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Alzheimer's disease (AD) is the most common cognitive disorder in the elderly. Its main clinical manifestations are cognitive decline (C), behavioral and psychological symptoms (B), and a decline in the activities of daily living (A), also known as ABC symptoms. Early identification and evaluation of ABC symptoms are helpful for establishing the accurate diagnosis, comprehensive treatment, and prognosis of AD. To guide Chinese clinical practice for optimization of the comprehensive management of AD, in 2018, The Academy of Cognitive Disorder of China gathered 22 neurologists and gerontologists in China to build a consensus on the comprehensive management of AD. Based on a review of the evidence, the consensus summarizes the pathogenesis, pathological changes, clinical manifestations, evaluation, diagnosis, drug and non-drug treatment, and patient care for AD. Focus group discussion was used to establish a flowchart of comprehensive ABC management for AD patients. The new consensus provides a feasible AD management process for clinicians.

Background Lewy body dementia (LBD), consisting of dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), is the second most common type of neurodegenerative dementia in older people. The current study aimed to investigate the clinical characteristics of LBD in Chinese memory clinics. Methods A total of 8405 dementia medical records were reviewed, revealing 455 patients with LBD. Demographic data, neuropsychological scores, and the scale for Medial Temporal lobe Atrophy (MTA) were then analyzed from nine memory clinics in the China Lewy Body Disease Collaborative Alliance. Results The clinical proportion of LBD among the subjects and among all dementia types was 5.4% (4.9–5.9%) and 7.3% (6.7–8.0%), respectively, with a mean onset age of 68.6 ± 8.4 years. Patients with DLB comprised 5.6% (n = 348, age of onset 69.1 ± 8.3), while PDD comprised 1.7% (n = 107, age of onset 66.7 ± 8.8) of all dementia cases. There were slightly more males than females with DLB (n = 177, 50.9%) and PDD (n = 62, 57.9%). Patients with DLB had a poorer performance compared to those with PDD on the MMSE (16.8 ± 7.1 vs. 19.5 ± 5.7, p = 0.001), the MoCA (11.4 ± 6.6 vs. 14.0 ± 5.8, pp = 0.002), and the MTA (1.8 ± 0.7 vs. 1.2 ± 0.6, p = 0.002). Diagnostic differences for LBD exist among the centers; their reported proportions of those with DLB ranged from 0.7 to 11.4 and those with PDD ranged from 0.0 to 2.9%. Conclusions Variations of diagnoses exists in different regions and the clinical proportion of LBD is likely to be underestimated in China and other regions.

Background: Identifying and classifying individuals with Cognitive Impairment-No Dementia (CIND) has further challenged diagnostic methods, since varying the cutoffs for objective impairment as well as the neuropsychological tests considered can significantly affect diagnosis. Therefore, we investigated the applicability of an actuarial neuropsychological approach for clinical subdivision of CIND and quantified the variability in diagnostic outcomes that results from diverse neuropsychologically derived definition of objective cognitive impairment. Methods: 1459 non-demented, clinic-based individuals were recruited from a monocentric memory clinic from 1/1/2016/ to 1/1/2018 and classified as Cognitively Normal (NC), Slight Cognitive Symptom (SCS), SSubtle Cognitive Decline (SCD) or Mild Cognitive Impairment (MCI) via different diagnostic strategies, which varied the composition of objective cognitive assessments involved in the diagnostic process. Results: We compared two methods of criteria proposed by Jak/Bondi and Petersen/Winblad to classify individuals with CIND. A substantial range of differences in the percentages recognized as NC, SCS, SCD, and MCI was presented, depending on the classification criteria adopted. Our data revealed that the application of a set of six neuropsychological scores dividing CIND into 4 subgroups (NC, SCS, SCD, and MCI) was able to classify all non-demented individuals without overlap or omission. Conclusion: Our study provided clinical support for an operational framework of the CIND classification system and underlined the value of applying comprehensive neuropsychological assessments for definition. The concept of SCS, considered appropriate for a preclinical stage, was proposed as the symptomatic definition for early intervention.

