Markers of neurodegeneration were elevated in patients hospitalized with Covid-19, a retrospective study found.

Of blood biomarkers measured at admission, total-tau (t-tau), phosphorylated tau-181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were significantly elevated in patients with encephalopathy and in those who died in-hospital, reported Thomas Wisniewski, MD, of New York University in New York City, and co-authors, in Alzheimer’s & Dementia.

Biomarker levels increased with older age and severity of Covid illness, the researchers noted.

“Furthermore, we found that levels of NfL, GFAP, and UCHL1 [ubiquitin carboxyl-terminal hydrolase L1] were as high as, or significantly higher than, those observed in non-Covid patients with Alzheimer’s dementia (AD), indicating a profound neurological insult in these patients,” they wrote.

“Traumatic brain injury, which is also associated with increases in these biomarkers, does not mean that a patient will develop Alzheimer’s or related dementia later on, but does increase the risk of it,” Wisniewski said in a press release. “Whether that kind of relationship exists in those who survive severe Covid-19 is a question we urgently need to answer with ongoing monitoring of these patients.”

The researchers analyzed data from a subset of patients (n=251; median age 71, males 63%) from the Study of Neurologic and Psychiatric Events in Acute Covid-19 cohort. All were admitted to New York City area hospitals between March 2020 and May 2020 and had reverse-transcriptase polymerase-chain-reaction (RT-PCR) positive SARS-CoV-2 infection. Patients with a history of any cognitive impairment, decline, or dementia were excluded.

Primary outcomes assessed markers that were measured once, at admission, in Covid-19 patients with toxic-metabolic encephalopathy (TME) or other encephalopathy versus those without; people who died in-hospital versus those who survived; and survivors discharged home versus discharged to places other than home.

A secondary outcome compared hospitalized Covid-19 patient markers with a control population of non-Covid, pre-pandemic patients who had blood banked before January 1, 2020. Controls were chosen from the NYU Alzheimer’s Disease Research Center Clinical Core cohort and included people who were cognitively normal (n=54, median age 71), had mild cognitive impairment (n=54, median age 77), and Alzheimer’s dementia (n=53, median age 82). All control group measurements were plasma rather than serum.

“Though NfL, GFAP, and UCHL1 levels are equivalent in serum and plasma, we were unable to compare t-tau, p-tau181, or Aβ levels to controls due to differences in specimen type,” the authors noted.

In addition to inflammatory markers like interleukin-6 (IL-6), C-reactive protein (CRP), and D-dimer, serum neurodegenerative markers that were assessed included:

  • NfL (n=246), an intermediate filament protein integral to axons in the central and peripheral nervous systems.
  • GFAP (n=246), an indicator of glial or astrocytic injury.
  • UCHL1 (n=246), a neuron specific protein.
  • Tau proteins, including t-tau (n=241), a neuron-specific protein; a phosphorylated form, p-tau181 (n=157), is specific for AD-type pathology.
  • Amyloid beta (Aβ) 40 (n=146) and Aβ-42 (n=120), which are specific biomarkers for AD pathology.

“Notably, UCHL1, GFAP, tau, and NfL are also elevated after blood–brain barrier disruption, which has been documented in neuropathological studies of Covid-19 decedents as well as in AD,” the authors wrote.

Of hospitalized Covid-19 patients, 31% were admitted to the ICU and intubated for a median of 11.6 ventilator days. Any new neurological event was seen in 48%, most frequently TME (30%) and hypoxic/ischemic brain injury (22%), any type of stroke (6%), seizure (4%), myopathy (2%), and movement disorder (1%). No cases of Guillain-Barre syndrome, encephalitis/meningitis, or myelopathy/myelitis were seen. Discharge was to home in 53% of patients, and 25% died in hospital.

Among hospitalized Covid-19 patients, per 10 pg/mL change in each biomarker:

  • P-tau 181 (HR 1.86, 95% OR 1.18-2.95, P=0.007) and UCHL-1 (HR 1.10, 95% OR 1.00-1.02, P=0.037) had significant associations for patients with TME.
  • GFAP (HR 1.004, 95% OR 1.000–1.01, P=0.027) and the ratio p-tau181/Aβ42 (per 1 unit change in ratio, HR 1.05, 95% OR 1.01–1.08, P=0.045) were associated with death.
  • T-tau (HR 0.02, 95% OR 0.001–0.37, P=0.008), GFAP (HR 0.99, 95% OR 0.99–1.00, P=0.012), and NfL (HR 0.94, 95% OR 0.91–0.97, P<0.001) had significant associations with discharge home.

“Higher admission levels of neuronal degeneration markers ptau181 and UCHL1 were significantly associated with TME, even after adjusting for age, sex, race, prior neurological disease, and severity of Covid-19 illness,” the authors noted. “Similarly, in multivariable analyses, elevations in total tau, NfL, and GFAP, in particular, were associated with reduced likelihood of discharge home.”

Limitations of the study include the possibility that some hospitalized Covid-19 patients had preclinical or undiagnosed dementia, though researchers excluded patients with a history of dementia or cognitive decline. In addition, biomarkers were measured at one time point only, and inflammatory markers (e.g., IL-6, CRP, D-dimer) were not available for control patients.


This study was funded by a grant from the National Institute on Aging.

Wisniewski was a board member of the NYC chapter of the Alzheimer’s Association; he holds patents unrelated to this manuscript.



Paul Smyth, MD, Contributing Writer, BreakingMED™

Kaiser Health News

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