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.

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) Aβ, 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.

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-β 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.

Background/objectives: Functional disability (FD) is common after stroke and associated with the occurrence of future adverse events; however, whether FD is as strong a risk factor as comorbid vascular risk factors for cardiovascular events and death is unclear. Methods: Consecutive patients 3-6 months after index ischemic stroke were assessed at baseline and followed up for documented new cardiovascular events (recurrent stroke, acute myocardial infarction, and sudden death) and death within 5 years. Comorbidity of vascular risk factors was stratified as low or intermediate-to-high risk according to the Stroke Prognostic Instrument II. Four mutually exclusive cohorts were identified (1) intermediate-to-high risk only, n = 505, (2) FD only, n = 78, (3) both intermediate-to-high risk and FD, n = 264, and (4) low risk and no FD, n = 240. Results: The incidence of cardiovascular events was lowest in patients free of FD with low risk, followed by patients with FD alone, intermediate-to-high risk alone, and both. Compared with intermediate-to-high risk only, patients free of FD with low risk had a significantly lower adjusted hazard ratio (HR) (HR: 0.56, 95% confidence interval [CI]: 0.33-0.94), patients with FD only had a similar HR (HR: 0.47, 95% CI: 0.19 -1.18), and patients with both FD and intermediate-to-high risk had a significantly higher HR (HR: 2.13, 95% CI: 1.53-2.98) of cardiovascular events. A similar trend but a larger HR was noted for all-cause death. Conclusion: FD 3-6 months after ischemic stroke is a risk equivalent to comorbidity of conventional vascular risk factors for the incidence of cardiovascular events and mortality of all-cause death.

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.

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.

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant disease caused by mutations in the colony stimulating factor 1 receptor (CSF1R) gene that often results in cognitive impairment, psychiatric disorders, motor dysfunction and seizure. We report familial cases of a novel CSF1R mutation causing HDLS similar to hydrocephalus. The patients initially presented with a gait disturbance and then developed progressive cognitive decline, urinary incontinence, epileptic seizures and became bedridden as the disease progressed. A brain magnetic resonance imaging (MRI) scan revealed striking ventricular enlargement and diffuse brain atrophy with frontotemporal predominance, which was later accompanied by white matter changes. Genetic testing in this family showed a novel c.2552T>C (p.L851P) mutation in exon 19 of the CSF1R gene. However, three gene carriers in the family remained clinically asymptomatic. Because of its heterogeneous clinical phenotypes, HDLS patients are often misdiagnosed with other diseases. This is the first genetically proven HDLS case resembling hydrocephalus, and the clinical symptoms of HDLS may be related to the specific genetic mutation.

Alterations of brain function were found in resting-state functional MRI (rsfMRI) analyses between Alzheimer's disease (AD) dementia patients and normal aging in monocentric studies. Until now, there has not been a consistent conclusion of the altered amplitude of low-frequency fluctuation pattern for brain regions in AD patients. Large samples from multicenter provide possibility to demonstrate the altered pattern in AD patients. The present study contains 688 subjects (215 normal control (NC), 221 aMCI and 252 AD) from six centers. All preprocessing steps were carried out using Brainnetome fMRI toolkit. Measurement of amplitude of local brain activity (AM) was used, which can provide a fast for mapping brain spontaneous activity across whole brain. Two-sample t-test was used to detect the group differences between patients with AD and NCs at each center. The statistical discrepancy diagrams were further analyzed with Stouffer's multicenter analysis with Liptak-Stouffer z-score method of meta-analysis (p values of six centers was converted to one statistical z-score), The resultant z map was then thresholded using P < 0.05 (Bonfferni Corrected) for each voxel and clusters to figure out regions with normalized amplitude index changed significantly in AD. Correlations between the normalized amplitude index of these regions and MMSE were computed for the AD and aMCI groups to evaluate the relationship between spontaneous brain activity and cognitive ability in the patients. Subjects with AD exhibited lower spontaneous brain activity (normalized AM) in default mode network compared with NCs (Figure 1). And increased AM in bilateral hippocampus/parahippocampus, thalamus, caudate nucleus, orbital part of middle frontal gyrus and left fusiform. Similar altered pattern was found among aMCI patients. Furthermore, significant correlations between normalized amplitude index and the MMSE were found for all the identified brain regions except for orbital part of middle frontal gyrus (Figure 2). Regions showed significant alteration in brain spontaneous activity (measured with normalized amplitude) of AD in comparison with normal controls. Scatterplot showing a significant association between MMSE scores for all patients and normalized amplitude values in the identified brain. MCI patients are indicated by red, and AD patients by blue. The present study provided robust impaired brain spontaneous activity patterns in AD based on multi-center rsfMRI data. A novel finding was the identification of the strong correlation between the identified brain regions and cognitive performances. This profile indicates the potential of spontaneous activity pattern in the resting state as biomarkers or predictors of disease progression in MCI/AD.

