title: Experimental Cerebral Malaria Spreads along the Rostral Migratory Stream.
abstract: It is poorly understood how progressive brain swelling in experimental cerebral malaria (ECM) evolves in space and over time, and whether mechanisms of inflammation or microvascular sequestration/obstruction dominate the underlying pathophysiology. We therefore monitored in the Plasmodium berghei ANKA-C57BL/6 murine ECM model, disease manifestation and progression clinically, assessed by the Rapid-Murine-Coma-and-Behavioral-Scale (RMCBS), and by high-resolution in vivo MRI, including sensitive assessment of early blood-brain-barrier-disruption (BBBD), brain edema and microvascular pathology. For histological correlation HE and immunohistochemical staining for microglia and neuroblasts were obtained. Our results demonstrate that BBBD and edema initiated in the olfactory bulb (OB) and spread along the rostral-migratory-stream (RMS) to the subventricular zone of the lateral ventricles, the dorsal-migratory-stream (DMS), and finally to the external capsule (EC) and brainstem (BS). Before clinical symptoms (mean RMCBS = 18.5±1) became evident, a slight, non-significant increase of quantitative T2 and ADC values was observed in OB+RMS. With clinical manifestation (mean RMCBS = 14.2±0.4), T2 and ADC values significantly increased along the OB+RMS (p = 0.049/p = 0.01). Severe ECM (mean RMCBS = 5±2.9) was defined by further spread into more posterior and deeper brain structures until reaching the BS (significant T2 elevation in DMS+EC+BS (p = 0.034)). Quantitative automated histological analyses confirmed microglial activation in areas of BBBD and edema. Activated microglia were closely associated with the RMS and neuroblasts within the RMS were severely misaligned with respect to their physiological linear migration pattern. Microvascular pathology and ischemic brain injury occurred only secondarily, after vasogenic edema formation and were both associated less with clinical severity and the temporal course of ECM. Altogether, we identified a distinct spatiotemporal pattern of microglial activation in ECM involving primarily the OB+RMS axis, a distinct pathway utilized by neuroblasts and immune cells. Our data suggest significant crosstalk between these two cell populations to be operative in deeper brain infiltration and further imply that the manifestation and progression of cerebral malaria may depend on brain areas otherwise serving neurogenesis.
authors.affiliation: Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.|Division of Experimental Radiology, Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Hoffmann
authors.affiliation: Centre for Infectious Diseases, Parasitology Unit, Heidelberg University Hospital, Heidelberg, Germany.|Center for Childhood and Adolescent Medicine, General Pediatrics, University Hospital, Heidelberg, Heidelberg, Germany.|German Centre for Infection Research (DZIF), Heidelberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Pfeil
authors.affiliation: Department of Clinical Neurobiology, Medical Faculty of Heidelberg University and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Julieta
authors.initials: J
authors.lastname: Alfonso
authors.affiliation: Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.|Division of Experimental Radiology, Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Felix T
authors.initials: FT
authors.lastname: Kurz
authors.affiliation: Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany; German Cancer Consortium (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Sahm
authors.affiliation: Division of Experimental Radiology, Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Heiland
authors.affiliation: Department of Clinical Neurobiology, Medical Faculty of Heidelberg University and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hannah
authors.initials: H
authors.lastname: Monyer
authors.affiliation: Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Bendszus
authors.affiliation: Centre for Infectious Diseases, Parasitology Unit, Heidelberg University Hospital, Heidelberg, Germany.|German Centre for Infection Research (DZIF), Heidelberg, Germany.
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Mueller
authors.affiliation: Division of Experimental Radiology, Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.|Experimental Physics V, University of Würzburg, Würzburg, Germany.|NeuroImaging Centre Research, Department of Neuroscience, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Xavier
authors.initials: X
authors.lastname: Helluy
authors.affiliation: Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Pham
mesh_terms: D000818:Animals; D000852:Anopheles / Q000469:parasitology*; D001921:Brain / Q000000981:diagnostic imaging; D004195:Disease Models, Animal; D005260:Female; D005500:Follow-Up Studies; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D016779:Malaria, Cerebral / Q000000981:diagnostic imaging* / Q000469:parasitology; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000000981:diagnostic imaging; D058953:Neural Stem Cells / Q000000981:diagnostic imaging; D009830:Olfactory Bulb / Q000000981:diagnostic imaging; D010962:Plasmodium berghei / Q000502:physiology*; D011859:Radiography