Pulmonary Hypertension Study Links Brain Changes to NCOA7-Related Inflammation

Pulmonary hypertension may affect brain function through the same inflammatory processes that damage blood vessels in the lungs and heart. A University of Pittsburgh and UPMC team found structural and communication changes in brain regions involved in memory, attention and planning, and linked them to inflammation associated with the NCOA7 gene.

The findings, published in the Journal of Clinical Investigation, bring together brain MRI, blood-based molecular analysis, patient tissue and mouse experiments. The researchers say the results suggest that cognitive symptoms can be part of pulmonary hypertension itself, rather than a secondary effect of low oxygen, impaired heart function or treatment.

“Patients often assume memory issues or trouble concentrating are unrelated to their pulmonary hypertension,” said study lead Stephen Chan, MD, PhD, the Vitalant Chair in Vascular Medicine and director of the Vascular Medicine Institute and Center for Pulmonary Vascular Biology and Medicine at the Pitt School of Medicine and UPMC. “Our findings suggest those symptoms are a central part of the disease process and deserve attention.”

Brain changes specific to pulmonary hypertension

The team compared brain scans from people with pulmonary hypertension (PH) with scans from people without the condition, using data from the UK Biobank and a smaller prospective UPMC patient group for validation. Across both groups, PH was associated with reduced cerebellar white matter, thinner frontal gyri and weaker connections between the cerebellum and frontal lobe.

These regions help support executive function and processing speed. The researchers also found poorer performance in those areas among patients with PH. The reported MRI analysis included 248 people with PH in the UK Biobank dataset. Similar brain changes did not appear in comparison groups with other heart, lung or psychiatric conditions.

The pattern matters because cognitive problems have increasingly been reported in PH, a condition usually understood through its effects on the heart and lungs. The disease raises blood pressure in the vessels supplying the lungs; common symptoms include shortness of breath, chest pain and lightheadedness. The new work connects that vascular disease to brain changes that may help explain memory and concentration complaints.

Chan and colleagues also examined whether the brain findings could be explained by factors associated with severe cardiopulmonary disease. Their analysis did not attribute the changes to low blood oxygen, poor heart function or PH medications, supporting a link with the disease’s own biology.

NCOA7 connects vascular and brain inflammation

The study builds on Chan’s earlier research into a variant of NCOA7, a gene that produces the NCOA7 protein. The variant is found in about a quarter of PH patients and is associated with inflammatory responses and worse survival odds. Chan suspected that the same genetic factor might also contribute to inflammation in the brain.

Genetic analysis and laboratory studies connected the variant to cerebellar inflammation in patients with PH. Examination of cerebellar tissue from patients and mice showed activated microglia, the brain’s immune cells, alongside signs of changes in neurons. In mice with PH, the absence of NCOA7 was associated with more severe cerebellar damage than in mice that developed PH but retained the gene. The result points to a role for NCOA7 in regulating brain inflammation in this disease.

The authors describe the combined findings as evidence of a pulmonary vascular and brain connection involving chronic neuroinflammation and NCOA7 dysfunction. Their paper, “Cerebellar and frontal lobe alterations in pulmonary hypertension implicate an inflammatory lung vascular/brain axis”, reports the MRI, molecular and experimental results.

Potential implications for care and further research

Current PH management guidelines do not include cognitive screening, and clinicians lack a biological marker to predict or track the condition’s effects on the brain. The team’s findings raise the possibility that inflammatory blood markers could help identify or monitor brain changes. They also point to inflammation as a target for research into preserving cognitive function.

Chan thinks the mechanism may extend beyond PH. “I believe that NCOA7 deficiency may underlie a spectrum of inflammatory conditions—including those that may contribute to dementia and aging,” he said. The authors say further work could test whether the brain changes associated with PH can be reversed through treatment.

For now, the study gives clinicians a reason to take concentration and memory complaints seriously when they arise alongside PH. Its next test is whether the links among NCOA7, inflammatory markers and brain function can lead to useful ways to identify or address cognitive effects in patients.

The report was first published by GEN - Genetic Engineering and Biotechnology News.