The characteristic patterns of individual brain susceptibility networks underlie Alzheimer's disease and white matter hyperintensity-related cognitive impairment.

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.

Lower cerebrovascular reactivity in prefrontal cortex and weaker negative functional connectivity between prefrontal cortex and insula contribute to white matter hyperintensity-related anxiety or depression.

BACKGROUND: White matter hyperintensities (WMHs) are associated with higher anxiety or depression (A/D) incidence. We investigated associations of WMHs with A/D, cerebrovascular reactivity (CVR), and functional connectivity (FC) to identify potential pathomechanisms. METHODS: Participants with WMH (n = 239) and normal controls (NCs, n = 327) were assessed for A/D using the Hamilton Anxiety Rating Scale (HAMA) and Hamilton Depression Rating Scale (HAMD). The CVR and FC maps were constructed from resting-state functional MRI. Two-way analysis of covariance with fixed factors A/D and WMH was performed to identify regional CVR abnormalities. Seed-based FC analyses were then conducted on regions with WMH × A/D interaction effects on CVR. Logistic regression models were constructed to examine the utility of these measurements for identifying WMH-related A/D. RESULTS: Participants with WMH related A/D exhibited significantly greater CVR in left insula and lower CVR in right superior frontal gyrus (SFG.R), and HAMA scores were negatively correlated with CVR in SFG.R (r = -0.156, P = 0.016). Insula-SFG.R negative FC was significantly weaker in WMH patients with suspected or definite A/D. A model including CVR plus FC changes identified WMH-associated A/D with highest sensitivity and specificity. In contrast, NCs with A/D exhibited greater CVR in prefrontal cortex and stronger FC within the default mode network (DMN) and between the DMN and executive control network. LIMITATIONS: This cross-sectional study requires validation by longitudinal and laboratory studies. CONCLUSIONS: Impaired CVR in SFG.R and weaker negative FC between prefrontal cortex and insula may contribute to WMH-related A/D, providing potential diagnostic imaging markers and therapeutic targets.

Stride length and cerebellar regulation: Key features of early gait disorder in cerebral small vessel disease.

OBJECTIVES: Gait disorder (GD) is a common problem in cerebral small vessel disease (CSVD). This study aimed to determine (1) the early characteristics of GD in CSVD, (2) cerebellar neuroimaging features related to GD in CSVD, and (3) the association of cognitive impairment with GD. METHODS: In total, 183 subjects were enrolled in this study: patients with CSVD with normal cognitive function (CSVD-NC) group (64 subjects), patients with CSVD with mild cognitive impairment (CSVD-MCI) group (66 subjects), and a healthy control (HC) group (53 subjects). The GD patterns were evaluated using the ReadyGo three-dimensional motion balance testing system. Meanwhile, we analyzed the cerebrum and cerebellum structurally and functionally. Correlation analyses were conducted among gait indicators, neuroimaging features, and neuropsychological tests. RESULTS: Both the CSVD-NC and CSVD-MCI groups had a reduced stride length, cortical atrophy in the left cerebellum VIIIb, and decreased functional connectivity between the left cerebellum VIIIb and left SFGmed compared with the HC group. In the correlation analysis, the gray matter probability of the left cerebellum VIIIb was closely related to stride length in the HC group. In the CSVD-MCI group, linguistic function, memory, and attention were significantly correlated with gait performance. CONCLUSION: Decreased stride length was the earliest characteristic of GD in CSVD. Structural and functional regulation of the left cerebellum VIIIb could play a particularly important role in early GD in CSVD.

Characteristic patterns of functional connectivity-mediated cerebral small vessel disease-related cognitive impairment and depression.

Cerebral small vessel disease is common in most individuals aged 60 years or older, and it is associated with cognitive dysfunction, depression, anxiety disorder, and mobility problems. Currently, many cerebral small vessel disease patients have both cognitive impairment and depressive symptoms, but the relationship between the 2 is unclear. The present research combined static and dynamic functional network connectivity methods to explore the patterns of functional networks in cerebral small vessel disease individuals with cognitive impairment and depression (cerebral small vessel disease-mild cognitive impairment with depression) and their relationship. We found specific functional network patterns in the cerebral small vessel disease-mild cognitive impairment with depression individuals (P < 0.05). The cerebral small vessel disease individuals with depression exhibited unstable dynamic functional network connectivity states (transitions likelihood: P = 0.040). In addition, we found that the connections within the lateral visual network between the sensorimotor network and ventral attention network could mediate white matter hyperintensity-related cognitive impairment (indirect effect: 0.064; 95% CI: 0.003, 0.170) and depression (indirect effect: -0.415; 95% CI: -1.080, -0.011). Cognitive function can negatively regulate white matter hyperintensity-related depression. These findings elucidate the association between cognitive impairment and depression and provide new insights into the underlying mechanism of cerebral small vessel disease-related cognitive dysfunction and depression.

