Convergent Neuroimaging and Molecular Signatures in Mild Cognitive Impairment and Alzheimer's Disease: A Data-Driven Meta-Analysis with N = 3,118.

The current study aimed to evaluate the susceptibility to regional brain atrophy and its biological mechanism in Alzheimer's disease (AD). We conducted data-driven meta-analyses to combine 3,118 structural magnetic resonance images from three datasets to obtain robust atrophy patterns. Then we introduced a set of radiogenomic analyses to investigate the biological basis of the atrophy patterns in AD. Our results showed that the hippocampus and amygdala exhibit the most severe atrophy, followed by the temporal, frontal, and occipital lobes in mild cognitive impairment (MCI) and AD. The extent of atrophy in MCI was less severe than that in AD. A series of biological processes related to the glutamate signaling pathway, cellular stress response, and synapse structure and function were investigated through gene set enrichment analysis. Our study contributes to understanding the manifestations of atrophy and a deeper understanding of the pathophysiological processes that contribute to atrophy, providing new insight for further clinical research on AD.

The efficacy of coaxial percutaneous iodine-125 seed implantation combined with arterial infusion chemotherapy for advanced pancreatic cancer: a randomized clinical trial.

BACKGROUND: This study aimed to evaluate the clinical efficacy of coaxial percutaneous Iodine-125 (125I) seed implantation in combination with arterial infusion chemotherapy for the treatment of advanced pancreatic cancer (PC) through a randomized controlled trial. METHODS: A total of 101 patients with advanced PC were randomized into two groups: control group treated with systemic intravenous chemotherapy and experimental group that received 125I seed implantation in combination with arterial infusion chemotherapy. Outcomes, including tumor control, abdominal pain relief, and survival time were compared between these two groups (Trial Registration No. KYKT2018-65). RESULTS: Pretreatment abdominal pain scores were comparable between the two groups, whereas the abdominal pain scores at 1- and 3-month post-treatment were significantly lower in the control group than those in the experimental group (1-month: 3.74 ± 1.54 vs. 4.48 ± 1.46, p = .015; 3-month: 3.64 ± 2.21 vs. 5.40 ± 1.56, p < .001). At 3-month post-treatment, computed tomography (CT) scan revealed a significantly higher disease control rate in the experimental group than that in the control group (94.0% vs. 74.5%, p = .007). The median survival time in the experimental group was significantly longer than that in the control group (15-month vs. 9-month, p < .001). CONCLUSION: The combination of coaxial percutaneous 125I seed implantation with arterial infusion chemotherapy could significantly alleviate abdominal pain, improve tumor control rates, and prolong survival time in patients with advanced PC.

A neuroimaging biomarker for Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN): a cross-sectional study.

Background: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that poses a worldwide public health challenge. A neuroimaging biomarker would significantly improve early diagnosis and intervention, ultimately enhancing the quality of life for affected individuals and reducing the burden on healthcare systems. Methods: Cross-sectional and longitudinal data (10,099 participants with 13,380 scans) from 12 independent datasets were used in the present study (this study was performed between September 1, 2021 and February 15, 2023). The Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN) score was developed via integrated regional- and network-based measures under an ensemble machine learning model based on structural MRI data. We systematically assessed whether IBRAIN could be a neuroimaging biomarker for AD. Findings: IBRAIN accurately differentiated individuals with AD from NCs (AUC = 0.92) and other neurodegenerative diseases, including Frontotemporal dementia (FTD), Parkinson's disease (PD), Vascular dementia (VaD) and Amyotrophic Lateral Sclerosis (ALS) (AUC = 0.92). IBRAIN was significantly correlated to clinical measures and gene expression, enriched in immune process and protein metabolism. The IBRAIN score exhibited a significant ability to reveal the distinct progression of prodromal AD (i.e., Mild cognitive impairment, MCI) (Hazard Ratio (HR) = 6.52 [95% CI: 4.42∼9.62], p < 1 × 10-16), which offers similar powerful performance with Cerebrospinal Fluid (CSF) Aß (HR = 3.78 [95% CI: 2.63∼5.43], p = 2.13 × 10-14) and CSF Tau (HR = 3.77 [95% CI: 2.64∼5.39], p = 9.53 × 10-15) based on the COX and Log-rank test. Notably, the IBRAIN shows comparable sensitivity (beta = -0.70, p < 1 × 10-16) in capturing longitudinal changes in individuals with conversion to AD than CSF Aß (beta = -0.26, p = 4.40 × 10-9) and CSF Tau (beta = 0.12, p = 1.02 × 10-5). Interpretation: Our findings suggested that IBRAIN is a biologically relevant, specific, and sensitive neuroimaging biomarker that can serve as a clinical measure to uncover prodromal AD progression. It has strong potential for application in future clinical practice and treatment trials. Funding: Science and Technology Innovation 2030 Major Projects, the National Natural Science Foundation of China, Beijing Natural Science Funds, the Fundamental Research Funds for the CentralUniversity, and the Startup Funds for Talents at Beijing Normal University.

