Thread by @AndreaLConroy

This paper has many interesting findings but I wanted to focus on the #brain-#kidney axis. What is the relationship between the kidneys and brain injury in malaria? Can measuring tau levels help us identify children at risk of long-term brain injury? Let's discuss! 🧵

Last year there were an estimated 627 000 malaria deaths with 80% of African deaths occurring in children <5 years of age. Unfortunately, due to COVID-19 disruptions in public health measures to control malaria, this is higher than in previous years.

Survivors are at risk of long-term brain injury. We need tools to identify children at risk of brain injury for early interventions so that every child has an opportunity to survive, and thrive.
who.int/teams/global-m….

Previously, the brilliant Dr. Datta discovered that tau-- a marker of axonal injury-- could identify children at risk of long-term cognitive injury following cerebral malaria. 👇👇👇 academic.oup.com/cid/advance-ar…

The tau findings suggested injury to the axons could be related to brain injury in children after cerebral malaria and could identify children at long-term risk of cognitive deficits. The problem? Lumbar punctures are invasive and only performed when clinically necessary.

What about measuring tau in blood? Normally the blood-brain barrier does a good job of preventing unwanted proteins from crossing into the brain from the blood (and vice versa). So you don't expect to see tau in the blood. EXCEPT...

Children with malaria have can have activated and leaky blood vessels which can lead to blood-brain barrier dysfunction. Also, there are new technologies making it possible to detect tau at very low concentrations.

Dibya used a new @QuanterixSimoa technology that is *ultra-sensitive* to see whether she could detect tau in the blood of children with severe malaria.

Using a population of Ugandan community children, we showed that children with BOTH cerebral malaria and severe anemia had elevated tau. And in children with coma, plasma tau correlated with tau in the cerebrospinal fluid.

Like in CSF, plasma tau predicted children long-term neurodisability and cognitive injury in children with cerebral malaria with those <5 years of age at the time of malaria at the highest risk of injury. Children with the highest tau were most at risk of severe, long-term injury

When evaluating risk factors associated with elevated tau levels, we found it was associated with established pathways of malaria pathogenesis including coagulopathy, cellular injury, and endothelial/blood-brain barrier dysfunction

But what about the kidney? Well, we see that acute kidney injury (#AKI) was associated with elevated tau in children with coma AND severe anemia. Previously, D43 student Benson Ouma showed that AKI was strongly associated with endothelial activation. 👇👇👇ow.ly/KF6b50BiXIy

This supports a growing body of evidence that #AKI is a risk factor for brain injury in children with sepsis and malaria. We need more studies to understand the common mechanisms of brain injury following critical illness.

These findings may suggest that blood vessel integrity is a common pathway of injury in critical illness. And in severe malaria, AKI is one of the strongest predictors of endothelial injury. This study also raises important questions ...👇

Could tau be a common marker of brain injury in children with #AKI? Would it be possible to use tau as a biomarker of brain injury in other clinical settings to facilitate early interventions in kids at risk? Let's wait and see! #PrecisionMedicine

Big thanks to our collaborators at @MakerereCHS @GHU_Official including @pbangirana and our funders @Fogarty_NIH @NINDSfunding.