Abstract Body (Do not enter title and authors here): Background: Connections between vascular and neurocognitive diseases are emerging but remain poorly defined. Cognitive impairments have been reported in pulmonary hypertension (PH), a disease traditionally viewed as limited to the heart and lungs.
Hypothesis: Given that inflammation is a shared feature of PH and neurodegenerative diseases, we investigated its role in driving brain and cognitive deficits in PH.
Methods and Results: Using structural and functional MRI data from UK Biobank (N=248 PH; N=11,656 controls) and a prospective validation cohort from University of Pittsburgh Medical Center (N=10 PAH, N=10 controls), we identified reduced cerebellar white matter volume, thinner frontal gyri, and weakened cerebellar-frontal connectivity in PH patients but not in other heart or lung diseases. These changes were accompanied by worsened executive function and processing speed. By unbiased Olink proteomic analysis, we uncovered the deficiencies in the left cerebellum-superior frontal gyrus (CRBL-SFG) axis were associated with several inflammatory plasma proteins. Notably, Gene Ontology Biological Process enrichment analysis of the top inversely associated proteins revealed significant enrichment in categories including microglial activation and neuroinflammatory response. We previously reported that the G-allele of the intronic NCOA7 single nucleotide polymorphism (SNP) rs11154337 exerts a protective effect in PH patients through the upregulation of NCOA7 expression. We have now identified an association between the G-allele and enhanced connectivity strength between the left CRBL and SFG. Immunofluorescence staining of PH patient brain revealed an increased number of IBA1+ microglia and activated morphology in the cerebellum. Additionally, there was a notable upregulation of the apoptotic marker cleaved caspase-3 in NeuN+ neuronal cells within the cerebellar molecular layer, indicating heightened microglial activation and neuronal apoptosis. Consistent with these human observations, an inflammatory Il6 transgenic PH mouse model displayed reduced cerebellar volume and an increased number of inflammatory microglia. Furthermore, Il6 transgenic mice crossed with Ncoa7 knockout mice exhibited a more severe phenotype.
Conclusions: These findings identify 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.