Directed Functional Connectivity Changes of Triple Networks for Stable and Progressive Mild Cognitive Impairment.

Mild cognitive impairment includes two distinct subtypes, namely progressive mild cognitive impairment and stable mild cognitive impairment. While alterations in extensive functional connectivity have been observed in both subtypes, limited attention has been given to directed functional connectivity. A triple network, composed of the central executive network, default mode network, and salience network, is considered to be the core cognitive network. We evaluated the alterations in directed functional connectivity within and between the triple network in progressive and stable mild cognitive impairment groups and investigated its role in predicting disease conversion. Resting-state functional magnetic resonance imaging was used to analyze directed functional connectivity within the triple networks. A correlation analysis was performed to investigate potential associations between altered directed functional connectivity within the triple networks and the neurocognitive performance of the participants. Our study revealed significant differences in directed functional connectivity within and between the triple network in the progressive and stable mild cognitive impairment groups. Altered directed functional connectivity within the triple network was involved in episodic memory and executive function. Thus, the directed functional connectivity of the triple network may be used as an imaging marker of mild cognitive impairment.

Shared and Specific Changes of Cortico-Striatal Functional Connectivity in Stable Mild Cognitive Impairment and Progressive Mild Cognitive Impairment.

Background: Mild cognitive impairment (MCI), the prodromal stage of Alzheimer's disease, has two distinct subtypes: stable MCI (sMCI) and progressive MCI (pMCI). Early identification of the two subtypes has important clinical significance. Objective: We aimed to compare the cortico-striatal functional connectivity (FC) differences between the two subtypes of MCI and enhance the accuracy of differential diagnosis between sMCI and pMCI. Methods: We collected resting-state fMRI data from 31 pMCI patients, 41 sMCI patients, and 81 healthy controls. We chose six pairs of seed regions, including the ventral striatum inferior, ventral striatum superior, dorsal-caudal putamen, dorsal-rostral putamen, dorsal caudate, and ventral-rostral putamen and analyzed the differences in cortico-striatal FC among the three groups, additionally, the relationship between the altered FC within the MCI subtypes and cognitive function was examined. Results: Compared to sMCI, the pMCI patients exhibited decreased FC between the left dorsal-rostral putamen and right middle temporal gyrus, the right dorsal caudate and right inferior temporal gyrus, and the left dorsal-rostral putamen and left superior frontal gyrus. Additionally, the altered FC between the right inferior temporal gyrus and right putamen was significantly associated with episodic memory and executive function. Conclusions: Our study revealed common and distinct cortico-striatal FC changes in sMCIs and pMCI across different seeds; these changes were associated with cognitive function. These findings can help us understand the underlying pathophysiological mechanisms of MCI and distinguish pMCI and sMCI in the early stage potentially.

Repetitive transcranial magnetic stimulation regulates effective connectivity patterns of brain networks in the spectrum of preclinical Alzheimer's disease.

Objectives: Subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) are considered as the spectrum of preclinical Alzheimer's disease (AD), with abnormal brain network connectivity as the main neuroimaging feature. Repetitive transcranial magnetic stimulation (rTMS) has been proven to be an effective non-invasive technique for addressing neuropsychiatric disorders. This study aims to explore the potential of targeted rTMS to regulate effective connectivity within the default mode network (DMN) and the executive control network (CEN), thereby improving cognitive function. Methods: This study included 86 healthy controls (HCs), 72 SCDs, and 86 aMCIs. Among them, 10 SCDs and 11 aMCIs received a 2-week rTMS course of 5-day, once-daily. Cross-sectional analysis with the spectral dynamic causal model (spDCM) was used to analyze the DMN and CEN effective connectivity patterns of the three groups. Afterwards, longitudinal analysis was conducted on the changes in effective connectivity patterns and cognitive function before and after rTMS for SCD and aMCI, and the correlation between them was analyzed. Results: Cross-sectional analysis showed different effective connectivity patterns in the DMN and CEN among the three groups. Longitudinal analysis showed that the effective connectivity pattern of the SCD had changed, accompanied by improvements in episodic memory. Correlation analysis indicated a negative relationship between effective connectivity from the left angular gyrus (ANG) to the anterior cingulate gyrus and the ANG.R to the right middle frontal gyrus, with visuospatial and executive function, respectively. In patients with aMCI, episodic memory and executive function improved, while the effective connectivity pattern remained unchanged. Conclusion: This study demonstrates that PCUN-targeted rTMS in SCD regulates the abnormal effective connectivity patterns in DMN and CEN, thereby improving cognition function. Conversely, in aMCI, the mechanism of improvement may differ. Our findings further suggest that rTMS is more effective in preventing or delaying disease progression in the earlier stages of the AD spectrum. Clinical Trial Registration: http://www.chictr.org.cn, ChiCTR2000034533.

