Cerebellar and frontal lobe alterations in pulmonary hypertension implicate an inflammatory lung vascular/brain axis

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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.

Authors

Satoshi Okawa, Yinan Shi, Somanshu Banerjee, Yi Yin Tai, Jamal Nabhanizadeh, Stefan Guenther, Anisha N. Shah, Siyi Jiang, Timothy Kim, Yassmin Al Aaraj, Caroline Pidro, Metin Aytekin, Omolara Fatukasi, Nishita Kalepalli, Joseph Mettenburg, Timothy D. Girard, James T. Becker, Kathiravan Kaliyappan, Shanshan Song, Sandra Breuils-Bonnet, Steeve Provencher, Sébastien Bonnet, Theodore Huppert, Lloyd D. Harvey, Seyed Mehdi Nouraie, Rajkumar Savai, Dandan Sun, Soban Umar, Soni S. Pullamsetti, Stephen Y. Chan