Subjective or objective subtle cognitive decline (SCD) is considered the preclinical manifestation of Alzheimer's disease (AD), which is a potentially crucial window for preventing or delaying the progression of the disease.To explore the potential mechanism of disease progression and identify relevant biomarkers, we comprehensively assessed the peripheral blood transcriptomic alterations in SCD, covering lncRNA, mRNA, and miRNA.Dysregulated protein-coding mRNA at both gene and isoform levels implicated impairment in the type I interferon signaling pathway in SCD. Specifically, this pathway was regulated by the transcription factor STAT1 and ncRNAs NRIR and has-miR-146a-5p. The miRNA-mRNA-lncRNA co-expression network revealed hub genes for the interferon module. Individuals with lower interferon signaling activity and lower expression of a hub gene STAT1 exhibited a higher conversion rate to mild cognitive impairment (MCI).Our findings illustrated the down-regulation of interferon signaling activity would potentially increase the risk of disease progression and thus serve as a pre-disease biomarker.This work was partly supported by National Key RD Program of China (2020YFA0712403), National Natural Science Foundation of China (61932008), Shanghai Municipal Science and Technology Major Project (2018SHZDZX01), the 111 Project (No. B18015) of China, Greater Bay Area Institute of Precision Medicine (Guangzhou) (Grand No. IPM21C008), Natural Science Foundation of Shanghai (21ZR1403200), and Shanghai Center for Brain Science and Brain-Inspired Technology.

PurposeRecent studies have suggested the significant relationship between follicle-stimulating hormone (FSH) and non-alcoholic fatty liver disease (NAFLD) in postmenopausal women. However, it is unknown whether FSH impacts the risk of NAFLD in men. This study aimed to investigate the association between serum FSH levels and NAFLD in elderly Chinese men aged 80–98, a particular group with worse outcomes of NAFLD.Patients and methodsA cross-sectional analysis was performed in 444 subjects in a geriatric health center. The highest quartile of serum FSH was used as reference. Hepatic steatosis was defined according to the results of liver ultrasound. Fibrosis-4 (FIB-4) Index> 2.67 was defined as advanced fibrosis.ResultsBased on liver ultrasound, 108 (24.3%) subjects had NAFLD. FSH level were negatively correlated with total testosterone, estradiol, nutritional risk, and the prevalence of high education level (allP P P = 0.057;P = 0.066, respectively). The percentage of subjects with NAFLD had a trend to increase following the quartiles of serum FSH (20.0% in quartile 1, 18.2% in quartile 2, 27.3% in quartile 3, and 31.6% in quartile 4). After adjustment for common pathogenic risk factors, nutritional risk, and other sex hormones, serum FSH were progressively associated with odds ratios for NAFLD. The adjusted odds ratios and 95% CIs for quartile 1, quartile 2, and quartile 3, compared with quartile 4 were 0.132 (0.034–0.516), 0.190 (0.052–0.702), and 0.404 (0.139–1.173), respectively. Obesity was not involved in the potential negative role of circulating FSH on the risk of NAFLD in our population. Furthermore, our results revealed no significant association between FSH and advance fibrosis, the OR (95% CI) for advanced fibrosis was 1.018 (0.983–1.054) (P = 0.316) after adjusting for the potential covariates, although a positive correlation of FSH and FIB-4 score was observed (r = 0.325,P = 0.001).ConclusionLow FSH level may decrease the risk of NAFLD in elderly Chinese men. These findings warrant replication in more extensive studies.

Recent advances in genetic sequencing have enabled comprehensive genetic analyses of human diseases, resulting in the identification of numerous genetic risk factors for heritable disorders including Alzheimer’s disease (AD). Such analyses enable AD risk prediction well before disease onset, which is critical for early interventions. However, current analytical approaches have limited ability to accurately estimate the risk effects of genetic variants owing to epistatic effects, which have been overlooked in most previous studies, resulting in unsatisfactory disease risk prediction. Herein, we modeled AD polygenic risk using deep learning methods, which outperformed existing models (i.e., weighted polygenic risk score and lasso models) for classifying disease risk. Moreover, by examining the associations between the outcomes from deep learning methods and multi-omics data obtained from our in-house Chinese AD cohorts, we identified the pathways that are potentially regulated by AD polygenic risk, including immune-associated signaling pathways. Thus, our results demonstrate the utility of deep learning methods for modeling the genetic risks of human diseases, which can facilitate both disease risk classification and the study of disease mechanisms.

