Researchers identify biomarkers to confirm the presence of NeuroCOVID in long-term COVID patients

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Researchers from Massachusetts General Hospital-USA and Meso Scale Diagnostics, LLC. (MSD), Maryland-USA have identified two biomarkers ie GFAP (Glial fibrillary astrocytic protein) and NF-L (Neurofilament light chain) of which their elevated levels typically indicate the presence of NeuroCOVID or neurological sequelae in Long COVID patients.

The study findings were published as an article in the peer reviewed journal: iScience. 

https://www.cell.com/iscience/fulltext/S2589-0042(22)01105-1

Even prior to the current omicron wave, the number of confirmed cases of COVID -19 mounted to 9.3 million in the UK and 46.4 million in the US with 14–30% of hospitalized patients requiring treatment in the ICU (Grasselli et al., 2020; Huang et al., 2020; Richardson et al., 2020; Worldometers.info, 2021).

Epidemiological studies suggest that a substantial number of patients recovered from acute COVID-19 infection suffer long-term sequelae, termed ‘long COVID’ (Moreno-Pérez et al., 2021; Nune et al., 2021; Taquet, Dercon, et al., 2021). Symptoms have been reported in as many as 1 in 3 patients 3-6 months after recovery from initial infection, with the risk increasing with disease severity (Taquet, Dercon, et al., 2021).

More specifically, epidemiological studies have also noted the increased likelihood of long-term neurological sequelae in recovered COVID-19 patients, with the likelihood rising with disease severity, but the pathophysiologic mechanism remains largely unknown (Graham et al., 2021; Logue et al., 2021; Taquet, Geddes, et al., 2021).

In our study, more than 34% of patients infected with SARS-CoV-2 developed persisting or newly presenting neurological symptoms after disease recovery, especially those that were treated in ICU setting. By this estimation, more than four hundred thousand and two million ICU patients in the UK and US respectively are at risk of developing neurologic symptoms after infection.

Yet, the underlying mechanism of this entity remains largely unknown, highlighting the need for both mechanistic understanding of long- COVID, and biomarkers that may help with diagnosis, prognosis, and prediction of outcomes.

It remains unclear if the development of neurological sequelae is driven solely by the degree of disease severity or if there are unique characteristics specific to the SARS-CoV2 virus that play a role in the pathogenesis of this entity. While our study confirms previous findings that disease severity is associated with neurological symptoms in patients, we further show that SARS-CoV-2 infection itself is additionally associated with the development of neurological sequelae when compared to a cohort of hospitalized patients matched for age and disease severity.

These findings are consistent with a prior epidemiological study that demonstrated the higher likelihood of neurological symptoms in patients with COVID-19 compared to patients infected with influenza (Taniguchi et al., 2022). Additionally, in our cohort, previously described markers of brain injury GFAP and NF-L, were elevated in patients with SARS-CoV-2 infection who developed neurologic symptoms during 1-year follow-up.

While these markers may be expected to increase in older patients and patients receiving ICU care (Chatterjee, Pedrini, Stoops, et al., 2021; Frithiof et al., 2021), our analysis (with residualization for age and disease severity) suggests association of these markers with neurological damage independent of their association with age and disease severity.

Markers of neural/glial injury and neuroinflammation have long been used in patients suffering TBI, showing diagnostic and prognostic utility (Ramlawi et al., 2006; Lumpkins et al., 2008; Shahim et al., 2017, 2020).

Recently, in COVID-19 patients astrocytic and neural injury markers have been correlated to COVID-19 severity but failed to predict subsequent long term neurological outcomes (Kanberg et al., 2021).

However, that study did not show a correlation of neurological outcome symptoms with disease severity which has been shown in several trials (Hopkins and Brett, 2005; Hopkins and Jackson, 2006; Herridge et al., 2016; Ibrahim et al., 2021). While it is clear that ICU level care and disease severity (likely associated with higher levels of peripheral inflammation and hypoxemia) in both COVID-19 patients and pre-COVID historical patients is associated with both neurological sequelae and elevated brain injury, infection with SARS-CoV2 infection itself appears to markedly increase the likelihood of developing subsequent neurological symptoms.

