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. 2023 Aug 12;13(1):13144.
doi: 10.1038/s41598-023-39698-y.

Central nervous system biomarkers GFAp and NfL associate with post-acute cognitive impairment and fatigue following critical COVID-19

Lovisa Bark  1 , Ing-Marie Larsson  2 , Ewa Wallin  2 , Joel Simrén  3   4 , Henrik Zetterberg  3   4   5   6   7 , Miklos Lipcsey  2   8 , Robert Frithiof  2 , Elham Rostami  9   10 , Michael Hultström  2   11   12   13
Affiliations

Central nervous system biomarkers GFAp and NfL associate with post-acute cognitive impairment and fatigue following critical COVID-19

Lovisa Bark et al. Sci Rep. .

Abstract

A high proportion of patients with coronavirus disease 2019 (COVID-19) experience post-acute COVID-19, including neuropsychiatric symptoms. Objective signs of central nervous system (CNS) damage can be investigated using CNS biomarkers such as glial fibrillary acidic protein (GFAp), neurofilament light chain (NfL) and total tau (t-tau). We have examined whether CNS biomarkers can predict fatigue and cognitive impairment 3-6 months after discharge from the intensive care unit (ICU) in critically ill COVID-19 patients. Fifty-seven COVID-19 patients admitted to the ICU were included with analysis of CNS biomarkers in blood at the ICU and at follow up. Cognitive dysfunction and fatigue were assessed with the Montreal Cognitive Assessment (MoCA) and the Multidimensional Fatigue inventory (MFI-20). Elevated GFAp at follow-up 3-6 months after ICU discharge was associated to the development of mild cognitive dysfunction (p = 0.01), especially in women (p = 0.005). Patients who experienced different dimensions of fatigue at follow-up had significantly lower GFAp in both the ICU and at follow-up, specifically in general fatigue (p = 0.009), physical fatigue (p = 0.004), mental fatigue (p = 0.001), and reduced motivation (p = 0.001). Women showed a more pronounced decrease in GFAp compared to men, except for in mental fatigue where men showed a more pronounced GFAp decrease compared to women. NfL concentration at follow-up was lower in patients who experienced reduced motivation (p = 0.004). Our findings suggest that GFAp and NfL are associated with neuropsychiatric outcome after critical COVID-19.Trial registration The study was registered à priori (clinicaltrials.gov: NCT04316884 registered on 2020-03-13 and NCT04474249 registered on 2020-06-29).

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Conflict of interest statement

HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, 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). All the other authors declare they have no conflicts of interest.

