Evaluating Neurodegenerative Biomarkers in Hospitalized Patients With COVID-19, Alzheimer Disease

Jennifer Frontera, MD

Data from a recent study evaluating patients hospitalized with COVID-19 suggest that these patients may experience significant neurodegenerative injury, as their levels of neurodegenerative biomarkers were elevated similarly to those observed in patients with Alzheimer disease (AD). In addition, these higher levels were associated with encephalopathy and worse outcomes when compared with those patients with COVID-19 who did not have neurological symptoms.

The study included a total of 251 patients without a history of dementia, with investigators comparing 7 neurodegenerative markers—serum total tau (t-tau), phosphorylated tau-181 (p-tau181), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), and amyloid-ß40-42—between those that did or did not have encephalopathy, died in-hospital or survived, and those that were discharged to home or other dispositions. 

For those who died in-hospital, levels of t-tau (P <.001), p-tau181 (P = .022), GFAP (P = .001), and NfL (P = .006) were significantly elevated at the time of admission; for those who were discharged to home, t-tau (P = .009), GFAP (P <.001), and NfL (P = .044) were significantly lower. Markers were found to correlate with COVID-19 severity; and NfL, GFAP, and UCHL1 were higher in patients with COVID-19 than in non-COVID controls with mild cognitive impairment (MCI) or AD.

Among those with COVID-19, 31% (n = 78) required mechanical ventilation, 25% (n = 64) died in-hospital, and 53% (n = 124) were discharged home. New neurological events during hospitalization occurred in 48% (n = 120) of patients, with the most common diagnoses being toxic metabolic encephalopathy in 63% (n = 75) and hypoxic/ischemic brain injury in 46% (n = 55). Due to the limited sample availability, there was variation in the number of patients tested for each biomarker: NfL, GFAP, and UCHL1 were assayed in 246 patients each, t-tau in 241 patients, p-tau181 157 patients, Aβ40 in 146 patients, and Aβ42 in 120 patients. In the control group, 161 individuals underwent neurodegenerative biomarker testing (cognitively normal, n = 54; MCI, n = 54; AD, n = 53).

To learn more about study findings, NeurologyLive^® sat down with lead author Jennifer Frontera, MD, professor of neurology, NYU Langone Grossman School of Medicine. In that conversation, Frontera outlined the key takeaways from the study, offering her perspective on the importance of preventative measures and directions for future long-term research. 

NeurologyLive^®: What were the motivations behind the study?

Jennifer Frontera, MD: We had a large cohort study during the first wave in New York City looking prospectively at neurological events in patients that were hospitalized with COVID. As part of this, we had banked blood specimens, through some of the other research networks and biorepositories at NYU. So, we had the opportunity to go back and look at some of these blood specimens using a relatively new technology, which is able to measure very, very small amounts of certain biomarkers within a blood sample—1 molecule in 1 mL of blood sample, it can measure, detect some of these neurodegenerative biomarkers, as well as inflammatory biomarkers, and so forth. 

Using this new technology, we wanted to look at these blood specimens for markers of neuronal injury, glial cell injury, axonal injury, etc., just to see if there's any correlation between the neurological symptomatology we were seeing in these patients, and more concrete evidence of actual brain cell injury, sort of like a troponin for the brain, in a way. We looked at those markers, that were primarily collected at the time of admission for COVID hospitalization, and then we correlated them with evidence of neurological injury—clinically, most commonly, encephalopathy, which was the most frequent neurological type of injury that we witnessed in these hospitalized COVID patients.

What were the key findings? Were any surprising in any way?

I was lucky enough to work with Thomas Wisniewski, MD, who is the head of our Alzheimer's Disease Research Center, which is an NIH-funded network of Alzheimer's and dementia specialty research centers. Effectively, we were able to leverage that by looking at a control population, pre-2020, that did not have COVID, obviously, but had clinical testing to categorize them into different areas of cognitive decline. There was a group of cognitively normal age-matched patients, patients with mild cognitive impairment, and then patients with Alzheimer's disease, based on established criteria. We were able to compare these biomarker levels in these groups, to the hospitalized COVID patients. 

