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Abstract Excessive iron accumulation in the brain cortex increases the risk of cognitive deterioration. However, interregional relationships (defined as susceptibility connectivity) of local brain iron have not been explored, which could provide new insights into the underlying mechanisms of cognitive decline. Seventy-six healthy controls (HC), 58 participants with mild cognitive impairment due to probable Alzheimer’s disease (MCI-AD) and 66 participants with white matter hyperintensity (WMH) were included. We proposed a novel approach to construct a brain susceptibility network by using Kullback‒Leibler divergence similarity estimation from quantitative susceptibility mapping and further evaluated its topological organization. Moreover, sparse logistic regression (SLR) was applied to classify MCI-AD from HC and WMH with normal cognition (WMH-NC) from WMH with MCI (WMH-MCI).The altered susceptibility connectivity in the MCI-AD patients indicated that relatively more connectivity was involved in the default mode network (DMN)-related and visual network (VN)-related connectivity, while more altered DMN-related and subcortical network (SN)-related connectivity was found in the WMH-MCI patients. For the HC vs. MCI-AD classification, the features selected by the SLR were primarily distributed throughout the DMN-related and VN-related connectivity (accuracy = 76.12%). For the WMH-NC vs. WMH-MCI classification, the features with high appearance frequency were involved in SN-related and DMN-related connectivity (accuracy = 84.85%). The shared and specific patterns of the susceptibility network identified in both MCI-AD and WMH-MCI may provide a potential diagnostic biomarker for cognitive impairment, which could enhance the understanding of the relationships between brain iron burden and cognitive decline from a network perspective.

Abstract Background Neuro-navigated repetitive transcranial magnetic stimulation (rTMS) is potentially effective in enhancing cognitive performance in the spectrum of Alzheimer’s disease (AD). We explored the effect of rTMS-induced network reorganization and its predictive value for individual treatment response. Methods Sixty-two amnestic mild cognitive impairment (aMCI) and AD patients were recruited. These subjects were assigned to multimodal magnetic resonance imaging scanning before and after a 4-week stimulation. Then, we investigated the neural mechanism underlying rTMS treatment based on static functional network connectivity (sFNC) and dynamic functional network connectivity (dFNC) analyses. Finally, the support vector regression was used to predict the individual rTMS treatment response through these functional features at baseline. Results We found that rTMS at the left angular gyrus significantly induced cognitive improvement in multiple cognitive domains. Participants after rTMS treatment exhibited significantly the increased sFNC between the right frontoparietal network (rFPN) and left frontoparietal network (lFPN) and decreased sFNC between posterior visual network and medial visual network. We revealed remarkable dFNC characteristics of brain connectivity, which was increased mainly in higher-order cognitive networks and decreased in primary networks or between primary networks and higher-order cognitive networks. dFNC characteristics in state 1 and state 4 could further predict individual higher memory improvement after rTMS treatment (state 1, R = 0.58; state 4, R = 0.54). Conclusion Our findings highlight that neuro-navigated rTMS could suppress primary network connections to compensate for higher-order cognitive networks. Crucially, dynamic regulation of brain networks at baseline may serve as an individualized predictor of rTMS treatment response. Relevance statement Dynamic reorganization of brain networks could predict the efficacy of repetitive transcranial magnetic stimulation in the spectrum of Alzheimer’s disease. Key points • rTMS at the left angular gyrus could induce cognitive improvement. • rTMS could suppress primary network connections to compensate for higher-order networks. • Dynamic reorganization of brain networks could predict individual treatment response to rTMS. Graphical Abstract

White matter hyperintensities (WMH) are widely observed in older adults and are closely associated with cognitive impairment. However, the underlying neuroimaging mechanisms of WMH-related cognitive dysfunction remain unknown. This study recruited 61 WMH individuals with mild cognitive impairment (WMH-MCI, n = 61), 48 WMH individuals with normal cognition (WMH-NC, n = 48) and 57 healthy control (HC, n = 57) in the final analyses. We constructed morphological networks by applying the Kullback-Leibler divergence to estimate interregional similarity in the distributions of regional gray matter volume. Based on morphological networks, graph theory was applied to explore topological properties, and their relationship to WMH-related cognitive impairment was assessed. There were no differences in small-worldness, global efficiency and local efficiency. The nodal local efficiency, degree centrality and betweenness centrality were altered mainly in the limbic network (LN) and default mode network (DMN). The rich-club analysis revealed that WMH-MCI subjects showed lower average strength of the feeder and local connections than HC (feeder connections: P = 0.034; local connections: P = 0.042). Altered morphological connectivity mediated the relationship between WMH and cognition, including language (total indirect effect: −0.010; 95 % CI: −0.024, −0.002) and executive (total indirect effect: −0.010; 95 % CI: −0.028, −0.002) function. The altered topological organization of morphological networks was mainly located in the DMN and LN and was associated with WMH-related cognitive impairment. The rich-club connection was relatively preserved, while the feeder and local connections declined. The results suggest that single-subject morphological networks may capture neurological dysfunction due to WMH and could be applied to the early imaging diagnostic protocol for WMH-related cognitive impairment.

