Article in brief
A study in Journal of Alzheimers & Dementia reported that hospitalized COVID-19 patients were at significant risk for brain damage and inflammation as well as elevated biomarkers associated with Alzheimer’s disease, resulting in worse neurological outcomes and an increased risk of death or discharge to a non-home environment.
Elevated levels of biomarkers associated with neurodegeneration, encephalitis, and Alzheimer’s disease in patients admitted with COVID-19 are associated with worse neurological outcomes and an increased risk of death or discharge to a non-home setting.
“In hospitalized COVID patients, there is evidence of very significant brain damage and inflammation, as well as elevation markers associated with Alzheimer’s disease,” said Thomas Wisniewski, MD, professor of neurology, pathology and psychiatry at New York University Grossman School of Medicine, lead author of a study published January 14 in Journal of Alzheimers & Dementia.
The study assessed the presence and levels of neurodegenerative biomarkers in patients admitted with COVID-19 and the association between new neurodegenerative disease on clinical outcomes.
The study is the first to include only patients without a previous history of neurological cognitive problems (eg pre-existing dementia or mild cognitive impairment) in the assessment of neurodegenerative biomarkers in COVID-19 patients – providing a clearer picture of the potential at-risk patients with severe COVID face in developing an acute or new neurological injury. Previous studies looking at neurodegenerative biomarkers in COVID patients have included patients with pre-existing dementia, and therefore the assessment of acute neurological damage related to COVID has been limited by this confusing factor.
In addition, it is the first study to evaluate phosphorylated tau-181 (p-tau181), a biomarker specific for Alzheimer’s disease, and therefore provides new information on the potential risk of severe COVID-19 in acute neurological damage, suggesting on Alzheimer’s disease.
The study included 251 patients from a large cohort of patients prospectively enrolled in the study of neurological and psychiatric events in acute COVID-19 (SNaP Acute COVID). All 251 patients were hospitalized with COVID-19 and gave consent for investigators to evaluate their knocked serum biopsies. The mean age of the patients was 71 years and 63 percent were men.
Using the serum bioassays, the researchers retrospectively analyzed the presence and levels of seven biomarkers: in glial fibrillar acid protein (GFAP), neurofilament light chain (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), total tau (t-tau), p-tau) tau181, and amyloid-beta (Abeta) 40 and Abeta 42, together with the ratio of Abeta 42 / Abeta 40 to the ratio of p-tau18 / Abeta 42.
They also looked retrospectively at diagnoses of new neurological diagnoses made during hospitalization attributed to COVID-19, as well as hospital outcomes such as mortality, discharge disposition (whether discharge to their home, nursing home or other care facility), hospital length of stay and number of days in respirator.
Overall, the study found a positive association between elevated biomarkers and older age and more severe COVID in patients who, for example, needed ventilators. They observed the strongest association between elevated t-tau, p-tau181 and NfL and the severity of the disease. Out of the 251 patients, 120 (48 percent) had new neurological events during hospitalization – toxic-metabolic encephalopathy [TME] was the most common in 75 (63 percent) patients. Patients diagnosed with TME were diagnosed with TME on or within three days of hospitalization. They died in the hospital with a median of 11 days from hospitalization and had a median hospital stay of 10 days.
For the primary outcome of the study, investigators compared serum levels of each of the biomarkers (and the ratio) between inpatient COVID-19 patients who developed TME versus those who did not, as well as on outcomes (e.g., hospitalized or discharged). to hospice versus survivor and discharged, or discharged home patients versus hospital death / hospice or type of facility).
The researchers found significantly elevated levels of t-tau, p-tau181, GFAP, and NfL in patients with TME or in those who died in the hospital, and significantly lower levels of t-tau, GFAP, and NfL in patients who survived COVID. and was discharged home.
