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.

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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: The spectrum of early Alzheimer's disease (AD) is thought to include subjective cognitive impairment, early mild cognitive impairment (eMCI), and late mild cognitive impairment (lMCI). Choline dysfunction affects the early progression of AD, in which the basal nucleus of Meynert (BNM) is primarily responsible for cortical cholinergic innervation. The aims of this study were to determine the abnormal patterns of BNM-functional connectivity (BNM-FC) in the preclinical AD spectrum (SCD, eMCI, and lMCI) and further explore the relationships between these alterations and neuropsychological measures.Methods: Resting-state functional magnetic resonance imaging (rs-fMRI) was used to investigate FC based on a seed mask (BNM mask) in 28 healthy controls (HC), 30 SCD, 24 eMCI, and 25 lMCI patients. Furthermore, the relationship between altered FC and neurocognitive performance was examined by a correlation analysis. The receiver operating characteristic (ROC) curve of abnormal BNM-FC was used to specifically determine the classification ability to differentiate the early AD disease spectrum relative to HC (SCD and HC, eMCI and HC, lMCI and HC) and pairs of groups in the AD disease spectrum (eMCI and SCD, lMCI and SCD, eMCI and lMCI).Results: Compared with HC, SCD patients showed increased FC in the bilateral SMA and decreased FC in the bilateral cerebellum and middle frontal gyrus (MFG), eMCI patients showed significantly decreased FC in the bilateral precuneus, and lMCI individuals showed decreased FC in the right lingual gyrus. Compared with the SCD group, the eMCI group showed decreased FC in the right superior frontal gyrus (SFG), while the lMCI group showed decreased FC in the left middle temporal gyrus (MTG). Compared with the eMCI group, the lMCI group showed decreased FC in the right hippocampus. Interestingly, abnormal FC was associated with certain cognitive domains and functions including episodic memory, executive function, information processing speed, and visuospatial function in the disease groups. BNM-FC of SFG in distinguishing eMCI from SCD; BNM-FC of MTG in distinguishing lMCI from SCD; BNM-FC of the MTG, hippocampus, and cerebellum in distinguishing SCD from HC; and BNM-FC of the hippocampus and MFG in distinguishing eMCI from lMCI have high sensitivity and specificity.Conclusions: The abnormal BNM-FC patterns can characterize the early disease spectrum of AD (SCD, eMCI, and lMCI) and are closely related to the cognitive domains. These new and reliable findings will provide a new perspective in identifying the early disease spectrum of AD and further strengthen the role of cholinergic theory in AD.

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.

Background: Mild cognitive impairment (MCI) represents a transitional state between normal aging and dementia disorders, especially Alzheimer's disease (AD). The disruption of the default mode network (DMN) is often considered to be a potential biomarker for the progression from MCI to AD. The purpose of this study was to assess MRI-specific changes of DMN in MCI patients by elucidating the convergence of brain regions with abnormal DMN function.Methods: We systematically searched PubMed, Ovid, and Web of science for relevant articles. We identified neuroimaging studies by using amplitude of low frequency fluctuation /fractional amplitude of low frequency fluctuation (ALFF/fALFF), regional homogeneity (ReHo), and functional connectivity (FC) in MCI patients. Based on the activation likelihood estimation (ALE) algorithm, we carried out connectivity modeling of coordination-based meta-analysis and functional meta-analysis.Results: In total, this meta-analysis includes 39 articles on functional neuroimaging studies. Using computer software analysis, we discovered that DMN changes in patients with MCI mainly occur in bilateral inferior frontal lobe, right medial frontal lobe, left inferior parietal lobe, bilateral precuneus, bilateral temporal lobe, and parahippocampal gyrus (PHG).Conclusions: Herein, we confirmed the presence of DMN-specific damage in MCI, which is helpful in revealing pathology of MCI and further explore mechanisms of conversion from MCI to AD. Therefore, we provide a new specific target and direction for delaying conversion from MCI to AD.