These findings are in line with several recent autopsy studies that have reported findings of acute hypoxic-injury, hemorrhage, mild to moderate non-specific inflammation, marked microglial activation, transcriptional changes in astroglial cells, and possible neuronal damage (Matschke et al., 2020; Puelles et al., 2020; Schaller et al., 2020; Schurink et al., 2020; Solomon et al., 2020; Wichmann et al., 2020; K. T. Thakur et al., 2021).

Of note, the direct neuroinvasiveness and neurotropism of SARS-CoV-2 has now been shown in animal experiments and CNS organoids, where SARS-CoV-2 infection was shown to have detrimental effects to both infected and neighboring neurons (Ramani et al., 2020; Zhang et al., 2020; Kumari et al., 2021; Song et al., 2021). Conversely, evidence for direct SARS-CoV-2 primary infection of brain cells has been limited; two of the largest recent brain autopsy studies from COVID-19 positive patients revealed hypoxic/ischaemic changes,

haemorrhagic infarcts, and microglial activation with microglial nodules, most prominently in the brainstem and periventricular subcortical white matter. However, in all cases viral RNA levels were very low to undetectable, and did not correlate with the histopathological alterations(Matschke et al., 2020; K. T. Thakur et al., 2021).

Interestingly, lesions in these areas of the brain were also confirmed in patients of our study cohort with neurological symptomatology who underwent brain MRI and exhibited scattered microhemorrhages and T2/FLAIR hyperintense foci in the subcortical and periventricular white matter of the cerebral hemispheres and parts of brainstem. In fact, this pattern of neuroimaging abnormalities has been described among the most common brain MRI parenchymal signal abnormalities that have been associated with SARS-CoV-2 (Gulko et al., 2020; Kihira et al., 2020; Kremer et al., 2020).

The brain injury biomarkers we have characterized have been studied in the context of other neurological diseases, including Alzheimer’s disease and traumatic brain injury (TBI) (Mondello et al., 2020; Thijssen et al., 2020; Chatterjee, Pedrini, Ashton, et al., 2021; Cicognola et al., 2021; Clarke et al., 2021). GFAP is an astrocytic biomarker that is elevated during neuronal injury, glial activation and scarring (Ramlawi et al., 2006; Kanberg et al., 2020; Lafrenaye et al., 2020; Frithiof et al., 2021).

NF-L is an intra-axonal structural protein that was found to be elevated after TBI and is also associated with COVID-19 disease severity (Shahim et al., 2017, 2020; Kanberg et al., 2020). Interestingly, we observed that there appears to be considerable biomarker and symptom overlap between patients with TBI and post-COVID neurological sequelae. While direct viral invasion of brain parenchyma is, to date, as mentioned above, limited to the detection of low levels of viral RNA and viral antigens in cranial nerves, in COVID-

19 patients, hypoxia along with neuroinflammation and microglial activation, as has been described both in TBI and more recently, in COVID-19 patients, may contribute to these effects in COVID-recovered patients (Matschke et al., 2020; K. T. Thakur et al., 2021). In fact, microglial hyperactivation in several regions of the brain such as brainstem and hippocampus may serve as the pathological common ground between the shared observed neuropathologies in COVID- 19 and TBI patients (Donat et al., 2017; Lier et al., 2020; Poloni et al., 2021).

In par with that, a recent study profiling COVID-19 patients’ brain tissue, found microglial activation and increased tissue GFAP levels (Yang et al., 2021). Microglial stimulating molecules such as MCP-4 and TIM-3 are implicated in monocyte activation, neutrophilic recruitment, neuroinflammation and microglial activation (Mendez-Enriquez and García-Zepeda, 2013; Koh et al., 2015). In our study, MCP-4 and TIM-3 were also significantly elevated in COVID-19 ICU patients who developed neurologic sequelae, although this likely reflects increased disease severity in these patients.

Nonetheless, immune-mediated neuro-astroglial destruction and hypoxic neuroinflammation could be one of the underlying mechanisms for long-term neurological symptomatology.

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