Evidence of functional abnormalities in the default mode network in bipolar depression: A coordinate-based activation likelihood estimation meta-analysis.

BACKGROUND: The default mode network (DMN) is thought to be involved in the pathophysiology of bipolar depression (BD). However, the findings of prior studies on DMN alterations in BD are inconsistent. Thus, this study aimed to systematically investigate functional abnormalities of the DMN in BD patients. METHODS: We systematically searched PubMed, Ovid, and Web of Science for functional neuroimaging studies on regional homogeneity, amplitude of low frequency fluctuations (ALFF), and functional connectivity of the DMN in BD patients published before March 18, 2022. The stereotactic coordinates of the reported altered brain regions were extracted and incorporated into a brain map using the coordinate-based activation likelihood estimation approach. RESULTS: A total of 43 original research studies were included in the meta-analysis. BD patients showed specific changes in the DMN including decreased ALFF/fractional ALFF in the left cingulate gyrus (CG) and bilateral precuneus (PCUN); increased functional connectivity (FC) in the left CG, left posterior CG, left PCUN, bilateral medial frontal gyrus, and bilateral superior frontal gyrus; and decreased FC in the left CG, left PCUN, left inferior parietal lobule, and left postcentral gyrus. LIMITATIONS: Conclusions are limited by the small number of studies, additional meta-analyses are needed to obtain more data in BD subgroup. CONCLUSION: This meta-analysis supports specific changes in DMN activity and FC in BD patients, which may be powerful biomarkers for the diagnosis of BD. The CG and PCUN were the most affected regions and are thus potential targets for clinical interventions to delay BD progression.

Altered structural and functional homotopic connectivity associated with the progression from mild cognitive impairment to Alzheimer's disease.

The progressive mild cognitive impairment (pMCI) is associated with an increased risk of Alzheimer's disease (AD). Many studies have reported the disrupted brain alteration during the imminent conversion from pMCI to AD. However, the subtle difference of structural and functional of inter-hemispheric between pMCI and stable mild cognitive impairment (sMCI) remains unknown. In the present study, we scanned the multimodal magnetic resonance imaging of 38 sMCI, 26 pMCI, and 50 healthy controls (HC) and assessed the cognitive function. The voxel-mirrored homotopic connectivity (VMHC) and volume of corpus callosum were calculated. A structural equation modeling (SEM) was established to determine the relationships between the corpus callosum, the inter-hemispheric connectivity, and cognitive assessment. Compared to sMCI, pMCI exhibited decreased VMHC in insular and thalamus, and reduced volume of corpus callosum. SEM results showed that decreased inter-hemispheric connectivity was directly associated with cognitive impairment and corpus callosum atrophy, and corpus callosum atrophy indirectly caused cognitive impairment by mediating inter-hemispheric connectivity in pMCI. In conclusion, the destruction of homotopic connectivity is related to cognitive impairment, and the corpus callosum atrophy partially mediates the association between the homotopic connectivity and cognitive impairment in pMCI.

Functional and structural alterations of dorsal attention network in preclinical and early-stage Alzheimer's disease.

