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Blood test could determine cause of brain injury in newborns and aid treatment decisions

12th February 2024

Patterns of gene expression that are detectable in the blood could determine the cause of hypoxic-ischemic encephalopathy (HIE) in babies, according to a new study.

This means that a simple blood test could show doctors whether a newborn is likely to respond to whole-body hypothermia – the standard treatment used in high-income countries.

The study, published in the journal JAMA Network Open and led by Imperial College London and its South Asian partners, considered whether genome expression profiles at birth in neonates with HIE in a high-income country differed from those of their counterparts in low-income countries.

It also sought to determine why babies with HIE in low-income countries appear to have worse outcomes and increased mortality risk when treated with therapeutic hypothermia when compared to those in high-income countries.

The researchers found that the disease mechanisms underlying HIE were primarily associated with acute hypoxia in the Italian cohort and nonacute hypoxia in the South Asia cohort.

This finding might explain the lack of hypothermic neuroprotection, they concluded.

Study co-author Professor Swati Manerkar, from Lokmanya Tilak Municipal Medical College in Mumbai, India, said: ‘We were expecting to see some differences in gene expression between babies in the cohorts – but not such a dramatic divergence.

‘It clearly shows that we are seeing are very different causes of brain injury between the two groups, with different characteristics which also helps to explain why some babies respond to cooling and others are harmed by it.’

Differing gene expression patterns

Blood samples were taken shortly after birth from 35 babies born with moderate or severe HIE in Italy (high-income country) and 99 babies born in India, Sri Lanka and Bangladesh (low-income countries).

A total of 14 babies from Italy were also included as healthy controls, and all cohorts were medically assessed at 18 months of age.

Half the babies in the South Asian cohort died or developed severe disabilities (51 of 99), as did a quarter of the Italian cohort (9 of 35).

A total of 1,793 significant genes in the Italian cohort and 99 significant genes in the South Asia cohort were associated with adverse outcome (false discovery rate <0.05).

Only 11 of these genes were in common, and all had opposite direction in fold change.

The most significant pathways associated with adverse outcome were downregulation of eukaryotic translation initiation factor 2 signalling in the Italian cohort (z score = −4.56; P < .001) and aldosterone signalling in epithelial cells in the South Asia cohort (z score = null; P < .001).

The genome expression profile of neonates with HIE (n = 35) at birth, 24 hours, 48 hours and 72 hours remained significantly different from that of age-matched healthy controls in the HIC cohort (n = 14).

Brain injury and socioeconomic factors

Lead investigator, Professor Sudhin Thayyil, professor of perinatal neuroscience and director of the Centre for Perinatal Neuroscience at Imperial College London, said: ‘The gene expression patterns we saw in babies from [low-income countries] were similar to what you would see in people with sleep apnoea, suggesting that they experienced intermittent hypoxia in the womb and at birth.

‘We believe this is brought on by multiple chronic stresses during pregnancy such as poor nutrition or infection, as well as the normal labour process and uterine contractions, which leads to further hypoxia and ultimately injury to the baby’s brain.’

He added: ‘On the other hand, gene expression patterns in babies from [high-income countries] suggested a single, acute cause of brain injury, for example complications during birth like maternal bleeding, leading to a sudden drop in blood oxygen levels in the foetus.’

The differences between the cohorts are not related to ethnicity, but rather socioeconomic factors, the researchers stressed.

As such, the type of chronic brain injury commonly seen in low-income countries is also likely to be present in deprived areas in high-income countries, they said.

Professor Thayyil concluded: ‘The key for clinicians, anywhere in the world, is to be able to identify which type of brain injury they are dealing with as soon as possible – and that’s something we’re currently working on.’

Neurofilament light prognostic biomarker of choice for neurological outcomes after cardiac arrest

7th March 2022

Neurofilament light is the best prognostic marker of neurological outcomes after a cardiac arrest in those with hypoxic ischaemic brain injury

Neurofilament light is the best biomarker for the assessment of brain injury in patients who experience hypoxic ischaemic brain injury (HIBI) after the return of spontaneous circulation following a cardiac arrest. This was main finding of a systematic review and meta-analysis by a team from the Division of Critical Care Medicine, Vancouver General Hospital, Vancouver, Canada.

Hypoxic-ischaemic brain injury, represents a recognised consequence of cardiac arrest. For example, in one study examining the cause of death after an out-of-hospital cardiac arrest, it was found that neurological injury was responsible for two-thirds of all deaths.

In fact, HIBI after cardiac arrest is a leading cause of mortality and long-term neurologic disability in survivors. Moreover, patients with HIBI are at a high risk for secondary brain injury from, for example, brain oedema, tissue ischaemia and haematoma expansion.

Biomarkers can be used to identify those at risk through the provision of prognostic information and two such marker, neuron specific enolase (NSE) and S-100B are released following injury to neurons and glial cells, respectively and their blood values are presumed to correlate with the extent of HIBI following a cardiac arrest.

Others include neurofilament light (which reflects white matter damage) and tau although the relative prognostic value of these biomarkers has not been evaluated.

For the present analysis, the Canadian team searched electronic databases for studies using biomarkers including neuron specific enolase, S100 beta, S100 calcium binding protein, tau and neurofilament light.

They included only those for which at least one of the biomarkers was used to prognosticate the neurological outcome for patients with HIBI after a cardiac arrest. The team calculated the summary receiver operating characteristic curve (SROC) for each biomarker at 48 hours after the cardiac arrest and used this as the primary outcome measure.

Subgroup analysis was performed comparing with targeted temperature management (TTM), which is a recognised method designed to minimise post-anoxic injury and improving neurological outcome after cardiac arrest.

Neurofilament light and predictive value for neurological outcomes

A total of 86 studies with 10, 567 patients and a mean age of 62.8 years (73.6% male) were included in the final analysis.

In terms of the SROC, neurofilament light had the highest area under the curve (AUC) for predictive value of unfavourable neurological outcomes, with a value of 0.92 (95% CI 0.84 – 0.97), followed by tau with an AUC of 0.89 (95% CI 0.71 – 0.97). This was higher than neuron-specific enolase (AUC = 0.84) and S100 calcium (AUC = 0.85).

When compared with TTM, SROC curves were calculated for each biomarker and the results did not differ appreciably and neurofilament light still had the highest AUC (0.92, 95% CI 0.86 – 0.95).

The authors concluded that neurofilament light which is a biomarker for white matter damage, was associated with the highest accuracy to predict unfavourable neurological outcomes in those with HIBI after a cardiac arrest.

Citation
Hoiland RL et al. Neurologic Prognostication After Cardiac Arrest Using Brain Biomarkers: A Systematic Review and Meta-analysis. JAMA Neurol 2022

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