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Convergent Neuroimaging and Molecular signatures in Mild Cognitive Impairment and alzheimer’s disease:A Data-Driven Meta-Analysis with N=3,118

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Neuroscience Bulletin 2024年第9期40卷 1274-1286页

作者： Xiaopeng Kang Dawei Wang Jiaji Lin Hongxiang Yao Kun Zhao Chengyuan song Pindong Chen Yida Qu Hongwei Yang Zengqiang Zhang Bo Zhou Tong Han Zhengluan Liao Yan Chen Jie Lu Chunshui Yu Pan Wang Xinqing Zhang Ming Li Xi Zhang Tianzi Jiang Yuying Zhou Bing Liu Ying Han Yong Liu The alzheimer’s disease Neuroimaging Initiative The multi-center alzheimer’s disease Imaging(MCADI)Consortium school of Artificial Intelligence University of Chinese Academy of SciencesBeijing100049China Brainnetome center and National Laboratory of Pattern Recognition Institute of AutomationChinese Academy of SciencesBeijing100190China Department of Radiology Qilu Hospital of Shandong UniversityJi’nan250063China Department of Neurology the Second Affiliated Hospital of Air Force Medical UniversityXi’an710032China Department of Radiology Chinese PLA General HospitalBeijing100853China Department of Radiology the Second Medical CentreNational Clinical Research Centre for Geriatric DiseasesChinese PLA General HospitalBeijing100853China school of Artificial Intelligence Beijing University of Posts and TelecommunicationsBeijing100191China Department of Neurology Qilu Hospital of Shandong UniversityJi’nan250063China Department of Radiology Xuanwu Hospital of Capital Medical UniversityBeijing100053China Branch of Chinese PLA General HospitalSanya572013China Department of Neurology the Second Medical CentreNational Clinical Research Centre for Geriatric DiseasesChinese PLA General HospitalBeijing100853China Department of Radiology Tianjin Huanhu HospitalTianjin300222China Department of Psychiatry People’s Hospital of Hangzhou Medical CollegeZhejiang Provincial People’s HospitalHangzhou310014China Department of Radiology Tianjin Medical University General HospitalTianjin300070China Department of Neurology Tianjin Huanhu HospitalTianjin300222China Department of Neurology Xuanwu Hospital of Capital Medical UniversityBeijing100053China Key Laboratory of Animal Models and Human disease Mechanisms of the Chinese Academy of sciences&Yunnan Province Kunming Institute of ZoologyChinese Academy of SciencesKunming650201YunnanChina state Key Lab of Cognition Neuroscience&Learning Beijing Normal UniversityBeijing100875China National Clinical Research center for Geriatric Disorders Beijing100053China center of alzheimer’s disease Beijing Institute for Brain DisordersBeijing1000

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 *** we introduced a set of radiogenomic analyses to investigate the biological basis of the atrophy patterns in *** 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 *** 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 *** 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.

关键词： alzheimer’s disease structural magnetic resonance imaging Meta-analysis Brain atrophy Gene set enrichment analysis

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Adaptive structured sparse multiview canonical correlation analysis for multimodal brain imaging association identification

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science China(Information sciences) 2023年第4期66卷 212-227页

作者： Lei DU Huiai WANG Jin ZHANG shu ZHANG Lei GUO Junwei HAN the alzheimer's disease Neuroimaging Initiative school of Automation Northwestern Polytechnical University school of Computer science Northwestern Polytechnical University

