Researchers at the University of Pittsburgh and UPMC have identified a possible biological explanation for cognitive problems reported by many people with pulmonary hypertension (PH). Using brain MRI scans, blood-based molecular profiling and functional studies in mice, the team linked changes in the brain to inflammatory processes associated with PH in the lungs and heart.
The findings, published in the Journal of Clinical Investigation in a paper titled “Cerebellar and frontal lobe alterations in pulmonary hypertension implicate an inflammatory lung vascular/brain axis,” suggest that cognitive impairment may be a central feature of PH rather than an unrelated symptom. The study also points to potential neural targets for future diagnostic, prognostic and therapeutic research.
The researchers compared MRI data from people with PH with data from individuals without the condition, using information from the UK Biobank and a prospective UPMC validation group. Across both groups of patients with PH, they observed reduced brain tissue and weaker communication between the cerebellum and frontal lobe, regions involved in memory, attention and planning.
The abnormalities included reduced cerebellar white matter volume, thinner frontal gyri and weakened cerebellar-frontal connectivity. They were associated with poorer executive function and slower processing speed. The same changes were not observed in participants with other heart, lung or psychiatric conditions.
The brain differences could not be explained by low blood oxygen, reduced heart function or medications used to treat PH. This supported the possibility that the changes were specifically connected to pulmonary hypertension rather than being secondary effects of the disease’s impact on the heart and lungs.
The team also investigated NCOA7, a gene variant previously associated with inflammatory responses and poorer survival in a subset of people with PH. Genetic analyses and laboratory studies connected the variant to inflammation in the cerebellum. Tissue analyses from patients and mice showed increased activity in microglia, the brain’s immune cells, along with signs of neuronal changes.
In mouse models, animals that developed PH and lacked NCOA7 showed more severe cerebellar damage than mice with PH alone. The result indicated that the gene has a causal role in regulating brain inflammation in the disease.
Stephen Chan, MD, PhD, the study’s senior author and a researcher-clinician at the University of Pittsburgh and UPMC, said patients often assume that memory problems or difficulty concentrating are unrelated to PH. The study’s results, he said, indicate that these symptoms deserve attention as part of the disease process.
Current PH management guidelines do not include cognitive screening, and there is no biological marker to predict or monitor the condition’s effects on the brain. The researchers say their findings could support the development of markers and treatments aimed at inflammation, although they note that further work is needed to determine whether the associated brain changes can be reversed.
Chan also suggested that NCOA7-related inflammation could be relevant to other inflammatory conditions, including diseases that contribute to dementia and aging. The study authors said the findings may help guide future diagnostic and prognostic strategies beyond pulmonary hypertension.