阿尔茨海默病以进行性认知功能减退为特点,严重影响患者的社会活动、生活质量及生活能力,目前缺少有效的治疗药物.为了治疗阿尔茨海默病,人们付出了巨大的努力,投入了巨额资金用于治疗药物的研发,至今尚无有效的药物临床试验结果.有效的药物治疗,依赖于对疾病病因及病理机制的了解.从临床角度出发,当对患者疾病的治疗无效时,要考虑诊断正确与否.针对阿尔茨海默病药物研发屡屡失败的结果,要寻找失败的原因,包括疾病的病因、病理机制、试验设计等因素对药物研发结果的影响.

Early-onset Alzheimer's disease (EOAD, onset <65 years) is the most common early-onset neurodegenerative dementia. According to the International Working Group-2, AD is classified as two different types, the amnestic form and the nonamnestic form, including posterior cortical atrophy (PCA) and logopenic variant of primary progressive aphasia (lvPPA). Different clinical presentations represent points in a phenotypic spectrum of neuroanatomical variation. However, there have been conflicting reports regarding the symptom-anatomical patterns seen in EOAD variants. The present study investigated the distribution of cortical atrophy and white matter tract damage related to performance in cognitive impairments and cortical dysfunction across EOAD variants to better understand the anatomical substrates of variant phenotypes. The study consisted of 26 healthy normal controls and 44 patients with the age of onset less than 65 year-old, of whom 18 had amnestic EOAD, 14 with PCA，12 with lvPPA. All participants received detailed neuropsychological assessments and brain MRI scans at 3.0T. Nonparametric method was used to compare cognitive performances between groups. Partial correlations and multivariate linear regressions were conducted to examine the association between cognitive performances and neuroanatomical regions affected across variants. Patients with aEOAD presented worse verbal and visual delayed recall, better executive function, visuospatial skills and language ability compared with PCA and lvPPA. Besides predominant visuospatial deficit and neglect, PCA showed more frequently Gerstmann syndrome compared with lvPPA. Patients with lvPPA showed obviously deficit in high-frequency word naming, repetition, verbal fluency and digit span. In addition, lvPPA had more ideomotor apraxia and less Gerstmann syndrome than PCA. Disease-specific syndromes occur in the three variants of EOAD and are likely associated with disease-specific cortical and subcortical changes. Loss of white matter integrity contributes as significantly as focal atrophy and clinical variant in EOAD .