Abstract Background Endogenous hydrogen sulfide (H2S)-responsive theranostic agents have attracted extensive attention due to their specificity for colon cancer. However, the development of such agents with high enrichment in tumors and excellent photothermal performance remains challenging. Results We prepared hyaluronic acid (HA)-coated Bi-doped cuprous oxide (Bi:Cu2O@HA) via a one-pot method. The HA specifically targets colon cancer tumor cells to improve the enrichment of Bi:Cu2O@HA at tumor sites, while the doped Bi both enhances the photothermal performance of the H2S-triggered Cu2O and serves as an agent for tumor imaging. The results in this work demonstrated that the Bi:Cu2O@HA nanoparticles exhibit good biocompatibility, target colon cancer tumor cells, facilitate computed tomography imaging, and enhanced H2S-responsive photothermal therapy performance, resulting in an excellent therapeutic effect in colon cancer. Conclusions The novel Bi:Cu2O@HA nanoparticles exhibit excellent tumor targeting and photothermal therapeutic effects, which provide new strategies and insights for colon cancer therapy. Graphical Abstract

Synaptic plasticity impairment plays a critical role in the pathogenesis of Alzheimer’s disease (AD), and emerging evidence has shown that microRNAs (miRs) are alternative biomarkers and therapeutic targets for synaptic dysfunctions in AD. In this study, we found that the level of miR-431 was downregulated in the plasma of patients with amnestic mild cognitive impairment and AD. In addition, it was decreased in the hippocampus and plasma of APPswe/PS1dE9 (APP/PS1) mice. Lentivirus-mediated miR-431 overexpression in the hippocampus CA1 ameliorated synaptic plasticity and memory deficits of APP/PS1 mice, while it did not affect amyloid-β levels. Smad4 was identified as a target of miR-431, and Smad4 knockdown modulated the expression of synaptic proteins, including SAP102, and protected against synaptic plasticity and memory dysfunctions in APP/PS1 mice. Furthermore, Smad4 overexpression reversed the protective effects of miR-431, indicating that miR-431 attenuated synaptic impairment at least partially by Smad4 inhibition. Thus, these results indicated that miR-431/Smad4 might be a potential therapeutic target for AD treatment.

Punding is a rare condition triggered by dopaminergic therapy in Parkinson’s disease (PD), characterized by a complex, excessive, repetitive, and purposeless abnormal movement, and its pathogenesis remains unclear. We aimed to assess the brain structure alterations related to punding by using multipametric magnetic resonance imaging (MRI). Thirty-eight PD patients (19 with punding and 19 without punding) from the Parkinson’s Progression Marker Initiative (PPMI) were included in this study. Cortical thickness was assessed with FreeSurfer, and the integrity of white matter fiber tracts and network topologies were analyzed by using FMRIB Software Library (FSL) and Pipeline for Analyzing braiN Diffusion imAges (PANDA). PD patients with punding showed a higher apathy score and more severe cortical atrophy in the left superior parietal, right inferior parietal, and right superior frontal gyrus, and worse integrity of the right cingulum cingulate tract compared to those without punding. On the other hand, no significant difference in structural network topologies was detected between the two groups. These data suggest that the specific area of destruction may be an MRI biomarker of punding risk, and these findings may have important implications for understanding the neural mechanisms of punding in PD.

BackgroundThe mechanism of gait and balance dysfunction (GBD) in cerebral small vessel disease (CSVD) remains unclear. Evidence supports cognition engages in GBD of CSVD. The cerebellum is important in motor and cognition, while little is known about the influence of the cerebellum on GBD in CSVD.MethodsThis study is a retrospective cohort study. All participants of this study were enrolled from the CSVD individuals in Nanjing Drum Tower Hospital from 2017 to 2021. The GBD of CSVD patients was defined as Tinetti Test score ≤ 23. Cerebral cortical thickness, cerebellar gray matter volume, the amplitude of low-frequency fluctuation, functional connectivity, and modular interaction were calculated to determine the cortical atrophy and activity patterns of CSVD patients with GBD. The effect of cognitive domains during GBD in CSVD patients was explored by correlation analyses.ResultsA total of 25 CSVD patients were recruited in CSVD patients with GBD group (Tinetti Test score ≤ 23, mean age ± standard deviation: 70.000 ± 6.976 years), and 34 CSVD patients were recruited in CSVD patients without GBD group (Tinetti Test score > 23, mean age ± standard deviation: 64.029 ± 9.453 years). CSVD patients with GBD displayed worse cognitive performance and cortical atrophy in the right cerebellum VIIIa and bilateral superior temporal gyrus than those without GBD. The right postcentral gyrus, left inferior temporal gyrus, right angular gyrus, right supramarginal gyrus and right middle frontal gyrus were functionally overactivated and showed decreased modular interaction with the right cerebellum. Tinetti Test scores were negatively related to the volume of the right cerebellum VIIIa in CSVD patients with GBD. Notably, memory, especially visuospatial memory, was greatly associated with GBD in CSVD.ConclusionThe cortical atrophy and altered functional activity in sensorimotor area and ventral attention network in the cerebellum and cerebrum may underlying the GBD in CSVD. Memory might be critically cognitively responsible for GBD in CSVD.