Radioactive 125I Seed Inhibits Cell Migration and Invasion and Promotes Apoptosis by Inactivating the VEGFR2 Signaling Pathway in Cholangiocarcinoma.

Objectives: To investigate the potential mechanisms of 125I seed implantation therapeutic treatment on inactivating the VEGFR2/PI3K/AKT pathway in cholangiocarcinoma. Methods: The human cholangiocarcinoma cell lines HCCC-9810 and HuCCT1 were purchased for in vitro studies. The BALB/c nude mice were obtained for in vivo studies. The proliferation of cells was detected by CCK-8, colony formation, and BrdU staining. The migration and invasion of cells were determined by wound healing assay and Transwell assay, respectively. Hematoxylin and eosin staining was utilized for histological evaluation. Protein expression was determined by western blotting and immunohistochemistry. Results: Compared with the control group, .6 mCi group and .8 mCi group inhibited cholangiocarcinoma cells proliferation, invasion, migration, and promoted apoptosis, the protein expression of p-VEGFR2, VEGFR2, PI3K, p-AKT/AKT, cyclin B1, cyclin A, CDK1, and Bcl-2 was decreased. Similar results were obtained from in vitro experiments. However, when VEGF is overexpressed, the inhibitory effect of .8 mCi was partially significantly reversed on cholangiocarcinoma cells. The in vivo studies further confirmed the inhibitory effects of .6 mCi group and .8 mCi group on cholangiocarcinoma. Conclusion: 125I seed irradiation could inhibit cholangiocarcinoma cells proliferation, migration, and invasion and promote apoptosis through inactivation of the VEGFR2/PI3K/AKT signaling pathway.

Reproducible Abnormalities and Diagnostic Generalizability of White Matter in Alzheimer's Disease.

Alzheimer's disease (AD) is associated with the impairment of white matter (WM) tracts. The current study aimed to verify the utility of WM as the neuroimaging marker of AD with multisite diffusion tensor imaging datasets [321 patients with AD, 265 patients with mild cognitive impairment (MCI), 279 normal controls (NC)], a unified pipeline, and independent site cross-validation. Automated fiber quantification was used to extract diffusion profiles along tracts. Random-effects meta-analyses showed a reproducible degeneration pattern in which fractional anisotropy significantly decreased in the AD and MCI groups compared with NC. Machine learning models using tract-based features showed good generalizability among independent site cross-validation. The diffusion metrics of the altered regions and the AD probability predicted by the models were highly correlated with cognitive ability in the AD and MCI groups. We highlighted the reproducibility and generalizability of the degeneration pattern of WM tracts in AD.

Altered large-scale dynamic connectivity patterns in Alzheimer's disease and mild cognitive impairment patients: A machine learning study.

