Hippocampal subregions (HIPsub) and their network connectivities are generally aberrant in patients with subjective cognitive decline (SCD). This study aimed to investigate whether repetitive transcranial magnetic stimulation (rTMS) could ameliorate HIPsub network connectivity by modulating one node of HIPsub network in SCD. In the first cohort, the functional connectivity (FC) of three HIPsub (i.e., hippocampal emotional, cognitive, and perceptual regions: HIPe, HIPc, and HIPp) were analyzed so as to identify alterations in HIPsub connectivity associated with SCD. Afterwards, a support vector machine (SVM) approach was applied using the alterations in order to evaluate to what extent we could distinguish SCD from healthy controls (CN). In the second cohort, a 2-week rTMS course of 5-day, once-daily, was used to activate the altered HIPsub network connectivity in a sham-controlled design. SCD subjects exhibited distinct patterns alterations of HIPsub network connectivity compared to CN in the first cohort. SVM classifier indicated that the abnormalities had a high power to discriminate SCD from CN, with 92.9% area under the receiver operating characteristic curve (AUC), 86.0% accuracy, 83.8% sensitivity and 89.1% specificity. In the second cohort, changes of HIPc connectivity with the left parahippocampal gyrus and HIPp connectivity with the left middle temporal gyrus demonstrated an amelioration of episodic memory in SCD after rTMS. In addition, SCD exhibited improved episodic memory after the rTMS course. rTMS therapy could improve the posterior hippocampus connectivity by modulating the precuneus in SCD. Simultaneous correction of the breakdown in HIPc and HIPp could ameliorate episodic memory in SCD. Thus, these findings suggested that rTMS manipulation of precuneus-hippocampal circuit might prevent disease progression by improving memory as the earliest at-risk state of Alzheimer’s disease in clinical trials and in practice.

Background Mild cognitive impairment (MCI) is an intermediate stage between normal aging and dementia. Amnestic MCI (aMCI) and non-amnestic MCI are the two subtypes of MCI with the former having a higher risk for progressing to Alzheimer's disease (AD). Compared with healthy elderly adults, individuals with MCI have specific functional alterations in the salience network (SN). However, no consistent results are documenting these changes. This meta-analysis aimed to investigate the specific functional alterations in the SN in MCI and aMCI.Methods: We systematically searched PubMed, Embase, and Web of Science for scientific neuroimaging literature based on three research methods, namely, functional connectivity (FC), regional homogeneity (ReHo), and the amplitude of low-frequency fluctuation or fractional amplitude of low-frequency fluctuation (ALFF/fALFF). Then, we conducted the coordinate-based meta-analysis by using the activation likelihood estimation algorithm.Results: In total, 30 functional neuroimaging studies were included. After extracting the data and analyzing it, we obtained specific changes in some brain regions in the SN including decreased ALFF/fALFF in the left superior temporal gyrus, the insula, the precentral gyrus, and the precuneus in MCI and aMCI; increased FC in the thalamus, the caudate, the superior temporal gyrus, the insula, and the cingulate gyrus in MCI; and decreased ReHo in the anterior cingulate gyrus in aMCI. In addition, as to FC, interactions of the SN with other networks including the default mode network and the executive control network were also observed mainly in the middle frontal gyrus and superior frontal gyrus in MCI and inferior frontal gyrus in aMCI.Conclusions: Specific functional alternations in the SN and interactions of the SN with other networks in MCI could be useful as potential imaging biomarkers for MCI or aMCI. Meanwhile, it provided a new insight in predicting the progression of health to MCI or aMCI and novel targets for proper intervention to delay the progression.Systematic Review Registration: [PROSPERO], identifier [No. CRD42020216259].