AimsThis research aimed to explore alterations in the local gyrification index (GI) and resting-state functional connectivity (RSFC) in type 2 diabetes mellitus (T2DM) patients with mild cognitive impairment (MCI).MethodsIn this study, 126 T2DM patients with MCI (T2DM-MCI), 154 T2DM patients with normal cognition (T2DM-NC), and 167 healthy controls (HC) were recruited. All subjects underwent a battery of neuropsychological tests. A multimodal approach combining surface-based morphometry (SBM) and seed-based RSFC was used to determine the structural and functional alterations in patients with T2DM-MCI. The relationships among the GI, RSFC, cognitive ability, and clinical variables were characterized.ResultsCompared with the T2DM-NC group and HC group, T2DM-MCI patients showed significantly reduced GI in the bilateral insular cortex. Decreased RSFC was found between the left insula and right precuneus, and the right superior frontal gyrus (SFG). The altered GI was correlated with T2DM duration, global cognition, and episodic memory. The mediation effects of RSFC on the association between GI and cognition were not statistically significant.ConclusionOur results suggest that GI may serve as a novel neuroimaging biomarker to predict T2DM-related MCI and help us to improve the understanding of the neuropathological effects of T2DM-related MCI.

ObjectiveThe cognitive performance of individuals with white matter hyperintensities (WMH) tends to vary considerably. This study aimed to explore the relationship of the synchronous spontaneous activities in homotopic areas across hemispheres, named as voxel-mirrored homotopic connectivity (VMHC), with the cognitive performance of individuals with WMH.Materials and MethodsEighty-two WMH subjects without cognitive impairment (CI), 56 WMH subjects with CI, and 92 healthy subjects (HS) underwent neuropsychological tests and multimodal magnetic resonance imaging scans. VMHC maps were analyzed among the three groups. Correlative analyses were performed between VMHC values and cognitive function.ResultsNo significant difference in WMH volume, brain volume, or gray matter atrophy rate was shown between WMH subjects with and without CI. In contrast, those with CI displayed lower VMHC in the bilateral cuneus and calcarine and higher VMHC in the lentiform nucleus and caudate nucleus (LNCN) than those without CI. Furthermore, the VMHC in the LNCN was negatively associated with the global function and the memory function in WMH subjects.ConclusionThe enhanced VMHC in the LNCN was associated with the development of CI in individuals with WMH. This finding may contribute to the exploration of surrogate markers for the CI caused by WMH.

BackgroundThe role of brain atrophy in cognitive decline related to cerebral small vessel disease (CSVD) remains unclear. This study used AccuBrain™ to identify major CSVD-related brain changes and verified the relationship between brain atrophy and different cognition domains in CSVD patients.MethodsAll enrolled 242 CSVD patients and 76 healthy participants underwent magnetic resonance imaging examinations and detailed neuropsychological scale assessments were collected at the same time. The AccuBrain™ technology was applied to fully automated image segmentation, measurement, and calculation of the acquired imaging results to obtain the volumes of different brain partitions and the volume of WMH for quantitative analysis. Correlation analyses were used to estimate the relationship between MRI features and different cognitive domains. Multifactor linear regression models were performed to analyze independent predictors of MTA and cognitive decline.ResultsCSVD patients exhibited multiple gray matter nucleus volume decreases in the basal ganglia regions and brain lobes, including the temporal lobe (P = 0.019), especially in the medial temporal lobe (p < 0.001), parietal lobe (p = 0.013), and cingulate lobe (p = 0.036) compare to HC. The volume of PWMH was an independent predictor of MTA for CSVD patients. Both medial temporal atrophy (MTA) and PWMH were associated with cognition impairment in CSVD-CI patients. MTA mediated the effect of PWMH on executive function in CSVD-CI patients.ConclusionsOur results showed that MTA was related to cognition impairment in CSVD patients, which might become a potential imaging marker for CSVD-CI.