OBJECTIVES: Subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) are known as the preclinical and early stage of Alzheimer's disease (AD). The dorsal attention network (DAN) is mainly responsible for the "top-down" attention process. However, previous studies mainly focused on single functional modality and limited structure. This study aimed to investigate the multimodal alterations of DAN in SCD and aMCI to assess their diagnostic value in preclinical and early-stage AD. METHODS: Resting-state functional magnetic resonance imaging (MRI) was carried out to measure the fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and functional connectivity (FC). Structural MRI was used to calculate the gray matter volume (GMV) and cortical thickness. Moreover, receiver-operating characteristic (ROC) analysis was used to distinguish these alterations in SCD and aMCI. RESULTS: The SCD and aMCI groups showed both decreased ReHo in the right middle temporal gyrus (MTG) and decreased GMV compared to healthy controls (HCs). Especially in the SCD group, there were increased fALFF and increased ReHo in the left inferior occipital gyrus (IOG), decreased fALFF and increased FC in the left inferior parietal lobule (IPL), and reduced cortical thickness in the right inferior temporal gyrus (ITG). Furthermore, functional and structural alterations in the SCD and aMCI groups were closely related to episodic memory (EM), executive function (EF), and information processing speed (IPS). The combination of multiple indicators of DAN had a high accuracy in differentiating clinical stages. CONCLUSIONS: Our current study demonstrated functional and structural alterations of DAN in SCD and aMCI, especially in the MTG, IPL, and SPL. Furthermore, cognitive performance was closely related to these significant alterations. Our study further suggested that the combined multiple indicators of DAN could be acted as the latent neuroimaging markers of preclinical and early-stage AD for their high diagnostic value.

Functional changes in the salience network of patients with amnesic mild cognitive impairment before and after repetitive transcranial magnetic stimulation.

BACKGROUND: Amnestic mild cognitive impairment (aMCI) is considered to be the prodromal stage of Alzheimer's disease (AD). The precuneus (PCUN) may be an imaging marker for monitoring the progression of AD. Meanwhile, cognitive impairment in AD patients is closely related to functional connectivity (FC) changes in the salience network (SN). We hypothesize that there are specific neuroimaging biomarkers in the SN and that FC changes in aMCI patients after repetitive transcranial magnetic stimulation (rTMS) intervention are associated with cognitive function. The purpose of this study was to first investigate the pattern of functional changes in aMCI patients and healthy controls (HCs) and then compare the functional changes in aMCI patients before and after rTMS targeting to PCUN and its correlation with cognitive function. METHODS: Thirty-six HCs and 61 aMCIs were recruited for our study. Eleven people in the aMCI group received rTMS intervention 5 days a week for 4 weeks. Using the right anterior insula as the seed-of-interest, we first compared FC changes in HC and aMCI patients and then compared cognitive function in aMCI patients before and after rTMS. The above is the functional connection analysis of seed-to-voxel. Moreover, we investigated the FC changes in aMCI patients after rTMS intervention and its correlation with cognitive function. RESULTS: Compared with HC, the aMCI group showed altered FC in bilateral parahippocampal gyrus, bilateral inferior parietal lobule, left middle frontal gyrus, and left middle temporal gyrus. Moreover, rTMS at PCUN improved the cognitive function of aMCI patients, which was related to the altered FC in posterior cerebellar lobes (CPL). CONCLUSIONS: Our findings suggest that rTMS targeting PCUN is a promising, noninvasive approach to ameliorating cognitive dysfunction in aMCI patients, and that this cognitive improvement is accompanied by brain connectivity modulation.

Aberrant spontaneous static and dynamic amplitude of low-frequency fluctuations in cerebral small vessel disease with or without mild cognitive impairment.

