Blood-brain barrier dysfunction and other brain structure changes may be key indicators for the development of brain fog in people with Long COVID, according to dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) findings from a new study.
For the study, which was recently published in Nature Neuroscience, researchers initially reviewed serum and plasma samples from 76 patients who had been hospitalized with COVID-19 in March and April 2020. After noting elevated biomarkers in patients with brain fog, including significantly increased levels of protein S100B, the study authors subsequently reviewed DCE-MRI data for 10 study participants who recovered from COVID-19, 11 people with Long COVID and 11 participants with Long COVID and brain fog.
The researchers found that people with Long COVID and brain fog had increased blood-brain barrier (BBB) permeability with significantly increased leakage in temporal lobes as well as the left and right frontal cortex. The study authors also noted a correlation between BBB permeability in the temporal lobes and anosmia duration.
“BBB disruption in the (temporal lobe) may be linked to anosmia because it contains important regions that form part of the primary olfactory cortex, including the piriform cortex, amygdala and entorhinal cortex, with direct connections to and from the olfactory bulb,” wrote Matthew Campbell, Ph.D., a professor in genetics and head of the department at the Smurfit Institute of Genetics at Trinity College Dublin in Ireland, and colleagues.
The study authors said there were no other differences with respect to anosmia status or duration and found no impact of age on those with BBB permeability and Long COVID.
However, Campbell and colleagues noted brain structure changes specific to those with Long COVID and brain fog, including reduced thickness in the middle and superior temporal gyrus. The researchers also found that BBB-disrupted voxels were associated with reduced global brain volume (GBV), white matter volume, cerebral volume and increased cerebrospinal fluid (CSF) volume.
“BBB dysfunction correlated with changes in brain volume and cortical thickness, most notably reduced GBV and increased CSF volume. Similar associations have been reported in bipolar disorder and systemic lupus erythematosus, where individuals with severe BBB disruption had more extensive brain volume loss or greater psychiatric morbidity,” pointed out Campbell and colleagues. “This implies that changes in BBB function are closely related to changes in brain structure and ultimately function.”
Three Key Takeaways
- Blood-brain barrier dysfunction in Long COVID with brain fog. The study highlights that individuals with Long COVID and brain fog exhibit increased permeability of the blood-brain barrier (BBB), particularly in the temporal lobes and frontal cortex. This suggests that BBB dysfunction may be a key factor contributing to the development of brain fog in Long COVID patients.
- Correlation between BBB permeability and anosmia. The researchers found a correlation between BBB permeability in the temporal lobes and the duration of anosmia (loss of smell). This suggests a potential link between blood-brain barrier disruption and anosmia, possibly due to the involvement of regions within the temporal lobe that are part of the primary olfactory cortex.
- Brain structure changes in Long COVID with brain fog. The study identifies specific structural changes in the brains of individuals with Long COVID and brain fog, including reduced thickness in the middle and superior temporal gyrus. Additionally, disrupted BBB is associated with changes in global brain volume, white matter volume, cerebral volume, and increased cerebrospinal fluid volume. These findings imply that alterations in BBB function are closely related to changes in brain structure and may contribute to the observed cognitive symptoms in patients with Long COVID and brain fog.
While the researchers emphasized the need for further research to clarify the longitudinal impact of BBB permeability, they said the current study findings may provide insights into treatment pathways for those with Long COVID-associated brain fog.
“ … Targeted regulation of BBB integrity could now potentially be considered for the treatment of patients with brain fog associated with long COVID,” added Campbell and colleagues.
(Editor’s note: For related content, see “Can Diffusion Microstructural Imaging Provide Insights into Long Covid Beyond Conventional MRI?,” “MRI Study: People with Past Hospitalization for COVID-19 Have Nearly Triple the Risk of Multiorgan Abnormalities” and “New Meta-Analysis Details Most Common Brain MRI Findings with COVID-19.”)
In regard to study limitations, the researchers acknowledged a small sample size and an inability to confirm molecular BBB breakdown in patients with brain fog due to a lack of access to cerebrospinal fluid sample from the study cohort. The study authors did not assess longitudinal BBB function changes and emphasized that ascertaining this information in future research could aid in the development of treatments in this patient population.
