A clinical and translational study from the University of Pittsburgh and UPMC has identified a potential biological explanation for the brain fog, memory problems and executive dysfunction reported by many people with pulmonary hypertension (PH). Published in the Journal of Clinical Investigation, the research links the cognitive symptoms to the same inflammatory process that damages the blood vessels in the lungs.
The investigators found structural brain atrophy and weakened communication between the cerebellum and the prefrontal cortex in patients with PH. These regions participate in working memory, attention and executive planning. The pattern was identified through brain MRI analyses involving a population-level dataset and a specialized cohort of patients treated at UPMC.
According to the study, the affected cerebrocerebellar circuits were not observed in control groups with other severe cardiovascular conditions, chronic pulmonary diseases or psychiatric illnesses. Statistical analyses also indicated that the brain changes could not be explained by low blood oxygen, right-heart failure or PH medications.
The research centered on NCOA7, a gene variant previously associated with heightened vascular inflammation in about 25% of patients with pulmonary hypertension. The team, led by Stephen Chan, MD, PhD, examined human cerebellar tissue and mouse models to determine whether the gene’s activity also affected the brain.
In PH models, microglia—the brain’s resident immune cells—showed a hyperactive, pro-inflammatory state in the cerebellum. This activation was associated with changes to neuronal synapses and dendrites. Mice with pulmonary hypertension that lacked functional NCOA7 developed more severe cerebellar inflammation and tissue breakdown than mice with normal NCOA7 function, supporting a causal role for the gene in the neuroinflammatory process.
The findings suggest that cognitive impairment may be a primary neurological manifestation of pulmonary hypertension, rather than only a secondary consequence of impaired lung function, reduced cardiac output or treatment side effects. The researchers say that identifying NCOA7 activity and related microglial pathways could eventually help assess the risk of cognitive problems and guide the development of targeted treatments.
Current international pulmonary hypertension guidelines do not recommend routine cognitive screening, according to the report. The researchers argue that symptoms such as memory difficulties and trouble concentrating should receive greater attention in the clinical management of the disease.
Chan said the results highlight how a condition typically viewed through its effects on the lungs and heart can affect multiple organ systems. The team also suggested that NCOA7-related inflammation could be relevant to other inflammatory or neurodegenerative conditions, although further research will be needed to evaluate that possibility.
The work was supported by the National Institutes of Health, the American Heart Association, NASA, the WoodNext Foundation, the U.S. Department of Veterans Affairs, the European Research Council and other listed research programs. Chan and Lloyd Harvey are inventors on patents and patent applications related to metabolism, inflammation and pharmacological targeting of NCOA7 in pulmonary hypertension.
Sources: Neuroscience News.