Alzheimer's disease (AD) is a common neurodegeneration disease associated with substantial disruptions in the brain network. However, most studies investigated static resting-state functional connections, while the alteration of dynamic functional connectivity in AD remains largely unknown. This study used group independent component analysis and the sliding-window method to estimate the subject-specific dynamic connectivity states in 1704 individuals from three data sets. Informative inherent states were identified by the multivariate pattern classification method, and classifiers were built to distinguish ADs from normal controls (NCs) and to classify mild cognitive impairment (MCI) patients with informative inherent states similar to ADs or not. In addition, MCI subgroups with heterogeneous functional states were examined in the context of different cognition decline trajectories. Five informative states were identified by feature selection, mainly involving functional connectivity belonging to the default mode network and working memory network. The classifiers discriminating AD and NC achieved the mean area under the receiver operating characteristic curve of 0.87 with leave-one-site-out cross-validation. Alterations in connectivity strength, fluctuation, and inter-synchronization were found in AD and MCIs. Moreover, individuals with MCI were clustered into two subgroups, which had different degrees of atrophy and different trajectories of cognition decline progression. The present study uncovered the alteration of dynamic functional connectivity in AD and highlighted that the dynamic states could be powerful features to discriminate patients from NCs. Furthermore, it demonstrated that these states help to identify MCIs with faster cognition decline and might contribute to the early prevention of AD.

Altered global signal topography in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease associated with widespread disruptions in intrinsic local specialization and global integration in the functional system of the brain. These changes in integration may further disrupt the global signal (GS) distribution, which might represent the local relative contribution to global activity in functional magnetic resonance imaging (fMRI). METHODS: fMRI scans from a discovery dataset (n = 809) and a validated dataset (n = 542) were used in the analysis. We investigated the alteration of GS topography using the GS correlation (GSCORR) in patients with mild cognitive impairment (MCI) and AD. The association between GS alterations and functional network properties was also investigated based on network theory. The underlying mechanism of GSCORR alterations was elucidated using imaging-transcriptomics. FINDINGS: Significantly increased GS topography in the frontal lobe and decreased GS topography in the hippocampus, cingulate gyrus, caudate, and middle temporal gyrus were observed in patients with AD (Padj < 0.05). Notably, topographical GS changes in these regions correlated with cognitive ability (P < 0.05). The changes in GS topography also correlated with the changes in functional network segregation (ρ = 0.5). Moreover, the genes identified based on GS topographical changes were enriched in pathways associated with AD and neurodegenerative diseases. INTERPRETATION: Our findings revealed significant changes in GS topography and its molecular basis, confirming the informative role of GS in AD and further contributing to the understanding of the relationship between global and local neuronal activities in patients with AD. FUNDING: Beijing Natural Science Funds for Distinguished Young Scholars, China; Fundamental Research Funds for the Central Universities, China; National Natural Science Foundation, China.

Four Distinct Subtypes of Alzheimer's Disease Based on Resting-State Connectivity Biomarkers.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder with significant heterogeneity. Different AD phenotypes may be associated with specific brain network changes. Uncovering disease heterogeneity by using functional networks could provide insights into precise diagnoses. METHODS: We investigated the subtypes of AD using nonnegative matrix factorization clustering on the previously identified 216 resting-state functional connectivities that differed between AD and normal control subjects. We conducted the analysis using a discovery dataset (n = 809) and a validated dataset (n = 291). Next, we grouped individuals with mild cognitive impairment according to the model obtained in the AD groups. Finally, the clinical measures and brain structural characteristics were compared among the subtypes to assess their relationship with differences in the functional network. RESULTS: Individuals with AD were clustered into 4 subtypes reproducibly, which included those with 1) diffuse and mild functional connectivity disruption (subtype 1), 2) predominantly decreased connectivity in the default mode network accompanied by an increase in the prefrontal circuit (subtype 2), 3) predominantly decreased connectivity in the anterior cingulate cortex accompanied by an increase in prefrontal cortex connectivity (subtype 3), and 4) predominantly decreased connectivity in the basal ganglia accompanied by an increase in prefrontal cortex connectivity (subtype 4). In addition to these differences in functional connectivity, differences between the AD subtypes were found in cognition, structural measures, and cognitive decline patterns. CONCLUSIONS: These comprehensive results offer new insights that may advance precision medicine for AD and facilitate strategies for future clinical trials.