Retinal imaging being a potential biomarker for Alzheimer’s disease is gradually attracting the attention of researchers. However, the association between retinal parameters and AD neuroimaging biomarkers, particularly structural changes, is still unclear. In this cross-sectional study, we recruited 25 cognitively impaired (CI) and 21 cognitively normal (CN) individuals. All subjects underwent retinal layer thickness and microvascular measurements with optical coherence tomography angiography (OCTA). Gray matter and white matter (WM) data such as T1-weighted magnetic resonance imaging and diffusion tensor imaging, respectively, were also collected. In addition, hippocampal subfield volumes and WM tract microstructural alterations were investigated as classical AD neuroimaging biomarkers. The microvascular and retinal features and their correlation with brain structural imaging markers were further analyzed. We observed a reduction in vessel density (VD) at the inferior outer (IO) sector (p = 0.049), atrophy in hippocampal subfield volumes, such as the subiculum (p = 0.012), presubiculum (p = 0.015), molecular_layer_HP (p = 0.033), GC-ML-DG (p = 0.043) and whole hippocampus (p = 0.033) in CI patients. Altered microstructural integrity of WM tracts in CI patients was also discovered in the cingulum hippocampal part (CgH). Importantly, we detected significant associations between retinal VD and gray matter volumes of the hippocampal subfield in CI patients. These findings suggested that the retinal microvascular measures acquired by OCTA may be markers for the early prediction of AD-related structural brain changes.

Alzheimer’s disease (AD) causes extensive neural network dysfunction. Memantine and donepezil are commonly used as monotherapy or in combination with non-drug interventions, such as repetitive transcranial magnetic stimulation (rTMS), for its treatment. However, no studies have reported any differences between the effects of combined neurotransmitter and rTMS interventions versus rTMS alone on the brain networks of patients with cognitive impairment. Therefore, it is crucial to explore the advantages of different intervention methods to guide clinical practice. We used resting-state functional magnetic resonance imaging (rs-fMRI) to investigate the impact of neurotransmitter superimposed rTMS and rTMS alone on the brain functional network of patients with cognitive impairment. We divided patients with cognitive impairment who had received rTMS into two groups based on whether they received neurotransmitters: the combined intervention group and the rTMS-alone intervention group. We conducted rs-fMRI scans and comprehensively assessed cognitive function in these patients. To examine the effects of the superimposed interventions, we utilized independent component analysis to evaluate the functional connectivity of brain networks in these patients. Compared to the rTMS-alone intervention group, co-intervention of neurotransmitter drugs and rTMS exhibited potential for cognitive enhancement via the reconstructed inter-network connectivity of the cerebellum and the enhanced intra-network connectivity of the frontal-parietal regions in these patients with cognitive impairment. We hypothesized that the combination of neurotransmitter drugs and rTMS intervention could have greater clinical benefits than rTMS intervention alone, leading to improved cognitive function in patients with cognitive impairment.

Cortical visual system dysfunction is closely related to the progression of Alzheimer’s Disease (AD), while retinal vascular structures play an important role in the integrity of the function of the visual network and are a potential biomarker of AD. This study explored the association between the cortical visual system and retinal vascular structures in AD-spectrum patients, and it established a screening tool to detect preclinical AD based on these parameters identified in a retinal examination. A total of 42 subjects were enrolled and were distributed into two groups: 22 patients with cognitive impairment and 20 healthy controls. All participants underwent neuropsychological tests, optical coherence tomography angiography and resting-state fMRI imaging. Seed-based functional connectivity analysis was used to construct the cortical visual network. The association of functional connectivity of the cortical visual system and retinal vascular structures was further explored in these subjects. This study found that the cognitive impairment group displayed prominently decreased functional connectivity of the cortical visual system mainly involving the right inferior temporal gyrus, left supramarginal gyrus and right postcentral gyrus. Meanwhile, we observed that retinal vascular structure characteristics deteriorated with the decline in functional connectivity in the cortical visual system. Our study provided novel insights into the aberrant cortical visual system in patients with cognitive impairment that strongly emphasized the critical role of retinal vascular structure characteristics, which could be used as potential biomarkers for diagnosing and monitoring the progression of AD.

AimsThis study aimed to investigate the relationships of impaired cerebrovascular reactivity (CVR) and abnormal functional connectivity (FC) with white matter hyperintensity (WMH)-related cognitive decline.MethodsA total of 233 WMH subjects were recruited and categorized into WMH-I (n = 106), WMH-II (n = 72), and WMH-III (n = 55) groups according to Fazekas visual rating scale. All participants underwent neuropsychological tests and multimodal MRI scans, including 3D-T1, and resting-state functional magnetic resonance imaging (rs-fMRI). The alterations of CVR maps and FC were further explored.ResultsSubjects with a higher WMH burden displayed a lower CVR in the left medial occipital gyrus (MOG). The FC analysis using MOG as a seed revealed that the FC of the left insula, left inferior parietal lobule, and thalamus changed abnormally as WMH aggravated. After adjusting for age, gender, and education years, the serial mediation analysis revealed that periventricular white matter hyperintensity contributes indirectly to poorer Mini-Mental State Examination (MMSE) scores (indirect effect: β = −0.1248, 95% CI: −0.4689, −0188), poorer Montreal Cognitive Assessment (MoCA) (indirect effect: β = −0.1436, 95% CI: −0.4584, −0.0292) scores, and longer trail making tests A (TMT-A) (indirect effect: β = 0.1837, 95% CI: 0.0069, 0.8273) times, specifically due to the lower CVR of the left MOG and the higher FC of the left insula-MOG.ConclusionThe CVR decline of the left MOG and the abnormal FC of the left insula-MOG attributed to WMH progression were responsible for the poor general cognition (MMSE and MoCA) and information processing speed (TMT-A). The left MOG may act as a connection, which is involved in the processing of cognitive biases by connecting with the left insula-cortical regions in WMH individuals.