BACKGROUND: Cerebral small vessel disease (CSVD) is considered an age-related degenerative neurological disorder and the most common risk factor for vascular cognitive impairment (VCI). The amplitude of fluctuation of low frequency (ALFF) can detect altered intrinsic brain activity in CSVD. This study explored the static and dynamic ALFFs in the early stage of CSVD with (CSVD-M) or without (CSVD-W) mild cognitive impairment (MCI) in these patients and how these changes contribute to cognitive deterioration. METHODS: Thirty consecutive CSVD cases and 18 healthy controls (HC) were included in this study. All the participants underwent a 3D magnetization-prepared rapid gradient-echo (MPRAGE) sequence to obtain structural T1-weighted images. Simultaneous multislice imaging 5(SMS5) was used for resting-state functional MRI (rs-fMRI), and Data Processing and Analysis of Brain Imaging software helped determine static ALFF (sALFF). The dynamic ALFF (dALFF) was calculated using the sliding window method of DynamicBC software. Analysis of Covariance (ANCOVA) and two-sample t-test were used to evaluate the sALFF and temporal variability of dALFF among the three groups. The subjects were rated on a broad standard neuropsychological scale. Partial correlation analysis was used to evaluate the correlation between sALFF and dALFF variability and cognition (Bonferroni correction, statistical threshold set at p < .05). RESULTS: Compared with HCs, the CSVD-M group indicated decreased sALFF values in the bilateral cerebellum posterior lobe (CPL) and the left inferior Parietal Lobule (IPL), with increased sALFF values in the right SFG. For dALFF analysis, the CSVD-W group had significant dALFF variability in the right fusiform gyrus compared with HC. Moreover, the postcentral gyrus (PoCG) was significantly high in the CSVD-W group. While in the CSVD-M group, the bilateral paracentral lobules (PL) revealed significantly elevated dALFF variability and low dALFF variability in the left CPL and right IPL compared with HCs. The CSVD-M group had high dALFF variability in the bilateral PL but low dALFF variability in the left middle temporal gyrus (MTG) and right PoCG compared with the CSVD-W group. The partial correlation analysis indicated that dALFF variability in the left MTG was positively associated with EM (r = 0.713, p = .002) in CSVD-W and CSVD-M groups. In the groups with CSVD-M and HC, altered dALFF variability in the bilateral PL was negatively correlated with EM (r = -0.560, p = .002). CONCLUSION: There were significant changes in sALFF and dALFF variability in CSVD patients. Abnormal spontaneous static and dynamic ALFFs may provide new insights into cognitive dysfunction in CSVD with MCI and may be valuable biomarkers for early diagnosis.

Differential Abnormality in Functional Connectivity Density in Preclinical and Early-Stage Alzheimer's Disease.

Background: Both subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) have a high risk of progression to Alzheimer's disease (AD). While most of the available evidence described changes in functional connectivity (FC) in SCD and aMCI, there was no confirmation of changes in functional connectivity density (FCD) that have not been confirmed. Therefore, the purpose of this study was to investigate the specific alterations in resting-state FCD in SCD and aMCI and further assess the extent to which these changes can distinguish the preclinical and early-stage AD. Methods: A total of 57 patients with SCD, 59 patients with aMCI, and 78 healthy controls (HC) were included. The global FCD, local FCD, and long-range FCD were calculated for each voxel to identify brain regions with significant FCD alterations. The brain regions with abnormal FCD were then used as regions of interest for FC analysis. In addition, we calculated correlations between neuroimaging alterations and cognitive function and performed receiver-operating characteristic analyses to assess the diagnostic effect of the FCD and FC alterations on SCD and aMCI. Results: FCD mapping revealed significantly increased global FCD in the left parahippocampal gyrus (PHG.L) and increased long-range FCD in the left hippocampus for patients with SCD when compared to HCs. However, when compared to SCD, patients with aMCI showed significantly decreased global FCD and long-range FCD in the PHG.L. The follow-up FC analysis further revealed significant variations between the PHG.L and the occipital lobe in patients with SCD and aMCI. In addition, patients with SCD also presented significant changes in FC between the left hippocampus, the left cerebellum anterior lobe, and the inferior temporal gyrus. Moreover, changes in abnormal indicators in the SCD and aMCI groups were significantly associated with cognitive function. Finally, combining FCD and FC abnormalities allowed for a more precise differentiation of the clinical stages. Conclusion: To our knowledge, this study is the first to investigate specific alterations in FCD and FC for both patients with SCD and aMCI and confirms differential abnormalities that can serve as potential imaging markers for preclinical and early-stage Alzheimer's disease (AD). Also, it adds a new dimension of understanding to the diagnosis of SCD and aMCI as well as the evaluation of disease progression.

An Activation Likelihood Estimation Meta-Analysis of Specific Functional Alterations in Dorsal Attention Network in Mild Cognitive Impairment.

