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. 2022 May;18(5):899-910.
doi: 10.1002/alz.12556. Epub 2022 Jan 13.

Comparison of serum neurodegenerative biomarkers among hospitalized COVID-19 patients versus non-COVID subjects with normal cognition, mild cognitive impairment, or Alzheimer's dementia

Jennifer A Frontera  1 , Allal Boutajangout  1 , Arjun V Masurkar  1 , Rebecca A Betensky  2 , Yulin Ge  1 , Alok Vedvyas  1 , Ludovic Debure  1 , Andre Moreira  1 , Ariane Lewis  1 , Joshua Huang  1 , Sujata Thawani  1 , Laura Balcer  1 , Steven Galetta  1 , Thomas Wisniewski  1
Affiliations

Comparison of serum neurodegenerative biomarkers among hospitalized COVID-19 patients versus non-COVID subjects with normal cognition, mild cognitive impairment, or Alzheimer's dementia

Jennifer A Frontera et al. Alzheimers Dement. 2022 May.

Abstract

Introduction: Neurological complications among hospitalized COVID-19 patients may be associated with elevated neurodegenerative biomarkers.

Methods: Among hospitalized COVID-19 patients without a history of dementia (N = 251), we compared 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 beta (Aβ40,42) between patients with or without encephalopathy, in-hospital death versus survival, and discharge home versus other dispositions. COVID-19 patient biomarker levels were also compared to non-COVID cognitively normal, mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia controls (N = 161).

Results: Admission t-tau, p-tau181, GFAP, and NfL were significantly elevated in patients with encephalopathy and in those who died in-hospital, while t-tau, GFAP, and NfL were significantly lower in those discharged home. These markers correlated with severity of COVID illness. NfL, GFAP, and UCHL1 were higher in COVID patients than in non-COVID controls with MCI or AD.

Discussion: Neurodegenerative biomarkers were elevated to levels observed in AD dementia and associated with encephalopathy and worse outcomes among hospitalized COVID-19 patients.

Keywords: Alzheimer's disease; COVID-19; SARS-CoV-2; biomarker; glial fibrillary acidic protein; mortality; neurodegeneration; neurofilament light chain; tau.

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Conflict of interest statement

Drs. J.A. Frontera, L. Balcer, and T. Wisniewski received support from NIH/NIA (PI: Wisniewski) COVID‐19 administrative supplement 3P30AG066512‐01, which supported the work of this manuscript. Drs. T. Wisniewski, A. Masurkar, R. Betensky, and A. Vedvyas received funding from P30AG066512‐01, which also supported the work of this manuscript. Dr. Y. Ge also received support from NIH grants RF1 NS11041, R01 NS108491, and R13 AG067684, as well as a grant from the Alzheimer's Association (AARG‐17‐533484) that supported his effort on this manuscript. Support outside the submitted work includes Dr. Frontera served on the advisory boards of NIH/NINDS SHINE and DSMB. Dr. Frontera is a member of these societies: Neurocritical Care Society and the American Neurological Association. Dr. A Boutajangout has received support from the Amylon Therapeutic Company and a grant from the Saudi Arabia Cultural Mission. Dr. A. Masurkar received support from NIH/NIA grants RF1AG072507, R21AG070880, P30AG066512, as well as BrightFocus Foundation A2019602S and AACF‐17‐524288. Dr. Masurkar has given a seminar at Rockefeller University. Dr. Masurkar also serves on the steering committee of the Alzheimer's Disease Cooperative Study (unpaid), the Council of the Alzheimer's Association International Research Grants Program (for which he received free ISTAART membership 2020 & 2021), the editorial advisory board of the Journal of Neuro‐Ophthalmology (unpaid). Dr. R. Betensky has received support from NIH grants 5R01NS094610‐05, 1R25AG067931‐01, 5P30DK040561‐24, 2P01AG036694‐11, and R01DA054990‐01. Dr. Betensky received payment for expert testimony from the attorneys for plaintiffs in Bard vena cava litigation, from Teva for a patent case, from Amarin for a patent case, and from Amazon. Dr. Betensky also is an advisor for the National Cancer Institute Board of Epidemiology and Clinical Sciences (and received consulting fees). Dr. Y. Ge has received support from NIH grants RF1NS11041, R01 NS108491, and R13AG067684, as well as from the Alzheimer's Association grant AARG‐17‐533484. Mr. A. Vedvyas has received support from NIH Grant P30AG066512. Mr. L. Debure has nothing to disclose. A. Moreira has served on the advisory board of the Olympus Corporation and is a member of the Binford Dammin Society of Infectious Disease Pathologists. A. Lewis received support from the ABPN. A. Lewis is a deputy editor of Seminars in Neurology (for which he receives payment) and is a member of Neurodiem Ology. A. Lewis has unpaid positions as Ethics committee chair, in the Neurocritical Care Society Steering committee, the World brain death project, and as a deputy editor of Neurology. Drs. J. Huang, and S. Thawani have nothing to disclose. Dr. S. Galetta has been a consultant for Biogen and Genentech. Other relationships/interests/activities include Dr. T. Wisniewski is chief editor of Frontiers in Aging Neuroscience. Dr. T. Wisniewski was a board member of the NYC chapter of the Alzheimer's Association. Drs. T. Wisniewski and A. Boutajangout hold patents unrelated to this manuscript. Dr. R. Betensky services on safety monitoring boards of Apotex, Reata, Biogen, PTI, and Alexion, as well as being an advisor to Alexion, Apotex, Reata, Biogen, and PTI. Dr. Betensky has given seminar at the University of Vigo.

Figures

FIGURE 1
FIGURE 1
Flowchart of patient inclusion. Aß, amyloid beta; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; pTau, phosphorylated tau; SNaP Acute COVID, Study of Neurologic and Psychiatric Events in Acute COVID‐19; UCHL1, ubiquitin carboxyl‐terminal hydrolase isozyme L1
FIGURE 2
FIGURE 2
Serum neurodegenerative biomarkers in hospitalized COVID‐19 patients (N = 251) with and without toxic metabolic encephalopathy (TME), in‐hospital death versus survival, and discharge home versus other discharge dispositions. GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; pTau, phosphorylated tau; UCHL1, ubiquitin carboxyl‐terminal hydrolase isozyme L1
FIGURE 3
FIGURE 3
Plasma neurodegenerative biomarkers in controls (N = 161 no cognitive impairment, mild cognitive impairment, and AD dementia patients) and serum biomarker levels in hospitalized COVID patients (N = 251). NfL, GFAP, and UCHL1 levels were significantly higher in COVID patients compared to no cognitive impairment, and MCI patients; and NfL and GFAP were additionally significantly higher than AD patients, after adjusting for age and sex differences between groups. Abeta, amyloid beta; AD, Alzheimer's disease; GFAP, glial fibrillary acidic protein; MCI, mild cognitive impairment; NfL, neurofilament light chain; pTau, phosphorylated tau; UCHL1, ubiquitin carboxyl‐terminal hydrolase isozyme L1
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