Cerebellar and frontal lobe alterations in pulmonary hypertension implicate an inflammatory lung vascular/brain axis.
16 affiliations
- 1Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine
- 2Department of Computational and Systems Biology; and
- 3McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
- 4Department of Anesthesiology and Perioperative Medicine, Division of Molecular Medicine, University of California, Los Angeles, Los Angeles, California, USA.
- 5Institute for Lung Health, Department of Internal Medicine, German Center for Lung Research (DZL), Cardio-pulmonary Institute (CPI), Justus Liebig University, Giessen, Germany.
- 6Max Planck Institute for Heart and Lung Research, DZL, CPI, Bad Nauheim, Germany.
- 7Cellular and Molecular Pathology Graduate Program, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
- 8Heart and Vascular Institute, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA.
- 9Department of Critical Care Medicine
- 10Department of Psychiatry
- 11Department of Radiology, and
- 12Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
- 13Pittsburgh Veteran’s Affairs Research Center, Pittsburgh, Pennsylvania, USA.
- 14PAH Research Group, Institut Universitaire de Cardiologie et Pneumologie de Québec Research Center, Department of Medicine, Université Laval, Quebec City, Québec, Canada.
- 15Department of Electrical and Computer Engineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
- 16Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Abstract
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.
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BibTeX
@article{okawa2026cerebellar,
title = {{Cerebellar and frontal lobe alterations in pulmonary hypertension implicate an inflammatory lung vascular/brain axis.}},
author = {Satoshi Okawa and Yinan Shi and Somanshu Banerjee and Yi Yin Tai and Jamal Nabhanizadeh and Stefan Guenther and Anisha N. Shah and Siyi Jiang and Timothy Kim and Yassmin Al Aaraj and Caroline Pidro and Metin Aytekin and Omolara Fatukasi and Nishita Kalepalli and Joseph Mettenburg and Timothy D. Girard and James T. Becker and Kathiravan Kaliyappan and Shanshan Song and Sandra Breuils-Bonnet and Steeve Provencher and Sébastien Bonnet and Theodore Huppert and Lloyd D. Harvey and Seyed Mehdi Nouraie and Rajkumar Savai and Dandan Sun and Soban Umar and Soni S. Pullamsetti and Stephen Y. Chan},
journal = {The Journal of clinical investigation},
year = {2026},
month = nov,
doi = {10.1172/jci195110},
url = {https://europepmc.org/article/MED/42969225},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cerebellar and frontal lobe alterations in pulmonary hypertension implicate an inflammatory lung vascular/brain axis.
AU - Satoshi Okawa
AU - Yinan Shi
AU - Somanshu Banerjee
AU - Yi Yin Tai
AU - Jamal Nabhanizadeh
AU - Stefan Guenther
AU - Anisha N. Shah
AU - Siyi Jiang
AU - Timothy Kim
AU - Yassmin Al Aaraj
AU - Caroline Pidro
AU - Metin Aytekin
AU - Omolara Fatukasi
AU - Nishita Kalepalli
AU - Joseph Mettenburg
AU - Timothy D. Girard
AU - James T. Becker
AU - Kathiravan Kaliyappan
AU - Shanshan Song
AU - Sandra Breuils-Bonnet
AU - Steeve Provencher
AU - Sébastien Bonnet
AU - Theodore Huppert
AU - Lloyd D. Harvey
AU - Seyed Mehdi Nouraie
AU - Rajkumar Savai
AU - Dandan Sun
AU - Soban Umar
AU - Soni S. Pullamsetti
AU - Stephen Y. Chan
PY - 2026
DA - 2026/11/02
JO - The Journal of clinical investigation
DO - 10.1172/jci195110
UR - https://europepmc.org/article/MED/42969225
AB - 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.
SN - 0021-9738
SN - 1558-8238
ER -