What we found was, not only were these biomarkers elevated in the COVID patients with neurological injury, compared to those without neurological injury, and were also elevated in patients who died in-hospital, and were significantly lower in the patients who were able to go home, but these neurodegenerative biomarker levels were actually as high as, or higher than, levels observed in patients with Alzheimer's disease. So, that indicates that there's a significant and substantial amount of brain injury that's occurring in some of these patients during their acute hospitalization for COVID. I should note that the patients that had more severe COVID—meaning [they] were more hypoxic, had multisystem organ failure—these were the patients that were more likely to demonstrate elevations in neurodegenerative biomarkers, as well as having symptomatology reflective of neurological injury.

What additional research is needed? What are the remaining questions that need to be answered?

We just looked at one time frame, so it would be important to look serially over time at what happens to these biomarkers. There are some studies suggesting that though they may be high in the acute setting, that they decline thereafter, in the context of COVID and also in the context of other non-COVID illnesses like traumatic brain injury. We also would like to be able to correlate levels of these markers, or trajectories of these markers, over time with actual neuropsychological testing specific for different stages of dementia, for example, or different stages of cognitive disability, as well as functional outcomes in these patients to see how they correlate over time. One long term use might be to be able to look at these biomarkers, which are now experimental, in a more robust clinical context for prognostication for different types of diseases, perhaps patients who have profound hypoxia or cardiac arrest, or any other spectrum of acute neurological injury. The would be the long-term, ideal application outside of the context of COVID itself.

Amid the ongoing COVID-19 pandemic, what are the implications of these findings for clinicians? What should they take away from this study?

The biomarkers underscore the idea that patients that have clinical symptomatology of encephalopathy or confusion are having actual brain cell injury or death, which is substantial and important. I think recognizing encephalopathy, treating the underlying etiologies is really important.

Of note, we excluded patients that were in several path due to sedative medications, but it might also be the case in those patients as well, that the sedatives themselves are detrimental, which we know from robust delirium literature. An easy application then is to really minimize, or limit, sedation use in critically ill patients, particularly, to avoid some of these secondary potential effects. I think, ultimately, unfortunately, the injuries that occur in the acute phase of COVID might have lasting effects, particularly if we know that some brain cells have died or have been substantially injured. [As] always, preventative medicine is crucial in terms of vaccinations, isolation, masking, etc. Some of the newer COVID antiviral medications may play a role also in mitigating neurological injury, including potentially some of the newer monoclonal antibodies that have efficacy against Omicron like sotrovimab.

I think overall, trying to keep patients out of the hospital with preventative medicine or early therapeutics is important because I think most people would agree that neurological injury following COVID is one of the worst-case scenarios. [It] has a profound impact on return to work, functional status, and even quality of life in terms of being able to participate in baseline activities, be it work, leisure, household chores, whatever—the impact can be long lasting. We're still looking at this and trying to uncover this, and this is part of the RECOVER initiative, which is a large multicenter grant. NYU is the Clinical Science Coordinating Center for this. This looks specifically at post-acute sequelae of COVID, and I think it's a robust study [with] large numbers and very well characterized control groups that will really help us understand what we're dealing with long-term, both in the severely affected and the more mildly affected COVID patients.

Transcript edited for clarity.

REFERENCES
1. Blood markers of brain damage are higher over short term in patients who have COVID-19 than in people who have Alzheimer’s disease. News release. NYU Langone Health. January 13, 2022. Accessed January 13, 2022. https://nyulangone.org/news/blood-markers-brain-damage-are-higher-over-short-term-patients-who-have-covid-19-people-who-have-alzheimers-disease
2. Frontera JA, Boutajangout A, Masurkar AV, et al. Comparison of serum neurodegenerative biomarkers among hospitalized COVID-19 patients versus non-COVID subjects with normal cognition, mild cognitive impairment, or Alzheimer’s dementia. Alzheimers Dement. Published online January 13, 2022. doi:10.1002/alz.12556.