Pulmonary hypertension may leave a mark on the brain

Clinical takeaway: Consider cognitive symptoms such as memory lapses, slower thinking, or impaired executive function as potential manifestations of pulmonary hypertension rather than unrelated complaints.

Cognitive impairment affects up to half of patients with pulmonary hypertension (PH), but its biological basis has remained unclear. This study suggests that PH is not solely a heart and lung disease, linking it instead to inflammation-driven changes in the brain that may help explain commonly reported cognitive symptoms.

Researchers combined brain MRI, cognitive testing, blood biomarker analyses, human tissue studies, and animal models to explore brain involvement in PH. Using data from 248 patients with PH and more than 11,000 healthy controls in the UK Biobank, they identified a distinctive pattern of abnormalities involving the cerebellum and superior frontal gyrus, regions important for attention, memory, planning, and executive function.

Compared with controls, patients with PH had about 4% less cerebellar white matter, roughly 2% thinner frontal cortex, and nearly 23% weaker connectivity between the affected brain regions. Similar findings were replicated in a separate UPMC cohort of patients with pulmonary arterial hypertension, where cerebellar-frontal connectivity was nearly 40% lower than in matched controls.

These structural changes were accompanied by poorer performance on tests of executive function, processing speed, reasoning, and working memory. The abnormalities were not explained by hypoxemia, impaired cardiac output, PH medications, or common cardiopulmonary comorbidities.

Blood analyses identified inflammatory and microglia-related protein signatures associated with the brain changes. Human cerebellar tissue from patients with PAH showed increased microglial activation, while mouse models demonstrated that deficiency of NCOA7, a gene previously linked to vascular inflammation in PH, worsened cerebellar inflammation and tissue loss. Together, the findings support the existence of an inflammatory lung vascular-brain axis that may help explain the cognitive symptoms commonly reported by patients with PH.

The findings also open the door to prospective studies testing whether inflammatory biomarkers can identify patients at risk for cognitive decline and whether therapies targeting the NCOA7 inflammatory pathway can preserve brain function. The authors suggest that pulmonary hypertension may provide a new model for studying how chronic vascular inflammation contributes to neurodegeneration more broadly.

“This changes the way we look at a disease like pulmonary hypertension,” said senior author Stephen Y. Chan, MD, PhD. “Our findings suggest those symptoms are a central part of the disease process and deserve attention.”

Source: Okawa S, et al. (2026 Nov 2) J Clin Invest. Cerebellar and frontal lobe alterations in pulmonary hypertension implicate an inflammatory lung vascular-brain axis