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

  1. Jennifer A. Frontera
  2. Allal Boutajangout
  3. Arjun V. Masurkar
  4. Rebecca A. Betensky
  5. Yulin Ge
  6. Alok Vedvyas
  7. Ludovic Debure
  8. Andre Moreira
  9. Ariane Lewis
  10. Joshua Huang
  11. Sujata Thawani
  12. Laura Balcer
  13. Steven Galetta
  14. Thomas Wisniewski

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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.

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  1. Version published to 10.1002/alz.12556
  2. ScreenIT

    SciScore for 10.1101/2021.09.01.21262985: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsConsent: For our current study, inclusion criteria were: hospital admission, reverse-transcriptase-polymerase-chain-reaction (RT-PCR) positive SARS-CoV-2 infection from nasopharyngeal sampling, and consent to store blood biospecimens in the NYU Center for Biospecimen Research and Development biorepository for use in experimental analyses.
    IRB: Standard Protocol Approvals and Patient Consents: This study was approved by the NYU Grossman School of Medicine Institutional Review Board.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    BlindingInvestigators running the experiments were blinded to study group assignments.
    Power AnalysisAssuming a power of 80% and an alpha=0.05, 42 TME cases and 126 non-TME patients (total N=168) would be needed to detect a 25% difference in NFL, 62 TME cases and 186 non-TME patients (total N=248) would be needed to detect a 25% difference in UCHL-1, 38 TME cases and 1114 non-TME patients (total N=152) would be needed to detect a 25% difference in GFAP, 104 TME cases and 312 non-TME patients (total N=416) would be needed to detect a 25% difference in total tau levels, 33 TME cases and 99 non-TME patients (total N=132) would be needed to detect a 25% difference in Aß-40 levels, and 40 TME cases and 120 non-TME patients (total N=160) would be needed to detect a 25% difference in Aβ-42 levels.

    Table 2: Resources

    Recombinant DNA
    SentencesResources
    Study Outcomes: The primary outcomes were serum levels of Tau, pTau181, NFL, GFAP, UCHL1, Aβ-40, Aβ-42, the ratio of Aβ-42/Aβ-40 and the ratio of pTau181/Aβ-42 compared between hospitalized COVID-19 patients who: 1) developed TME versus those who did not, 2) died in-hospital/discharged to hospice versus those who survived to discharge, and 3) were discharged home versus other discharge dispositions (in-hospital death/hospice, discharge to a nursing home, long-term acute care facility, acute or subacute rehabilitation facility).
    pTau181/Aβ-42
    suggested: None
    Software and Algorithms
    SentencesResources
    Control populations of non-COVID-19 subjects with blood samples banked prior to January 1, 2020 (prior to the first reported cases of SARS-CoV-2 infection in NYC) were selected from the NYU Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort.
    ADRC
    suggested: None
    Analyses were conducted using IBM SPSS Statistics for Mac V25 (IBM Corp., Armonk, NY) and R studio V1.1.456.
    SPSS
    suggested: (SPSS, RRID:SCR_002865)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    We did not, however, identify correlates with blood Aβ-40 or Aβ-42 levels, which may indicate limitations in this assay or lack of a relationship in our cohort. Elevations in blood and CSF NFL, GFAP and total tau among COVID-19 patients have been described by others, and in some cases, compared to normal control groups (4-6, 8, 9, 40-44). However, none of these studies explicitly excluded COVID-19 patients with a baseline history of dementia or cognitive decline, which likely would confound results. Additionally, NFL is not specific to the CNS and can be elevated in the context of peripheral neuropathy (45-47), including COVID-related critical illness neuropathy/myopathy (7) and Guillain-Barre Syndrome(47). Similarly, elevated GFAP has been reported in COVID-19 patients with critical illness neuropathy/myopathy and levels correlate with nerve amplitudes (7). More AD-specific biomarkers, such as pTau181 have not previously been explored in COVID-19 patients. In neuropathological studies of plasma pTau181 and NFL, both biomarkers accurately distinguish pathology confirmed AD from healthy controls, but only pTau181 distinguished AD from non-AD dementia cases and showed specificity for neuritic plaque pathology and Braak stage (14, 48). Similarly, pTau181 levels escalate progressively with worsening clinical dementia rating (CDR) scores and correlate with multiple cognitive domains, while NFL, total tau and amyloid ß levels do not perform as well(15, 49). We identified elevations...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  3. Version published to 10.1101/2021.09.01.21262985v1 on medRxiv