Background: Mild cognitive impairment (MCI) is known as the prodromal stage of the Alzheimer's disease (AD) spectrum. The recent studies have advised that functional alterations in the dorsal attention network (DAN) could be used as a sensitive marker to forecast the progression from MCI to AD. Therefore, our aim was to investigate specific functional alterations in the DAN in MCI. Methods: We systematically searched PubMed, EMBASE, and Web of Science and chose relevant articles based on the three functional indicators, the amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), and functional connectivity (FC) in the DAN in MCI. Based on the activation likelihood estimation, we accomplished the aggregation of specific coordinates and the analysis of functional alterations. Results: A total of 38 studies were involved in our meta-analysis. By summing up included articles, we acquired specific brain region alterations in the DAN mainly in the superior temporal gyrus (STG), middle temporal gyrus (MTG), superior frontal gyrus (SFG), middle frontal gyrus (MFG), inferior frontal gyrus (IFG), precentral gyrus (preCG), inferior parietal lobule (IPL), superior parietal lobule (SPL). At the same time, the key area that shows anti-interaction with default mode network included the IPL in the DAN. The one showing interactions with executive control network was mainly in the MFG. Finally, the frontoparietal network showed a close connection with DAN especially in the IPL and IFG. Conclusion: This study demonstrated abnormal functional markers in the DAN and its interactions with other networks in MCI group, respectively. It provided the foundation for future targeted interventions in preventing the progression of AD. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42021287958].

Synergetic reorganization of the contralateral structure and function in patients with unilateral frontal glioma.

Objective: This study aimed to investigate the contralateral structural and functional plasticity induced by frontal gliomas. Methods: Patients with left (n = 49) or right (n = 52) frontal diffuse glioma were enrolled along with 35 age- matched healthy controls (HCs). The gray-matter volumes (GMVs) of the contralesional region were measured using the voxel-based morphometry (VBM) analysis. Additionally, the amplitude of low-frequency fluctuation (ALFF) of the contralesional region was calculated via resting state functional magnetic resonance imaging (MRI) to assess functional alterations. Result: The GMV of the contralateral orbitofrontal cortex of the right or left frontal gliomas was significantly larger than the corresponding GMV in the controls. In the patients with right frontal glioma, the GMV and ALFF in the left inferior frontal gyrus were significantly increased compared with those in the controls. Conclusion: Glioma invasion of the frontal lobe can induce contralateral structural compensation and functional compensation, which show synergy in the left inferior frontal gyrus. Our findings explain why patients with unilateral frontal glioma can have functional balance, and offer the possibility of preserving the brain function while maximizing tumor removal.

Hyperconnectivity Associated with Anosognosia Accelerating Clinical Progression in Amnestic Mild Cognitive Impairment.

The incidence and prevalence of anosognosia are highly variable in amnestic mild cognitive impairment (aMCI) patients. The study aims to explore the neuropathological mechanism of anosognosia in aMCI patients using two different but complementary technologies, including 18F-flortaucipir positron emission tomography and resting state functional magnetic resonance imaging. The study found that anosognosia was related to higher tau accumulation in the left medial orbitofrontal cortex (OFC), left posterior cingulate cortex, and right precuneus in aMCI patients. Intrinsic functional connectivity analyses found significant correlations between anosognosia index and hypoconnectivity between the left medial OFC and left middle temporal gyrus (MTG), right precuneus and left lingual gyrus. Longitudinally, the connectivity of these brain regions as well as the right precuneus and right cuneus showed hyperconnectivity in aMCI patients with anosognosia. The anosognosia index was also correlated with AD pathological markers (i.e., Aß, t-tau, and p-tau) and brain glucose metabolism in aMCI patients. In conclusion, anosognosia in aMCI patients is associated with the dysfunction of medial OFC-MTG circuit and the precuneus-visual cortex circuit and accelerates clinical progression to AD dementia.

Hippocampal-Subregion Mechanisms of Repetitive Transcranial Magnetic Stimulation Causally Associated with Amelioration of Episodic Memory in Amnestic Mild Cognitive Impairment.

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.

Convergent functional changes of the episodic memory impairment in mild cognitive impairment: An ALE meta-analysis.

Background: Mild cognitive impairment (MCI) is considered to be an intermediate stage between normal aging and Alzheimer's disease (AD). The earliest and most common symptom of MCI is impaired episodic memory. When episodic memory is impaired in MCI patients, specific functional changes occur in related brain areas. However, there is currently a lack of a unified conclusion on this change. Therefore, the purpose of this meta-analysis is to find MRI-specific functional changes in episodic memory in MCI patients. Methods: Based on three commonly used indicators of brain function: functional connectivity (FC), the amplitude of low-frequency fluctuation /fractional amplitude of low-frequency fluctuation (ALFF/fALFF), and regional homogeneity (ReHo), we systematically searched PubMed, Web of Science and Ovid related literature and conducted the strict screening. Then we use the activation likelihood estimation (ALE) algorithm to perform the coordinate-based meta-analysis. Results: Through strict screening, this meta-analysis finally included 21 related functional neuroimaging research articles. The final result displays that functional changes of episodic memory in MCI patients are mainly located in the parahippocampal gyrus, precuneus, posterior cingulate gyrus, cuneus, middle temporal gyrus, middle frontal gyrus, lingual gyrus, and thalamus. Conclusions: There are specific functional changes in episodic memory brain regions in MCI patients, and the brain functional network can regulate episodic memory through these brain regions. And these specific changes can assist in the early diagnosis of MCI, providing new ideas and directions for early identification and intervention in the process of MCI.

