Reconfigured metabolism brain network in asymptomatic microtubule-associated protein tau mutation carriers: a graph theoretical analysis

Abstract

Background Studies exploring topological properties of the metabolic network during the presymptomatic stage of genetic frontotemporal dementia (FTD) are scarce. However, such knowledge is important for understanding brain function and disease pathogenesis. Therefore, we aimed to explore FTD-specific patterns of metabolism topology reconfiguration in microtubule-associated protein tau (MAPT) mutation carriers before the onset of symptoms. Methods Six asymptomatic carriers of the MAPT P301L mutation were compared with 12 non-carriers who all belonged to the same family of FTD. For comparison, we included 32 behavioral variant FTD (bvFTD) patients and 33 unrelated healthy controls. Each participant underwent neuropsychological assessments, genetic testing, and a hybrid positron emission tomography (PET)/magnetic resonance imaging (MRI) scan. Voxel-wise gray matter volumes and standardized uptake value ratios were calculated and compared for structural MRI and fluorodeoxyglucose (FDG)-PET, separately. The sparse inverse covariance estimation method (SICE) was applied to topological properties and metabolic connectomes of brain functional networks derived from 18F-FDG PET/MRI data. Independent component analysis was used to explore the metabolic connectivity of the salience (SN) and default mode networks (DMN). Results The asymptomatic MAPT carriers performed normal global parameters of the metabolism network, whereas bvFTD patients did not. However, we revealed lost hubs in the ventromedial prefrontal, orbitofrontal, and anterior cingulate cortices and reconfigured hubs in the anterior insula, precuneus, and posterior cingulate cortex in asymptomatic carriers compared with non-carriers, which overlapped with the comparisons between bvFTD patients and controls. Similarly, significant differences in local parameters of these nodes were present between asymptomatic carriers and non-carriers. The reduction in the connectivity of lost hub regions and the enhancement of connectivity between reconfigured hubs and components of the frontal cortex were marked during the asymptomatic stage. Metabolic connectivity within the SN and DMN was enhanced in asymptomatic carriers compared with non-mutation carriers but reduced in bvFTD patients relative to controls. Conclusions Our findings showed that metabolism topology reconfiguration, characterized by the earliest involvement of medial prefrontal areas and active compensation in task-related regions, was present in the presymptomatic phase of genetic FTD with MAPT mutation, which may be used as an imaging biomarker of increased risk of FTD.

Age-Related Oxidative Redox and Metabolic Changes Precede Intraneuronal Amyloid-β Accumulation and Plaque Deposition in a Transgenic Alzheimer’s Disease Mouse Model

“…Indeed, the mutations introduced in 3xTg-AD mice have been shown to alter metabolism and GSH levels. The MAPT P301L mutation has been shown using fluorodeoxyglucose-positron emission tomography (FDG-PET) to disrupt brain metabolism in pre-symptomatic human patients [ 61 ]. A reduction in GSH was observed in lymphoblasts with presenilin1 and AβPP mutations [ 62 ], and AβPP overexpression perturbed metabolism by decreasing mitochondrial respiration and enhancing glycolysis in SH-SY5Y cells [ 63 ].…”

Altered Anterior Insular Metabolic Connectivity in Asymptomatic MAPT P301L Carriers

“…Demographic characteristics, cognitive status, and linguistic and behavioral features of asymptomatic MAPT P301L carriers (a MAPT +), asymptomatic MAPT noncarriers (a MAPT –), bvFTD patients, and controls are shown in Table 1 . The demographic data of MAPT carriers and noncarriers have been previously reported [ 8 ]. There were no significant differences in age and sex between a MAPT + and a MAPT – groups or between bvFTD and control groups.…”

“…However, few studies have specifically examined the associated changes in brain function with P301L mutations. One study reported hypometabolism of anterior cingulate gyrus in the preclinical stage in 6 MAPT P301L mutation carriers from 5 families [ 7 ], and we previously found that the metabolic network was altered with the insula as a reconfigured hub in patients with MAPT P301L mutations, suggesting complex functional alterations of insula before the onset of symptoms [ 8 ].…”

Clinical relevance of disrupted topological organization of anatomical connectivity in behavioral variant frontotemporal dementia

“…Previous neuroimaging studies on bvFTD have revealed disruption of some topological properties, using modalities such as T1, resting-state functional magnetic resonance imaging, fluorodeoxyglucose positron emission tomography, and single-photon emission computed tomography to construct structural covariance, functional, or metabolic connectivity ( Agosta et al, 2013 ; Filippi et al, 2017 ; Liu et al, 2022 ; Malpetti et al, 2019 ; Ng et al, 2021 ; Nigro et al, 2021 ; Reyes et al, 2018 ; Saba et al, 2019 ; Sedeño et al, 2016 ; Sedeño et al, 2017 ; Vijverberg et al, 2017 ; Zhou et al, 2021 ). The brain structural covariance and functional networks of bvFTD patients showed preserved small-worldness organization but alterations in global network properties, such as lower average clustering coefficient, reduced global efficiency, and longer characteristic path length representing impairment in both the integration and segregation of information process ( Agosta et al, 2013 ; Nigro et al, 2021 ; Saba et al, 2019 ; Sedeño et al, 2016 ; Sedeño et al, 2017 ; Vijverberg et al, 2017 ).…”

“…At the local level of the network, disruption of nodal metrics like nodal degree or local efficiency was reported, which was particularly predominant over frontal regions ( Agosta et al, 2013 ; Filippi et al, 2017 ; Malpetti et al, 2019 ; Sedeño et al, 2016 ). In addition, extensive reconfigurations of the nodes were observed in the bvFTD group ( Agosta et al, 2013 ; Liu et al, 2022 ; Malpetti et al, 2019 ; Zhou et al, 2021 ). However, few studies have correlated graph analysis metrics with clinical status, to explore the potential clinical relevance of network graph metrics ( Ng et al, 2021 ; Nigro et al, 2021 ; Reyes et al, 2018 ; Vijverberg et al, 2017 ).…”