LATEST! Researchers From Massachusetts General Hospital Identify Biomarkers That Can Be Used To Confirm NeuroCOVID Presence In Long COVID Patients

NeuroCOVID: 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.

 
It has been found that individuals with SARS-CoV-2 infection (COVID-19) risk developing long-term neurologic symptoms after infection.
 
The study team identified biomarkers associated with neurologic sequelae one year after hospitalization for SARS-CoV-2 infection. SARS-CoV-2 positive patients were followed using post-SARS-CoV-2 online questionnaires and virtual visits. Hospitalized adults from the pre-SARS-CoV-2 era served as historical controls.
 
More than 40% of hospitalized patients develop neurological sequelae in the year after recovery from acute COVID-19 infection. Age, disease severity, and COVID-19 infection itself was associated with additional risk for neurological sequelae in our cohorts.
 
The NeuroCOVID study findings found that Glial fibrillary astrocytic protein (GFAP) and Neurofilament light chain (NF-L) were significantly elevated in SARS-CoV-2 infection. After adjusting for age, sex, and disease severity, GFAP and NF-L remained significantly associated with longer-term neurological symptoms in patients with SARS-CoV-2 infection.
 
The study team said that GFAP and NF-L warrant exploration as biomarkers for long-term neurologic complications after SARS-CoV-2 infection.
 
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
 
The key findings of the study were:
 
-40% of hospitalized COVID-19 patients developed neurological sequelae after recovery

-Age, disease severity and COVID-19 infection were associated with neurological sequelae
 
-GFAP and NF-L were significantly elevated in SARS-CoV-2 infection compared to controls
 
-GFAP and NF-L were elevated in patients with long-term neurological symptoms
 
The study involved 61 patients with COVID-19. Eight patients (13%) had early in-hospital fatal outcomes and thus were excluded from all further analysis. 21 (40%) patients developed neurologic symptoms within one year after the recovery, of which 20 were from the hospitalized cohort, and only 1 was from the outpatient cohort. 14 patients had more than one neurological symptoms. More specifically, 14 patients developed cognitive impairment, seven patients developed CNS symptoms, 7 patients manifested PNS symptoms, and 9 patients showed signs of musculoskeletal weakness. Of the patients with neurological symptoms, the majority (16 patients, 76%) had received ICU level of care. Within the control population without COVID-19 infection but matched for age, sex and disease severity (n=60), follow-up data was available in 47 patients (78%), of whom 7 (14%) developed neurologic symptoms within one year after hospitalization. Of those, 3 patients ha d received ICU level treatment and 4 were treated in a non-ICU setting. Six of the patients that developed neurologic symptoms and 2 patients from the non-neurologic group had undergone brain Magnetic Resonance Imaging (MRI).
 
In the 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.
 
Biomarkers of neural/glial injury and neuroinflammation have long been used in patients suffering TBI (Traumatic Brain Injury), showing diagnostic and prognostic utility. 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.  https://pubmed.ncbi.nlm.nih.gov/32546655/
 
That study however did not show a correlation of neurological outcome symptoms with disease severity.
 
Although 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. 
 
Importantly 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.
https://pubmed.ncbi.nlm.nih.gov/33031735/
 
https://pubmed.ncbi.nlm.nih.gov/32402155/
 
https://pubmed.ncbi.nlm.nih.gov/32437497/
 
https://pubmed.ncbi.nlm.nih.gov/33015653/
 
https://pubmed.ncbi.nlm.nih.gov/32530583/
 
https://pubmed.ncbi.nlm.nih.gov/33856027/
 
https://pubmed.ncbi.nlm.nih.gov/32374815/
 
It should be noted that the direct neuro-invasiveness 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.
https://pubmed.ncbi.nlm.nih.gov/32876341/
 
https://pubmed.ncbi.nlm.nih.gov/32753756/
 
https://pubmed.ncbi.nlm.nih.gov/33477869/
 
https://pubmed.ncbi.nlm.nih.gov/33433624/
 
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/ischemic changes, hemorrhagic 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.
https://pubmed.ncbi.nlm.nih.gov/33031735/
 
https://pubmed.ncbi.nlm.nih.gov/33856027/
 
Interestingly, lesions in these areas of the brain were also confirmed in patients of the 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-.
https://pubmed.ncbi.nlm.nih.gov/32883670/
 
https://pubmed.ncbi.nlm.nih.gov/32816764/
 
https://pubmed.ncbi.nlm.nih.gov/32544034/
 
The brain injury biomarkers that the study team have characterized have been studied in the context of other neurological diseases, including Alzheimer’s disease and traumatic brain injury (TBI).
 
GFAP is an astrocytic biomarker that is elevated during neuronal injury, glial activation and scarring.
https://pubmed.ncbi.nlm.nih.gov/32546655/
 
https://www.nature.com/articles/s41598-020-70266-w
 
https://pubmed.ncbi.nlm.nih.gov/33875374/
 
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.
https://pubmed.ncbi.nlm.nih.gov/28404801/
 
https://pubmed.ncbi.nlm.nih.gov/32546655/
 
https://pubmed.ncbi.nlm.nih.gov/34333238/
 
The study team interestingly observed that there appears to be considerable biomarker and symptom overlap between patients with TBI and post-COVID neurological sequelae.
 
Although 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.
 
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.
 
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).
https://www.nature.com/articles/s41586-021-03710-0
 
Microglial stimulating molecules such as MCP-4 and TIM-3 are implicated in monocyte activation, neutrophilic recruitment, neuroinflammation microglial activation.
 
 In the 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.
 
The study team said that further studies are warranted to evaluate the effectives of using these two biomarkers to identify Long COVID patients with NeuroCOVID conditions.
 
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