Is technetium-99m dimercaptosuccinic acid renal scintigraphy available for predicting vesicoureteral reflux in children with first febrile urinary tract infection under the age of 24 months?

OBJECTIVE: Vesicoureteral reflux (VUR) is a common complication after urinary tract infection (UTI) and can lead to irreversible renal scar. Voiding cystourethrogram is the most reliable technology to detect VUR and its severity, but it is restricted in children's examinations for various shortcomings. This study aimed to evaluate and compare the efficiency of Tc-99m DMSA renal scintigraphy and conventional ultrasonography (USG) in predicting VUR with the gold standard of cystourethrogram results. METHODS: This retrospective study consisted of 285 first febrile UTI children under the age of 24 months who completed inflammatory indicator examinations, USG, Tc-99m DMSA renal scintigraphy and underwent cystourethrography after controlling infection with prophylactic antibiotics. The efficiency of Tc-99m DMSA renal scintigraphy and USG in predicting VUR was calculated and compared. RESULTS: Abnormal USG (40.23% vs. 21.72%, P = 0.001) and Tc-99m DMSA renal scintigraphy results (87.36% vs. 71.72%, P = 0.004) were more common in VUR children. The sensitivity of USG in predicting VUR was only 40.23%, whereas the sensitivity and negative predictive value of Tc-99m DMSA renal scintigraphy reached 87.63 and 83.58%, respectively. Tc-99m DMSA renal scintigraphy had a higher efficacy than USG in predicting high-grade reflux kidneys (73.87% vs. 33.33%; P < 0.001), but there was no significant difference in predicting low-grade reflux kidneys ( P = 0.703). CONCLUSION: Tc-99m DMSA renal scintigraphy had a significant higher efficiency in predicting VUR (a common cause of renal scarring, detected on DMSA) in first febrile urinary tract infection children under the age of 24 months as compared with USG, especially in high-grade reflux.

The efficacy and safety of biliary stenting alone versus stenting combined with iodine-125 seed strand implantation for the treatment of cholangiocarcinoma with malignant obstructive jaundice: a prospective, nonrandomized, controlled clinical study.

BACKGROUND: Many patients with cholangiocarcinoma also present with malignant obstructive jaundice (MOJ), which requires biliary drainage and stent placement. Recently, clinicians have tried to implant iodine-125 seeds into the biliary tract. However, we know very little about this treatment. This study aimed to compare biliary stenting alone and stenting combined with iodine-125 seed strand implantation to evaluate the safety and efficacy of this technique. METHODS: Sixty patients of cholangiocarcinoma with MOJ were enrolled into the study. According to voluntary choices, 30 received biliary stenting combined with iodine-125 seed strand implantation (study group), and 30 received biliary stent implantation alone (control group). Various biochemical indicators and the manifestation of computed tomography (CT) or magnetic resonance imaging (MRI) were compared before and after operation. We evaluated the safety and efficacy of these treatments by observing patients' symptoms, biochemical indicators and imaging data. Individualized antitumor therapy and regular follow-up were given according to the patients' condition. RESULTS: All 60 patients successfully completed operation. There were no statistically significant differences in baseline data between two groups (P>0.05). Before and 4 weeks after operation, the average total bilirubin levels decreased from 268.14±114.97 to 54.00±80.78 µmol/L in study group, and decreased from 228.89±162.04 to 58.80±61.14 µmol/L in control group. The difference between two groups was not statistically significant (P=0.796). Before and 4 weeks after operation, the average Child-Pugh scores decreased from 7.83±0.59 to 6.20±1.03 points in study group, and decreased from 7.93±1.08 to 7.07±1.39 points in control group, with a statistically significant difference between two groups (P=0.008). The median patency time of stents was 41.71±3.46 weeks in study group and 29.00±5.81 weeks in control group, with a statistically significant difference between the two groups (P=0.037). A statistically significant difference in disease control rate (DCR) was observed between the two groups (P=0.045). CONCLUSIONS: This study demonstrated biliary stenting combined with iodine-125 seed strand implantation may be consider as a safe treatment option for the patients of cholangiocarcinoma with MOJ, and this treatment may improve liver function, reduce the incidence of in-stent restenosis, and improve DCR.