Functional network connectivity patterns predicting the efficacy of repetitive transcranial magnetic stimulation in the spectrum of Alzheimer's disease.

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.

Magnetic Resonance Imaging Biomarkers of Punding in Parkinson's Disease.

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.

Neuro-Navigated rTMS Improves Sleep and Cognitive Impairment via Regulating Sleep-Related Networks' Spontaneous Activity in AD Spectrum Patients.

Study Objectives: By examining spontaneous activity changes of sleep-related networks in patients with the Alzheimer's disease (AD) spectrum with or without insomnia disorder (ID) over time via neuro-navigated repetitive transcranial magnetic stimulation (rTMS), we revealed the effect and mechanism of rTMS targeting the left-angular gyrus in improving the comorbidity symptoms of the AD spectrum with ID. Methods: A total of 34 AD spectrum patients were recruited in this study, including 18 patients with ID and the remaining 16 patients without ID. All of them were measured for cognitive function and sleep by using the cognitive and sleep subscales of the neuropsychiatric inventory. The amplitude of low-frequency fluctuation changes in sleep-related networks was revealed before and after neuro-navigated rTMS treatment between these two groups, and the behavioral significance was further explored. Results: Affective auditory processing and sensory-motor collaborative sleep-related networks with hypo-spontaneous activity were observed at baseline in the AD spectrum with ID group, while substantial increases in activity were evident at follow-up in these subjects. In addition, longitudinal affective auditory processing, sensory-motor and default mode collaborative sleep-related networks with hyper-spontaneous activity were also revealed at follow-up in the AD spectrum with ID group. In particular, longitudinal changes in sleep-related networks were associated with improvements in sleep quality and episodic memory scores in AD spectrum with ID patients. Conclusion: We speculated that left angular gyrus-navigated rTMS therapy may enhance the memory function of AD spectrum patients by regulating the spontaneous activity of sleep-related networks, and it was associated with memory consolidation in the hippocampus-cortical circuit during sleep. Clinical Trial Registration: The study was registered at the Chinese Clinical Trial Registry, registration ID: ChiCTR2100050496, China.

Altered morphological connectivity mediated white matter hyperintensity-related cognitive impairment.

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.

MiR-431 attenuates synaptic plasticity and memory deficits in APPswe/PS1dE9 mice.

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-ß 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.

Altered static and dynamic functional network connectivity related to cognitive decline in individuals with white matter hyperintensities.

White matter hyperintensities (WMH) of assumed vascular origin are common in elderly individuals and are closely associated with cognitive decline. However, the underlying neural mechanisms of WMH-related cognitive impairment remain unclear. After strict screening, 59 healthy controls (HC, n = 59), 51 patients with WMH and normal cognition (WMH-NC, n = 51) and 68 patients with WMH and mild cognitive impairment (WMH-MCI, n = 68) were included in the final analyses. All individuals underwent multimodal magnetic resonance imaging (MRI) and cognitive evaluations. We investigated the neural mechanism underlying WMH-related cognitive impairment based on static and dynamic functional network connectivity (sFNC and dFNC) approaches. Finally, the support vector machine (SVM) method was performed to identify WMH-MCI individuals. The sFNC analysis indicated that functional connectivity within the visual network (VN) could mediate the impairment of information processing speed related to WMH (indirect effect: 0.24; 95% CI: 0.03, 0.88 and indirect effect: 0.05; 95% CI: 0.001, 0.14). WMH may regulate the dFNC between the higher-order cognitive network and other networks and enhance the dynamic variability between the left frontoparietal network (lFPN) and the VN to compensate for the decline in high-level cognitive functions. The SVM model achieved good prediction ability for WMH-MCI patients based on the above characteristic connectivity patterns. Our findings shed light on the dynamic regulation of brain network resources to maintain cognitive processing in individuals with WMH. Crucially, dynamic reorganization of brain networks could be regarded as a potential neuroimaging biomarker for identifying WMH-related cognitive impairment.