Figures

Figure 1
Figure 1
Flowchart over enrolled patients. A total of 121 critical ill COVID-19 patients were included when admitted to the ICU. Three patients were later PCR-confirmed COVID-19 negative. Twenty-three patients died before follow-up and 36 patients did not consent to follow-up. One patient was excluded due to severe neurological disease. Sixty-one patients were available at follow-up 3–6 months after discharge from the ICU, 2 patients had incomplete follow-up questionnaires and 2 patients had incomplete biomarker analysis. A total of 57 patients had complete follow-up and biomarker data, however one patient had incomplete MoCA therefore 56 patients were available for cognitive impairment analysis. ICU Intensive care unit. MoCA Montreal cognitive assessment score.
Figure 2
Figure 2
The CNS biomarkers GFAp, NfL and t-tau in correlation to age. (a) GFAp concentration correlation to age. GFAp levels increases with increasing age. (b) NfL concentration correlation to age. NfL levels increases with increasing age. (c) T-tau concentration correlation to age. T-tau levels increases slightly with increasing age. ICU intensive care unit. GFAp Glial fibrillary acidic protein. NfL Neurofilament light chain.
Figure 3
Figure 3
The glial biomarker GFAp concentration at ICU and at follow-up after 3–6 months in correlation to the MFI-20 dimensions of fatigue in 57 critically ill COVID-19 patients. No fatigue ICU, fatigue ICU, no fatigue follow-up, and fatigue follow-up, reflects fatigue status and whether GFAp was collected at the ICU or at follow-up. GFAp is higher during acute COVID-19 and decreases at follow-up (†). For general fatigue, physical fatigue, mental fatigue, and reduced motivation, GFAp is lower in those with fatigue. GFAp Glial fibrillary acidic protein. ICU intensive care unit. MFI-20 Multidimensional Fatigue inventory.
Figure 4
Figure 4
GFAp concentration in relation to gender. No fatigue female, fatigue female, no fatigue male, and fatigue male, reflects fatigue status and gender. GFAp is higher during acute COVID-19 and show significant effects in gender, being higher in women (†). For general fatigue, physical fatigue, mental fatigue, and reduced motivation, GFAp is lower in those with fatigue. Additionally, the effect is more pronounced in women, except for mental fatigue where it is more pronounced in men. GFAp Glial fibrillary acidic protein. ICU intensive care unit. MFI-20 Multidimensional Fatigue inventory.
Figure 5
Figure 5
The axonal biomarker NfL concentration at ICU and at follow-up after 3–6 months in correlation to the MFI-20 dimensions of fatigue in 57 critical ill COVID-19 patients. No fatigue ICU, fatigue ICU, no fatigue follow-up, and fatigue follow-up, reflects fatigue status and whether NfL was collected at the ICU or at follow-up. NfL is high during acute critical COVID-19 and decreases to follow-up but show no strong relation to fatigue in the dimensions general fatigue, physical fatigue, mental fatigue or reduced activity. Patients experiencing reduced motivation (†) actually show a lower concentration. ICU intensive care unit. NfL Neurofilament light chain. MFI-20 Multidimensional Fatigue inventory.
Figure 6
Figure 6
The neuronal biomarker t-tau concentration at ICU and at follow-up after 3–6 months in correlation to the MFI-20 dimensions of fatigue in 57 critical ill COVID-19 patients. No fatigue ICU, fatigue ICU, no fatigue follow-up, and fatigue follow-up, reflects fatigue status and whether the t-tau was collected at the ICU or at follow-up. T-tau concentration is slightly higher at follow-up compared to acute critical COVID-19 but large variation. No association to level of fatigue in any dimension. T-tau total-tau. ICU intensive care unit. MFI-20 Multidimensional Fatigue inventory.
Figure 7
Figure 7
The biomarkers NfL, t-tau and GFAp concentrations at ICU and at follow-up after 3–6 months in correlation to MoCA assessing cognitive dysfunction in 56 critical ill COVID-19 patients. No fatigue ICU, fatigue ICU, no fatigue follow-up, and fatigue follow-up, reflects fatigue status and whether the CNS biomarkers were collected at the ICU or at follow-up. (a) The axonal biomarker NfL was significantly higher during the acute illness and normalized after 3–4 months. High levels of NfL were not associated with cognitive dysfunction. (b) The neuronal biomarker t-tau levels were slightly higher on average at follow-up, but any differences were minor. Indicating that neuronal damage was not increased during critical COVID-19, and was not associated with cognitive dysfunction. (c) The glial biomarker GFAp was higher during the acute critical COVID-19 and in patients with at least mild cognitive dysfunction at follow-up. (d) The glial biomarker GFAp showed significant effects on both age and gender. NfL Neurofilament light chain. T-tau total tau. GFAp Glial fibrillary acidic protein. ICU intensive care unit. MoCA Montreal cognitive assessment score.
Figure 8
Figure 8
Graphical abstract of the study. Patients with acute COVID-19 admitted to the ICU were assessed with MoCA and MFI-20 at follow-up after 3–6 months. Both at the ICU and at follow-up analysis of CNS biomarkers GFAp and NfL were made and related to fatigue and cognitive impairment at follow-up. ICU intensive care unit. GFAp Glial fibrillary acidic protein. NfL Neurofilament light chain. MoCA Montreal cognitive assessment score. MFI-20 Multidimensional Fatigue inventory.
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