BackgroundThis study aimed to explore the level and changes in handgrip strength among preclinical Alzheimer’s disease (AD) and AD patients and to evaluate the association between handgrip strength and cognitive function.MethodsA total of 1431 participants from the memory clinic of Shanghai JiaoTong University Affiliated Sixth People’s Hospital and community were enrolled in the final analysis, including 596 AD, 288 mild cognitive impairment (MCI), and 547 normal individuals (NC). All participants received a comprehensive neuropsychological assessment. Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment-Basic (MoCA-BC), and the Chinese version of Addenbrooke’s Cognitive Examination III (ACE-III-CV) were used as cognitive tests. The receiver operating characteristic curve (ROC) was plotted to assess the power of handgrip strength as a screening measure to discriminate AD and MCI.ResultsThe results showed that handgrip strength in the MCI group was significantly lower than that of NC group, and the AD group had a further decline (bothP ). Multivariate logistic regression was performed with the handgrip strength quartiles, and the results showed that the ORs of AD for increasing levels of handgrip strength were 1.00, 0.58 (0.46–0.78), 0.51 (0.36–0.73), and 0.50 (0.35–0.68), showing a decreasing trend (Pfor trend<0.01). The ROC curve demonstrated that the handgrip strength cutoff points for the identification of AD were 16.8 and 20.7 kg among the female participants above and under 70 yrs and 24.4 and 33.3 kg for the male participants above and under 70 yrs, respectively. Similarly, for the identification of MCI, cutoff points were 17.5 and 21.9 kg for females above 70 yrs and under 70 yrs, and 25.8 and 36.2 kg for males above 70 yrs and under 70 yrs, respectively.ConclusionsOur study provided the further knowledge on the relationship between noncognitive features and cognition in populations with differing cognitive status, revealed that the stronger handgrip strength was associated with better performances on cognitive function. It can be speculated that handgrip strength can help early recognition of Chinese AD patients.

Background Several studies have demonstrated that the elevated fasting blood glucose (FBG) may increase the risk of incident dementia in older adults with or without diabetes mellitus (DM). However, similar results are rarely reported in Chinese population. Objective This study aimed to demonstrate the association between FBG and risk of incident cognitive decline in older Chinese adults. Methods We prospectively followed up 1,555 dementia-free participants with baseline FBG measurement in the Shanghai Aging Study. Results We identified 126 incident dementia cases across a mean of 5.2 years. Cumulative dementia incidence in type II DM participants with higher FBG (>6.1 mmol/L) increased most dramatically, second with that of non-DM participants with higher FBG, than that of participants with lower FBG (≤6.1 mmol/L). DM participants had a significant higher risk of incident dementia (adjusted HR 1.51, 95% CI 1.25-1.82) by every 1 mmol/L increment of FBG. Among DM participants, baseline FBG was positively related to the rate of annual decline of MMSE (β= 0.10, p = 0.0018). Conclusions Our results suggest that especially in people with type II DM, effective blood glucose control may help to prevent cognitive impairment in later life.

Background & Objective: The purpose of this study is to identify the risk factors associated with the conversion from Mild Cognitive Impairment (MCI) to Alzheimer’s Disease (AD) dementia for the early detection of AD.Methods:The study comprised a prospective cohort study that included 400 MCI subjects with annual follow-ups for 3 years.Results:During the first 12 months’ follow-up, 42 subjects converted to Alzheimer’s dementia (21 probable AD and 21 possible AD), two subjects converted to other types of dementia and 56 subjects lost follow. The factors associated with a greater risk of conversion from MCI to AD included gender, whole brain volume, and right hippocampal volume (rt. HV), as well as scores on the Revised Chinese version of the Alzheimer’s Disease Assessment Scale-Cognitive subscale 13 (ADAS-Cog-C), Clock Drawing Test (CDT), Symbol Digit Modalities Test (SDMT), and Rey-Osterrieth Complex Figure Test (ROCFT). The risk classification of the combined ADAS-Cog-C and Alzheimer Cognitive Composite (ACC) score with the rt. HV and left Entorhinal Cortex Volume (lt. ECV) showed a conversion difference among the groups.Conclusion:Early detection of AD and potential selection for clinical trial design should utilize the rt. HV, as well as neuropsychological test scores, including those of the ADAS-Cog-C and ACC.

