Imaging Experimental Cerebral MalariaIn Vivo: Significant Role of Ischemic Brain Edema

Abstract

The first in vivo magnetic resonance study of experimental cerebral malaria is presented. Cerebral involvement is a lethal complication of malaria. To explore the brain of susceptible mice infected with Plasmodium berghei ANKA, multimodal magnetic resonance techniques were applied (imaging, diffusion, perfusion, angiography, spectroscopy). They reveal vascular damage including blood-brain barrier disruption and hemorrhages attributable to inflammatory processes. We provide the first in vivo demonstration for blood-brain barrier breakdown in cerebral malaria. Major edema formation as well as reduced brain perfusion was detected and is accompanied by an ischemic metabolic profile with reduction of high-energy phosphates and elevated brain lactate. In addition, angiography supplies compelling evidence for major hemodynamics dysfunction. Actually, edema further worsens ischemia by compressing cerebral arteries, which subsequently leads to a collapse of the blood flow that ultimately represents the cause of death. These findings demonstrate the coexistence of inflammatory and ischemic lesions and prove the preponderant role of edema in the fatal outcome of experimental cerebral malaria. They improve our understanding of the pathogenesis of cerebral malaria and may provide the necessary noninvasive surrogate markers for quantitative monitoring of treatment.

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

“…Brain edema or swelling was documented in infected wild-type mice during acute CM by measuring 3 distances in the brain ( Figure 2D): (1) line 1 from the pituitary gland to the aqueduct of Sylvius, (2) median line 2 crossing the medial cerebellar nucleus, and (3) medium line 3 stemming from the cerebellar obex. 26 Distances 1 and 3 were significantly increased and distance 2 was significantly reduced in infected wild-type mice compared with noninfected mice (Figure 2D), in agreement with data from Penet et al 26 In contrast, these metric parameters were not significantly altered in infected PKC--deficient mice compared with noninfected PKC--deficient or wild-type mice ( Figure 2D). …”

In the Eye of Experimental Cerebral Malaria

“…As previously described, 4 severe CM was associated with massive brain edema and focal parenchymal lesions that were detected as hyperintensities or hypointensities on T 2 -weighted images ( Figure 1 A-D). Alteration of the external and internal capsules ( Figure 1, A and D) and cerebral hemorrhages ( Figure 1E) were detected in all cases of severe CM.…”

“…Hyperintense parenchymal lesions in the caudate putamen, corpus callosum, and external capsule were detected on sagittal and axial T 2 -weighted images in severe CM animals 4 but not in early CM mice ( Figure 1, A and B). In addition, hyperintensities in the piriform cortex and in the olfactory bulbs were observed in severe CM animals (Figure 1, A and B).…”

“…The small number of experimental CM (ECM) imaging studies 4 -7 conducted have identified hallmarks of the disease at its most acute stage and at an earlier stage already characterized by significant brain swelling. 4 However, the field lacks a thorough and extensive account of early MRI-detectable markers of CM visible before the onset of cerebral edema. It is essential, therefore, that early sensitive indices of disease be identified.…”

“…The use of MRI in a clinically relevant animal model is an approach that allows investigation of the acute effects of parasitic infection and host immune response on the brain. Previously, we performed the first in vivo MRI studies of ECM-susceptible or ECM-resistant mice infected with Plasmodium berghei ANKA (PbA) at 4.7 T. 4,8 We showed that ECM is characterized by blood-brain barrier breakdown, hemorrhages, reduced brain perfusion, ischemia, hemodynamic dysfunction, and brain edema. We identified that a potential cause of death in CM was compression of the cerebral arteries by a swollen cerebrum, resulting in a severe reduction in cerebral blood flow.…”