PurposeCombined the number, volume, and location of cerebral microbleeds (CMBs), this study aimed to explore the different features of CMBs and their correlation with cognitive ability in patients with type 2 diabetes mellitus (T2DM).MethodsThis study recruited 95 patients with T2DM and 80 healthy control (HC) individuals. AccuBrain®, an automated tool, was used to obtain the number and volume of CMBs. The scores on global cognition and five cognitive domains were derived from a battery of cognitive tests. The logistic regression and multivariate linear regression were conducted to determine the relationship between the CMBs (number, volume, and location) and cognitive ability in patients with T2DM.ResultsAfter adjusting for several variables, the total volume of CMBs (OR = 0.332, 95%CI: 0.133–0.825, and p = 0.018) was independent risk factor for cognitive impairment, whereas the total number of CMBs was not (OR = 0933, 95%CI: 0.794–1.097, and p = 0.400). Furthermore, the volume of CMBs in lobar regions was independently associated with working memory (β = −0.239, 95%CI: −0.565 to −0.035, and p = 0.027). However, no significant correlation between the number of CMBs (both lobar and deep/infratentorium) and any cognitive domains was observed.ConclusionsLobar CMBs was related with cognitive impairment in patients with T2DM and might be a potential early warning signal. Compared with the counting analysis, the quantitative method offered a more sensitive and objective measurement for studying imaging features of CMBs.

Both episodic memory and executive function are impaired in amnestic mild cognitive impairment (aMCI) subjects, but it is unclear if these impairments are independent or interactive. The present study aimed to explore the relationship between episodic memory deficits and executive function deficits, and the underlying functional mechanisms in aMCI subjects. Thirty-one aMCI subjects and 27 healthy subjects underwent neuropsychological tests and multimodal magnetic resonance imaging (MRI) scans. Hippocampal networks and medial prefrontal cortex (MPFC) networks were identified based on resting-sate functional MRI (fMRI) data. AMCI subjects displayed lower episodic memory scores and executive function scores than control subjects, and the episodic memory scores were positively correlated with the executive function scores in aMCI subjects. Brain network analyses showed an interaction between the hippocampal networks and the MPFC networks, and the interaction was significantly associated with the episodic memory scores and the executive function scores. Notably, aMCI subjects displayed higher functional connectivity (FC) of the right hippocampal network with the right prefrontal cortex than did control subjects, but this difference disappeared when controlling for the MPFC networks. Furthermore, the effects of the MPFC networks on the hippocampal networks were significantly associated with the episodic memory scores in aMCI subjects. The present findings suggested that the episodic memory deficits in aMCI subjects could be partially underpinned by the modulation of the MPFC networks on the hippocampal networks.

Glymphatic dysfunction has been linked to cognitive decline in several neurodegenerative diseases. In cerebral small vessel disease (CSVD), the mechanism of white matter hyperintensities (WMH)-related cognitive impairment (CI) is still under investigation. The diffusion tensor image (DTI) analysis along the perivascular space (ALPS) method has been considered to be a reliable parameter to evaluate glymphatic function. Therefore, we applied the ALPS-index to determine the influence of glymphatic function on CI in CSVD. In total, 137 CSVD patients (normal cognitive group, mild CI group, and dementia group) and 52 normal controls were included in this study. The ALPS-index was calculated based on the DTI. Correlation analyses and mediation analysis were conducted to examine the relationship between glymphatic function and cognition. Remarkable differences in the ALPS-index were observed between subjects with and without CI. The ALPS-index was negatively correlated with age, WMH volume, and general cognitive function in all CSVD patients. In the mild CI group, the ALPS-index was independently positively related to episodic memory, and mediated the relationship between WMH volume and episodic memory. In conclusion, the ALPS-index is a potential marker for early recognition of CI in CSVD. Glymphatic dysfunction mediates the relationship between WMH and CI in CSVD.

