To our best, the present study was the first study analyzing the DFC variability of SCD and aMCI patients based on the triple-network model and the association with cognitive decline. The primary findings of the study were that SCD and aMCI had similar and distinct change pattern of DFC variability within the triple networks. Moreover, altered DFC variability within ECN has been found to be significantly correlated to cognitive performances in SCD and aMCI. Most important of all, altered DFC variability combined with the triple-network model can serve as an important biomarker for their higher diagnostic efficiency of SCD and aMCI.
The present study showed that the DFC variability within the triple networks, including DMN, SN, and ECN, has changed to different degrees in the SCD and aMCI. Actually, the DMN can be divided into aDMN and pDMN, and has been considered to be independent in a wide range of cognitive tasks. To be specific, the aDMN is involved in self-referential mental idealization while the pDMN in episodic memory retrieval . In the present study, SCD showed decreased DFC variability in the right MTG within pDMN compared to HC while aMCI showed decreased DFC variability in the right angular gyrus and right SFG within the aDMN. The impaired brain regions are involved in functions of language processing (angular gyrus), spatial orientation (angular gyrus), motor planning and executive (SFG), and visual information (MTG). This might mean that impairment in DMN may lead to extensive cognitive decline. Moreover, a prior static FC study indicated that the FC of aDMN first increased and then decreased with progression of AD spectrum disease, which was consistent with our results that DFC variability of aDMN was decreased in aMCI compared to HC while SCD remained stable . Notably, the previous DFC studies demonstrated that higher DFC variability of brain regions may reflect greater complexity and greater ability in information processing . Decreased DFC variability may indicate decreased information processing ability of SCD and aMCI . The decreased DFC variability within DMN subnetworks of SCD in the present study means that SCD already had the potential tendency of impaired information processing ability. In addition, SCD showed altered DFC variability majorly in pDMN while aMCI showed altered DFC variability mainly in aDMN, which seemed to confirmed the specificity of AD spectrum in DFC variability within DMN.
In our study, the SCD and aMCI groups both showed increased DFC variability in the left putamen within SN, while aMCI additionally showed increased DFC variability in the left insula within SN. The putamen is part of neostriatum, which was identified as one of the first brain areas affected by amyloid deposition in healthy elderly . Previous studies regarded that the putamen involves in the working memory and probabilistic learning and might be an appropriate clinical biomarker for neurodegenerative disease [44, 45]. Research reported that the decline of ALFF and volume in putamen was significantly related to cognitive decline in AD spectrum [46, 47]. The insula, a major region of SN, is believed to play an important role in the maintenance of memory performance in the early stage of the AD spectrum . One study suggested that the left insula has the higher node degree and participation coefficient in the brain network and associated to episodic memory . Increased DFC variability of SN in patients verified the “brain reserve” hypothesis that enhanced FC of SN in SCD and aMCI might be a compensatory mechanism for the decreased DMN function so that it can resist amyloid protein deposition and maintain relatively normal cognitive function [22, 49].
Our results showed that the altered DFC variability within ECN in SCD and aMCI. ECN, with the prefrontal lobe as the core, acts an important role in the regulation of cognition and behavior, the integration of perception and memory information, and working memory . The MFG and IFG are responsible for executive cognitive function and working memory. The present research found that SCD showed increased DFC variability in left MFG compared to HC while aMCI showed decreased DFC variability in right MFG compared to SCD. This might reveal that the DFC variability decreased as the AD spectrum progresses, representing a gradual decline in information processing ability.
Combined with those findings, we can speculate that SCD and aMCI have common and unique disruption in the triple networks. Actually, the triple networks are involved in a wide range of cognitive tasks through direct or indirect means. Disruption of any network of the triple networks will result in aberrant in goal-related stimuli and internal psychological events . Previous research findings suggested that abnormal organization and function of the triple networks were prominent features of neuropsychiatric diseases. However, the specific changes in static FC within the triple networks of SCD and aMCI were not consistent. For example, some researches claimed that aMCI showed increased static FC in SN while several reported disrupted static FC in SN [21, 23, 38]. One possible reason for the inconsistency of the results may be that the FC pattern was dynamic rather than static during the entire rsfMRI scan, leading to different FC patterns in different scan periods . Therefore, our study confirmed that the DFC of the triple networks were disrupted in SCD and aMCI, suggesting DFC analysis can be used as a complement and verification of static FC analysis.
The present study showed observably negatively associations in SCD and aMCI between the altered DFC variability in the left IFG and cognitive domains, including EM and EF. The results demonstrated that the disruption of DFC significantly related to the declined cognition performance in SCD and aMCI. As EM and EF impaired, the DFC variability of SCD and aMCI in left IFG increased. Moreover, it showed a tread that aMCI exhibited a higher DFC variability while its EM and EF impaired compared to SCD. This might mean that the increased DFC variability of left IFG was to compensate for the impairment of EM and EF in the progression of preclinical AD spectrum. Furthermore, EF refers to the cognitive process of goal-oriented behavior from goal formulation to successful execution and processing of results [52, 53]. The correlation between the altered DFC variability in the left IFG within ECN and EF confirmed the fact that the ECN is widely used to investigate the mechanism of altered EF in patients . Interestingly, SCD and aMCI showed significantly correlation between the altered DFC variability within ECN and EM. A previous study suggested that the EM deficits in aMCI patients were associated with the right DLPFC functional network . Our results provided a new evidence for the interaction between impaired EF and memory impairment. Taken together, the study suggested that DFC in SCD and aMCI were disrupted, which extended the current understanding of functional network, and showed the importance of evaluating changes in dynamic functional connectivity in preclinical AD spectrum.
The most excellent finding in the current study was that the best-fitting model in diagnosing and characterizing SCD and aMCI was based on the multivariable models. They combined altered DFC variability within triple networks and declined cognitive function. It can be seen that the models had the higher AUC values with high sensitivity and specificity compared to models. Especially, the model was highly specific for aMCI with 98.2% specificity, so the risk of false-positive error is very low, suggesting that the DFC analysis could be a reliable potential biomarker for diagnosing aMCI patients. Specifically speaking, the DFC variability of left putamen played a vital role in the diagnosis of SCD while the DFC variability of right AG played a major role in the diagnosis of aMCI for their higher AUC values. Meanwhile, the DFC variability of right MFG and left IFG acted dominant roles in the differentiation of SCD and aMCI. Those might provide additional information in the research of specific braIn region changes in the SCD and aMCI. Additionally, researches indicated that the classification accuracy of static FC was lower than DFC because time-averaged analysis could not account for microscopic changes of brain states [34, 56, 57]. Studies have shown that DFC contain significantly more behavioral information than static FC [34, 58]. In a word, such reliable methods will have tremendous value for early detection of AD-related pathology.