multimodal brain imaging data can be obtained conveniently through rapidly advancing neuroimaging techniques. These multimodal data, which characterize the brain from distinct perspectives, offer a rare opportunity to comprehensively understand the neuropathology of complex brain disorders. Thus,identifying hidden relationships among multimodal brain imaging data is essential and meaningful. The pairwise correlation between two imaging modalities has been extensively studied. However, the multi-way association among more than three modalities remains unclear and is highly challenging. The difficulty and indeterminacy are largely due to the loss imbalances caused by multiple modalities fusion and the lack of reasonable consideration of the relationship implicated in different brain areas. To address both issues, we propose a structured sparse multiview canonical correlation analysis(sMCCA) with adaptive loss balancing and a novel graph-group penalty. The adaptive loss balancing technique encourages sMCCA to fairly optimize each sub-objective. The graph-group constraint penalizes the brain's regions of interest(ROIs)hierarchically with different regularizations at different levels. We derive an efficient algorithm and present its convergence. Experimental results on synthetic and real neuroimaging data confirm that, compared with state-of-the-art methods, our method is a better alternative as it identifies higher or comparable correlation coefficients and better canonical weights. Importantly, delivered by the canonical weights, the identified ROIs of each modality show a high correlation to each other and brain disorders, which demonstrates the potential of our method for untangling the intricate relationship among multimodal brain imaging data.

关键词： multimodal brain imaging correlation sparse multiview canonical correlation analysis task imbalance adaptive loss balancing graph-group penalty

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Reproducible Abnormalities and Diagnostic Generalizability of White Matter in alzheimer’s disease

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Neuroscience Bulletin 2023年第10期39卷 1533-1543页

作者： Yida Qu Pan Wang Hongxiang Yao Dawei Wang Chengyuan song Hongwei Yang Zengqiang Zhang Pindong Chen Xiaopeng Kang Kai Du Lingzhong Fan Bo Zhou Tong Han Chunshui Yu Xi Zhang Nianming Zuo Tianzi Jiang Yuying Zhou Bing Liu Ying Han Jie Lu Yong Liu multi-center alzheimer’s disease Imaging(MCADI)Consortium Brainnetome center and National Laboratory of Pattern Recognition Institute of AutomationChinese Academy of SciencesBeijing 100190China school of Artificial Intelligence University of Chinese Academy of SciencesBeijing 100049China Department of Neurology Tianjin Huanhu HospitalTianjin UniversityTianjin 300222China Department of Radiology Department of Epidemiology and Health StatisticsSchool of Public HealthQilu Hospital of Shandong UniversityJi’nan 250063China Department of Neurology Qilu Hospital of Shandong UniversityJi’nan 250063China Department of Radiology Xuanwu Hospital of Capital Medical UniversityBeijing 100053China Branch of Chinese PLA General HospitalSanya 572022China Department of Neurology The Second Medical CentreNational Clinical Research Centre for Geriatric DiseasesChinese PLA General HospitalBeijing 100089China Department of Radiology Tianjin Huanhu HospitalTianjin 300222China Department of Radiology Tianjin Medical University General HospitalTianjin 300052China Department of Neurology Xuanwu Hospital of Capital Medical UniversityBeijing 100053China Beijing Institute of Geriatrics Beijing 100053China National Clinical Research center for Geriatric Disorders Beijing 100053China center of alzheimer’s disease Beijing Institute for Brain DisordersBeijing 100053China state Key Lab of Cognition Neuroscience&Learning Beijing Normal UniversityBeijing 100091China school of Artificial Intelligence Beijing University of Posts and TelecommunicationsBeijing 100876China 不详

alzheimer’s disease(AD)is associated with the impairment of white matter(WM)*** 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 *** fiber quantification was used to extract diffusion profiles along ***-effects meta-analyses showed a reproducible degeneration pattern in which fractional anisotropy significantly decreased in the AD and MCI groups compared with *** learning models using tract-based features showed good generalizability among independent site *** 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 *** highlighted the reproducibility and generalizability of the degeneration pattern of WM tracts in AD.

