Serum and cerebrospinal fluid biomarker profiles in acute SARS-CoV-2-associated neurological syndromes

Ross W Paterson^{1

2

3}, Laura A Benjamin^{2

4

5

6}, Puja R Mehta², Rachel L Brown^{2

7}, Dilan Athauda^{2

8}, Nicholas J Ashton^{9

10}, Claire A Leckey^{1

2}, Oliver J Ziff⁸, Judith Heaney^{2

11}, Amanda J Heslegrave^{1

2

12}, Andrea L Benedet⁹, Kaj Blennow⁹, Anna M Checkley^{13

14}, Catherine F Houlihan^{13

15}, Catherine J Mummery^{1

2}, Michael P Lunn^{1

2}, Hadi Manji², Michael S Zandi^{1

2}, Stephen Keddie^{1

2}, Michael Chou^{1

2}, Deepthi Vinayan Changaradil³, Tom Solomon^{16

17}, Ashvini Keshavan^{1

2}, Suzanne Barker^{1

2}, Hans Rolf Jäger^{1

2}, Francesco Carletti^{1

2}, Robert Simister^{1

2}, David J Werring^{2

4}, Moira J Spyer¹¹, Eleni Nastouli^{11

15}, Serge Gauthier^{18

19

20}, Pedro Rosa-Neto^{18

19

20}; UCLH Queen Square COVID-19 Biomarker Study Group; Henrik Zetterberg^{1

9

12}, Jonathan M Schott^{1

2}

Affiliations

¹ University College London, Queen Square Institute of Neurology, London WC1N 3BG, UK.
² National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London WC1N 3BG, UK.
³ Darent Valley Hospital, Dartford, Kent DA2 8DA, UK.
⁴ UCL Institute of Neurology, Stroke Research Centre, Russell Square House, London WC1B 5EH, UK.
⁵ University of Liverpool, Brain Infections Group, Liverpool, Merseyside L69 3GA, UK.
⁶ Laboratory of Molecular and Cell Biology, UCL, London WC1E 6BT, UK.
⁷ University College London Institute of Immunity and Transplantation, London NW3 2QG, UK.
⁸ Francis Crick Institute, London NW1 1AT, UK.
⁹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal 431 41, Sweden.
¹⁰ King's College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London SE5 9RT, UK.
¹¹ Advanced Pathogens Diagnostic Unit, University College London Hospitals NHS Foundation Trust, London WC1H 8NJ, UK.
¹² UK Dementia Research Institute, London WC1E 6BT, UK.
¹³ Department of Infection and Immunity, University College London, London WC1E 6BT, UK.
¹⁴ Hospital for Tropical Diseases, University College Hospitals London, London WC1E 6BT, UK.
¹⁵ Department of Clinical Virology, University College London Hospitals NHS Foundation Trust, London WC1H 8NJ, UK.
¹⁶ National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L69 7BE, UK.
¹⁷ Walton Centre NHS Foundation Trust, Liverpool L9 7LJ, UK.
¹⁸ Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Montreal H4H 1R3, Canada.
¹⁹ Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Montreal H4H 1R3, Canada.
²⁰ Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal H4H 1R3, Canada.

PMID: 34396099
PMCID: PMC8194666
DOI: 10.1093/braincomms/fcab099

Serum and cerebrospinal fluid biomarker profiles in acute SARS-CoV-2-associated neurological syndromes

Ross W Paterson et al. Brain Commun. 2021.

. 2021 May 12;3(3):fcab099.

doi: 10.1093/braincomms/fcab099. eCollection 2021.

Authors

Affiliations

¹ University College London, Queen Square Institute of Neurology, London WC1N 3BG, UK.
² National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London WC1N 3BG, UK.
³ Darent Valley Hospital, Dartford, Kent DA2 8DA, UK.
⁴ UCL Institute of Neurology, Stroke Research Centre, Russell Square House, London WC1B 5EH, UK.
⁵ University of Liverpool, Brain Infections Group, Liverpool, Merseyside L69 3GA, UK.
⁶ Laboratory of Molecular and Cell Biology, UCL, London WC1E 6BT, UK.
⁷ University College London Institute of Immunity and Transplantation, London NW3 2QG, UK.
⁸ Francis Crick Institute, London NW1 1AT, UK.
⁹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal 431 41, Sweden.
¹⁰ King's College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London SE5 9RT, UK.
¹¹ Advanced Pathogens Diagnostic Unit, University College London Hospitals NHS Foundation Trust, London WC1H 8NJ, UK.
¹² UK Dementia Research Institute, London WC1E 6BT, UK.
¹³ Department of Infection and Immunity, University College London, London WC1E 6BT, UK.
¹⁴ Hospital for Tropical Diseases, University College Hospitals London, London WC1E 6BT, UK.
¹⁵ Department of Clinical Virology, University College London Hospitals NHS Foundation Trust, London WC1H 8NJ, UK.
¹⁶ National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L69 7BE, UK.
¹⁷ Walton Centre NHS Foundation Trust, Liverpool L9 7LJ, UK.
¹⁸ Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Montreal H4H 1R3, Canada.
¹⁹ Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Montreal H4H 1R3, Canada.
²⁰ Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal H4H 1R3, Canada.