Background For detecting mild cognitive impairment (MCI), brief cognitive screening tools are increasingly required for the advantage of time saving and no need for special equipment or trained raters. We aimed to develop a modified Chinese version of Mini‐Addenbrooke's Cognitive Examination (C‐MACE) and further evaluate its validation in detecting MCI. Methods A total of 716 individuals aged from 50 to 90 years old were recruited, including 431 cognitively normal controls (NC) and 285 individuals with MCI. The effect size of Cramer's V was used to explore which items in the Chinese version of Addenbrooke's Cognitive Examination‐III (ACE‐III‐CV) best associated with MCI and to form the C‐MACE. Receiver operating characteristic (ROC) analyses were carried out to explore the ability of C‐MACE, ACE‐III‐CV, Chinese version of Montreal Cognitive Assessment‐Basic (MoCA‐BC), and Mini‐Mental State Examination (MMSE) in discriminating MCI from NC. Results Five items with greatest effect sizes of Cramer's V were selected from ACE‐III‐CV to form the C‐MACE: Memory Immediate Recall, Memory Delayed Recall, Memory Recognition, Verbal Fluency Animal and Language Naming. With a total score of 38, the C‐MACE had a satisfactory classification accuracy in detecting MCI (area under the ROC curve, AUC = 0.892), superior to MMSE (AUC = 0.782) and comparable to ACE‐III‐CV (AUC = 0.901) and MoCA‐BC (AUC = 0.916). In the subgroup of Age > 70 years, Education ≤ 12 years, the C‐MACE got a highest classification accuracy (AUC = 0.958) for detecting MCI. Conclusion In the Chinese‐speaking population, C‐MACE derived from ACE‐III‐CV may identify MCI with a good classification accuracy, especially in aged people with low education., Five items from ACE‐III‐CV were selected to form C‐MACE, including: Immediate Recall, Delayed Recall, Recognition, Verbal Fluency and Naming. This C‐MACE had a satisfactory classification accuracy in detecting MCI than MMSE and comparable to the ACE‐III‐CV and Chinese version of MoCA‐Basic.

Background Blood based biomarkers for Alzheimer’s disease (AD) are becoming increasingly promising. Although plasma amyloid-β (Aβ) and total tau (t-tau) showed a potential ability in identifying cerebral amyloid deposition and AD. Comparisons of these plasma biomarkers along with Aβ-PET in a cohort of normal controls (NC), subjective cognitive decline (SCD), objectively-defined subtle cognitive decline (Obj-SCD), mild cognitive impairment (MCI) and AD remained lacking. Methods A total of 407 individuals aged from 40 to 90 years old were recruited, including 76 of NC, 77 of SCD, 61 of obj-SCD, 92 of MCI and 101 of AD. Plasma Aβ40, Aβ42 and t-tau were examined via single-molecule array (Simoa) immunoassay. A subset of 132 individuals underwent cerebral amyloid scans with 18F-florbetapir PET. Comparisons of plasma t-tau, Aβ40, Aβ42 and Aβ42/Aβ40 ratio were conducted between different diagnostic groups and cerebral Aβ burdens. Pearson correlation analysis was used to evaluate the correlation between Aβ42, Aβ42/Aβ40 ratio and 18F-florbetapir SUVR. Receiver operating characteristic (ROC) curve analyses were carried out to evaluate the capacity of plasma biomarkers in identifying high brain Aβ burden and diagnosis of AD. Results Plasma Aβ42 was significantly higher in SCD and obj-SCD than NC, MCI and AD. Plasma Aβ40 was significantly higher in SCD and obj-SCD than NC and AD. The lowest levels of plasma Aβ42 and Aβ42/Aβ40 ratio were found in AD. No significant difference of plasma t-tau was found among groups. Plasma Aβ42 and Aβ42/Aβ40 ratio were inversely correlated with 18F-florbetapir SUVR (r=-0.272, P = 0.003; r=-0.211, P = 0.021 respectively). Aβ42/Aβ40 ratio performed well in predicting high brain Aβ burden (area under the curve, AUC = 0.762). Plasma Aβ42 and Aβ42/Aβ40 ratio had acceptable diagnostic accuracy for AD (AUC = 0.714 and 0.706 respectively), even in Aβ-PET (+) individuals (AUC = 0.728 and 0.808 respectively). Conclusions Plasma Aβ40 and Aβ42 measured by Simoa immunoassay showed a significantly bidirectional trend of initially increasing from NC to SCD and obj-SCD, and then declining to MCI and AD. In addition, plasma Aβ was significantly correlated with 18F-florbetapir PET SUVR and showed potential value in predicting cerebral Aβ deposition and risk of AD.