Structural and functional connectivity abnormalities of the default mode network in patients with Alzheimer's disease and mild cognitive impairment within two independent datasets.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive dementia, and amnestic mild cognitive impairment (aMCI) has been defined as a transitional stage between normal aging and AD. Accumulating evidence has shown that altered functional connectivity (FC) and structural connectivity (SC) in the default mode network (DMN) is the prominent hallmarks of AD. However, the relationship between the changes in SC and FC of the DMN is not yet clear. In the present study, we derived the FC and SC matrices of the DMN with functional magnetic resonance imaging (fMRI) and diffusion-weighted imaging (DWI) data and further assessed FC and SC abnormalities within a discovery dataset of 120 participants (39 normal controls, 34 patients with aMCI and 47 patients with AD), as well as a replication dataset of 122 participants (43 normal controls, 37 patients with aMCI and 42 patients with AD). Disrupted SC and FC were found among DMN components (e.g., the posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC), and hippocampus) in patients in the aMCI and AD groups in the discovery dataset; most of the disrupted connections were also identified in the replication dataset. More importantly, some SC and FC elements were significantly correlated with the cognitive ability of patients with aMCI and AD. In addition, we found structural-functional decoupling between the PCC and the right hippocampus in patients in the aMCI and AD groups. These findings of the alteration of DMN connectivity in neurodegenerative cohorts deepen our understanding of the pathophysiological mechanisms of AD.

Abnormal characterization of dynamic functional connectivity in Alzheimer's disease.

Numerous studies have shown abnormal brain functional connectivity in individuals with Alzheimer's disease (AD) or amnestic mild cognitive impairment (aMCI). However, most studies examined traditional resting state functional connections, ignoring the instantaneous connection mode of the whole brain. In this case-control study, we used a new method called dynamic functional connectivity (DFC) to look for abnormalities in patients with AD and aMCI. We calculated dynamic functional connectivity strength from functional magnetic resonance imaging data for each participant, and then used a support vector machine to classify AD patients and normal controls. Finally, we highlighted brain regions and brain networks that made the largest contributions to the classification. We found differences in dynamic function connectivity strength in the left precuneus, default mode network, and dorsal attention network among normal controls, aMCI patients, and AD patients. These abnormalities are potential imaging markers for the early diagnosis of AD.

Global Hotspots and Prospects of I-131 Therapy in Thyroid Carcinoma via Bibliometric Analysis.

