. 2022 Apr;161(2):146-157.

doi: 10.1111/jnc.15585. Epub 2022 Mar 2.

Amyloid processing in COVID-19-associated neurological syndromes

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.

PMID: 35137414
PMCID: PMC9115071
DOI: 10.1111/jnc.15585

Amyloid processing in COVID-19-associated neurological syndromes

Oliver J Ziff et al. J Neurochem. 2022 Apr.

. 2022 Apr;161(2):146-157.

doi: 10.1111/jnc.15585. Epub 2022 Mar 2.

Authors

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.

PMID: 35137414
PMCID: PMC9115071
DOI: 10.1111/jnc.15585

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.

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Conflict of interest statement

All authors have completed the ICMJE conflict of interest statement. OJZ, NJA, PRM, RB, DA, JH, AJH, ALB, AMC, and CFH report no conflicts of interest. SG has served as a consultant on the scientific advisory boards of Alzheon, Boeringher, Cerveau, and TAURX and has given lectures sponsored by Lundbeck. KB has served as a consultant or at advisory boards for Axon, Biogen, COGRX, Lilly, MAGQU, Novartis, and Roche Diagnostics, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. PRN has served as a consultant for Cerveau, Enigma, and is a clinical trials site investigator with TAURX, Jannssn, Eli Lilly, Eisai, and Biogen. JMS declares personal fees from Axon Neuroscience, Roche, Eli Lilly, General Electric Healthcare, Merck Sharp & Dohme, Oxford University Press, Biogen, and EU Horizon 2020 outside the submitted work. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and COGRX, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). LB reports a research grant from GLAXOSMITHKLINE, outside the submitted work. RWP is co‐principal investigator of the Neurofilament Light consortium, an industry‐funded consortium, and has received honoraria from GE Healthcare, outside the scope of this study.

Figures

**FIGURE 1**
(a) Scatter plot of soluble amyloid precursor protein (sAPP)‐ɑ (x‐axis) against sAPPβ (y‐axis). Linear regression correlation spearman coefficient R = +0.89. Red dots represent COVID‐19 neurological patients (n = 21), while green dots represent non‐COVID controls (n = 23). (b–c) Boxplots of (b) sAPPɑ and (c) sAPPβ in COVID neurological syndromes (red) and non‐COVID controls (green). (d) Scatter plot of amyloid‐β (Aβ) 40 (x‐axis) against Aβ42 (y‐axis). Linear regression correlation spearman coefficient R = +0.9. (e–g) Boxplots of (e) Aβ40, (f) Aβ42 and (g) Aβ42/Aβ40 ratio in COVID neurological syndromes and non‐COVID controls. ****p < 0.0001 ***p < 0.001, **p < 0.01, *p < 0.05 from Wilcoxon test; ns, non‐significant. (h–k) Scatterplots for sAPPɑ (left facet) and sAPPβ (right facet) on x‐axis against Aβ40, Aβ42, Aβ42/Aβ40 ratio, total tau (y‐axis). Wilcoxon test *p < 0.05, **<0.01, ***<0.001, ****<0.0001

**FIGURE 2**
Boxplots (left) and scatterplots (right) of (a) serum neurofilament light (NfL), (b) cerebrospinal fluid (CSF) NfL, (c) serum glial fibrillary acidic protein (GFAp), (d) CSF GFAp in COVID neurological syndromes (red, n = 21) and non‐COVID controls (green, n = 23). Scatterplots show soluble amyloid precursor protein (sAPP) ɑ (left facet) and sAPPβ (right facet) on x‐axis against Log₁₀ NfL and GFAp (y‐axis). Correlation coefficients and p‐values are shown in each scatterplot for non‐COVID controls (green), COVID neurological patients (red). Wilcoxon test *p < 0.05, **<0.01, ***<0.001, ns, non‐significant

**FIGURE 3**
Boxplots (left) and scatterplots (right) of cerebrospinal fluid (CSF) (a) tissue necrosis factor (TNF) ɑ, (b) interleukin (IL) 6, (c) IL1β, (d) IL8 in COVID neurological syndromes (red, n = 21) and non‐COVID controls (green, n = 23). Scatterplots show soluble amyloid precursor protein (sAPP) ɑ (left facet) and sAPPβ (right facet) on x‐axis against Log₁₀ TNFɑ, IL6, IL1β, IL8 (y‐axis). Correlation coefficients and p‐values are shown in each scatterplot for non‐COVID controls (green), COVID neurological patients (red). Wilcoxon test *p < 0.05, **<0.01, ***<0.001

**FIGURE 4**
Boxplots comparing COVID‐19‐associated Guillain–Barre syndrome (GBS, red, n = 8) versus central nervous system (CNS) syndromes (blue, n = 13). Statistics shown are from the Wilcoxon test *p < 0.05; ns, non‐significant

See this image and copyright information in PMC

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Amyloid processing in COVID-19-associated neurological syndromes

Affiliations

Amyloid processing in COVID-19-associated neurological syndromes

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

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