Altered anterior cingulate cortex subregional connectivity associated with cognitions for distinguishing the spectrum of pre-clinical Alzheimer's disease.

Background: Subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) are considered part of the early progression continuum of Alzheimer's disease (AD). The anterior cingulate cortex (ACC), a hub of information processing and regulation in the brain, plays an essential role in AD pathophysiology. In the present study, we aimed to systematically identify changes in the functional connectivity (FC) of ACC subregions in patients with SCD and aMCI and evaluate the association of these changes with cognition. Materials and methods: Functional connectivity (FC) analysis of ACC sub-regions was performed among 66 patients with SCD, 71 patients with aMCI, and 78 healthy controls (HCs). Correlation analyses were performed to examine the relationship between FC of altered ACC subnetworks and cognition. Results: Compared to HCs, SCD patients showed increased FC of the bilateral precuneus (PCUN) and caudal ACC, left superior frontal gyrus (SFG) and subgenual ACC, left inferior parietal lobule (IPL) and dorsal ACC, left middle occipital gyrus (MOG) and dorsal ACC, and left middle temporal gyrus (MTG) and subgenual ACC, while aMCI patients showed increased FC of the left inferior frontal gyrus (IFG) and dorsal ACC and left medial frontal gyrus (MFG) and subgenual ACC. Compared to patients with SCD, patients with aMCI showed increased FC of the right MFG and dorsal ACC and left ACC and subgenual ACC, while the left posterior cingulate cortex (PCC) showed decreased FC with the caudal ACC. Moreover, some FC values among the altered ACC subnetworks were significantly correlated with episodic memory and executive function. Conclusion: SCD and aMCI, part of the spectrum of pre-clinical AD, share some convergent and divergent altered intrinsic connectivity of ACC subregions. These results may serve as neuroimaging biomarkers of the preclinical phase of AD and provide new insights into the design of preclinical interventions.

An ALE Meta-Analysis of Specific Functional MRI Studies on Subcortical Vascular Cognitive Impairment.

Background: Subcortical vascular cognitive impairment (sVCI), caused by cerebral small vessel disease, accounts for the majority of vascular cognitive impairment, and is characterized by an insidious onset and impaired memory and executive function. If not recognized early, it inevitably develops into vascular dementia. Several quantitative studies have reported the consistent results of brain regions in sVCI patients that can be used to predict dementia conversion. The purpose of the study was to explore the exact abnormalities within the brain in sVCI patients by combining the coordinates reported in previous studies. Methods: The PubMed, Embase, and Web of Science databases were thoroughly searched to obtain neuroimaging articles on the amplitude of low-frequency fluctuation, regional homogeneity, and functional connectivity in sVCI patients. According to the activation likelihood estimation (ALE) algorithm, a meta-analysis based on coordinate and functional connectivity modeling was conducted. Results: The quantitative meta-analysis included 20 functional imaging studies on sVCI patients. Alterations in specific brain regions were mainly concentrated in the frontal lobes including the middle frontal gyrus, superior frontal gyrus, medial frontal gyrus, and precentral gyrus; parietal lobes including the precuneus, angular gyrus, postcentral gyrus, and inferior parietal lobule; occipital lobes including the lingual gyrus and cuneus; temporal lobes including the fusiform gyrus and middle temporal gyrus; and the limbic system including the cingulate gyrus. These specific brain regions belonged to important networks known as the default mode network, the executive control network, and the visual network. Conclusion: The present study determined specific abnormal brain regions in sVCI patients, and these brain regions with specific changes were found to belong to important brain functional networks. The findings objectively present the exact abnormalities within the brain, which help further understand the pathogenesis of sVCI and identify them as potential imaging biomarkers. The results may also provide a basis for new approaches to treatment.