BACKGROUND: Hundreds of studies have reported the application of iodine-131 (I-131) in thyroid carcinoma (THCA) in past years. However, the status of research in the field and other related topics have not been investigated. This study aimed to identify the cooperation of authors, countries, and institutions, as well as explore the hot topics and prospects regarding I-131 therapy in THCA based on previous studies. METHODS: Publications from 2010 to 2020 were retrieved from Web of Science Core Collection according to research strategy. Bibliometric analyses were performed using VOSviewer 1.6.15 and CiteSpace 5.7.3 to evaluate and visualize the cooperation network, hot topic, and research frontier. RESULTS: The number of publications showed a trend of fluctuation between 2010 and 2020. We identified 1387 publications related to I-131 therapy in THCA, which were published by 1628 institutions from 82 countries. The largest proportion of publications were emanated from the USA, and the majority of papers were published by Thyroid. Shanghai Jiao Tong University of China contributed the most papers. Although many authors participated in the research of this field, high-yield authors were few. Co-occurrence analysis classified keywords into five clusters, including assessment, efficacy measurement, monitoring, hormone regulation, and guidelines of I-131 therapy. The terms "bone marrow dosimetry and time" were among the latest hotspots. The research frontier topic in I-131 therapy focused on the "P53 and anti-Müllerian hormone". CONCLUSION: The attention to I-131 therapy in THCA should be increased considerably. It was necessary to construct active co-operations between authors, countries, and institutions to promote the development of this field. Recent researches referred to the timing and dose assessment of I-131 therapy in THCA. Future studies likely focused on targeted therapy and adverse effects evaluation were worthy of research as well.

Altered Volume and Structural Connectivity of the Hippocampus in Alzheimer's Disease and Amnestic Mild Cognitive Impairment.

Background: Hippocampal atrophy is a characteristic of Alzheimer's disease (AD). However, alterations in structural connectivity (number of connecting fibers) between the hippocampus and whole brain regions due to hippocampal atrophy remain largely unknown in AD and its prodromal stage, amnestic mild cognitive impairment (aMCI). Methods: We collected high-resolution structural MRI (sMRI) and diffusion tensor imaging (DTI) data from 36 AD patients, 30 aMCI patients, and 41 normal control (NC) subjects. First, the volume and structural connectivity of the bilateral hippocampi were compared among the three groups. Second, correlations between volume and structural connectivity in the ipsilateral hippocampus were further analyzed. Finally, classification ability by hippocampal volume, its structural connectivity, and their combination were evaluated. Results: Although the volume and structural connectivity of the bilateral hippocampi were decreased in patients with AD and aMCI, only hippocampal volume correlated with neuropsychological test scores. However, positive correlations between hippocampal volume and ipsilateral structural connectivity were displayed in patients with AD and aMCI. Furthermore, classification accuracy (ACC) was higher in AD vs. aMCI and aMCI vs. NC by the combination of hippocampal volume and structural connectivity than by a single parameter. The highest values of the area under the receiver operating characteristic (ROC) curve (AUC) in every two groups were all obtained by combining hippocampal volume and structural connectivity. Conclusions: Our results showed that the combination of hippocampal volume and structural connectivity (number of connecting fibers) is a new perspective for the discrimination of AD and aMCI.

Generalizable, Reproducible, and Neuroscientifically Interpretable Imaging Biomarkers for Alzheimer's Disease.

Precision medicine for Alzheimer's disease (AD) necessitates the development of personalized, reproducible, and neuroscientifically interpretable biomarkers, yet despite remarkable advances, few such biomarkers are available. Also, a comprehensive evaluation of the neurobiological basis and generalizability of the end-to-end machine learning system should be given the highest priority. For this reason, a deep learning model (3D attention network, 3DAN) that can simultaneously capture candidate imaging biomarkers with an attention mechanism module and advance the diagnosis of AD based on structural magnetic resonance imaging is proposed. The generalizability and reproducibility are evaluated using cross-validation on in-house, multicenter (n = 716), and public (n = 1116) databases with an accuracy up to 92%. Significant associations between the classification output and clinical characteristics of AD and mild cognitive impairment (MCI, a middle stage of dementia) groups provide solid neurobiological support for the 3DAN model. The effectiveness of the 3DAN model is further validated by its good performance in predicting the MCI subjects who progress to AD with an accuracy of 72%. Collectively, the findings highlight the potential for structural brain imaging to provide a generalizable, and neuroscientifically interpretable imaging biomarker that can support clinicians in the early diagnosis of AD.