Effects of Combined Intervention of rTMS and Neurotransmitter Drugs on the Brain Functional Networks in Patients with Cognitive Impairment.

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.

Retinal Alterations as Potential Biomarkers of Structural Brain Changes in Alzheimer's Disease Spectrum Patients.

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.

Altered neuroimaging patterns of cerebellum and cognition underlying the gait and balance dysfunction in cerebral small vessel disease.

Background: The 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. Methods: This 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. Results: A 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. Conclusion: The 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.

Multi-networks connectivity at baseline predicts the clinical efficacy of left angular gyrus-navigated rTMS in the spectrum of Alzheimer's disease: A sham-controlled study.

INTRODUCTION: Neuro-navigated repetitive transcranial magnetic stimulation (rTMS) is effective in alleviating cognitive deficits in Alzheimer's disease (AD). However, the strategy for target determination and the mechanisms for cognitive improvement remain unclear. METHODS: One hundred and thirteen elderly subjects were recruited in this study, including both cross-sectional (n = 79) and longitudinal experiments (the rTMS group: n = 24; the sham group: n = 10). The cross-sectional experiment explored the precise intervention target based on the cortical-hippocampal network. The longitudinal experiment investigated the clinical efficacy of neuro-navigated rTMS treatment over a four-week period and explored its underlying neural mechanism using seed-based and network-based analysis. Finally, we applied connectome-based predictive modeling to predict the rTMS response using these functional features at baseline. RESULTS: RTMS at a targeted site of the left angular gyrus (MNI: -45, -67, 38) significantly induced cognitive improvement in memory and language function (p < 0.001). The improved cognition correlated with the default mode network (DMN) subsystems. Furthermore, the connectivity patterns of DMN subsystems (r = 0.52, p = 0.01) or large-scale networks (r = 0.85, p = 0.001) at baseline significantly predicted the Δ language cognition after the rTMS treatment. The connectivity patterns of DMN subsystems (r = 0.47, p = 0.019) or large-scale networks (r = 0.80, p = 0.001) at baseline could predict the Δ memory cognition after the rTMS treatment. CONCLUSION: These findings suggest that neuro-navigated rTMS targeting the left angular gyrus could improve cognitive function in AD patients. Importantly, dynamic regulation of the intra- and inter-DMN at baseline may represent a potential predictor for favorable rTMS treatment response in patients with cognitive impairment.

Subsystem mechanisms of default mode network underlying white matter hyperintensity-related cognitive impairment.

Functional changes of default mode network (DMN) have been proven to be closely associated with white matter hyperintensity (WMH) related cognitive impairment (CI). However, subsystem mechanisms of DMN underlying WMH-related CI remain unclear. The present study recruited WMH patients (n = 206) with mild CI and normal cognition, as well as healthy controls (HC, n = 102). Static/dynamic functional connectivity (FC) of the DMN's three subsystems were calculated using resting-state functional MRI. K-means clustering analyses were performed to extract distinct dynamic connectivity states. Compared with the WMH-NC group, the WMH-MCI group displayed lower static FC within medial temporal lobe (MTL) and core subsystem, between core-MTL subsystem, as well as between core and dorsal medial prefrontal cortex subsystem. All these static alterations were positively associated with information processing speed (IPS). Regarding dynamic FC, the WMH-MCI group exhibited higher dynamic FC within MTL subsystem than the HC and WMH-NC groups. Altered dynamic FC within MTL subsystem mediated the relationship between WMH and memory span (indirect effect: -0.2251, 95% confidence interval [-0.6295, -0.0267]). Additionally, dynamic FCs of DMN subsystems could be clustered into two recurring states. For dynamic FCs within MTL subsystem, WMH-MCI subjects exhibited longer mean dwell time (MDT) and higher reoccurrence fraction (RF) in a sparsely connected state (State 2). Altered MDT and RF in State 2 were negatively associated with IPS. Taken together, these findings indicated static/dynamic FC of DMN subsystems can provide relevant information on cognitive decline from different aspects, which provides a comprehensive view of subsystem mechanisms of DMN underlying WMH-related CI.

