Patients with pulmonary hypertension show reduced cerebellar white matter volume, thinner frontal gyri, weakened cerebellar-frontal connectivity and worse executive function and processing speed, linked to inflammatory proteins and the NCOA7 variant rs11154337, with Ncoa7 deficiency worsening cerebellar inflammation and atrophy in PH mice, which identifies NCOA7-linked inflammatory dysfunction in the cerebellar-frontal axis in PH.
Patients with pulmonary hypertension have structural brain alterations in the cerebellum and frontal lobe that were not seen in other heart or lung diseases.
Patients with PH have weakened functional connectivity between the cerebellum and frontal lobe.
The brain changes in PH were accompanied by worse executive function and processing speed.
Inflammatory plasma proteins and an NCOA7 single nucleotide polymorphism, rs11154337, were linked to the brain and cognitive deficits in PH.
The PH cerebellum shows increased microglial activation and white matter derangement.
Ncoa7 deficiency worsened cerebellar inflammation and atrophy in PH mice.
Ncoa7-dependent lysosomal, inflammatory, and cell-specific mechanisms were implicated in cerebellar pathobiology.
The study identifies NCOA7-linked inflammatory dysfunction in the cerebellar-frontal axis as a neurologic consequence of PH.
This study asked whether pulmonary hypertension (PH), a disease of high blood pressure in the lung arteries, also affects the brain. Using brain MRI scans from the UK Biobank (248 people with PH) and a separate group of patients, the researchers found that people with PH had less white matter in the cerebellum, thinner areas in the frontal part of the brain, and weaker communication between these two regions. These changes were not seen in people with other heart or lung diseases, and they occurred alongside poorer executive function and slower processing speed. The researchers then looked for causes. Blood proteins related to inflammation and a common genetic variant in a gene called NCOA7 were linked to the brain and thinking problems. Examination of PH cerebellar tissue showed more activated microglia (the brain's immune cells) and damaged white matter. In mice with PH, lacking Ncoa7 made cerebellar inflammation and shrinkage worse, and further lab analyses pointed to problems involving lysosomes (the cell's recycling structures) and inflammation. This research suggests that PH may have effects on the brain and thinking, driven in part by inflammation, and not just on the heart and lungs. It may point toward new ways to detect or monitor brain involvement and toward possible treatment targets, but the findings do not yet show any specific treatment, and much of the mechanistic work was done in mice.
Okawa S, Shi Y, Banerjee S, Tai Y, Nabhanizadeh J, Guenther S, et al.. (2026). Cerebellar and frontal lobe alterations in pulmonary hypertension implicate an inflammatory lung vascular/brain axis.. The Journal of clinical investigation. https://doi.org/10.1172/JCI195110