Characterizing white matter connectivity in Alzheimer's disease and mild cognitive impairment: An automated fiber quantification analysis with two independent datasets.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive dementia. Diffusion tensor imaging (DTI) has been widely used to show structural integrity and delineate white matter (WM) degeneration in AD. The automated fiber quantification (AFQ) method is a fully automated approach that can rapidly and reliably identify major WM fiber tracts and evaluate WM properties. The main aim of this study was to assess WM integrity and abnormities in a cohort of patients with amnestic mild cognitive impairment (aMCI) and AD as well as normal controls (NCs). For this purpose, we first used AFQ to identify 20 major WM tracts and assessed WM integrity and abnormalities in a cohort of 120 subjects (39 NCs, 34 aMCI patients and 47 AD patients) in a discovery dataset and 122 subjects (43 NCs, 37 aMCI patients and 42 AD patients) in a replicated dataset. Pointwise differences along WM tracts were identified in the discovery dataset and simultaneously confirmed in the replicated dataset. Next, we investigated the utility of DTI measures along WM tracts as features to distinguish patients with AD from NCs via multilevel cross validation using a support vector machine. Correlation analysis revealed the identified microstructural WM alterations and classification output to be highly associated with cognitive ability in the patient groups, suggesting that they may be a robust biomarker of AD. This systematic study provides a pipeline to examine WM integrity and its potential clinical application in AD and may be useful for studying other neurological and psychiatric disorders.

Grab-AD: Generalizability and reproducibility of altered brain activity and diagnostic classification in Alzheimer's Disease.

Alzheimer's disease (AD) is associated with disruptions in brain activity and networks. However, there is substantial inconsistency among studies that have investigated functional brain alterations in AD; such contradictions have hindered efforts to elucidate the core disease mechanisms. In this study, we aim to comprehensively characterize AD-associated functional brain alterations using one of the world's largest resting-state functional MRI (fMRI) biobank for the disorder. The biobank includes fMRI data from six neuroimaging centers, with a total of 252 AD patients, 221 mild cognitive impairment (MCI) patients and 215 healthy comparison individuals. Meta-analytic techniques were used to unveil reliable differences in brain function among the three groups. Relative to the healthy comparison group, AD was associated with significantly reduced functional connectivity and local activity in the default-mode network, basal ganglia and cingulate gyrus, along with increased connectivity or local activity in the prefrontal lobe and hippocampus (p < .05, Bonferroni corrected). Moreover, these functional alterations were significantly correlated with the degree of cognitive impairment (AD and MCI groups) and amyloid-ß burden. Machine learning models were trained to recognize key fMRI features to predict individual diagnostic status and clinical score. Leave-one-site-out cross-validation established that diagnostic status (mean area under the receiver operating characteristic curve: 0.85) and clinical score (mean correlation coefficient between predicted and actual Mini-Mental State Examination scores: 0.56, p < .0001) could be predicted with high accuracy. Collectively, our findings highlight the potential for a reproducible and generalizable functional brain imaging biomarker to aid the early diagnosis of AD and track its progression.

Aberrant Hippocampal Functional Connectivity Is Associated with Fornix White Matter Integrity in Alzheimer's Disease and Mild Cognitive Impairment.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in older individuals, and amnestic mild cognitive impairment (aMCI) is currently considered the prodromal stage of AD. The hippocampus and fornix interact functionally and structurally, with the fornix being the major efferent white matter tract from the hippocampus. OBJECTIVE: The main aim of this study was to examine the impairments present in subjects with AD or aMCI and the relationship of these impairments with the microstructure of the fornix and the functional connectivity (FC) and gray matter volume of the hippocampus. METHODS: Forty-four AD, 34 aMCI, and 41 age- and gender-matched normal controls (NCs) underwent neuropsychological assessments and multimode MRI. We chose the bilateral hippocampi as the region of interest in which gray matter alterations and FC with the whole brain were assessed and the fornix body as the region of interest in which the microstructural integrity of the white matter was observed. We also evaluated the relationship among gray matter alterations, the abnormal FC of the hippocampus and the integrity of the fornix in AD/aMCIResults:Compared to the NC group, the AD and aMCI groups demonstrated decreased gray matter volume, reduced FC between the bilateral hippocampi and several brain regions in the default mode network and control network, and damaged integrity of the fornix body (decreased fractional anisotropy and increased diffusivity). We also found that left hippocampal FC with some regions, the integrity of the fornix body, and cognition ability were significantly correlated. Therefore, our findings suggest that damage to white matter integrity may partially explain the reduced resting-state FC of the hippocampus in AD and aMCI. CONCLUSION: AD and aMCI are diseases of disconnectivity including not only functional but also structural disconnectivity. Damage to white matter integrity may partially explain the reduced resting-state FC in AD and aMCI. These findings have significant implications for diagnostics and modeling and provide insights for understanding the disconnection syndrome in AD.