PMID: 34396099
PMCID: PMC8194666
DOI: 10.1093/braincomms/fcab099

Abstract

Preliminary pathological and biomarker data suggest that SARS-CoV-2 infection can damage the nervous system. To understand what, where and how damage occurs, we collected serum and CSF from patients with COVID-19 and characterized neurological syndromes involving the PNS and CNS (n = 34). We measured biomarkers of neuronal damage and neuroinflammation, and compared these with non-neurological control groups, which included patients with (n = 94) and without (n = 24) COVID-19. We detected increased concentrations of neurofilament light, a dynamic biomarker of neuronal damage, in the CSF of those with CNS inflammation (encephalitis and acute disseminated encephalomyelitis) [14 800 pg/ml (400, 32 400)], compared to those with encephalopathy [1410 pg/ml (756, 1446)], peripheral syndromes (Guillain-Barré syndrome) [740 pg/ml (507, 881)] and controls [872 pg/ml (654, 1200)]. Serum neurofilament light levels were elevated across patients hospitalized with COVID-19, irrespective of neurological manifestations. There was not the usual close correlation between CSF and serum neurofilament light, suggesting serum neurofilament light elevation in the non-neurological patients may reflect peripheral nerve damage in response to severe illness. We did not find significantly elevated levels of serum neurofilament light in community cases of COVID-19 arguing against significant neurological damage. Glial fibrillary acidic protein, a marker of astrocytic activation, was not elevated in the CSF or serum of any group, suggesting astrocytic activation is not a major mediator of neuronal damage in COVID-19.

Keywords: ADEM; COVID-19; NfL; encephalitis.

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Figures

**Figure 1**
**Cohort overview.** Flowchart describing cohorts.

**Figure 2**
**NfL and GFAp: scatter plot graphs of CSF against serum and boxplots by clinical groups.** (i) Scatter plot graphs of serum NfL against CSF NfL for COVID-neurological cases and non-COVID controls (A); Scatter plot graphs of serum GFAp against CSF serum GFAp for COVID-neurological cases and non-COVID controls (B); (ii) Boxplots of CSF NfL (C) and GFAp (E) for neurological groups; and (iii) Boxplots of serum NfL (D) and GFAp (F) for neurological group. Serum and CSF NfL and serum and CSF GFAp are log¹⁰ transformed. GFAp, glial fibrillary acidic protein; NfL, neurofilament light. *<0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.000, ns, non-significant.

**Figure 3**
**Boxplots of CSF and serum NfL for CNS group, radiological subtype and clinical outcome.** Boxplots of CSF and serum NfL for (i) CNS group (clinical subtype: encephalopathy; encephalitis; ADEM) and non-COVID controls; (ii) radiological subtype (AMWRC); and (iii) clinical outcome. The boxplots show the median and interquartile range (lower Q1 and upper Q3 quartiles) and the whiskers represent the entire range. Serum and CSF NfL are log¹⁰ transformed. ADEM: acute disseminated encephalomyelitis; ARWMC, age-related white matter scale category; NfL; serum neurofilament light.

See this image and copyright information in PMC

References

1. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683–690. - PMC - PubMed
1. Paterson RW, Brown RL, Benjamin L, et al. The emerging spectrum of COVID-19 neurology: Clinical, radiological and laboratory findings. Brain. 2020;143(10):3104–3120. - PMC - PubMed
1. Varatharaj A, Thomas N, Ellul MA, et al. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: A UK-wide surveillance study. Lancet Psychiatry. 2020;7(10):875–882. - PMC - PubMed
1. Kremer S, Lersy F, Anheim M, et al. Neurologic and neuroimaging findings in patients with COVID-19: A retrospective multicenter study. Neurology. 2020;95(13):e1868–e1882. - PubMed
1. Jaunmuktane Z, Mahadeva U, Green A, et al. Microvascular injury and hypoxic damage: Emerging neuropathological signatures in COVID-19. Acta Neuropathol. 2020;140(3):397–400. - PMC - PubMed

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Serum and cerebrospinal fluid biomarker profiles in acute SARS-CoV-2-associated neurological syndromes

Affiliations

Serum and cerebrospinal fluid biomarker profiles in acute SARS-CoV-2-associated neurological syndromes

Authors

Affiliations

Abstract

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous