A large prospective study has uncovered two blood biomarker profiles measured during acute COVID-19 that are associated with cognitive deficits months later.
Higher fibrinogen and lower C-reactive protein predict both objective and subjective cognitive impairment.
Higher D-dimer and lower C-reactive protein predict subjective deficits and occupational impact.
- In 1,837 COVID-19 patients, two acute blood biomarker profiles predict cognitive deficits 6-12 months later.
- High fibrinogen and normal C-reactive protein links to objective and subjective deficits.
- High D-dimer and normal C-reactive protein links to subjective deficits and work difficulties.
- Findings replicated in 90 million patient electronic records.
- Biomarker profiles may aid prognosis and suggest treatment targets.
Source: Nature Medicine (2023)
Deciphering Long COVID Brain Fog: Biomarker Analysis
Up to one in three COVID-19 survivors experience lasting neuropsychiatric symptoms, including memory and concentration problems dubbed “brain fog”.
These cognitive deficits often persist for months, disrupt work and daily life, yet their biological basis remains unknown.
Now, an international team has uncovered possible clues by linking acute blood biomarker profiles to later onset of cognitive impairment in two large longitudinal studies.
Their findings, published in Nature Medicine, point to two distinct biological pathways that could be driving post-COVID brain fog in different patient subsets.
The discovery of predictive blood biomarkers could enable better prognosis for cognitive outcomes and suggest targets for treatments and prevention.
These results help delineate the complex mechanisms underlying cognitive deficits in post-COVID syndrome and point towards specific biological processes that could be targeted by future treatments.
Tracking Biomarkers and Cognition in 1,837 COVID Patients (Study)
The team analyzed data from the Post-Hospitalization COVID-19 Study (PHOSP-COVID), which is following over 6,000 COVID-19 survivors discharged from dozens of UK hospitals.
Focusing on 1,837 patients who completed blood tests and cognitive assessments, the researchers used a technique called canonical correlation analysis to link blood biomarker profiles during acute COVID-19 to scores on cognitive tests 6-12 months later.
The cognitive assessments included both objective tools like the Montreal Cognitive Assessment (MoCA) and subjective self-reports of “brain fog” symptoms like trouble concentrating.
This enabled the team to tease apart biomarkers linked to measurable vs. perceived deficits.
2 Distinct Blood Biomarker Signatures Discovered
The analysis revealed two specific blood biomarker signatures.
Profile 1: High Fibrinogen, Normal CRP = Objective + Subjective Deficits
The first biomarker profile combined:
- High fibrinogen levels
- Normal C-reactive protein (CRP)
This profile during acute COVID-19 was linked to both objectively measurable cognitive deficits on the MoCA 6-12 months later, as well as subjectively reported “brain fog” symptoms.
Profile 2: High D-Dimer, Normal CRP = Subjective Deficits + Work Difficulties
The second biomarker profile combined:
- High D-dimer levels
- Normal CRP
This acute profile predicted subjective cognitive complaints 6-12 months later, as well as self-reported difficulty working and occupational changes.
However, it was not linked to objectively measured deficits on the MoCA.
The team confirmed that these biomarker-cognitive relationships were independent of illness severity and not explained by pre-COVID cognition.
The findings also replicated in a separate analysis of medical records from over 90 million patients.
Possible Mechanisms of Brain Fog & Cognitive Impairment in Long-COVID
Profile 1, combining high fibrinogen with normal CRP, points towards hypercoagulation and inflammation in the brain.
Fibrinogen is essential for blood clotting and also spurs immune activation.
The researchers hypothesize SARS-CoV-2 may damage the blood-brain barrier so fibrinogen can enter the brain, triggering microglial inflammation, neuronal damage, and amyloid buildup.
Meanwhile, Profile 2, with high D-dimer and normal CRP, may signify vascular blood clots leading to inadequate oxygen supply.
D-dimer is a marker of thrombotic events, which are common in severe COVID-19.
COVID-related lung clots could limit oxygenation, starving the brain and impairing cognition.
Supporting this, the D-dimer-cognition link was mediated by shortness of breath and fatigue.
Alternatively, D-dimer may tag small clots in brain blood vessels themselves.
The cognitive effects appeared subjective rather than objective, so brain oxygen lack may have been milder.
Future studies must investigate these hypotheses directly.
But the findings provide plausible biological leads for the first time.
Clinical Implications for Prognosis & Treatment
By uncovering blood biomarkers that presage cognitive impairment, this study could enable better prognosis for individual patients based on profiles during acute infection.
For example, an acute phase combining high fibrinogen and normal CRP predicts both subjective and objective deficits are likely to follow.
Meanwhile, high D-dimer with normal CRP foretells subjective complaints and potential work difficulties.
Beyond prognosis, identifying predictive biomarker profiles sheds light on biological processes driving cognitive decline after COVID-19.
This clues clinicians into possible interventions that could prevent or mitigate deficits.
For instance, the fibrinogen-associated profile suggests anti-clotting treatment and controlling neuroinflammation may protect cognition.
The D-dimer-associated profile implies anticoagulants and maximizing oxygenation could be of benefit.
Moving forward, researchers must confirm that intervening on these pathways yields cognitive benefits.
But now, doctors can monitor relevant blood biomarkers for signs of risk during acute COVID-19.
Future Directions: Testing Causal Hypotheses
This observational study sets the stage for future work to nail down causality.
Experimentally manipulating the biomarker pathways implicated would strengthen evidence they directly drive cognitive deficits.
Researchers could mimic high fibrinogen levels in animal models, then track effects on cognition.
Does blocking fibrinogen prevent cognitive decline?
Similar experiments could model blood clots and oxygen lack.
In human patients, researchers could test treatments targeting the biomarkers, like anticoagulants for high D-dimer.
Do interventions prevent associated cognitive impacts?
Finally, imaging studies can evaluate the hypothesized brain effects.
Does high acute phase fibrinogen correlate with microvascular damage or inflammation visible on MRI months later?
Do lacunar infarcts from small vessel clots appear?
By elucidating testable mechanisms, this study focuses the search for causal explanations of post-COVID brain fog.
The quest ahead is to definitively connect the dots from acute blood biomarkers to long-term neurological manifestations.
Humanizing the Post-COVID Cognitive Struggle
- 1 in 3 patients affected by cognitive problems post-COVID
- Brain fog disrupts daily life and work
- Findings offer patients hope science is unraveling the biology
This recent study illuminates biological mechanisms that may drive post-COVID cognitive impairment, indicated by predictive blood biomarker profiles.
This advances understanding and points to future directions for confirming causality and improving care.
But perhaps most importantly, it validates the experience of patients living with cloudy thinking and reminds us to keep seeking solutions for their sake.
- Paper: Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization (2023)
- Authors: Maxime Taquet et al.