Independent and reproducible hippocampal radiomic biomarkers for multisite Alzheimer's disease: diagnosis, longitudinal progress and biological basis.

Hippocampal morphological change is one of the main hallmarks of Alzheimer's disease (AD). However, whether hippocampal radiomic features are robust as predictors of progression from mild cognitive impairment (MCI) to AD dementia and whether these features provide any neurobiological foundation remains unclear. The primary aim of this study was to verify whether hippocampal radiomic features can serve as robust magnetic resonance imaging (MRI) markers for AD. Multivariate classifier-based support vector machine (SVM) analysis provided individual-level predictions for distinguishing AD patients (n = 261) from normal controls (NCs; n = 231) with an accuracy of 88.21% and intersite cross-validation. Further analyses of a large, independent the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (n = 1228) reinforced these findings. In MCI groups, a systemic analysis demonstrated that the identified features were significantly associated with clinical features (e.g., apolipoprotein E (APOE) genotype, polygenic risk scores, cerebrospinal fluid (CSF) Aß, CSF Tau), and longitudinal changes in cognition ability; more importantly, the radiomic features had a consistently altered pattern with changes in the MMSE scores over 5 years of follow-up. These comprehensive results suggest that hippocampal radiomic features can serve as robust biomarkers for clinical application in AD/MCI, and further provide evidence for predicting whether an MCI subject would convert to AD based on the radiomics of the hippocampus. The results of this study are expected to have a substantial impact on the early diagnosis of AD/MCI.

ASAF: altered spontaneous activity fingerprinting in Alzheimer's disease based on multisite fMRI.

Several monocentric studies have noted alterations in spontaneous brain activity in Alzheimer's disease (AD), although there is no consensus on the altered amplitude of low-frequency fluctuations in AD patients. The main aim of the present study was to identify a reliable and reproducible abnormal brain activity pattern in AD. The amplitude of local brain activity (AM), which can provide fast mapping of spontaneous brain activity across the whole brain, was evaluated based on multisite rs-fMRI data for 688 subjects (215 normal controls (NCs), 221 amnestic mild cognitive impairment (aMCI) 252 AD). Two-sample t-tests were used to detect group differences between AD patients and NCs from the same site. Differences in the AM maps were statistically analyzed via the Stouffer's meta-analysis. Consistent regions of lower spontaneous brain activity in the default mode network and increased activity in the bilateral hippocampus/parahippocampus, thalamus, caudate nucleus, orbital part of the middle frontal gyrus and left fusiform were observed in the AD patients compared with those in NCs. Significant correlations (P < 0.05, Bonferroni corrected) between the normalized amplitude index and Mini-Mental State Examination scores were found in the identified brain regions, which indicates that the altered brain activity was associated with cognitive decline in the patients. Multivariate analysis and leave-one-site-out cross-validation led to a 78.49% prediction accuracy for single-patient classification. The altered activity patterns of the identified brain regions were largely correlated with the FDG-PET results from another independent study. These results emphasized the impaired brain activity to provide a robust and reproducible imaging signature of AD.