A new study published in Nature Medicine has identified two biological profiles, based on routine blood tests during COVID-19 hospitalization, that can predict patients’ risk of developing post-COVID brain fog months later.
Key Facts:
- The study analyzed data from over 1,800 COVID-19 patients hospitalized in the UK. It linked certain patterns of blood biomarkers during hospitalization to cognitive deficits at 6 and 12 month follow-ups.
- One profile – high fibrinogen relative to C-reactive protein (CRP) – predicted worse performance on objective cognitive tests as well as more subjective complaints of brain fog at 6 and 12 months.
- The other profile – high D-dimer relative to CRP – predicted more subjective cognitive problems and difficulty working at 6 and 12 months but did not predict objective test performance.
- These links remained even after accounting for factors like age, pre-existing conditions, and mental health symptoms.
- The findings were replicated in a separate large database of electronic health records.
Source: Nature Medicine (31 Aug 2023)
Uncovering the Biology Behind Post-COVID Brain Fog
Many COVID-19 survivors report lingering ‘brain fog’ and other cognitive problems like memory loss and confusion months after their initial infections.
But the biological mechanisms underlying these post-COVID neurological symptoms have remained poorly understood.
This new study aimed to identify possible biological predictors of post-COVID brain fog detectable during the acute infection stage.
The researchers analyzed data from over 1,800 COVID-19 patients hospitalized in the UK who had blood tests during admission and completed cognitive assessments at 6-month and 12-month follow-up visits.
The researchers focused on six blood biomarkers measured during hospitalization that provide information about inflammation, clotting, and immune system activity: C-reactive protein (CRP), D-dimer, fibrinogen, lymphocytes, neutrophils, and platelets.
They used statistical techniques to identify patterns among these blood biomarkers that correlated with worse performance on objective cognitive tests or more subjective complaints of brain fog months later.
Two Robust Biological Signatures Emerge
The analyses revealed two biological profiles during acute COVID-19 that predicted cognitive impairments months down the line.
These associations held even after accounting for relevant factors like patient age, education level, pre-existing neurological conditions, and mental health symptoms.
Profile #1: High Fibrinogen Relative to CRP Predicts Objective and Subjective Deficits
The first profile associated with future brain fog was high fibrinogen levels relative to CRP levels.
Fibrinogen is a protein involved in clotting and inflammation. CRP is a key inflammatory marker that typically rises and falls in tandem with fibrinogen.
This suggests that elevated fibrinogen levels disproportionate to CRP may reflect hypercoagulation (excessive clotting).
Patients with this high fibrinogen biological signature during COVID-19 hospitalization performed significantly worse on objective cognitive tests at 6 and 12 month follow-ups.
They also reported substantially more subjective problems like confusion, difficulty communicating, and memory loss at both timepoints.
Profile #2: High D-Dimer Relative to CRP Predicts Subjective Deficits and Work Difficulties
The second profile linked high D-dimer levels relative to CRP to increased risk of brain fog.
D-dimer levels spike when blood clots form in the body.
Patients with high D-dimer but comparatively low CRP levels during COVID-19 hospitalization reported more subjective cognitive issues and work-related difficulties 6 and 12 months later – but did not show objective deficits on cognitive testing.
This suggests that patients whose blood formed clots more readily during acute COVID-19 infection tend to experience more persistent cognitive symptoms like brain fog, even without measurable cognitive impairment on testing.
Brain imaging studies will be important to determine whether these patients have more microclots in the brain.
Replication in Large Electronic Health Records Database
To evaluate the reliability of these findings, the researchers replicated the analysis in a huge database of electronic health records from over 90 million patients, mostly in the United States.
The links between high fibrinogen and future cognitive impairment held up.
High D-dimer levels also continued to predict cognitive problems after COVID-19 but not other respiratory infections.
This suggests that excessive clotting during acute COVID-19 specifically sets patients up for lingering brain fog.
Insights On Mechanisms and Treatments
Together, these findings provide intriguing clues into the possible biological underpinnings of post-COVID neurological problems like brain fog.
They suggest that hypercoagulation and excessive clotting during acute COVID-19 could trigger microvascular damage and microclots that disturb blood flow and oxygen delivery to the brain.
Brain autopsies of patients who died from COVID-19 have revealed evidence of multifocal vascular damage.
The study also hints that lung clots and injuries during acute COVID-19 that impair oxygen circulation throughout the body may separately contribute to subjective cognitive symptoms like brain fog.
Additional research measuring lung and brain imaging alongside cognitive testing will help clarify these relationships.
In the meantime, these results suggest some promising avenues for treatment and prevention studies.
Clinical trials are warranted to test whether anticoagulant therapies during acute COVID-19 may mitigate lasting brain fog in high-risk patients.
More aggressive prevention of lung clots in hospitalized patients could also be beneficial.
Moving forward, fibrinogen and D-dimer testing could potentially be incorporated into predictive models to identify COVID-19 patients at elevated risk for post-acute neurological sequalae who may benefit from targeted monitoring and early intervention.
Key Limitations
The study was observational, so it does not prove causation between acute biological profiles and later brain fog.
The cohort consisted of patients hospitalized early in the pandemic before vaccines and new variants. Findings may differ today.
Only hospitalized patients were included. Outpatients may show different patterns.
Better understanding is needed of how these biological signatures directly damage the brain and lungs.
The Bottom Line
This well-powered study uncovered two biological signatures based on routine blood tests that may predict which COVID-19 patients are most vulnerable to lingering brain fog and other cognitive symptoms months later.
The findings provide clues to the mechanisms driving post-COVID neurological problems and highlight potential new therapeutic targets like anticoagulation.
Further research is warranted to translate these results into clinical predictive tools and tailored interventions for at-risk patients.
References
- Study: Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization
- Authors: Maxime Taquet et al. (2023)