关键词： alzheimer’s disease Diffusion tensor imaging White matter tracts Cross-validation

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Cortical and subcortical Grey Matter Abnormalities in White Matter Hyperintensities and subsequent Cognitive Impairment

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Neuroscience Bulletin 2021年第6期37卷 789-803页

作者： Wenhao Zhu Hao Huang shiqi Yang Xiang Luo Wenzhen Zhu shabei Xu Qi Meng Chengchao Zuo Yong Liu Wei Wang alzheimer’s disease Neuroimaging Initiative Department of Neurology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Radiology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Brainnetome center and National Laboratory of Pattern Recognition Institute of AutomationChinese Academy of SciencesBeijing 100190China school of Artificial Intelligence Beijing University of Posts and TelecommunicationsBeijing 100876China University of the Chinese Academy of sciences Beijing 100049China 不详

Grey matter(GM)alterations may contribute to cognitive decline in individuals with white matter hyperintensities(WMH)but no consensus has yet ***,we investigated cortical thickness and grey matter volume in 23 WMH patients with mild cognitive impairment(WMH-MCI),43 WMH patients without cognitive impairment,and 55 healthy *** WMH groups showed GM atrophy in the bilateral thalamus,fronto-insular cortices,and several parietal-temporal regions,and the WMH-MCI group showed more extensive and severe GM *** GM atrophy in the thalamus and fronto-insular cortices was associated with cognitive decline in the WMH-MCI patients and may mediate the relationship between WMH and cognition in WMH ***,the main results were well replicated in an independent dataset from the alzheimer's disease Neuroimaging Initiative database and in other control *** comprehensive results provide robust evidence of specific GM alterations underlying WMH and subsequent cognitive impairment.

关键词： White matter hyperintensities Cognitive impairment Cortical thickness Grey matter volume Replication

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Cerebrospinal fluid phosphorylated tau,visinin-like protein-1,and chitinase-3-like protein 1 in mild cognitive impairment and alzheimer’s disease

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Translational Neurodegeneration 2018年第1期7卷 221-232页

作者： Hua Zhang Kok Pin Ng Joseph Therriault Min su Kang Tharick APascoal Pedro Rosa-Neto serge Gauthier the alzheimer’s disease Neuroimaging Initiative Department of Neurology the First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Neurology National Neuroscience InstituteSingaporeSingapore The McGill University Research Centre for studies in Aging McGill UniversityMontrealCanada 不详

Background:Visinin-like protein-1(VILIP-1)and chitinase-3-like protein 1(CHI3L1 or YKL-40)in cerebrospinal fluid(CsF)are newly discovered markers indicating neuronal damage and microglial activation,*** tau(p-tau)reflects the neuropathology of alzheimer’s disease(AD)and is useful as diagnostic markers for ***,it is unknown whether these biomarkers have similar or complementary information in ***:We stratified 121 participants from the alzheimer’s disease Neuroimaging Initiative(ADNI)database into cognitively normal(CN),stable mild cognitive impairment(sMCI),progressive MCI(pMCI),and dementia due to *** of covariance(ANOVA)and chi-square analyses,spearman correlation,and logistic regression models were performed to test the demographic,associations between biomarkers,and diagnostic accuracies,*** mixed-effects models were used to evaluate the effects of CsF amyloid-β(Aβ)on above biomarkers within diagnostic groups,the combination of diagnostic group and Aβstatus as predictor,and CsF biomarkers as predictors of AD features,including cognition measured by Mini–Mental state Examination(MMsE)and brain structure and white matter hyperintensity(WMH)measured by magnetic resonance imaging(MRI).Results:P-tau,VILIP-1,and YKL-40 were all predictors of AD diagnosis,but combinations of biomarkers did not improve the diagnostic accuracy(AUC 0.924 for p-tau,VILIP-1,and YKL-40)compared to p-tau(AUC 0.922).P-tau and VILIP-1 were highly correlated(r=0.639,pstrongly associated with Aβpathology across clinical stages of AD,while YKL-40 was correlated with Aβpathology in CN and AD ***-1 was associated with acceleration of cognitive decline,hippocampal atrophy,and expansion of ventricles in longitudinal ***-40 was associated with hippocampal atrophy at baseline and follow-up,while p-tau was only associated with worsening WMH at ***:CsF levels of p-tau,VILIP-1,and YKL-40 may have uti

关键词： alzheimer’s disease Amyloid-β Chitinase-3-like protein 1 Phosphorylated tau Visinin-like protein-1