Mechanisms underlying cognitive impairment (CI) in hypertensive patients remain relatively unclear. The present study aimed to explore the relationship among serum exosomal microRNAs (miRNAs), cerebrovascular reactivity (CVR), and cognitive function in hypertensive patients. Seventy-three hypertensive patients with CI (HT-CI), 67 hypertensive patients with normal cognition (HT-NC), and 37 healthy controls underwent identification of exosomal miRNA, multimodal magnetic resonance imaging (MRI) scans, and neuropsychological tests. CVR mapping was investigated based on resting-state functional MRI data. Compared with healthy subjects and HT-NC subjects, HT-CI subjects displayed decreased serum exosomal miRNA-330-3p. The group difference of CVR was mainly found in the left frontal lobe and demonstrated that HT-CI group had a lower CVR than both HT-NC group and control group. Furthermore, both the CVR in the left medial superior frontal gyrus and the miRNA-330-3p level were significantly correlated with executive function (r = −0.275, P = 0.021, and r = −0.246, P = 0.04, respectively) in HT-CI subjects, and the CVR was significantly correlated with the miRNA-330-3p level (r = 0.246, P = 0.040). Notably, path analysis showed that the CVR mediated the association between miRNA-330-3p and executive function. In conclusion, decreased miRNA-330-3p might contribute to CI in hypertensive patients by decreasing frontal CVR and could be a biomarker of early diagnosis.

BackgroundStructural network alterations in Alzheimer’s disease (AD) are related to worse cognitive impairment. The aim of this study was to quantify the alterations in gray matter associated with impaired cognition and their pathological biomarkers in AD-spectrum patients.MethodsWe extracted gray matter networks from 3D-T1 magnetic resonance imaging scans, and a graph theory analysis was used to explore alterations in the network metrics in 34 healthy controls, 70 mild cognitive impairment (MCI) patients, and 40 AD patients. Spearman correlation analysis was computed to investigate the relationships among network properties, neuropsychological performance, and cerebrospinal fluid pathological biomarkers (i.e., Aβ, t-tau, and p-tau) in these subjects.ResultsAD-spectrum individuals demonstrated higher nodal properties and edge properties associated with impaired memory function, and lower amyloid-β or higher tau levels than the controls. Furthermore, these compensations at the brain regional level in AD-spectrum patients were mainly in the medial temporal lobe; however, the compensation at the whole-brain network level gradually extended from the frontal lobe to become widely distributed throughout the cortex with the progression of AD.ConclusionThe findings provide insight into the alterations in the gray matter network related to impaired cognition and pathological biomarkers in the progression of AD. The possibility of compensation was detected in the structural networks in AD-spectrum patients; the compensatory patterns at regional and whole-brain levels were different and the clinical significance was highlighted.

Background: The degenerative pattern of white matter (WM) microstructures during Alzheimer's disease (AD) and its relationship with cognitive function have not yet been clarified. The present research aimed to explore the alterations of the WM microstructure and its impact on amnestic mild cognitive (aMCI) and AD patients. Mechanical learning methods were used to explore the validity of WM microstructure lesions on the classification in AD spectrum disease.Methods: Neuropsychological data and diffusion tensor imaging (DTI) images were collected from 28 AD subjects, 31 aMCI subjects, and 27 normal controls (NC). Tract-based spatial statistics (TBSS) were used to extract diffusion parameters in WM tracts. We performed ANOVA analysis to compare diffusion parameters and clinical features among the three groups. Partial correlation analysis was used to explore the relationship between diffusion metrics and cognitive functions controlling for age, gender, and years of education. Additionally, we performed the support vector machine (SVM) classification to determine the discriminative ability of DTI metrics in the differentiation of aMCI and AD patients from controls.Results: As compared to controls or aMCI patients, AD patients displayed widespread WM lesions, including in the inferior longitudinal fasciculus, inferior fronto-occipital fasciculi, and superior longitudinal fasciculus. Significant correlations between fractional anisotropy (FA), mean diffusivity (MD), and radial diffusion (RD) of the long longitudinal tract and memory deficits were found in aMCI and AD groups, respectively. Furthermore, through SVM classification, we found DTI indicators generated by FA and MD parameters can effectively distinguish AD patients from the control group with accuracy rates of up to 89 and 85%, respectively.Conclusion: The WM microstructure is extensively disrupted in AD patients, and the WM integrity of the long longitudinal tract is closely related to memory, which would hold potential value for monitoring the progression of AD. The method of classification based on SVM and WM damage features may be objectively helpful to the classification of AD diseases.

Neuroimaging evidence has suggested white matter microstructure are heavily affected in Alzheimer's disease (AD). However, whether white matter dysfunction is localized at the specific regions of fiber tracts and whether they would be a potential biomarker for AD remain unclear. By automated fiber quantification (AFQ), we applied diffusion tensor images from 25 healthy controls (HC), 24 amnestic mild cognitive impairment (aMCI) patients and 18 AD patients to create tract profiles along 16 major white matter fibers. We compared diffusion metrics [Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (DA), and radial diffusivity (DR)] between groups. To assess the diagnostic value, we applied a random forest (RF) classifier, a type of machine learning method. In the global tract level, we found that aMCI and AD patients showed higher MD, DA, and DR values in some fiber tracts mostly in the left hemisphere compared to HC. In the point-wise level, widespread disruption were distributed on specific locations of different tracts. The point-wise MD measurements presented the best classification performance with respect to differentiating AD from HC. The two most important variables were localized in the prefrontal potion of left uncinate fasciculus and anterior thalamic radiation. In addition, the point-wise DA in the posterior component of the left cingulum cingulate displayed the most robust discriminative ability to identify AD from aMCI. Our findings provide evidence that white matter abnormalities based on the AFQ method could be as a diagnostic biomarker in AD.

