Author: John Murphy, President, COVID-19 Long-haul Foundation

Abstract

Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), presents with a constellation of neurological symptoms including brain fog, memory loss, and executive dysfunction. Emerging evidence implicates neurovascular dysregulation as a central mechanism, driven by blood-brain barrier (BBB) disruption, cerebral microclots, hypoperfusion, and neuroinflammation. This article synthesizes recent findings from neuroimaging, transcriptomics, and clinical cohorts to propose a unified model of cognitive impairment in Long COVID. We examine the role of glial activation, synaptic remodeling, and microvascular injury, and highlight diagnostic and therapeutic implications.

1. Introduction

Since the onset of the COVID-19 pandemic, neurological symptoms have been reported in both acute and post-acute phases of SARS-CoV-2 infection. In Long COVID, cognitive impairment—often described as “brain fog”—has emerged as one of the most disabling and persistent sequelae. Patients report difficulties with memory, attention, processing speed, and executive function, often months after viral clearance.

While early hypotheses focused on viral neuroinvasion or psychological stress, recent studies suggest that neurovascular injury and microvascular dysfunction are key drivers of cognitive decline. This article explores the mechanisms underlying neurovascular dysregulation in Long COVID, integrating findings from PET imaging, cerebrovascular reactivity studies, and transcriptomic analyses.

2. Blood-Brain Barrier Disruption

The blood-brain barrier (BBB) is a critical interface that regulates the exchange of molecules between the bloodstream and the central nervous system. SARS-CoV-2 spike protein has been shown to bind to ACE2 receptors on endothelial cells, triggering inflammation and increased permeability.

Ashfaque et al. (2025) identified transcriptomic signatures of BBB disruption in Long COVID patients with cognitive symptoms, including upregulation of claudin-5 and downregulation of tight junction proteins. These changes compromise barrier integrity and allow peripheral cytokines and immune cells to enter the brain, promoting neuroinflammation.

3. Cerebral Microclots and Hypoperfusion

Microclots—small fibrinaloid aggregates resistant to fibrinolysis—have been detected in cerebral vessels of Long COVID patients. These clots impair oxygen delivery and contribute to regional hypoperfusion.

Pommy et al. (2025) used functional MRI to assess cerebrovascular reactivity in older adults with Long COVID, finding reduced perfusion in the default mode and frontoparietal networks. These regions are critical for attention, working memory, and executive function. The presence of microclots correlates with cognitive deficits and fatigue.

4. Neuroinflammation and Glial Activation

Neuroinflammation is a hallmark of Long COVID, with evidence of microglial and astrocyte activation. PET imaging studies using [11C]K-2—a marker for AMPA receptor density—have revealed widespread synaptic remodeling in patients with cognitive symptoms.

Japanese researchers at YCU Advanced Medical Research Center confirmed increased AMPA receptor activity in brain regions associated with memory and attention, suggesting excitotoxicity and synaptic dysregulation. These findings support a model of persistent neuroinflammation driving cognitive decline.

5. Clinical Manifestations

The cognitive symptoms of Long COVID are diverse and often fluctuate over time. Common complaints include:

• Brain fog: Difficulty concentrating, slowed thinking, and mental fatigue
• Memory loss: Impaired short-term recall and working memory
• Executive dysfunction: Problems with planning, decision-making, and multitasking

Panagea et al. (2025) conducted a systematic review of neuropsychological assessments in Long COVID, finding deficits in verbal fluency, attention, and processing speed across multiple cohorts. These impairments persist for months and are not explained by mood disorders alone.

6. Diagnostic and Therapeutic Implications

Diagnostics

• PET imaging: [11C]K-2 scans reveal synaptic changes linked to AMPA receptor density
• fMRI: Measures cerebrovascular reactivity and regional perfusion deficits
• Transcriptomics: Identifies biomarkers of BBB disruption and neuroinflammation

Therapeutics

• Anti-inflammatory agents: Target microglial activation and cytokine signaling
• Fibrinolytics: Address cerebral microclots and improve perfusion
• Cognitive rehabilitation: Tailored interventions to restore executive function

7. Conclusion

Neurovascular dysregulation is a central mechanism in Long COVID cognitive impairment. Blood-brain barrier disruption, cerebral microclots, and glial activation converge to impair synaptic function and cerebral perfusion. These findings underscore the need for vascular-centered diagnostics and therapeutics, and call for longitudinal studies to track recovery and guide intervention.

📎 References

1. PET Imaging Study Links Synaptic Changes to Long COVID Cognitive Impairment
2. Cognitive Performance Remains Intact 1 Year After COVID-19 in Middle-Aged Adults
3. Long-term neurological and cognitive impact of COVID-19: a systematic review and meta-analysis
4. Neurocognitive Impairment in Long COVID: A Systematic Review
5. Changes in cerebrovascular reactivity within functional networks in older adults with long-COVID
6. Distinct Transcriptomic Biomarkers and Pathways Associated with Neurovascular Dysregulation in Long COVID Brain Fog
7. Scientists Finally Reveal What’s Behind Long COVID’s Brain Fog