Amyloid processing in COVID-19-associated neurological syndromes

Oliver J Ziff; Nicholas J Ashton; Puja R Mehta; Rachel Brown; Dilan Athauda; Judith Heaney; Amanda J Heslegrave; Andrea Lessa Benedet; Kaj Blennow; Anna M Checkley; Catherine F Houlihan; Serge Gauthier; Pedro Rosa-Neto; Nick C Fox; Jonathan M Schott; Henrik Zetterberg; Laura A Benjamin; Ross W Paterson

doi:10.1111/jnc.15585

Amyloid processing in COVID-19-associated neurological syndromes

J Neurochem. 2022 Apr;161(2):146-157. doi: 10.1111/jnc.15585. Epub 2022 Mar 2.

Authors

Oliver J Ziff^{1

2

3}, Nicholas J Ashton^{4

5}, Puja R Mehta^{1

2}, Rachel Brown^{2

6}, Dilan Athauda^{1

2

3}, Judith Heaney^{2

7}, Amanda J Heslegrave^{1

2

8}, Andrea Lessa Benedet⁴, Kaj Blennow⁴, Anna M Checkley^{2

7}, Catherine F Houlihan^{2

7}, Serge Gauthier^{9

10

11}, Pedro Rosa-Neto^{9

10

11}, Nick C Fox^{1

2

8}, Jonathan M Schott^{1

2}, Henrik Zetterberg^{1

4

8}, Laura A Benjamin^{1

2

12

13}, Ross W Paterson^{1

2

8

14}

Affiliations

¹ Queen Square Institute of Neurology, University College London, London, UK.
² National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London, UK.
³ Francis Crick Institute, London, UK.
⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁵ King's College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, UK.
⁶ Institute of Immunity and Transplantation, University College London, London, UK.
⁷ Advanced Pathogens Diagnostic Unit, University College London Hospitals NHS Foundation Trust, London, UK.
⁸ UK Dementia Research Institute, University College London, London, UK.
⁹ Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Montreal, Canada.
¹⁰ Alzheimer's Disease Research Unit, Montréal, Canada.
¹¹ Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, Canada.
¹² University of Liverpool, Brain Infections Group, Merseyside, Liverpool, UK.
¹³ Laboratory of Molecular and Cell Biology, UCL, London, UK.
¹⁴ Darent Valley Hospital, Kent, UK.

Abstract

SARS-CoV-2 infection can damage the nervous system with multiple neurological manifestations described. However, there is limited understanding of the mechanisms underlying COVID-19 neurological injury. This is a cross-sectional exploratory prospective biomarker cohort study of 21 patients with COVID-19 neurological syndromes (Guillain-Barre Syndrome [GBS], encephalitis, encephalopathy, acute disseminated encephalomyelitis [ADEM], intracranial hypertension, and central pain syndrome) and 23 healthy COVID-19 negative controls. We measured cerebrospinal fluid (CSF) and serum biomarkers of amyloid processing, neuronal injury (neurofilament light), astrocyte activation (GFAp), and neuroinflammation (tissue necrosis factor [TNF] ɑ, interleukin [IL]-6, IL-1β, IL-8). Patients with COVID-19 neurological syndromes had significantly reduced CSF soluble amyloid precursor protein (sAPP)-ɑ (p = 0.004) and sAPPβ (p = 0.03) as well as amyloid β (Aβ) 40 (p = 5.2 × 10^-8 ), Aβ42 (p = 3.5 × 10^-7 ), and Aβ42/Aβ40 ratio (p = 0.005) compared to controls. Patients with COVID-19 neurological syndromes showed significantly increased neurofilament light (NfL, p = 0.001) and this negatively correlated with sAPPɑ and sAPPβ. Conversely, GFAp was significantly reduced in COVID-19 neurological syndromes (p = 0.0001) and this positively correlated with sAPPɑ and sAPPβ. COVID-19 neurological patients also displayed significantly increased CSF proinflammatory cytokines and these negatively correlated with sAPPɑ and sAPPβ. A sensitivity analysis of COVID-19-associated GBS revealed a non-significant trend toward greater impairment of amyloid processing in COVID-19 central than peripheral neurological syndromes. This pilot study raises the possibility that patients with COVID-19-associated neurological syndromes exhibit impaired amyloid processing. Altered amyloid processing was linked to neuronal injury and neuroinflammation but reduced astrocyte activation.

Keywords: APP; Alzheimer's disease; COVID-19; amyloid processing; beta amyloid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / cerebrospinal fluid
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor / cerebrospinal fluid
Amyloidosis*
Biomarkers / cerebrospinal fluid
COVID-19* / complications
Cohort Studies
Cross-Sectional Studies
Humans
Pilot Projects
Prospective Studies
SARS-CoV-2

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Biomarkers

Abstract

Publication types

MeSH terms

Substances

Grants and funding