Introduction: To identify individuals with preclinical cognitive impairment, researchers proposed the concept of objectively-defined subtle cognitive decline (Obj-SCD). However, it is not clear whether Obj-SCD has characteristic brain function changes. In this study, we aimed at exploring the changing pattern of brain function activity in Obj-SCD individuals and the similarities and differences with mild cognitive impairments (MCI).Method: 37 healthy control individuals, 25 Obj-SCD individuals (with the impairment in memory and language domain), and 28 aMCI individuals were included. Resting-state fMRI and neuropsychological tests were performed. fALFF was used to reflect the local functional activity and compared between groups. Finally, we analyzed the correlation between the fALFF values of significantly changed regions and neuropsychological performance.Results: We found similar functional activity enhancements in some local brain regions in the Obj-SCD and aMCI groups, including the left orbital part of the inferior frontal gyrus and the left median cingulate and paracingulate gyri. However, some changes in local functional activities of the Obj-SCD group showed different patterns from the aMCI group. Compared with healthy control (HC), the Obj-SCD group showed increased local functional activity in the right middle occipital gyrus, decreased local functional activity in the left precuneus and the left inferior temporal gyrus. In the Obj-SCD group, in normal band, the fALFF value of the right middle occipital gyrus was significantly negatively correlated with Mini-Mental State Examination (MMSE) score (r = −0.450, p = 0.024) and Animal Verbal Fluency Test (AFT) score (r = −0.402, p = 0.046); the left inferior temporal gyrus was significantly positively correlated with MMSE score (r = 0.588, p = 0.002). In slow-4 band, the fALFF value of the left precuneus was significantly positively correlated with MMSE score (r = 0.468, p = 0.018) and AFT score (r = 0.600, p = 0.002). In the aMCI group, the fALFF value of the left orbital part of the inferior frontal gyrus was significantly positively correlated with Auditory Verbal Learning Test (AVLT) long delay cued recall score (r = 0.506, p = 0.006).Conclusion: The Obj-SCD group showed a unique changing pattern; the functional changes of different brain regions have a close but different correlation with cognitive impairment, indicating that there may be a complex pathological basis inside. This suggests that Obj-SCD may be a separate stage of cognitive decline before aMCI and is helpful to the study of preclinical cognitive decline.

IntroductionSubjective cognitive decline (SCD) is the preclinical stage of Alzheimer’s disease and may develop into amnestic mild cognitive impairment (aMCI). Finding suitable biomarkers is the key to accurately identifying SCD. Previous resting-state functional magnetic resonance imaging (rs-fMRI) studies on SCD patients showed functional connectivity disorders. Our goal was to explore whether local neurological homogeneity changes in SCD patients, the relationship between these changes and cognitive function, and similarities of neurological homogeneity changes between SCD and aMCI patients.Materials and Methods37 cases of the healthy control (HC) group, 39 cases of the SCD group, and 28 cases of the aMCI group were included. Participants underwent rs-fMRI examination and a set of neuropsychological test batteries. Regional homogeneity (ReHo) was calculated and compared between groups. ReHo values were extracted from meaningful regions in the SCD group, and the correlation between ReHo values with the performance of neuropsychological tests was analyzed.ResultsOur results showed significant changes in the ReHo among groups. In the SCD group compared with the HC group, part of the parietal lobe, frontal lobe, and occipital lobe showed decreased ReHo, and the temporal lobe, part of the parietal lobe and the frontal lobe showed increased ReHo. The increased area of ReHo was negatively correlated with the decreased area, and was related to decrease on multiple neuropsychological tests performance. Simultaneously, the changed areas of ReHo in SCD patients are similar to aMCI patients, while aMCI group’s neuropsychological test performance was significantly lower than that of the SCD group.ConclusionThere are significant changes in local neurological homogeneity in SCD patients, and related to the decline of cognitive function. The increase of neurological homogeneity in the temporal lobe and adjacent area is negatively correlated with cognitive function, reflecting compensation for local neural damage. These changes in local neurological homogeneity in SCD patients are similar to aMCI patients, suggesting similar neuropathy in these two stages. However, the aMCI group’s cognitive function was significantly worse than that of the SCD group, suggesting that this compensation is limited. In summary, regional neural activity homogeneity may be a potential biomarker for identifying SCD and measuring the disease severity.

