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Two distinct blood biomarker profiles predicted cognitive deficits 6 and 12 months after COVID-19, prospective U.K. data showed.

Both biomarker profiles featured proteins involved in coagulation, reported Maxime Taquet, PhD, of the University of Oxford in England, and co-authors in .

Among 1,800 patients hospitalized for COVID-19 during the first wave of the pandemic, a blood profile that included high levels of fibrinogen correlated with both objective and subjective cognitive deficits. A second profile linked elevated D-dimer relative to C-reactive protein (CRP) with subjective cognitive deficits and occupational impact, which was partly mediated by fatigue and shortness of breath.

The results could not be explained by cognitive problems preceding the infection, nor by depression or anxiety, the researchers noted. The D-dimer relationship appeared specific to COVID infection, whereas high fibrinogen was a risk factor for cognitive deficits, regardless of the cause.

The findings provide a clue about one mechanism that might cause post-COVID cognitive deficits, Taquet told MedPage Today. "The observation that raised levels of fibrinogen and D-dimer relative to CRP levels are associated with later cognitive deficits suggests that hypercoagulation is likely to be involved," he said.

"Subsequent analyses and interpretations in our research suggest three potentially distinct mechanisms," Taquet added. "One involves blood clots in the brain directly affecting cognition; another relates to the direct effect of fibrinogen on the brain; and a third one involves blood clots in the lungs [that] might lead to subsequent hypoxia or fatigue, which can have cognitive manifestations."

Brain fog and other cognitive problems often persist after COVID -- especially among patients hospitalized with acute SARS-CoV-2 infection -- but how and why they develop remain unknown.

Cognitive deficits appear to occur more frequently after COVID than other respiratory tract infections, Taquet noted. "In one of our studies, we showed they were ," he said. While they're less common after other infections, it's possible that mechanisms are similar: "COVID-19 may serve as a window into the possible brain consequences of respiratory infections," he suggested.

Taquet and colleagues studied 1,837 patients in the cohort who had been hospitalized for COVID-19 in the U.K. between January 2020 and November 2021. Mean age was 58, and 37% were women.

The researchers used canonical correlation analysis to find covariation patterns between a set of six blood biomarkers measured on admission to hospital (CRP, D-dimer, fibrinogen, lymphocyte, and neutrophil and platelet counts) with a set of cognitive scores measured 6 and 12 months later. Cognitive scores included components of the Montreal Cognitive Assessment (MoCA) to assess objective deficits and cognitive items from the Patient Symptom Questionnaire (C-PSQ) to gauge subjective deficits.

In a subset of patients with C-PSQ scores before and after SARS-CoV-2 infection, subjective cognitive function declined at 6 and 12 months on average. High fibrinogen or high D-dimer levels relative to CRP were not more common in people with pre-existing cognitive deficits.

The researchers reproduced their analysis using electronic health records from a network of 57 healthcare organizations primarily in the U.S., and found that acute D-dimer level was significantly associated with post-COVID cognitive changes. Acutely raised fibrinogen level also was linked with post-COVID cognitive deficits.

The findings are limited to people who had COVID-19 in the first wave and who were ill enough to have been hospitalized, Taquet and colleagues emphasized. Blood samples were assessed only at the time of acute infection. Mechanisms are speculative, and further studies are needed to better delineate them, the researchers acknowledged.

"We're excited to see whether and how our findings will inform future research into possible treatments, which people currently living with post-COVID cognitive deficits urgently need," Taquet said.

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