Background: Mild cognitive impairment (MCI) is regarded as a transitional stage between normal aging and Alzheimer's disease (AD) dementia. MCI individuals with deficits in executive function are at higher risk for progressing to AD dementia. Currently, there is no consistent result for alterations in the executive control network (ECN) in MCI, which makes early prediction of AD conversion difficult. The aim of the study was to find functional MRI-specific alterations in ECN in MCI patients by expounding on the convergence of brain regions with functional abnormalities in ECN. Methods: We searched PubMed, Embase, and Web of Science to identify neuroimaging studies using methods including the amplitude of low frequency fluctuation/fractional amplitude of low-frequency fluctuation, regional homogeneity, and functional connectivity in MCI patients. Based on the Activation Likelihood Estimation algorithm, the coordinate-based meta-analysis and functional meta-analytic connectivity modeling were conducted. Results: A total of 25 functional imaging studies with MCI patients were included in a quantitative meta-analysis. By summarizing the included articles, we obtained specific brain region changes, mainly including precuneus, cuneus, lingual gyrus, middle frontal gyrus, posterior cingulate cortex, and cerebellum posterior lobe, in the ECN based on these three methods. The specific abnormal brain regions indicated that there were interactions between the ECN and other networks. Conclusions: This study confirms functional imaging specific abnormal markers in ECN and its interaction with other networks in MCI. It provides novel targets and pathways for individualized and precise interventions to delay the progression of MCI to AD.

Background: Subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) were considered to be a continuum of Alzheimer's disease (AD) spectrum. The abnormal topological architecture and rich-club organization in the brain functional network can reveal the pathology of the AD spectrum. However, few studies have explored the disrupted patterns of diverse club organizations and the combination of rich-and diverse-club organizations in SCD and aMCI. Methods: We collected resting-state functional magnetic resonance imaging data of 19 SCDs, 29 aMCIs, and 28 healthy controls (HCs) from the Alzheimer's Disease Neuroimaging Initiative. Graph theory analysis was used to analyze the network metrics and rich-and diverse-club organizations simultaneously. Results: Compared with HC, the aMCI group showed altered small-world and network efficiency, whereas the SCD group remained relatively stable. The aMCI group showed reduced rich-club connectivity compared with the HC. In addition, the aMCI group showed significantly increased feeder connectivity and decreased local connectivity of the diverse club compared with the SCD group. The overlapping nodes of the rich club and diverse club showed a significant difference in nodal efficiency and shortest path length (L p) between groups. Notably, the L p values of overlapping nodes in the SCD and aMCI groups were significantly associated with episodic memory. Conclusion: The present study demonstrates that the network properties of SCD and aMCI have varying degrees of damage. The combination of the rich club and the diverse club can provide a novel insight into the pathological mechanism of the AD spectrum. The altered patterns in overlapping nodes might be potential biomarkers in the diagnosis of the AD spectrum.

Background: Altered hippocampal subregions (HIPsub) and their network connectivity relate to episodic memory decline in amnestic mild cognitive impairment (aMCI), which is significantly limited by over-dependence on correlational associations. Objective: To identify whether restoration of HIPsub and its network connectivity using repetitive transcranial magnetic stimulation (rTMS) is causally linked to amelioration of episodic memory in aMCI. Methods: In the first cohort, analysis of HIPsub grey matter (GM) and its functional connectivity was performed to identify an episodic memory-related circuit in aMCI by using a pattern classification approach. In the second cohort, this circuit was experimentally modulated with rTMS. Structural equation modeling was employed to investigate rTMS regulatory mechanism in amelioration of episodic memory. Results: First, in the first cohort, this study identified HIPsub circuit pathology of episodic memory decline in aMCI patients. Second, in the second cohort, restoration of HIPc GM and its connectivity with left middle temporal gyrus (MTG.L) are causally associated with amelioration of episodic memory in aMCI after 4 weeks of rTMS. Especially important, the effects of HIPc GM changes on the improvement of episodic memory were significantly mediated by HIPc connectivity with MTG.L changes in aMCI. Conclusion: This study provides novel experimental evidence about a biological substrate for the treatment of the disabling episodic memory in aMCI patients. Correction of breakdown in HIPc structure and its connectivity with MTG can causally ameliorate episodic memory in aMCI.