BACKGROUND AND PURPOSE The diagnosis and monitoring of semantic variant primary progressive aphasia (sv-PPA) are clinically challenging. We aimed to establish a distinctive metabolic pattern in sv-PPA for diagnosis and severity evaluation. METHODS Fifteen sv-PPA patients and 15 controls were enrolled to identify sv-PPA-related pattern (sv-PPARP) by principal component analysis of 18 F-fluorodeoxyglucose positron emission tomography. Eighteen Alzheimer disease dementia (AD) and 14 behavioral variant frontotemporal dementia (bv-FTD) patients were enrolled to test the discriminatory power. Correspondingly, regional metabolic activities extracted from the voxelwise analysis were evaluated for the discriminatory power. RESULTS The sv-PPARP was characterized as decreased metabolic activity mainly in the bilateral temporal lobe (left predominance), middle orbitofrontal gyrus, left hippocampus/parahippocampus gyrus, fusiform gyrus, insula, inferior orbitofrontal gyrus, and striatum, with increased activity in the bilateral lingual gyrus, cuneus, calcarine gyrus, and right precentral and postcentral gyrus. The pattern expression had significant discriminatory power (area under the curve [AUC] = 0.98, sensitivity = 100%, specificity = 94.4%) in distinguishing sv-PPA from AD, and the asymmetry index offered complementary discriminatory power (AUC = 0.91, sensitivity = 86.7%, specificity = 92.9%) in distinguishing sv-PPA from bv-FTD. In sv-PPA patients, the pattern expression correlated with Boston Naming Test scores at baseline and showed significant increase in the subset of patients with follow-up. The voxelwise analysis showed similar topography, and the regional metabolic activities had equivalent or better discriminatory power and clinical correlations with Boston Naming Test scores. The ability to reflect disease progression in longitudinal follow-up seemed to be inferior to the pattern expression. CONCLUSIONS The sv-PPARP might serve as an objective biomarker for diagnosis and progression evaluation.

BackgroundThis study aimed to explore the level and changes of handgrip strength in pre-clinical Alzheimer’s disease (AD) and AD participates, and to evaluate the association between handgrip strength and cognitive function.Methods1431 participants from the memory clinic of Shanghai JiaoTong University Affiliated Sixth People’s Hospital and community were enrolled into the final analysis, included 596 AD, 288 mild cognitive impairment (MCI), and 547 normal individuals (NC). All participants received a comprehensive neuropsychological assessment. Mini-mental state examination (MMSE), montreal cognitive assessment-Basic (MoCA-BC), and the Chinese version of the Addenbrooke’s cognitive examination (ACE-III-CV) were used as cognitive tests. The receiver operating characteristic curve (ROC) was plotted to assess the power of the handgrip strength as a screening measure to discriminate AD and MCI.ResultsThe results showed that participants with lower handgrip strength had lower MMSE, MoCA-BC, and ACE-III-CV scores (P ). Handgrip strength in the mild cognitive impairment (MCI) group was significantly lower than that of normal individuals (NC), and the AD group had a further decline (both P). Multivariate logistic regression was performed with the handgrip strength quartiles, the results showed ORs of AD for increasing levels of handgrip strength were 1.00, 0.58 (0.46–0.78), 0.51 (0.36–0.73), and 0.50 (0.35–0.68), showing a decreasing trend (Pfor trend < 0.001). The receiver operating characteristic curve demonstrated that the handgrip strength cut-off points for identification of AD were16.8 kg and 20.7 kg among the female participates above and under 70 yrs, 24.4 kg and 33.3 kg for the male participates above and under 70 yrs, respectively.ConclusionsStronger handgrip strength was associated with better performances on cognitive function, handgrip strength could be an early predictor of cognitive impairment in the Chinese population. The current study provides a foundation for non-cognitive features as early predictors of cognitive impairment, researches on the association between frailty and cognition will be further developed in the future.

