Study uncovers why pulmonary hypertension patients report symptoms of cognitive decline

University of Pittsburgh and UPMC researcher-clinicians have uncovered why many pulmonary hypertension patients report symptoms of cognitive decline.

The new study, published in the Journal of Clinical Investigation today, links specific brain abnormalities in pulmonary hypertension to the same inflammatory processes that drive the disease in the lungs and heart, suggesting that cognitive decline may be present in other vascular and inflammatory conditions beyond pulmonary hypertension. The findings also point to a biological marker that could be used to screen people for future cognitive issues.

Millions of people are affected by pulmonary hypertension, which causes high blood pressure in the blood vessels of the lungs. Common symptoms include shortness of breath, chest pain and lightheadedness. The researchers found that cognitive issues such as impaired executive function and memory problems are often also present in pulmonary hypertension, and they have uncovered a biological reason for the phenomenon.

This changes the way we look at a disease like pulmonary hypertension. In medicine, we typically treat the symptoms of one organ system; but the reality is that our bodies are very complex, and disease processes may be affecting multiple parts of the body in a variety of ways."

Stephen Chan, M.D., Ph.D., Vitalant Chair in Vascular Medicine and director of the Vascular Medicine Institute and Center for Pulmonary Vascular Biology and Medicine, Pitt School of Medicine and UPMC

Recent research by Chan identified a genetic variant in a gene called NCOA7, which produces a protein of the same name. In a quarter of pulmonary hypertension patients, this variant drives inflammatory responses and worsens the odds of survival. Chan hypothesized that the same variant might be connected to brain inflammation that leads to cognitive impairment in people with pulmonary hypertension.

To test that theory, Chan and colleagues used brain MRI scans and blood tests to look for brain changes that were unique to pulmonary hypertension. They first compared the brain scans of people with pulmonary hypertension against those without, using data from a large public health database and a smaller group of UPMC patients to test and confirm their hypothesis.

Patients with pulmonary hypertension in both test groups had a consistent and substantial loss of brain tissue and weakened communication between two brain regions involved in memory, attention and planning - the cerebellum, at the base of the brain, and the frontal lobe, just behind the forehead. Notably, the same brain changes were absent in people with other heart, lung and psychiatric conditions. And the brain differences could not be explained by low blood oxygen, poor heart function or the medications used to treat the disease - evidence that the changes are specific to pulmonary hypertension, rather than a side effect of the disease's effects on the heart and lungs.

By analyzing genetic data from both groups of patients and conducting additional laboratory studies, the team found that the NCOA7 variant already linked to blood vessel inflammation in pulmonary hypertension is also connected to inflammation in the cerebellum of these patients.

Examining cerebellum tissue from patients and mice with pulmonary hypertension, they saw signs that the brain's immune cells - microglia - had become overactive, and evidence that neurons were changing in response. Mice that both developed the disease and lacked the NCOA7 gene had more severe cerebellar damage than mice with pulmonary hypertension alone - establishing that the gene plays a causal role in regulating brain inflammation in this disease.

Chan suspects that this mechanism is active in other diseases beyond pulmonary hypertension.

"I believe that NCOA7 deficiency may underlie a spectrum of inflammatory conditions - including those that may contribute to dementia and aging," Chan said. "If so, these findings could introduce new diagnostic and therapeutic avenues for preserving brain function in a much broader group of people."

Current guidelines for managing pulmonary hypertension do not include cognitive screening, and no biological marker exists to predict or track how much the disease affects the brain. This study points to a potential marker and identifies inflammation as a potential therapeutic target for preserving brain function and quality of life.

"Patients often assume memory issues or trouble concentrating are unrelated to their pulmonary hypertension," Chan said. "Our findings suggest those symptoms are a central part of the disease process and deserve attention."