The kynurenine pathway relates to post-acute COVID-19 objective cognitive impairment and PASC

Lucette A Cysique; David Jakabek; Sophia G Bracken; Yasmin Allen-Davidian; Benjamin Heng; Sharron Chow; Mona Dehhaghi; Ananda Staats Pires; David R Darley; Anthony Byrne; Chansavath Phetsouphanh; Anthony Kelleher; Gregory J Dore; Gail V Matthews; Gilles J Guillemin; Bruce J Brew

doi:10.1002/acn3.51825

The kynurenine pathway relates to post-acute COVID-19 objective cognitive impairment and PASC

Ann Clin Transl Neurol. 2023 Aug;10(8):1338-1352. doi: 10.1002/acn3.51825. Epub 2023 Jun 15.

Authors

Lucette A Cysique^{1

2}, David Jakabek³, Sophia G Bracken², Yasmin Allen-Davidian^{1

4}, Benjamin Heng^{5

6}, Sharron Chow⁵, Mona Dehhaghi^{5

6}, Ananda Staats Pires⁵, David R Darley^{7

8}, Anthony Byrne^{7

8}, Chansavath Phetsouphanh⁹, Anthony Kelleher^{9

10}, Gregory J Dore^{9

10}, Gail V Matthews^{9

10}, Gilles J Guillemin^{5

6}, Bruce J Brew^{1

3

7}

Affiliations

¹ Peter Duncan Neuroscience Research Unit, St. Vincent's Centre for Applied Medical Research, Darlinghurst, New South Wales, Australia.
² School of Psychology, UNSW, Sydney, New South Wales, Australia.
³ Neurology Department, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia.
⁴ School of Psychology, Macquarie University, Sydney, New South Wales, Australia.
⁵ Macquarie Medical School, Macquarie University, Sydney, New South Wales, Australia.
⁶ PANDIS.org, Sydney, New South Wales, Australia.
⁷ Faculty of Medicine, UNSW, Sydney, New South Wales, Australia.
⁸ Respiratory Medicine Department, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia.
⁹ Kirby Institute, UNSW, Sydney, New South Wales, Australia.
¹⁰ Infectious Disease and Immunology Department, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia.

Abstract

Objective: To determine the prevalence and natural history of post-acute COVID-19 objective cognitive impairment and function, and their relationship to demographic, clinical factors, post-acute sequelae of COVID-19 (PASC), and biomarkers.

Methods: A total of 128 post-acute COVID-19 patients (age = 46 ± 15; 42% women, acute disease severity: not hospitalized: 38.6% mild: 0-1 symptoms, 52% 2+ symptoms; 9.4% hospitalized) completed standard cognition, olfaction, and mental health examinations 2-, 4-, and 12-month post diagnosis. Over the same time frame, WHO-defined PASC was determined. Blood cytokines, peripheral neurobiomarkers, and kynurenine pathway (KP) metabolites were measured. Objective cognitive function was demographically/practice corrected, and impairment prevalence was determined using the evidence-based Global Deficit Score method to detect at least mild cognitive impairment (GDS > 0.5). Linear mixed effect regression models with time effect (month post diagnosis) evaluated the relationships to cognition.

Results: Across the 12-month study period, mild to moderate cognitive impairment ranged from 16% to 26%, and 46.5% were impaired at least once. Impairment associated with poorer work capacity (p < 0.05), and 2-month objectively tested anosmia (p < 0.05). PASC with (p = 0.01) and without disability (p < 0.03) associated with acute COVID-19 severity. KP measures showed prolonged activation (2 to 8 months) (p < 0.0001) linked to IFN-beta in those with PASC. Of the blood analytes, only the KP metabolites (elevated quinolinic acid, 3-hydroxyanthranilic acid, kynurenine, the kynurenine/tryptophan ratio) associated (p < 0.001) with poorer cognitive performance and greater likelihood of impairment. PASC, independent of disability associated with abnormal kynurenine/tryptophan (p < 0.03).

Interpretation: The kynurenine pathway relates to post-acute COVID-19 objective cognitive impairment and PASC, thereby enabling biomarker and therapeutic possibilities.

Publication types

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

MeSH terms

Adult
Biomarkers
COVID-19* / complications
Cognitive Dysfunction* / diagnosis
Cognitive Dysfunction* / etiology
Female
Humans
Kynurenine
Male
Middle Aged
Post-Acute COVID-19 Syndrome
Tryptophan

Substances

Kynurenine
Tryptophan
Biomarkers

Grants and funding

This work was funded by National Health and Medical Research Council grant 1176660; St Vincent's Hospital Sydney; St. Vincent's Applied Medical Research Centre Peter Duncan Neuroscience Unit.