Systemic inflammation relates to neuroaxonal damage associated with long-term cognitive dysfunction in COVID-19 patients.

BACKGROUND AND OBJECTIVES: Cognitive deficits are increasingly recognized as a long-term sequela of severe COVID-19. The underlying processes and molecular signatures associated with these long-term neurological sequalae of COVID-19 remain largely unclear, but may be related to systemic inflammation-induced effects on the brain. We studied the systemic inflammation-brain interplay and its relation to development of long-term cognitive impairment in patients who survived severe COVID-19. Trajectories of systemic inflammation and neuroaxonal damage blood biomarkers during ICU admission were analyzed and related to long-term cognitive outcomes. METHODS: Prospective longitudinal cohort study of patients with severe COVID-19 surviving ICU admission. During admission, blood was sampled consecutively to assess levels of inflammatory cytokines and neurofilament light chain (NfL) using an ultrasensitive multiplex Luminex assay and single molecule array technique (Simoa). Cognitive functioning was evaluated using a comprehensive neuropsychological assessment six months after ICU-discharge. RESULTS: Ninety-six patients (median [IQR] age 61 [55-69] years) were enrolled from March 2020 to June 2021 and divided into two cohorts: those who received no COVID-19-related immunotherapy (n = 28) and those treated with either dexamethasone or dexamethasone and tocilizumab (n = 68). Plasma NfL concentrations increased in 95 % of patients during their ICU stay, from median [IQR] 23 [18-38] pg/mL at admission to 250 [160-271] pg/mL after 28 days, p < 0.001. Besides age, glomerular filtration rate, immunomodulatory treatment, and C-reactive protein, more specific markers of systemic inflammation at day 14 (i.e., interleukin (IL)-8, tumour necrosis factor, and IL-1 receptor antagonist) were significant predictors of blood NfL levels at day 14 of ICU admission (R2 = 44 %, p < 0.001), illustrating the association between sustained systemic inflammation and neuroaxonal damage. Twenty-six patients (27 %) exhibited cognitive impairment six months after discharge from the ICU. NfL concentrations showed a more pronounced increase in patients that developed cognitive impairment (p = 0.03). Higher NfL predicted poorer outcome in information processing speed (Trail Making Test A, r = -0.26, p = 0.01; Letter Digit Substitution Test, r = -0.24, p = 0.02). DISCUSSION: Prolonged systemic inflammation in critically ill COVID-19 patients is related to neuroaxonal damage and subsequent long-term cognitive impairment. Moreover, our findings suggest that plasma NfL concentrations during ICU stay may possess prognostic value in predicting future long-term cognitive impairment in patients that survived severe COVID-19.

Cytological development and sesquiterpene lactone secretion in capitate glandular trichomes of sunflower.

The secretion of sesquiterpene lactones (STL) in capitate glandular trichomes from the anther appendages of Helianthus annuus L. (Asteraceae) was observed by light and fluorescence microscopy and HPLC analysis. Disk flowers within the sunflower capitulum showed the known ontogenetic progression from the centre to the margin. During development of the florets, the trichomes in the anther appendages secreted their metabolites into the subcuticular secretion storage space in front of the two apical cells. All stages of forming the cuticular globe, from the pre-secretory to the post-secretory phase, could be observed microscopically and secretory activity was simultaneously monitored. Six germacrolides and heliangolides of known structure were selected for quantitative analysis. The increase in STL content during extension of the subcuticular space was monitored by HPLC analysis. Thereby, the start and termination of STL biosynthesis was defined in relation to other developmental stages of floret ontogenesis, particularly, the pollen formation. Part of the secreted material showed autofluorescence which could be attributed to a hydroxy-trimethoxy-flavone, as determined by NMR and mass spectroscopy. The anther trichomes were cytologically and chemically similar to foliar glandular trichomes of sunflower and represent the multicellular capitate glandular trichome type common to many Asteraceae. The ease with which anther trichomes of H. annuus can be harvested and analyzed suggests that they can provide a valuable model system for investigation of STL and flavonoid metabolism in Asteraceae.