phagocytosable iron oxide nanoparticle MRI contrast agent. Firstly, the dosages of 0.1, 1.0 and 10 micromol Fe/kg body weight dissolved in 500 nl of artificial cerebrospinal fluid, delivered by stereotaxic surgery were evaluated 4 h after surgery in 7 wild type mice using 7 T MRI. Secondly, the dosage of 1.0 micromol Fe/kg body weight was investigated in 6 APP23 mice. The distribution of iron oxide particles was evaluated histologically. The injection of 0.1 micromol Fe/kg body weight did not result in any signal alterations, 10 micromol resulted in strong signal artifacts. The delivery of 1.0 micromol Fe/kg body weight in wild type mice resulted in MRI signal alterations throughout the ventricular system without large artifacts. It was regarded superior to other dosages for the study of the transgenic mice. There was no difference in MRI signal alterations and the distribution of iron particles in the histology between APP23 and wild type mice using the dosage of 1.0 micromol Fe/kg body weight. Upon intraventricular injection, the phagocytosable contrast agent VSOP-C184 distributes throughout the ventricular system, whereas it does not reach the periphery of amyloid plaques in APP23 mice in a concentration sufficient to cause MRI signal alterations