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Hospitalized patients with COVID-19 and no prior history of dementia had elevated levels of brain injury biomarkers, an observational study showed.

Blood levels of total tau (t-tau), phosphorylated tau181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were significantly elevated in COVID-19 patients with encephalopathy and those who died in the hospital, reported Thomas Wisniewski, MD, of New York University Grossman School of Medicine in New York City, and co-authors.

Levels of NfL, GFAP, and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) were as high or higher in the short term among hospitalized COVID-19 patients without a history of dementia than they were among Alzheimer's patients who never had COVID-19, Wisniewski and colleagues wrote in .

NfL, a marker of axonal injury, was 179% higher in COVID-19 patients than in Alzheimer's patients (73.2 vs 26.2 pg/ml). GFAP, a sign of glial or astrocytic injury, was 65% higher (443.5 vs 275.1 pg/ml); UCHL1, an enzyme found in nerve cells, was 13% higher (43 vs 38.1 pg/ml).

These findings indicate "a profound neurological insult in these patients," the researchers 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 statement.

"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," he added.

The effect of COVID-19 on the brain is a complex question, noted Heather Snyder, PhD, of the Alzheimer's Association, who wasn't involved with the study. "There's a lot that may be happening, and work like this is helping us better understand what underlying biology may be affected in some individuals who experience COVID-19," she told MedPage Today.

"I don't think we yet know what this means long-term," Snyder continued. "It will be really important to follow these individuals and individuals like them so we can understand who may be affected, why they might be affected, and what this might mean for their long-term risk for Alzheimer's and other brain diseases."

The researchers looked at data from 251 hospitalized COVID-19 patients without a history of dementia, assessing seven serum markers of neurodegeneration: t-tau, p-tau181, GFAP, NfL, UCHL1, amyloid beta 40, and amyloid beta 42. Patients were hospitalized in New York City early in the pandemic, from March to May 2020. Blood samples were drawn at hospital admission.

Biomarker levels of hospitalized COVID patients also were compared with 161 controls without COVID-19, including 54 people with no cognitive impairment, 54 people with mild cognitive impairment, and 53 people with Alzheimer's disease dementia. Control populations had blood samples banked before January 2020, before the first reported SARS-CoV-2 cases in New York City. Control samples were of plasma, not serum; this limited some comparisons with COVID-19 patients.

Median age of COVID-19 patients was 71 and 63% were men. In contrast, people in the Alzheimer's dementia group had a median age of 82 and 40% were men.

Of the hospitalized COVID-19 patients, 31% required mechanical ventilation, 25% died in the hospital, and 53% were discharged home. New neurological events during hospitalization occurred in 48% of patients, most commonly toxic-metabolic encephalopathy (TME) and hypoxic/ischemic brain injury.

Elevations in neurodegenerative biomarkers in COVID-19 patients were correlated with older age and increased severity of illness. Higher levels of t-tau, NfL, GFAP, p-tau181, and UCHL1 were seen in COVID-19 patients with TME than in COVID-19 patients without TME.

"Indeed, higher admission levels of neuronal degeneration markers p-tau181 and UCHL1 were significantly associated with TME, even after adjusting for age, sex, race, prior neurological disease, and severity of COVID-19 illness," Wisniewski and co-authors wrote.

"Similarly, in multivariable analyses, elevations in total tau, NfL, and GFAP, in particular, were associated with reduced likelihood of discharge home," they observed. GFAP and the ratio of p-tau181/amyloid beta 42 were associated with in-hospital death.

The analysis had several limitations, the researchers acknowledged. Some COVID-19 patients may have had undiagnosed or preclinical cognitive impairment. In addition, biomarkers were measured only at one time point and the study did not include data about the trajectories of these markers.

"The association of these biomarkers with formal cognitive testing after the acute phase of COVID-19 has not been demonstrated and is an active area of research needed to unravel the long-term cognitive implications of elevated neurodegenerative biomarkers," Wisniewski and colleagues noted.

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