Purpose: There is a high correlation between white matter hyperintensity (WMH) and cognitive impairment (CI) in elderly people. However, not all WMH will develop into CI, and the potential mechanism of WMH-related CI is still unclear. This study aimed to investigate the topological properties of white matter structural network in WMH-related CI.Methods: Forty-one WMH subjects with CI (WMH-CI), 42 WMH subjects without CI (WMH-no-CI), and 52 elderly healthy controls (HC) were recruited. Diffusion tensor imaging (DTI) fiber tractography and graph theoretical analysis were applied to construct the structural network. We compared network properties and clinical features among the three groups. Multiple linear regression analysis was performed to investigate the relationships among WMH volumes, impaired network properties, and cognitive functions in the WMH-CI group.Results: Compared with the controls, both WMH groups showed decreased network strength, global efficiency, and increased characteristic path length (Lp) at the level of the whole brain. The WMH-CI group displayed more profound impairments of nodal efficiency and nodal path length (NLp) within multiple regions including precentral, cingulate, and medial temporal gyrus. The disrupted network properties were associated with CI and WMH burdens in the WMH-CI group. Furthermore, a mediation effect of NLp in the left inferior frontal gyrus was observed for the association between periventricular WMH (PWMH) and memory deficit.Conclusions: Brain structural network in WMH-CI is significantly disturbed, and this disturbance is related to the severity of WMH and CI. Increased NLp in the left opercular part of inferior frontal gyrus (IFGoperc.L) was shown to be a mediation framework between PWMH and WMH-related memory, which shed light on investigating the underlying mechanisms of CI caused by WMH.

Background and Objective: Subjective cognitive decline (SCD) is considered a preclinical state of Alzheimer’s disease (AD) and may represent a more advanced preclinical status than amnestic mild cognitive impairment (aMCI). Our aim was to explore changes in the white matter (WM) microstructure and their correlation with cognitive function in these AD-spectrum patients.Methods: Diffusion tensor images from 43 individuals with normal cognition (NC), 38 SCD patients, and 36 aMCI patients were compared using an atlas-based segmentation strategy. The correlation between diffusion parameters and cognitive function was further analyzed.Results: The anatomical pattern of WM impairment was generally similar between SCD and aMCI patients. However, aMCI patients showed significantly lower fractional anisotropy (i.e., corpus callosum forceps major and forceps minor) and increased mean diffusivity [i.e., bilateral anterior thalamic radiation (ATR), left corticospinal tract (CST), forceps minor, left cingulum (cingulate gyrus), left cingulum hippocampus, and left inferior fronto-occipital fasciculus (IFO)] in some tracts than did SCD subjects, indicating a disruption in WM microstructural integrity in the aMCI. Individuals with microstructural disruption in forceps minor, left cingulum (cingulate gyrus), and left cingulum hippocampus tracts performed worse in general cognition and memory function tests, as indicated by line regression analysis.Conclusion: SCD individuals had extensive WM microstructural damage in a pattern similar to that seen in aMCI, although presenting a cognitive performance comparable with that of cognitively healthy individuals. Our results suggest that WM integrity might precede objectively measurable memory decline and may be a potential early biomarker for AD.

White matter hyperintensity (WMH) is widely observed in the elderly population and serves as a key indicator of cognitive impairment (CI). However, the underlying mechanism remains to be elucidated. Herein, we investigated the topological patterns of resting state functional networks in WMH subjects and the relationship between the topological measures and CI. A graph theory-based analysis was employed in the resting-state functional magnetic resonance scans of 112 subjects (38 WMH subjects with cognitive impairment without dementia (CIND), 36 WMH subjects with normal cognition and 38 healthy controls (HCs), and we found that WMH-CIND subjects displayed decreased global efficiency at the levels of the whole brain, specific subnetworks [fronto-parietal network (FPN) and cingulo-opercular network (CON)] and certain nodes located in the FPN and CON, as well as decreased local efficiency in subnetworks. Our results demonstrated that nodal global efficiency in frontal and parietal regions mediated the impairment of information processing speed related to periventricular WMH (PWMH). Additionally, we performed support vector machine (SVM) analysis and found that altered functional efficiency can identify WMH-CIND subjects with high accuracy, sensitivity and specificity. These findings suggest impaired functional networks in WMH-CIND individuals and that decreased functional efficiency may be a feature of CI in WMH subjects.