Objectives:To examine the psychometric properties of the Chinese version of the Relevant Outcome Scale for Alzheimer’s disease (CROSA) among persons with AD (PWAD) and their caregivers in China.Design:A single-arm, open-label, multi-center study.Setting:Two tertiary general hospitals in Shanghai.Participants:A total of 336 PWAD and their family caregivers.Intervention:The PWAD completed a 12-week treatment with memantine after a baseline assessment.Measurements:The CROSA and the Chinese versions of the Mini-Mental State Examination, the Alzheimer’s Disease Assessment Scale-Cognitive Subscale, the Disability Activity of Dementia, the Neuropsychiatric Inventory Questionnaire, the Zarit Caregiver Burden Interview and the Self-Efficacy Questionnaire for Chinese Family Caregivers.Results:The Cronbach’s alpha for the total scale was 0.900, and the intraclass correlation coefficient and Pearson’s correlation coefficient were 0.910 (P < 0.001) and 0.836 (P < 0.001), respectively. Confirmatory factor analysis revealed the two-factor model to be consistent with the original version. For the known-group validity, the total score of the CROSA classified the PWAD into three stages and three MMSE score groups. Moderate to large correlations with the validated scales confirmed the criteria validity of the CROSA, and the convergent validity was confirmed via testing a hypothesized caregiving model; however, only minimal responsiveness was found among the deterioration group after 12 weeks of treatment with memantine.Conclusions:The reliability and validity of the CROSA was good or acceptable for use in daily clinical settings. Further studies are needed to examine the psychometric properties of the scale.

Background: Previous studies have suggested that Alzheimer's disease (AD) and semantic dementia (SD) are both associated with emotional processing impairment. However, the degree and type of emotional symptoms between the two types of dementia have not been previously compared.Method: We used the Apathy Evaluation Scale (AES), the Toronto Empathy Questionnaire (TEQ), the Geriatric Depression Scale (GDS) and the Self-rating Anxiety Scale (SAS) to examine apathy, empathy, depression and anxiety, respectively.Results: Between mild AD and mild SD, moderate-to-severe AD and moderate-to-severe SD, the total scores of TEQ are significantly different, but the total scores of GDS, SAS and AES have no significant differences. In addition, normal individuals, AD and SD patients got the similar scores in SAS and GDS.Conclusions: Empathy emotion in SD patients is more severe than that in AD patients. However, apathy, depression and anxiety emotion is similar between the two groups.

Background New therapies are urgently needed for Alzheimer’s disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide with a novel proposed mechanism of action. The first phase 3 clinical trial of GV-971 has been completed in China. Methods We conducted a phase 3, double-blind, placebo-controlled trial in participants with mild-to-moderate AD to assess GV-971 efficacy and safety. Participants were randomized to placebo or GV-971 (900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC+), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI). Safety and tolerability were monitored. Results A total of 818 participants were randomized: 408 to GV-971 and 410 to placebo. A significant drug-placebo difference on the ADAS-Cog12 favoring GV-971 was present at each measurement time point, measurable at the week 4 visit and continuing throughout the trial. The difference between the groups in change from baseline was − 2.15 points (95% confidence interval, − 3.07 to − 1.23; p Conclusions GV-971 demonstrated significant efficacy in improving cognition with sustained improvement across all observation periods of a 36-week trial. GV-971 was safe and well-tolerated. Trial registration ClinicalTrials.gov, NCT02293915. Registered on November 19, 2014

Aims Mild cognitive impairment due to semantic dementia represents the preclinical stage, involving cognitive decline dominated by semantic impairment below the semantic dementia standard. Therefore, studying mild cognitive impairment due to semantic dementia may identify changes in patients before progression to dementia. However, whether changes in local functional activity occur in preclinical stages of semantic dementia remains unknown. Here, we explored local functional changes in patients with mild cognitive impairment due to semantic dementia using resting‐state functional MRI. Methods We administered a battery of neuropsychological tests to twenty‐two patients with mild cognitive impairment due to semantic dementia (MCI‐SD group) and nineteen healthy controls (HC group). We performed structural MRI to compare gray matter volumes, and resting‐state functional MRI with multiple sub‐bands and indicators to evaluate functional activity. Results Neuropsychological tests revealed a significant decline in semantic performance in the MCI‐SD group, but no decline in other cognitive domains. Resting‐state functional MRI revealed local functional changes in multiple brain regions in the MCI‐SD group, distributed in different sub‐bands and indicators. In the normal band, local functional changes were only in the gray matter atrophic area. In the other sub‐bands, more regions with local functional changes outside atrophic areas were found across various indicators. Among these, the degree centrality of the left precuneus in the MCI‐SD group was positively correlated with general semantic tasks (oral sound naming, word‐picture verification). Conclusion Our study revealed local functional changes in mild cognitive impairment due to semantic dementia, some of which were located outside the atrophic gray matter. Driven by functional connectivity changes, the left precuneus might play a role in preclinical semantic dementia. The study proved the value of frequency‐dependent sub‐bands, especially the slow‐2 and slow‐3 sub‐bands., This study uses resting‐state fMRI with multiple sub‐bands and indicators to explore functional activity in patients with preclinical semantic dementia. The study find local functional changes in some regions distant from gray matter atrophy areas. Moreover, the left precuneus may play a role in the decline of semantic function.

