Neurofilament light chain plasma levels are associated with area of brain damage in experimental cerebral malaria.

Neurofilament light chain (NfL), released during central nervous injury, has evolved as a powerful serum marker of disease severity in many neurological disorders, including infectious diseases. So far NfL has not been assessed in cerebral malaria in human or its rodent model experimental cerebral malaria (ECM), a disease that can lead to fatal brain edema or reversible brain edema. In this study we assessed if NfL serum levels can also grade disease severity in an ECM mouse model with reversible (n = 11) and irreversible edema (n = 10). Blood-brain-barrier disruption and brain volume were determined by magnetic resonance imaging. Neurofilament density volume as well as structural integrity were examined by electron microscopy in regions of most severe brain damage (olfactory bulb (OB), cortex and brainstem). NfL plasma levels in mice with irreversible edema (317.0 ± 45.01 pg/ml) or reversible edema (528.3 ± 125.4 pg/ml) were significantly increased compared to controls (103.4 ± 25.78 pg/ml) by three to five fold, but did not differ significantly in mice with reversible or irreversible edema. In both reversible and irreversible edema, the brain region most affected was the OB with highest level of blood-brain-barrier disruption and most pronounced decrease in neurofilament density volume, which correlated with NfL plasma levels (r = - 0.68, p = 0.045). In cortical and brainstem regions neurofilament density was only decreased in mice with irreversible edema and strongest in the brainstem. In reversible edema NfL plasma levels, MRI findings and neurofilament volume density normalized at 3 months' follow-up. In conclusion, NfL plasma levels are elevated during ECM confirming brain damage. However, NfL plasma levels fail short on reliably indicating on the final outcomes in the acute disease stage that could be either fatal or reversible. Increased levels of plasma NfL during the acute disease stage are thus likely driven by the anatomical location of brain damage, the olfactory bulb, a region that serves as cerebral draining pathway into the nasal lymphatics.

Transcellular blood-brain barrier disruption in malaria-induced reversible brain edema.

Brain swelling occurs in cerebral malaria (CM) and may either reverse or result in fatal outcome. It is currently unknown how brain swelling in CM reverses, as brain swelling at the acute stage is difficult to study in humans and animal models with reliable induction of reversible edema are not known. In this study, we show that reversible brain swelling in experimental murine CM can be induced reliably after single vaccination with radiation-attenuated sporozoites as proven by in vivo high-field magnetic resonance imaging. Our results provide evidence that brain swelling results from transcellular blood-brain barrier disruption (BBBD), as revealed by electron microscopy. This mechanism enables reversal of brain swelling but does not prevent persistent focal brain damage, evidenced by microhemorrhages, in areas of most severe BBBD. In adult CM patients magnetic resonance imaging demonstrate microhemorrhages in more than one third of patients with reversible edema, emphasizing similarities of the experimental model and human disease. Our data suggest that targeting transcellular BBBD may represent a promising adjunct therapeutic approach to reduce edema and may improve neurological outcome.