Abstract
Mild cognitive impairment (MCI) is a transitional state between the cognitive changes in normal aging and Alzheimer’s disease (AD), which induces abnormalities in specific brain regions. Previous studies showed that paired helical filaments Tau (PHF-Tau) protein is a potential pathogenic protein which may cause abnormal brain function and structure in MCI and AD patients. However, the understanding of the PHF-Tau protein network in MCI patients is limited. In this study, 225 subjects with PHF-Tau Positron Emission Tomography (PET) images were divided into four groups based on whether they carried Apolipoprotein E ε4 (APOE 4) or abnormal cerebrospinal fluid Total-Tau (CSF T-Tau). They are two important pathogenic factors that might cause cognitive function impairment. The four groups were: individuals harboring CSF T-Tau pathology but no APOE 4 (APOE 4−T+); APOE 4 carriers with normal CSF T-Tau (APOE 4+T−); APOE 4 carriers with abnormal CSF T-Tau (APOE 4+T+); and APOE 4 noncarriers with abnormal CSF T-Tau (APOE 4−T−). We explored the topological organization of PHF-Tau networks in these four groups and calculated five kinds of network properties: clustering coefficient, shortest path length, Q value of modularity, nodal centrality and degree. Our findings showed that compared with APOE 4−T− group, the other three groups showed different alterations in the clustering coefficient, shortest path length, Q value of modularity, nodal centrality and degree. Simultaneously, voxel-level analysis was conducted and the results showed that compared with APOE 4−T− group, the other three groups were found increased PHF-Tau distribution in some brain regions. For APOE 4+T+ group, positive correlation was found between the value of PHF-Tau distribution in altered regions and Functional Assessment Questionnaire (FAQ) score. Our results indicated that the effects of APOE 4 and abnormal CSF T-Tau may induce abnormalities of PHF-Tau protein and APOE 4 has a greater impact on PHF-Tau than abnormal CSF T-Tau. Our results may be particularly helpful in uncovering the pathophysiology underlying the cognitive dysfunction in MCI patients.
Highlights
Alzheimer’s disease (AD) is generally considered as a cognitive dysfunction, neurodegenerative disease
Results showed that the distribution of paired helical filaments Tau (PHF-Tau) protein was significantly increased in the bilateral temporal lobe, left amygdala, bilateral fusiform, and bilateral parahippocampal gyrus in the Apolipoprotein E ε4 (APOE 4)+T+ group and the increased distribution of PHF-Tau protein was distributed in the left amygdala, right parahippocampal gyrus, bilateral temporal lobe and left occipital lobe in APOE 4+T− group, while the significant increased distribution of PHF-Tau was only found in the left middle frontal gyrus for APOE 4−T+ group
We found that APOE 4 and cerebrospinal fluid (CSF) total Tau (T-Tau) affected regions might be related to Mild cognitive impairment (MCI), and an important factor in transforming MCI into AD
Summary
Alzheimer’s disease (AD) is generally considered as a cognitive dysfunction, neurodegenerative disease. A previous study discovered that the paired helical Tau (PHF-Tau) protein was a highly disease-related factor in the brain that may induce the development of MCI (Cho et al, 2016). Tau in cerebrospinal fluid (CSF) and Apolipoprotein E ε4 (APOE 4) are all associated with increased risk of progression from MCI to dementia (Arnold et al, 2010) and they are the robust predictors of AD (Blom et al, 2009). CSF-Tau contains phosphorylated Tau (P-Tau) and total Tau (T-Tau), which are two important biomarkers of CSF in MCI patients. We only paid attention to how the CSF T-Tau and APOE 4 affected on PHF-Tau network. PHF-Tau, APOE 4, and CSF T-Tau are all the important disease-related factors, joint studies on these three factors are limited
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