Poor gas exchange in lungs may help explain prolonged brain symptoms in Long COVID

New imaging reveals how subtle changes in the lungs can affect sleep and brain activity years after COVID, offering clues as to why symptoms persist even when routine tests appear normal.

Study: Long COVID: lung pathophysiology and its relationship to cognitive dysfunction. Image credit: designium / Shutterstock

In a recent study published in the journal Scientific Reportsresearchers looked at whether lung abnormalities were associated with cognitive symptoms and brain scans in people with long-term coronavirus disease 2019 (COVID 19) symptoms, a mean of 32±5 months (range=24–43 months) after infection. Lower lung gas exchange efficiency within the Long COVID 19 group was associated with worse sleep symptoms, poorer executive function, and higher cerebral perfusion, suggesting a possible lung-brain pathway contributing to persistent symptoms.

Persistent respiratory and cognitive symptoms in prolonged COVID

Millions worldwide experience persistent symptoms, shortness of breath, fatigue, exercise intolerance and “brain fog” beyond three months after acute infection. Despite common breathing problems, conventional lung examinations often appear normal. Hyperpolarized xenon-129 (129Xe) MRI can sensitively measure peripheral ventilation and gas exchange, offering diagnostic value. Cognitive complaints are also common and earlier MRI studies demonstrate gray matter changes, diffusion abnormalities, and altered perfusion. However, the link between lung physiology and brain lesions remains poorly understood.

Inclusion criteria for lung, brain and cognitive assessment

Adults aged 18 years and older were recruited from meta-COVID 19 clinic if they experience persistent shortness of breath or fatigue. Eligibility required a negative PCR examination and either previous hospitalization, abnormal lung or chest exams CT anomalies. Individuals with active respiratory infections or other cardiopulmonary diseases were excluded. A subset that completed 129Xe MRIbrain MRIand cognitive tests during the same session formed the baseline sample.

Multimodal screening: symptoms, cognitive function, pulmonary function, and brain imaging

Participants completed questionnaires assessing cognitive complaints, mood, fatigue, dyspnea, pain and sleep. Objective knowledge was assessed using it NIH Toolbox Cognition Battery with built-in validity indicators. Pulmonary testing followed standard guidelines. Brain MRI included structural imaging, diffusion tensor imaging, and arterial spin labeling to quantify volumetry, white matter hyperintensities, diffusion measurements, and cerebral perfusion. 129Xe MRI ventilation defects and gas exchange efficiency were assessed. healthy controls completed only the lung imaging component. Some age-adjusted correlations linked lung measurements with symptoms, cognition, and MRI measure.

The symptom profile shows persistent complaints but intact objective cognition

The final sample included 12 Long COVID 19 participants and 10 matched controls, nearly three years after infection. Long COVID 19 Participants frequently reported fatigue, shortness of breath, headaches, and significant cognitive concerns. However, objective cognitive performance remained normal for all but one participant, who showed domain-specific deficits in executive function, processing speed, and language. Pulmonary function tests were normal for all but one subject and no group differences emerged 129Xe gas exchange rates.

Lung gas exchange correlates with sleep problems and brain perfusion

Even without group-level lung abnormalities, within-group correlations were notable. Lower 129Xe Gas exchange ratios were associated with worse sleep disturbance, higher cerebral perfusion, and poorer executive function. Cerebral perfusion itself was strongly associated with sleep problems. Gas exchange efficiency showed positive correlations with executive function and a trend with global cognitive scores. These remained after adjusting for anxiety and depression. No associations with subjective cognitive problems, brain volumes, diffusion measurements, or white matter abnormalities emerged after adjusting for age.

Interpreting the Lung-Brain Connection in Long COVID

The findings suggest that disturbed lung gas exchange may be associated with altered cerebral perfusion and sleep disturbance, forming a potential physiological pathway affecting Long COVID 19 symptoms. The discrepancy between subjective cognitive difficulties and normal objective cognition is consistent with previous research and may reflect fluctuating deficits, heightened symptom awareness, or psychological factors.

Study limitations and future directions for longitudinal research on COVID

Strengths include a multimodal design incorporating lung, brain imaging MRIcognitive assessment and symptom profile; However, the small sample, partial imaging datasets, and lack of cognitive testing in controls limit generalizability. Age effects and a broad composite score may mask subtle deficits. Taken together, the results highlight the interconnected nature of gas exchange, cerebral perfusion, and sleep disturbance in Long COVID 19highlighting the need for larger, controlled studies with comprehensive brain and cognitive assessments to elucidate mechanisms and inform targeted interventions.