Reconfigured metabolism brain network in asymptomatic Creutzfeldt-Jakob disease

Yu Kong; Zhongyun Chen; Jing Zhang; Yihao Wang; Min Chu; Haitian Nan; Yue Cui; Deming Jiang; Liyong Wu

doi:10.1016/j.nbd.2025.106805

Reconfigured metabolism brain network in asymptomatic Creutzfeldt-Jakob disease

Neurobiol Dis. 2025 Jan 13:106805. doi: 10.1016/j.nbd.2025.106805. Online ahead of print.

Authors

Yu Kong¹, Zhongyun Chen², Jing Zhang², Yihao Wang², Min Chu², Haitian Nan², Yue Cui², Deming Jiang², Liyong Wu³

Affiliations

¹ Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
² Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.
³ Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China. Electronic address: wmywly@hotmail.com.

PMID: 39814269
DOI: 10.1016/j.nbd.2025.106805

Abstract

Background: Investigating brain metabolic networks is crucial for understanding the pathogenesis and functional alterations in Creutzfeldt-Jakob disease (CJD). However, studies on presymptomatic individuals remain limited. This study aimed to examine metabolic network topology reconfiguration in asymptomatic carriers of the PRNP G114V mutation.

Methods: Seven asymptomatic PRNP G114V mutation carriers from a familial genetic CJD (gCJD) cohort, 43 CJD patients, and 35 healthy controls were included. All participants underwent neuropsychological assessments, genetic testing, and ¹⁸F-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/MRI scans. Voxel-based gray matter volume and FDG PET standardized uptake value ratios (SUVRs) were analyzed between asymptomatic PRNP G114V mutation carriers and healthy controls and between CJD patients and controls. Graph theory and sparse inverse covariance estimation (SICE) were used to assess the whole-brain metabolic connectomes and topological properties. Spatial independent component analysis (ICA) was used to evaluate subnetworks, including the default mode network (DMN), salience network (SN), and central executive network (CEN).

Results: With respect to global properties, assortativity was significantly increased in asymptomatic carriers, which was consistent with the findings in CJD patients. We revealed lost hubs in the right anterior cingulate, left ventral prefrontal lobe, left parahippocampal gyrus, and left lingual gyrus and reconfigured hubs in prefrontal lobes, including right ventromedial prefrontal cortex, right anterior prefrontal cortex, and right middle frontal gyrus of the orbit in asymptomatic carriers compared with healthy controls, which overlapped with the comparisons between CJD patients and controls. Alterations in the local parameters and metabolic connectivity in the left parahippocampal gyrus were most pronounced. Among the subnetworks, asymptomatic carriers presented higher assortativity and lower hierarchy in the SN, whereas the global parameters of the DMN and CEN were not significantly altered. The DMN and SN showed partial hypoconnectivity and hyperconnectivity, whereas the CEN mainly showed significantly enhanced connectivity in asymptomatic PRNP carriers.

Conclusions: This study revealed altered brain metabolic topology and connectomics in asymptomatic PRNP G114V mutation carriers, which could be detected before gray matter or regional metabolic changes, suggesting that metabolism topology reconfiguration may serve as a sensitive imaging biomarker for investigating early CJD pathological changes.

Keywords: Brain network; Creutzfeldt-Jakob disease; FDG PET; Graph theory; PRNP mutation.