Sporadic Creutzfeldt–Jakob disease is associated with reorganization of metabolic connectivity in a pathological brain network

Abstract

Background and purpose: Although sporadic Creutzfeldt-Jakob disease (sCJD) is a rare cause of dementia, it is critical to understand its functional networks as the prion protein spread throughout the brain may share similar mechanisms with other more common neurodegenerative disorders. In this study, the metabolic brain network associated with sCJD was investigated and its internal network organization was explored. Methods:We explored 2-[ 18 F]fluoro-2-deoxyd-glucose positron emission tomography (FDG-PET) brain scans of 29 sCJD patients, 56 normal controls (NCs) and 46 other dementia patients from two independent centers. sCJD-related pattern (CJDRP) was identified in a cohort of 16 pathologically proven sCJD patients and 16 age-matched NCs using scaled subprofile modeling/principal component analysis and was prospectively validated in an independent cohort of 13 sCJD patients and 20 NCs. The pattern's specificity was tested on other dementia patients and its clinical relevance by clinical correlations. The pattern's internal organization was further studied using graph theory methods. Results:The CJDRP was characterized by relative hypometabolism in the bilateral caudate, thalami, middle and superior frontal gyri, parietal lobe and posterior cingulum in association with relative hypermetabolism in the hippocampi, parahippocampal gyri and cerebellum. The pattern's expression significantly discriminated sCJD from NCs and other dementia patients (p < 0.005; receiver operating characteristic analysis CJD vs. NCs area under the curve [AUC] 0.90-0.96, sCJD vs. Alzheimer's disease AUC 0.78, sCJD vs. behavioral variant of frontotemporal dementia AUC 0.84). The pattern's expression significantly correlated with cognitive, functional decline and disease duration. The metabolic connectivity analysis revealed inefficient information transfer with specific network reorganization. Conclusions:The CJDRP is a robust metabolic biomarker of sCJD. Due to its excellent clinical correlations it has the potential to monitor disease in emerging disease-modifying trials.

Metabolic Brain Changes Can Predict the Underlying Pathology in Neurodegenerative Brain Disorders: A Case Report of Sporadic Creutzfeldt–Jakob Disease with Concomitant Parkinson’s Disease

“…Expression levels of both CJDRP and PDRP brain networks were significantly elevated compared to those of healthy subjects (HS). The standardized value for CJDRP expression was 5.5 standard deviations (SD) above HS (i.e., z = 5.5), falling within the range observed in CJD patients (z = 6.5 ± 2.4) [12]. Similarly, the expression of PDRP was elevated (z = 2.2) compared to HS, falling within the range observed in PD patients (z = 3.4 ± 2.2) (see Figure 2).…”

“…Additionally, we performed metabolic network analysis of the patient's FDG PET scan as described by Spetsieris et al [17]. Alongside exploring the expression of the CJD-related pattern (CJDRP) [12], we also investigated expression of PD-related pattern (PDRP) [18] due to hypermetabolism in basal ganglia found on visual inspection.…”

“…Alongside traditional visual exploration and univariate statistical methods like statistical parametric mapping (SPM) [10], which independently explore brain metabolism voxel by voxel, advanced multivariate analytical approaches like scaled-subprofile model/principal component analysis (SSM/PCA) have enabled the identification of disease-specific metabolic brain networks [11]. Several research groups worldwide have identified and validated robust metabolic brain networks specific for disorders like AD, Parkinson's disease (PD), the behavioral variant of frontotemporal dementia (bvFTD), sCJD, and others [11][12][13][14]. The extent of specific network expression observed in these disorders has been shown to correlate with the severity of its clinical impairment [11].…”

Prion propagation and cellular dysfunction in prion disease: Disconnecting the dots

“…During human prion diseases changes are also seen in brain metabolism including glucose usage and mitochondrial function [ 23 , 24 ]. The D178N FFI organoids showed significantly increased oxidative stress associated with altered bioenergetics, including increased mitochondrial activity [ 10 ] but decreased glucose utilization, and caused a general blockage of glycolysis.…”

Unmet needs of biochemical biomarkers for human prion diseases

“…Another field of emerging techniques is the Positron Emission Tomography (PET). Changes in brain metabolism might help in the differential diagnosis of neurodegenerative disorders by studying disease-specific metabolic networks in individual patients [ 30 ].…”