Background: Subjective cognitive decline and amnestic mild cognitive impairment (aMCI) were widely thought to be preclinical AD spectrum disorders, characterized by aberrant functional connectivity (FC) within the triple networks of the default mode network (DMN), the salience network (SN), and the executive control network (ECN). Dynamic FC (DFC) analysis can capture temporal fluctuations in brain FC during the scan, which static FC analysis cannot. The purpose of the current study was to explore the changes in dynamic FC within the triple networks of the preclinical AD spectrum and further reveal their potential diagnostic value in diagnosing preclinical AD spectrum disorders.Methods: We collected resting-state functional magnetic resonance imaging data from 44 patients with subjective cognitive decline (SCD), 49 with aMCI, and 58 healthy controls (HCs). DFC analysis based on the sliding time-window correlation method was used to analyze DFC variability within the triple networks in the three groups. Then, correlation analysis was conducted to reveal the relationship between altered DFC variability within the triple networks and a decline in cognitive function. Furthermore, logistic regression analysis was used to assess the diagnostic accuracy of altered DFC variability within the triple networks in patients with SCD and aMCI.Results: Compared with the HC group, the groups with SCD and aMCI both showed altered DFC variability within the triple networks. DFC variability in the right middle temporal gyrus and left inferior frontal gyrus (IFG) within the ECN were significantly different between patients with SCD and aMCI. Moreover, the altered DFC variability in the left IFG within the ECN was obviously associated with a decline in episodic memory and executive function. The logistic regression analysis showed that multivariable analysis had high sensitivity and specificity for diagnosing SCD and aMCI.Conclusions: Subjective cognitive decline and aMCI showed varying degrees of change in DFC variability within the triple networks and altered DFC variability within the ECN involved episodic memory and executive function. More importantly, altered DFC variability and the triple-network model proved to be important biomarkers for diagnosing and identifying patients with preclinical AD spectrum disorders.

Salience network (SN), playing a vital role in advanced cognitive function, is regarded to be impaired in subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI). The purpose of the study was to explore the importance of structural and functional features of SN in the diagnosis of SCD and aMCI. Structural and resting-state functional magnetic resonance imaging were collected from SCD, aMCI, and healthy control (HC). Cortex thickness, gray matter (GM) volume, spontaneous brain activity, functional connectivity (FC) within SN, and its relationship with cognitive function were analyzed. Moreover, the receiver operating characteristic analysis was performed to assess diagnostic efficacy of altered indictors for SCD and aMCI. Compared to HC, both SCD and aMCI showed decreased GM volume, decreased spontaneous brain activity, and increased FC within SN, while aMCI showed additional decreased cortex thickness. Furthermore, the altered FC in SCD and aMCI was significantly correlated with cognitive function. Particularly, the best-fitting classification models of SCD and aMCI were based on the combined multiple indicators. In conclusion, structure and function of SN were disrupted in SCD and aMCI, which involved in cognitive decline. The combined multiple indicators of SN provided powerful biomarkers for the diagnosis of SCD and aMCI.

Background: Voxel-based morphometry studies have not yielded consistent results among patients with mild cognitive impairment (MCI) and subjective cognitive decline (SCD). Objective: Therefore, we aimed to conduct a meta-analysis of gray matter (GM) abnormalities acquired from these studies to determine their respective neuroanatomical changes. Methods: We systematically searched for voxel-based whole-brain morphometry studies that compared MCI or SCD subjects with healthy controls in PubMed, Web of Science, and EMBASE databases. We used the coordinate-based method of activation likelihood estimation to determine GM changes in SCD, MCI, and MCI sub-groups (amnestic MCI and non-amnestic MCI). Results: A total of 45 studies were included in our meta-analysis. In the MCI group, we found structural atrophy of the bilateral hippocampus, parahippocampal gyrus (PHG), amygdala, right lateral globus pallidus, right insula, and left middle temporal gyrus. The aMCI group exhibited GM atrophy in the bilateral hippocampus, PHG, and amygdala. The naMCI group presented with structural atrophy in the right putamen, right insula, right precentral gyrus, left medial/superior frontal gyrus, and left anterior cingulate. The right lingual gyrus, right cuneus, and left medial frontal gyrus were atrophic GM regions in the SCD group. Conclusion: Our meta-analysis identified unique patterns of neuroanatomical alternations in both the MCI and SCD group. Structural changes in SCD patients provide new evidence for the notion that subtle impairment of visual function, perception, and cognition may be related to early signs of cognitive impairment. In addition, our findings provide a foundation for future targeted interventions at different stages of preclinical Alzheimer’s disease.