To gain a better understanding of the degree of brain damage found in the study, the researchers compared the neurodegenerative biomarker levels for the admitted COVID-19 patients with three control populations without COVID-19: an age-matched cognitive normal cohort, a cohort with mild cognitive impairment, and a cohort of patients with Alzheimer’s disease. Plasma blood samples from all three cohorts were obtained through the NYU Alzheimer’s Disease Research Center.
The results indicate that the neurological damage suffered by the admitted COVID-19 patients is significant, as evidenced by the discovery that these patients had significantly higher levels of NfL, GFAP and UCHL1 compared to all non-COVID-19 patients. patient cohorts, including those with Alzheimer’s disease.
For example, the study found that NfL was 179 percent higher in inpatients COVID-19 patients compared to patients with Alzheimer’s and 400 percent higher compared to age-matched controls.
“Markers of neurodegeneration and neuroinflammation were much higher than what is seen in patients with Alzheimer’s disease and much higher than in age-matched controls,” said Dr. Wisniewski. “Although this is only a cross-sectional analysis at a time, it speaks to the severity of involvement of the central nervous system.”
Despite the differences in the type of blood samples used for this comparison – serum samples for the admitted COVID-19 patients and plasma samples for non-COVID-19 comparison cohorts – Dr. Wisniewski stressed that the comparative results for NfL, GFAP, and UCHL1 are reliable given that when you run the assay for these biomarkers on plasma and serum, you get the same number.
This is not the case when comparing values for t-tau and p-tau181, he said. “For biomarkers like t-tau and p-tau181 you can not compare the values you get between serum and plasma,” he said, adding that serum samples for t-tau and p-tau181 are not reliable and contain too much deviation for to enable a direct comparison with plasma samples.
Although the study did not directly address the risk of worse neurological outcomes or death in patients with COVID-19 and pre-existing neurodegenerative biomarkers, Dr. Wisniewski that it is likely that the increases in neurodegenerative biomarkers in these patients would be more extreme than those found in COVID-19 patients without pre-existing neurodegenerative damage given the significant increases seen in the study in the latter group. In light of these findings, Drs. Wisniewski neurologists and others to recognize the increased incidence and risk of neurodegenerative disorders in post-COVID-19 patients. ‘ them appropriately. “
Tamara Fong, MD, PhD, assistant professor of neurology at Harvard Medical School, said the study was well-designed and provided an important “snapshot” of what might happen to some patients admitted with COVID-19. However, she stressed that it does not confirm causality.
“What we do not yet know is whether there is causality between these biomarkers and long-term cognitive decline,” she said.
The finding of higher levels of tau- and p-tau181, she said, may indicate external influences such as COVID infection and / or TME, which may somehow trigger or accelerate pathology related to Alzheimer’s disease.
“If this is true, then COVID and / or TME prevention is an important approach to minimizing the onset or acceleration of cognitive impairment,” she said.
Eric McDade, DO, associate professor in the department of neurology at the Washington University School of Medicine, pointed to the higher levels of p-tau181 found in the study as one of the most recent contributions from the study. “The team demonstrated that higher levels of p-tau181, which is a relatively specific marker for Alzheimer’s related pathology and not typically associated with acute neurological damage, were also elevated in those with worse neurological outcomes,” he said.
However, he called some of the results “counterintuitive,” such as the discovery that showed a greater chance of being discharged home for every 10 pg / ml increase in serum t-tau levels. “I would expect the opposite,” he said. He also questioned the statistically significant risk patterns for all outcomes found with a few of the biomarkers. “[This] suggests a likely contribution to statistical chance, “he said.
That said, he stressed that the study shows that “the greater the number of brain-related proteins that are elevated when measured in the blood of elderly people hospitalized for COVID-19, the worse the outcome and the higher the probability for acute neurological events. ”
Dr. McDade said the inability to compare serum with plasma samples for t-tau and p-tau181 between COVID-19 patients and non-COVID controls “prohibits this study from testing whether they have abnormal biomarkers of Alzheimer’s disease in the environment” of a non-COVID controller. – Dementia diagnosis significantly increases the risk of worse neurological outcome or death if hospitalized with COVID-19. “