Objective To ovserve the clinical features of adrenal leukodystrophy ( ALD) characterized with spasmodic paraplegia but without abnormal cerebral white matter signals , and to avoid to be diagnosed as hereditary spastic paraplegia ( HSP) .Methods The clinical data of 3 ALD patients who were main characterized as spasmodic paraplegia and without abnormal cerebral white matter signals and misdiagnosed as HSP were reviewed retrospectively .Results Three patients were all manifested as significant spastic paraplegia with an insidious onset and slow progression , and with or without autonomic nerve or peripheral nerve impairment .There were no abnormal signals in the brain white matter .Three patients were all diagnosed as adrenomyeloneuropathy ( AMN ) by next generation sequencing after the misdiagnosis as HSP .Gene sequencing showed that ABCD 1 gene exon 2 c.961_963del deletion mutantion , ABCD1 gene exon 1 c.310C>T missense mutation and ABCD1 gene exon 3 c.1202G>A missense mutation , separately .The family verification of case 1 and case 2 showed that both of their mothers had corresponding genetic mutations .Conclusions AMN is one clinical manifestation of ALD , characterized as spastic paraplegia in the lower limbs .Patients without abnormal siginals in brain white matter are easily to be misdiagnosed as HSP.So plasma very long chain fatty acids ( VLCFA) testing or gene testing should be used for the patients who are clinically suspected HSP , especially in male patients , in order to identify ALD .

目的:基于静息态fMRI观察不同程度AD患者的ALFF值在不同频段上的变化。方法:对年龄、性别匹配的27名健康对照组（healthy control,HC）、40名AD患者（17名轻度AD和23名中度AD）进行功能磁共振扫描,获取slow-5、slow-4两频段低频振幅信息,根据频段和组别的交互作用分析,获得AD患者ALFF改变有显著性差异的脑区,观察这些脑区在不同程度患者间不同频段上的ALFF变化。结果:（1）AD患者ALFF有显著改变的脑区包括:双侧楔叶\距状回、双侧丘脑、左侧顶下小叶、左侧楔前叶;（2）在slow-4频段,轻度、中度AD患者与HC三组在上述脑区的ALFF值差异无显著性;在slow-5频段,轻度AD组双侧丘脑、左侧顶下小叶ALFF值明显升高,双侧楔叶/距状回ALFF值明显下降;中度AD组与正常对照组相比ALFF差异无明显性;与轻度AD组相比,ALFF值在左侧楔前叶出现明显下降,在双侧楔叶/距状回出现回升。结论:（1）轻、中度AD患者的静息态fMRI低频振幅与正常人不同,主要体现在slow-5频段,slow-5频段的低频振幅变化更能反映AD患者随病情进展出现的脑功能改变;（2）在轻度AD阶段,双侧丘脑、左侧顶下小叶的活动增强起代偿作用,在中度AD阶段,双侧楔叶/距状回活动增强发挥代偿作用。

记忆力下降的异常表现 老年痴呆最突出的表现是记忆力减退,而且与正常老化的记忆力减退有本质的区别.正常老年人都会有一定的记忆力减退,但这种减退一般不会影响到以下两方面:一是不会影响正常社会活动和生活.

帕金森病也称震颤麻痹症,曾被称为“慢性癌症”,是发生于中老年人中枢神经系统的神经变性疾病.一般起病年龄在55岁以上,发病率随年龄的增长而增加,在60岁以上人群中患病率约为10％.

从临床角度阐述帕金森病、帕金森叠加综合征的相关概念.介绍了帕金森叠加综合征四种常见类型(多系统萎缩、进行性核上性麻痹、皮层基底节变性、路易体痴呆)的病理生理学基础、分型、诊断标准、影像学特点等.结合临床经验,讲述帕金森叠加综合征几种常见类型所致痴呆的临床特点及相关的治疗.

星形胶质细胞是维持中枢神经系统内环境稳定、实现防御和再生功能的基石.星形胶质细胞功能缺失和反应性下降导致了大脑的生理老化和神经系统变性病的发生.星形胶质细胞在大脑老化以及阿尔茨海默病(AD)的病理生理机制中起重要作用,且参与人脑能量代谢.药物干预可以调节星形胶质细胞的形态和功能,这提示星形胶质细胞有可能被用来作为治疗AD的靶点.本文就星形胶质细胞在正常老化机制及AD发病机制中的作用进行综述.

