Cerebellar and frontal lobe alterations in pulmonary hypertension implicate an inflammatory lung vascular/brain axis
Connections between vascular and neurocognitive diseases are emerging but remain poorly defined. Cognitive impairment is increasingly recognized in pulmonary hypertension (PH), a disease traditionally viewed as limited to the heart and lungs. Given that inflammation is shared by PH and neurodegenerative diseases, we investigated its role in driving brain and cognitive deficits in PH. Using structural and functional MRI data from UK Biobank (N = 248 PH) and a prospective validation cohort, we identified reduced cerebellar white matter volume, thinner frontal gyri, and weakened cerebellar-frontal connectivity in patients with PH but not in other heart or lung diseases. These changes were accompanied by worsened executive function and processing speed. Olink proteomics and targeted genomics linked inflammatory plasma proteins and a PH-associated nuclear receptor coactivator 7 (NCOA7) single nucleotide polymorphism, rs11154337, to these deficits. PH cerebellum showed increased microglial activation and white matter derangement. In PH mice, Ncoa7 deficiency worsened cerebellar inflammation and atrophy. Microglial functional assays, cerebellar single-nucleus RNA sequencing, and spatial transcriptomic analyses further implicated Ncoa7-dependent lysosomal, inflammatory, and cell-specific mechanisms of cerebellar pathobiology. These findings identify NCOA7-linked inflammatory dysfunction in the cerebellar-frontal axis in PH, redefining this disease with neurologic consequences and thus offering neural targets for diagnostic, prognostic, and therapeutic development.
Authors
- Anisha N Shah (ORCID: https://orcid.org/0000-0003-3813-6707)
- Somanshu Banerjee (ORCID: https://orcid.org/0000-0002-8043-2457)
- Omolara Fatukasi
- Kathiravan Kaliyappan (ORCID: https://orcid.org/0000-0002-0028-1274)
- Timothy D. Girard (ORCID: https://orcid.org/0000-0002-9833-4871)
- Joseph Mettenburg (ORCID: https://orcid.org/0000-0002-3049-6268)
- Stephen Y. Chan (ORCID: https://orcid.org/0000-0002-9520-7527)
- Satoshi Okawa (ORCID: https://orcid.org/0000-0003-3916-3109)
- Steeve Provencher (ORCID: https://orcid.org/0000-0001-7535-9972)
- Sébastien Bonnet (ORCID: https://orcid.org/0000-0001-5753-1900)
- Soban Umar (ORCID: https://orcid.org/0000-0001-8036-3079)
- Soni Savai Pullamsetti (ORCID: https://orcid.org/0000-0003-0440-8831)
- Timothy Kim
- Sandra Breuils‐Bonnet (ORCID: https://orcid.org/0009-0007-8613-8455)
- Theodore J. Huppert (ORCID: https://orcid.org/0000-0001-8426-5759)
- Rajkumar Savai (ORCID: https://orcid.org/0000-0003-1538-2091)
- Yassmin Al Aaraj (ORCID: https://orcid.org/0000-0002-3252-8606)
- Yi‐Yin Tai (ORCID: https://orcid.org/0000-0003-3674-0783)
- Caroline J. Pidro
- Lloyd D. Harvey (ORCID: https://orcid.org/0000-0001-5934-9934)
- James T. Becker (ORCID: https://orcid.org/0000-0003-4425-4726)
- Jamal Nabhanizadeh
- Yinan Shi
- Siyi Jiang (ORCID: https://orcid.org/0000-0002-5481-2771)
- Metin Aytekin (ORCID: https://orcid.org/0000-0002-9784-0377)
- Nishita Kalepalli
- Seyed Mehdi Nouraie (ORCID: https://orcid.org/0000-0001-7465-0581)
- Dandan Sun
- Stefan Guenther (5992991)
- Shanshan Song
Institutions
- University of California, Los Angeles (US)
- University of Pittsburgh (US)
- Justus-Liebig-Universität Gießen (DE)
- UPMC Health System (US)
- Max Planck Institute for Heart and Lung Research (DE)
- German Center for Lung Research (DE)
- University of Pittsburgh Medical Center (US)
- Institut universitaire de cardiologie et de pneumologie de Québec (CA)
- Cardio-Pulmonary Institute (DE)
- McGowan Institute for Regenerative Medicine (US)
- Université Laval (CA)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2026-11-01
- DOI
- https://doi.org/10.1172/jci195110
- Citations
- 1
- Primary Topic
- Pulmonary Hypertension Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 4.65
Funders
- National Aeronautics and Space Administration
- American Heart Association
- Veterans Administration Medical Center
- Deutsche Forschungsgemeinschaft