Blood-brain barrier breakdown in COVID-19 ICU survivors: an MRI pilot study, 2023, Shi et al.

[SNT Gatchaman]

Blood-brain barrier breakdown in COVID-19 ICU survivors: an MRI pilot study
Wen Shi; Dengrong Jiang; Hannah Rando; Shivalika Khanduja; Zixuan Lin; Kaisha Hazel; George Pottanat; Ebony Jones; Cuimei Xu; Doris Lin; Sevil Yasar; Sung-Min Cho; Hanzhang Lu

Objectives
Coronavirus disease 2019 (COVID-19) results in severe inflammation at the acute stage. Chronic neuroinflammation and abnormal immunological response have been suggested to be the contributors to neuro-long-COVID, but direct evidence has been scarce. This study aims to determine the integrity of the blood-brain barrier (BBB) in COVID-19 intensive care unit (ICU) survivors using a novel MRI technique.

Methods
COVID-19 ICU survivors (n=7) and age and sex-matched control participants (n=17) were recruited from June 2021 to March 2023. None of the control participants were hospitalized due to COVID-19 infection. The COVID-19 ICU survivors were studied at 98.6 ± 14.9 days after their discharge from ICU. A non-invasive MRI technique was used to assess the BBB permeability to water molecules, in terms of permeability surface area-product (PS) in the units of mL/100 g/min.

Results
PS was significantly higher in COVID-19 ICU survivors (p=0.038) when compared to the controls, with values of 153.1 ± 20.9 mL/100 g/min and 132.5 ± 20.7 mL/100 g/min, respectively. In contrast, there were no significant differences in whole-brain cerebral blood flow (p=0.649) or brain volume (p=0.471) between the groups.

Conclusions
There is preliminary evidence of a chronic BBB breakdown in COVID-19 survivors who had a severe acute infection, suggesting a plausible contributor to neurological long-COVID symptoms.

Link | PDF (NeuroImmune Pharmacology and Therapeutics)

 

[SNT Gatchaman]

Inflammation is thought to be one major contributor to brain abnormalities in severe COVID-19. Prior studies have revealed that increased pro-inflammatory cytokines such as interleukin-10 (IL-10), granulocyte colonystimulating factor (GCSF), and tumor necrosis factor (TNFα) were observed in intensive care unit (ICU) patients compared with non-ICU patients. Serum cytokines induced by systemic inflammation can impact blood-brain barrier
(BBB) function and promote BBB disruption.

At a chronic phase, it has also been reported that proteins related to neuroinflammation such as matrix metalloproteinase 9 (MMP9) and glial fibrillary acidic protein (GFAP) were elevated in patients with neurological symptoms. It is therefore plausible that BBB breakdown is a long-lasting pathophysiological alteration that will persist beyond the acute phase of COVID-19. However, to date, BBB assessment in COVID-19 patients has been limited, part of which is due to the scarcity of tools to probe BBB function in humans.

A novel magnetic resonance imaging (MRI) technique, referred to as water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST) MRI, was developed to non-invasively measure BBB permeability to water, without requiring exogenous (gadolinium) contrast agents. The goal of the present study was therefore to use WEPCAST MRI to assess BBB integrity in COVID-19 patients at a chronic phase. We note that patients who underwent ICU hospitalization are most likely to have experienced severe cytokine storm thereby suffering from long-lasting BBB damage. Therefore, in this pilot study, we recruited a group of COVID-19 ICU survivors approximately 3 months after their discharge from the ICU and compared them to a group of age and sex-matched control participants without any history of hospitalization due to COVID-19.

 

[SNT Gatchaman]

Prior paper — Non-contrast MR imaging of blood-brain barrier permeability to water (2018, Magnetic Resonance in Medicine)

 

[SNT Gatchaman]

In addition to BBB permeability, this study investigated other brain anatomic and function parameters such as brain volume and CBF. We found that whole-brain volume and CBF were not significantly different between COVID-19 ICU survivors and controls, suggesting that BBB breakdown may be a more sensitive measure of brain dysfunction in neuro long-COVID, in the absence of apparent anatomic or perfusion abnormalities.

Here, cerebral blood flow as assessed by MRI is with the patient supine, so dynamic orthostatic factors won't be represented. Cerebral blood (and CSF) flow supine vs upright has been looked at in healthy people, eg —

Postural effects on cerebral blood flow and autoregulation (2017, Physiological Reports)

Cerebrovascular reactivity and cerebral autoregulation are improved in the supine posture compared to upright in healthy men and women (2020, PLOS ONE)

Upright versus supine MRI: effects of body position on craniocervical CSF flow (2021, Fluids and Barriers of the CNS)

Both blood flow and CSF flow could be compared with MRI, supine vs upright in ME and LC. I think to date upright MRI has only been used to look at the craniocervical junction. I think Michael VanElzakker's current study is at 7T for increased resolution, which will be supine only with current technology. Tilt-table with cerebral NIRS and extra- / trans-cranial Doppler ultrasound has been much more straightforward to evaluate, eg van Campen et al.