Convergent Functional Changes of Default Mode Network in Mild Cognitive Impairment Using Activation Likelihood Estimation.

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.

Altered Insular Subregional Connectivity Associated With Cognitions for Distinguishing the Spectrum of Pre-clinical Alzheimer's Disease.

Background: Subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) are regarded as part of the pre-clinical Alzheimer's disease (AD) spectrum. The insular subregional networks are thought to have diverse intrinsic connectivity patterns that are involved in cognitive and emotional processing. We set out to investigate convergent and divergent altered connectivity patterns of the insular subregions across the spectrum of pre-clinical AD and evaluated how well these patterns can differentiate the pre-clinical AD spectrum. Method: Functional connectivity (FC) analyses in insular subnetworks were carried out among 38 patients with SCD, 56 patients with aMCI, and 55 normal controls (CNs). Logistic regression analyses were used to construct models for aMCI and CN, as well as SCD and CN classification. Finally, we conducted correlation analyses to measure the relationship between FCs of altered insular subnetworks and cognition. Results: Patients with SCD presented with reduced FC in the bilateral cerebellum posterior lobe and increased FC in the medial frontal gyrus and the middle temporal gyrus. On the other hand, patients with aMCI largely presented with decreased FC in the bilateral inferior parietal lobule, the cerebellum posterior lobe, and the anterior cingulate cortex, as well as increased FC in the medial and inferior frontal gyrus, and the middle and superior temporal gyrus. Logistic regression analyses indicated that a model composed of FCs among altered insular subnetworks in patients with SCD was able to appropriately classify 83.9% of patients with SCD and CN, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.876, 81.6% sensitivity, and 81.8% specificity. A model consisting of altered insular subnetwork FCs in patients with aMCI was able to appropriately classify 86.5% of the patients with aMCI and CNs, with an AUC of 0.887, 80.4% sensitivity, and 83.6% specificity. Furthermore, some of the FCs among altered insular subnetworks were significantly correlated with episodic memory and executive function. Conclusions: Patients with SCD and aMCI are likely to share similar convergent and divergent altered intrinsic FC patterns of insular subnetworks as the pre-clinical AD spectrum, and presented with abnormalities among subnetworks. Based on these abnormalities, individuals can be correctly differentiated in the pre-clinical AD spectrum. These results suggest that alterations in insular subnetworks can be utilized as a potential biomarker to aid in conducting a clinical diagnosis of the spectrum of pre-clinical AD.

Impaired Memory Awareness and Loss Integration in Self-Referential Network Across the Progression of Alzheimer's Disease Spectrum.

BACKGROUND: Anosognosia, or unawareness of memory deficits, is a common manifestation of Alzheimer's disease (AD), but greatly variable in subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) subjects. Self-referential network (SRN) is responsible for self-referential processing and considered to be related to AD progression. OBJECTIVE: Our aim is to explore connectivity changes of SRN and its interaction with memory-related network and primary sensorimotor network (SMN) in the AD spectrum. METHODS: About 444 Alzheimer's Disease Neuroimaging Initiative subjects (86 cognitively normal [CN]; 156 SCD; 146 aMCI; 56 AD) were enrolled in our study. The independent component analysis (ICA) method was used to extract the SRN, SMN, and memory-related network from all subjects. The alteration of functional connectivity (FC) within SRN and its connectivity with memory-related network/SMN were compared among four groups and further correlation analysis between altered FC and memory awareness index as well as episodic memory score were performed. RESULTS: Compared with CN group, individuals with SCD exhibited hyperconnectivity within SRN, while aMCI and AD patients showed hypoconnectivity. Furthermore, aMCI patients and AD patients both showed the interruption of the FC between the SRN and memory-related network compared to CN group. Pearson correlation analysis showed that disruptive FC within SRN and its interaction with memory-related network were related to memory awareness index and episodic memory scores. CONCLUSION: In conclusion, impaired memory awareness and episodic memory in the AD spectrum are correlated to the disconnection within SRN and its interaction with memory-related network.

Disrupted Dynamic Functional Connectivity in Distinguishing Subjective Cognitive Decline and Amnestic Mild Cognitive Impairment Based on the Triple-Network Model.

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.