Applying Retinal Vascular Structures Characteristics Coupling with Cortical Visual System in Alzheimer's Disease Spectrum Patients.

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.

Distinct reserve capacity impacts on default-mode network in response to left angular gyrus-navigated repetitive transcranial magnetic stimulation in the prodromal Alzheimer disease.

Default-mode network (DMN) may be the earliest affected network and is associated with cognitive decline in Alzheimer's disease (AD). Repetitive transcranial magnetic stimulation (rTMS) may help to modulate DMN plasticity. Still, stimulation effects substantially vary across studies and individuals. Global left frontal cortex (gLFC) connectivity, a substitute for reserve capacity, may contribute to the heterogeneous physiological effects of neuro-navigated rTMS. This study investigated the effects of left angular gyrus-navigated rTMS on DMN connectivity in different reserve capacity participants. gLFC connectivity, was computed through resting-state fMRI correlations. Thirty-one prodromal AD patients were divided into low connection group (LCG) and high connection group (HCG) by the median of gLFC connectivity. Distinct reserve capacity impacts on DMN in response to rTMS were identified in these two groups. Then, brain-behavior relationships were examined. gLFC connectivity within a certain range is directly proportional to cognitive reserve ability (i.e., LCG), and the effectiveness of functional connectivity beyond this range decreases (i.e, HCG). Moreover, LCG exhibited increased DMN connectivity and significantly positive memory improvements, while HCG showed a contrary connectivity decline and maintained or slightly improved their cognitive function after neuro-navigated rTMS treatment. The prodromal AD patients with the distinct reserve capacity may benefit differently from left angular gyrus-navigated rTMS, which may lead to increasing attention in defining personalized medicine approach of AD.

Macrophage-mediated delivery of magnetic nanoparticles for enhanced magnetic resonance imaging and magnetothermal therapy of solid tumors.

Magnetothermal therapy (MHT) has attracted significant attention due to the advantages of non-/minimal invasiveness, high efficiency, and excellent tissue penetration. However, developing small MHT agents (<50 nm) with excellent magnetothermal conversion performance and high tumor enrichment is a great challenge. Herein, a macrophage-mediated delivery of small Fe@Fe3O4-DHCA nanoparticles (∼14 nm) was designed for enhanced magnetic resonance imaging (MRI) and MHT of solid tumors. Based on the "Trojan horse" loading properties of the macrophages (RAW267.4 cells), the aggregation of Fe@Fe3O4-DHCA nanoparticles in the cells results in an enhanced MRI and magnetothermal performance in vitro. In addition, the MHT effect of RAW267.4 loaded with Fe@Fe3O4-DHCA in vivo is better than that of Fe@Fe3O4-DHCA alone, due to the tumor-targeting performance of RAW267.4 cells. This macrophage-mediated delivery provides a new strategy for the enhanced treatment effect of MHT based on Fe@Fe3O4-DHCA nanoparticles, and has great application potential for clinic tumor therapy.

Glymphatic Dysfunction Mediates the Influence of White Matter Hyperintensities on Episodic Memory in Cerebral Small Vessel Disease.

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.

Sn species modified mesoporous zeolite TS-1 with oxygen vacancy for enzyme-free electrochemical H2O2 detecting.

Sn species modified zeolite TS-1 with a unique mesopore structure (Sn-TS-1) and rich oxygen vacancy defects has been designed via a sol-gel method and an ion-exchange process, which can be used as an enzyme-free electrochemical sensor for H2O2 detection. The resultant composite Sn-TS-1 has a high BET surface area of 191 cm2 g-1, fast electron transfer, rich oxygen vacancies, and abundant active sites, showing super performance in H2O2 reduction with a low detection limit (0.27 µM, S/N = 3). The current is linear with H2O2 concentration from 1 to 1000 and 1000 to 11 000 µM, and the corresponding sensitivities are 360.4 and 80.44 µA mM-1 cm-1, respectively. More importantly, this Sn-TS-1 sensor also shows excellent anti-interference ability and stability. This work provides a new idea for an enzyme-free sensor for H2O2 detection in biological environments, which has promising potential in point-of-care (POC) testing for H2O2.