Arjun Sangani

Background:  Long-COVID is a disease state following COVID-19 infection, characterized by prolonged symptoms such as fatigue, pain, and shortness of breath.⁴ Among these, “brain fog” describes cognitive dysfunction including memory impairment and slower cognition. Due to the subjective nature of these complaints, brain fog can be challenging for clinicians to distinguish from other pathologies. This cognitive burden can significantly impact patients’ quality of life, underscoring the need for objective diagnostic markers to support timely treatment⁴.

Objective:  In this review, we explore the clinical biomarkers of Long COVID-associated brain fog.

Methods:  Online searches in Google Scholar and PubMed were conducted using the following key words: “Long COVID brain fog”, “Long COVID biomarkers”, “Long COVID brain fog biomarkers”, “Long COVID brain fog imaging”, “Long COVID brain fog serum markers”.

Results:  Prospective cohort studies reveal that elevated fibrinogen levels relative to C-Reactive Protein (CRP) in acute infection are prognostic of cognitive dysfunction, as measured by standard assessments. These findings are consistent across larger database studies, surprisingly both in COVID-positive and COVID-negative patients.⁷ Another study identified two notable biomarkers specifically elevated in COVID patients with brain fog compared to those without. First, significantly higher levels of Transforming Growth Factor-β (TGF-β) was observed, suggesting immune dysregulation.¹ Second, increased blood-brain barrier (BBB) permeability was detected via Dynamic-Contrast Enhanced MRI (DCE-MRI), particularly in the frontal and temporal lobes—areas responsible for memory and cognition. This suggests BBB dysfunction may play a role in brain fog’s pathogenesis.^1,6  Interestingly, transcranial direct current stimulation (tDCS), a therapy reported to benefit some patients with brain fog,^2,3 has also been shown in animal models to affect BBB permeability⁵. This may represent a potential mechanism for its therapeutic effects, though further research is necessary to establish clinical relevance.

Conclusions:  This review identifies several biomarkers potentially associated with Long-COVID brain fog: elevated fibrinogen:CRP ratios during acute infection, increased serum TGF-β levels, and greater BBB permeability as seen on DCE-MRI. Although findings are promising, limitations include small cohort sizes and reliance on subjective criteria to define brain fog. Unfortunately, these biomarkers are not exclusive to Long-COVID and may be present in other conditions, which appears to be the case for elevated fibrinogen:CRP⁷. Future research should aim to validate these findings in larger populations and develop more objective measures to distinguish Long-COVID brain fog from other disease states.

Works Cited:

1. Greene, C., Connolly, R., Brennan, D., Laffan, A., O’Keeffe, E., Zaporojan, L., O’Callaghan, J., Thomson, B., Connolly, E., Argue, R., Meaney, J. F. M., Martin-Loeches, I., Long, A., Cheallaigh, C. N., Conlon, N., Doherty, C. P., & Campbell, M. (2024). Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nature Neuroscience, 27(3), 421–432. https://doi.org/10.1038/s41593-024-01576-9
2. Marrón, E. M., Grueso, S., Fernández, J. G., Ciongoli, F., Calabria, M., Cano, N., & Garolera, M. (2025). Remote tDCS intervention for cognitive alterations and fatigue in post-COVID19 syndrome. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 18(1), 545. https://doi.org/10.1016/j.brs.2024.12.963
3. Mischke, M., & Zaehle, T. (2025). Evaluating the efficacy of repetitive anodal transcranial direct current stimulation on cognitive fatigue in long COVID: A randomized controlled trial. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 18(3), 733–735. https://doi.org/10.1016/j.brs.2025.03.011
4. Nordvig, A. S., Rajan, M., Lau, J. D., Kingery, J. R., Mahmud, M., Chiang, G. C., De Leon, M. J., & Goyal, P. (2023). Brain fog in long COVID limits function and health status, independently of hospital severity and preexisting conditions. Frontiers in Neurology, 14, 1150096. https://doi.org/10.3389/fneur.2023.1150096
5. O’Hashi, K., Okazaki, Y., & Kobayashi, M. (2025). Transcranial direct current stimulation (tDCS) as a potential tool for Blood-brain barrier opening and closing. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 18(1), 482. https://doi.org/10.1016/j.brs.2024.12.780
6. Paharia, P. T. (2023, September 7). Specialized astrocyte subpopulation discovery sheds light on brain health and treatment avenues. News-Medical. https://www.news-medical.net/news/20230907/Specialized-astrocyte-subpopulation-discovery-sheds-light-on-brain-health-and-treatment-avenues.aspx
7. Taquet, M., Skorniewska, Z., Hampshire, A., Chalmers, J. D., Ho, L.-P., Horsley, A., Marks, M., Poinasamy, K., Raman, B., Leavy, O. C., Richardson, M., Elneima, O., McAuley, H. J. C., Shikotra, A., Singapuri, A., Sereno, M., Saunders, R. M., Harris, V. C., Houchen-Wolloff, L., … Harrison, P. J. (2023). Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization. Nature Medicine, 29(10), 2498–2508. https://doi.org/10.1038/s41591-023-02525-y