ObjectiveWhite matter hyperintensities (WMH) is an important cause of vascular cognitive impairment (CI). However, a considerable portion of individuals with WMH do not develop CI. The present study aimed to investigate distinctive regional brain activity and connectivity patterns in WMH subjects with and without CI, who displayed comparable WMH burden.MethodsFourteen WMH subjects with CI, 16 WMH subjects without CI and 37 healthy subjects underwent multimodal MRI scans and neuropsychological tests. All WMH subjects displayed Fazekas grade 2 of WMH. Regional Homogeneity (ReHo) and functional connectivity (FC) patterns were identified based on resting-state functional MRI data.ResultsNo significant differences in WMH volume, the number of WMH lesions and brain volume were shown between the 2 WMH groups. In contrast, the WMH with CI group showed higher ReHo in bilateral superior parietal gyrus (SPG)/superior occipital gyrus (SOG) than the WMH without CI group. Compared with the WMH without CI group, the WMH with CI group also displayed higher FC of the left SPG/SOG with frontal regions, and higher FC of the right SPG/SOG with parietal regions. Furthermore, higher FC of the left SPG/SOG with frontal regions were significantly associated with less worse executive dysfunction in WMH with CI subjects, suggesting a compensatory effect.ConclusionHigher local coherence of activities in the SPG/SOG and higher connectivity of the SPG/SOG with parietal and frontal regions are related to CI in WMH subjects. The findings provide novel insights into functional alterations underlying the cognitive variety in WMH subjects.

Background: Cerebral small vessel disease (SVD) is a common cause of cognitive dysfunction. However, little is known whether the altered reconfiguration pattern of brain modular architecture regulates cognitive dysfunction in SVD.Methods: We recruited 25 cases of SVD without cognitive impairment (SVD-NCI) and 24 cases of SVD with mild cognitive impairment (SVD-MCI). According to the Framingham Stroke Risk Profile, healthy controls (HC) were divided into 17 subjects (HC-low risk) and 19 subjects (HC-high risk). All individuals underwent resting-state functional magnetic resonance imaging and cognitive assessments. Graph-theoretical analysis was used to explore alterations in the modular organization of functional brain networks. Multiple regression and mediation analyses were performed to investigate the relationship between MRI markers, network metrics and cognitive performance.Results: We identified four modules corresponding to the default mode network (DMN), executive control network (ECN), sensorimotor network and visual network. With increasing vascular risk factors, the inter- and intranetwork compensation of the ECN and a relatively reserved DMN itself were observed in individuals at high risk for SVD. With declining cognitive ability, SVD-MCI showed a disrupted ECN intranetwork and increased DMN connection. Furthermore, the intermodule connectivity of the right inferior frontal gyrus of the ECN mediated the relationship between periventricular white matter hyperintensities and visuospatial processing in SVD-MCI.Conclusions: The reconfiguration pattern of the modular architecture within/between the DMN and ECN advances our understanding of the neural underpinning in response to vascular risk and SVD burden. These observations may provide novel insight into the underlying neural mechanism of SVD-related cognitive impairment and may serve as a potential non-invasive biomarker to predict and monitor disease progression.

Aims: The prevalence of white matter hyperintensities (WMH) rises dramatically with aging. Both the progression of WMH and changing patterns of default mode network (DMN) have been proven to be closely associated with cognitive function. The present study hypothesized that changes in functional connectivity and structural connectivity of DMN contributed to WMH related cognitive impairment. Methods: A total of 116 subjects were enrolled from the Cerebral Small Vessel Disease Register in Drum Tower Hospital of Nanjing University, and were distributed across three categories according to Fazekas rating scale: WMH I (n = 57), WMH II (n = 34), and WMH III(n = 25). All participants underwent neuropsychological tests and multimodal MRI scans, including diffusion tensor imaging and resting-state fMRI imaging. The alterations of functional connectivity and structural connectivity within the DMN were further explored. Results: Age and hypertension were risk factors for WMH progression. Subjects with a higher WMH burden displayed higher DMN functional connectivity in the medial frontal gyrus, while lower DMN functional connectivity in the thalamus. After adjusting for aging, gender, and education, the increased DMN functional connectivity in the medial frontal gyrus, and the increased mean diffusivity of the white matter tracts between the hippocampus and posterior cingulate cortex were independent indicators of worse performance in memory. Moreover, the decreased DMN functional connectivity in the thalamus and increased mean diffusivity of the white matter tracts between the thalamus and posterior cingulate cortex were independent risk factors for a slower processing speed. Conclusion: The changes in functional connectivity and structural connectivity within the DMN attributed to WMH progression were responsible for the development of cognitive impairment. Keywords: White matter hyperintensities, Cognitive impairment, Default mode network, Functional connectivity, Structural connectivity