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Genetic profiles of familial late-onset alzheimer’s disease in China:The shanghai FLOAD study

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Genes & diseases 2022年第6期9卷 1639-1649页

作者： Xin-Yi Xie Qian-Hua Zhao Qiang Huang a Eric Dammer sheng-di Chen Ru-Jing Ren Gang Wang the alzheimer’s disease Neuroimaging Initiative Department of Neurology and Institute of Neurology Ruijin Hospital Affiliated with Shanghai JiaoTong University School of MedicineShanghai 200025PR China Institute of Neurology Huashan HospitalFudan UniversityShanghai 200040PR China National Clinical Research center for Aging and Medicine Huashan HospitalFudan UniversityShanghai 200040PR China Department of Biochemistry Center for Neurodegenerative DiseaseEmory University School of MedicineAtlantaGA 30322USA

Compared with early-onset familial AD(FAD),the heritability of most familial lateonset alzheimer’s disease(FLOAD)cases still remains ***,there are few reported genetic profiles of FLOAD to *** the present study,targeted sequencing of selected candidate genes was conducted for each of 90 probands with FLOAD and 101 unrelated matched normal controls among Chinese Han *** show a significantly lower rate of mutation in APP and PsENs,and APOE e4 genetic risk is higher for *** the Chinese FLOAD population,the most frequent variant was CR1 rs116806486[5.6%,95%CI(1.8%,12.5%)],followed by coding variants of TREM2(4.4%,95%CI(1.2%,10.9%))and novel mutations of ACE[3.3%,95%CI(0.7%,9.4%)].Next,we found that novel pathogenic mutations in ACE including frame-shift and nonsense mutations were in association with FLOAD regardless of APOE e4 *** from the alzheimer’s disease Neuroimaging Initiative(ADNI)database also supported this finding in different *** of in vitro analysis suggest that frame-shift and nonsense mutations in ACE may be involved in LOAD through decreased ACE protein levels without affecting direct processing of APP.

关键词： ACE alzheimer’s disease Familial late-onset alzheimer’s disease Gene Mutation

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Revisiting cerebral endothelial cells in alzheimer’s disease

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Neural Regeneration Research 2025年第10期20卷 2911-2912页

作者： Amira s.Hanafy Department of Neurosurgery University Hospital BonnBonnGermany

alzheimer’s disease(AD)is the most common neurodegenerative disorder characterized by slow and progressive decline of cognitive and memory *** only approximately 5%of the cases,AD is familial,as often predisposed by genetic mutations(Hoogmartens et al.,2021),while sporadic AD accounts for approximately 95%of the *** amyloid cascade hypothesis is one of the fundamental hypotheses put out to explain AD pathogenesis as dysregulated homeostasis of amyloid-β(Aβ)peptides that leads to the accumulation of Aβplaques in the parenchyma,an anatomical hallmark of AD.

关键词： alzheimer Aβ cerebral

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Aberrant functional connectivity network in subjective memory complaint individuals relates to pathological biomarkers

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Translational Neurodegeneration 2018年第1期7卷 275-284页

作者： Kaicheng Li Xiao Luo Qingze Zeng Yeerfan Jiaerken Xiaojun Xu Peiyu Huang Zhujing shen Jingjing Xu Chao Wang Jiong Zhou Min-Ming Zhang the alzheimer’s disease Neuroimaging Initiative Department of Radiology 2nd Affiliated Hospital of Zhejiang University School of MedicineNo.88 Jie-fang RoadShang-cheng DistrictHangzhou 310009China Department of Neurology 2nd Affiliated Hospital of Zhejiang University School of MedicineZhejiangChina 不详