Objectives: The pieces of evidence regarding whether metabolic syndrome (MetS) is a better predictor than its individual components, especially diabetes, for recurrent stroke are limited. This study aimed to examine these associations. Methods: A total of 1087 ischemic stroke patients were recruited consecutively from 2003 to 2004. They were followed up until the end of 2008. Baseline clinical and laboratory characteristics and new stroke event during follow-up were recorded. MetS was defined by the definition issued by the Chinese Medical Association/Chinese Diabetes Society. Results: One hundred forty-three new stroke cases were recorded. After adjusting for baseline age, gender, education, marriage status, subtype stroke, length of index stroke to baseline assessment, history of cardiac diseases, smoking status, drinking status, clinics, aspirin treatment, and fibrinogen by Cox regression models, the risk of recurrent stroke was 43% higher in MetS patients than in non-MetS patients (hazard ratio [HR] = 1.43, 95% confidence interval [CI]: 1.01-2.01). The strength of this association is weaker than MetS individual components such as elevated glycemia (adjusted HR = 1.78, 95% CI: 1.26-2.52), elevated blood pressure (adjusted HR = 1.91, 95% CI: 1.11-3.30), or low high-density lipoprotein cholesterol (adjusted HR = 1.57, 95% CI: 1.08-2.51). Compared with the group with neither MetS nor diabetes, the adjusted risk of recurrent stroke was highest in the group with diabetes (HR = 2.77, 95% CI: 1.66-4.63), followed by those with both MetS and diabetes (HR = 1.91, 95% CI: 1.25-2.94). The risk of recurrent stroke in patients with MetS in the absence of diabetes was similar to those with neither. Conclusion: MetS is not superior to its individual components in predicting future recurrent stroke in patients who experience mild-to-moderate ischemic stroke.

Background: The parahippocampal gyrus (PHG) is an important region of the limbic system that plays an important role in episodic memory. Elucidation of the PHG connectivity pattern will aid in the understanding of memory deficits in neurodegenerative diseases.Objective: To investigate if disease severity associated altered PHG connectivity in Alzheimer's disease (AD) exists.Methods: We evaluated resting-state functional magnetic resonance imaging data from 18 patients with amnestic mild cognitive impairment (MCI), 35 patients with AD, and 21 controls. The PHG connectivity pattern was examined by calculating Pearson's correlation coefficients between the bilateral PHG and whole brain. Group comparisons were performed after controlling for the effects of age and gender. The functional connectivity strength in each identified region was correlated with the MMSE score to evaluate the relationship between connectivity and cognitive ability.Results: Several brain regions of the default mode network showed reduced PHG connectivity in the AD patients, and PHG connectivity was associated with disease severity in the MCI and AD subjects. More importantly, correlation analyses showed that there were positive correlations between the connectivity strengths of the left PHG-PCC/Pcu and left PHG-left MTG and the Mini-Mental State Examination, indicating that with disease progression from MCI to severe AD, damage to the functional connectivity of the PHG becomes increasingly severe.Conclusions: These results indicate that disease severity is associated with altered PHG connectivity, contributing to knowledge about the reduction in cognitive ability and impaired brain activity that occur in AD/MCI. These early changes in the functional connectivity of the PHG might provide some potential clues for identification of imaging markers for the early detection of MCI and AD.

Background: Hereditary spastic paraplegia (HSP) is a neurodegenerative disease that is characterized by progressive weakness and spasticity of the lower extremities; HSP can present as complicated forms with additional neurological signs. More than 70 disease loci have been described with different modes of inheritance. Methods: In this study, nine subjects from a Chinese family that included two individuals affected by HSP were examined through detailed clinical evaluations, physical examinations, and genetic tests. Targeted exome capture technology was used to identify gene mutations. Results: Two novel compound heterozygous mutations in the SPG 11 gene were identified, c. 4001_4002 insATAAC and c. 4057C>G. The c. 4001_4002 insATAAC mutation leads to a reading frame shift during transcription, resulting in premature termination of the protein product. The missense mutation c. 4057C>G (p.H1353D) is located in a highly conserved domain and is predicted to be a damaging substitution. Conclusions: Based on the results described here, we propose that these novel compound heterozygous mutations in SPG 11 are the genetic cause of autosomal recessive HSP in this Chinese family.