Background:Individuals with subjective memory complaints(sMC)feature a higher risk of cognitive decline and clinical progression of alzheimer’s disease(AD).However,the pathological mechanism underlying sMC remains *** aimed to assess the intrinsic connectivity network and its relationship with AD-related pathologies in sMC ***:We included 44 sMC individuals and 40 normal controls who underwent both resting-state functional MRI and positron emission tomography(PET).Based on graph theory approaches,we detected local and global functional connectivity across the whole brain by using degree centrality(DC)and eigenvector centrality(EC)***,we analyzed amyloid deposition and tauopathy via florbetapir-PET imaging and cerebrospinal fluid(CsF)*** voxel-wise two-sample T-test analysis was used to examine between-group differences in the intrinsic functional network and cerebral amyloid ***,we correlated these network metrics with pathological ***:The sMC individuals showed higher DC in the bilateral hippocampus(HP)and left fusiform gyrus and lower DC in the inferior parietal region than *** all subjects,the DC of the bilateral HP and left fusiform gyrus was positively associated with total tau and phosphorylated ***,no significant between-group difference existed in EC and cerebral amyloid ***:We found impaired local,but not global,intrinsic connectivity networks in sMC *** the relationships between DC value and tau level,we hypothesized that functional changes in sMC individuals might relate to pathological biomarkers.

关键词： subjective memory complaint Functional connectivity Graph theoretical analysis Neuropathology Eigenvector centrality Degree centrality

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Emerging structures and dynamic mechanisms ofγ-secretase for alzheimer’s disease

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Neural Regeneration Research 2025年第1期20卷 174-180页

作者： Yinglong Miao Michael s.Wolfe Computational Medicine Program and Department of Pharmacology University of North Carolina–Chapel HillChapel HillNCUSA Department of Medicinal Chemistry University of KansasLawrenceKSUSA

γ-secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface *** inγ-secretase and amyloid precursor protein lead to early-onset familial alzheimer’s disease.γ-secretase has thus served as a critical drug target for treating familial alzheimer’s disease and the more common late-onset alzheimer’s disease as ***,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-*** this review,we focus on recent studies of structural dynamic mechanisms ofγ-*** mechanisms,including the“Fit-stay-Trim,”“sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics *** an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental *** approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-*** addition,controversy over the effects of familial alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is ***,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial alzheimer’s disease mutations

关键词： alzheimer’s disease amyloid precursor protein cryo-EM structures drug design intramembrane proteolysis molecular dynamics Notch

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MR影像体素形态学的阿尔茨海默病自动分类方法

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东南大学学报（自然科学版） 2015年第2期45卷 260-265页

作者：郭圣文池敏越岑桂英匡翠立牛传筱赖春任吴效明 The alzheimer's disease Neuroimaging Initiative (ADNI) 华南理工大学材料科学与工程学院广州510006

为了确定轻度认知功能障碍(MCI)与阿尔茨海默病(AD)患者发生萎缩的重要脑区,实现正常老年人(NC)对照组、MCI与AD三组人群的分类,选择了178名被试的脑部MR影像,利用体素形态学与方差分析方法,考察NC,MCI与AD三组人群的MR影像中灰质体积差... 详细信息

为了确定轻度认知功能障碍(MCI)与阿尔茨海默病(AD)患者发生萎缩的重要脑区,实现正常老年人(NC)对照组、MCI与AD三组人群的分类,选择了178名被试的脑部MR影像,利用体素形态学与方差分析方法,考察NC,MCI与AD三组人群的MR影像中灰质体积差异;然后,采用递归特征消去法对特征进行降维;最后,利用线性支持向量机对这3种人群进行分类.实验结果表明,MCI组与NC组、MCI组与AD组、AD组与NC组的平均分类准确率分别为(90.2±1.3)%,(74.7±0.9)%,100%.对分类产生重要影响的脑区包括海马、海马旁回、杏仁核、梭状回和嗅皮层等.所提方法不仅能有效揭示NC,MCI,AD三组人群的脑灰质差异,阐明MCI患者与AD患者脑区发生萎缩的过程与特性,而且能准确区分这3组人群,具有显著的临床应用价值.

关键词：阿尔茨海默病轻度认知功能障碍体素形态学支持向量机递归特征消除

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