The current status of the diagnosis and management of poststroke aphasia (PSA) in China is unknown. To analyze the physicians’ strategy and knowledge about the management of PSA in clinical practice and the needs for standardization of diagnosis and treatment. This survey was conducted in March-August 2019 at 32 tertiary hospitals in 16 provinces/municipalities in China. The attending physicians from the Neurology and Neuro-rehabilitation/Rehabilitation Departments were included. The online questionnaire inquired about patient information, physicians’ diagnosis and treatment behavior for PSA, and physicians’ understanding of PSA. A total of 236 physicians completed the survey. Regarding PSA assessment, 99.2% of the physicians reported using medical history and physical examination, 93.2% reported using neuroimaging, and 76.3% reported using dedicated scales. Most physicians used a combination of drug and non-drug treatment. Neuro-regenerators/cerebral activators and anti-dementia drugs were the most common pharmacotherapies; butylphthalide, edaravone, and memantine were most frequently prescribed. Six months poststroke was rendered as a spontaneous language recovery period, and a ≥6-month treatment for PSA was suggested by many physicians. The lack of standardized treatment regimen/clinical guidelines and the limited number of approved drugs for PSA were the primary challenges encountered by physicians during practice. The majority of the physicians agreed with the necessity of guidelines or consensus for the diagnosis and treatment of PSA. The knowledge gaps exist among physicians in China regarding the assessment and management of PSA. The improved awareness of the available guidelines/consensus could improve the performance of the physicians.

Background To identify the applicability of the Chinese Version of Mattis Dementia Rating Scale (DRS-CV). Methods The DRS-CV was administered to 483 participants, including 136 normal controls, 167 patients with mild cognition impairment (MCI), and 180 patients with Alzheimer’s disease (AD). Receiver Operating Characteristic (ROC) curve was used to evaluate the sensitivity and specificity of the scale. Results The scores of DRS-CV were ranked in the order of NC > MCI > mild AD > moderate AD group. Memory was the sensitive function affected at a relatively earlier stage of AD. ROC curve analysis indicated the DRS-CV total score and memory subscale showed excellent sensitivity and specificity in the discrimination between MCI from mild AD and mild AD from moderate AD, but poor sensitivity and specificity in the discrimination between MCI and NC. Conclusion The DRS-CV is useful to the early diagnosis and severity of AD, not to the early identification of MCI.

Objectives To investigate the bilateral hippocampal subfield volumetric differences in four types of mild dementia, namely typical Alzheimer's disease (tAD), dementia with Lewy bodies (DLB), semantic dementia (SD), and posterior cortical atrophy (PCA), to assist differential diagnosis. Methods One hundred three participants, including 22 tAD, 34 SD (17 left SD and 17 right SD), 15 DLB, 12 PCA patients, and 20 normal controls (NC), were recruited. All subjects received standard neuropsychological assessments and magnetic resonance imaging (MRI). The hippocampal subfields were automatically segmented via Freesurfer. The study compared the volumetric differences and used the receiver operating characteristic (ROC) curves to estimate the efficacy of each hippocampal subfield to distinguish between groups. Spearman correlation analysis was used to investigate the relationship between memory recall scores and hippocampal subfield volumes. Results The hippocampal subfield atrophy varied in different groups: tAD, SD, and PCA patients had subregional atrophy in bilateral hippocampi compared to NC, and DLB patients showed preserved volumes; left SD patients suffered the most severe atrophy of the left hippocampus, and right SD patients were atrophied mostly in the right hippocampus. There was no significant difference in the volume of hippocampal subregions between tAD and PCA subjects, but the former tended to be atrophied more asymmetrically. ROC analysis showed that, for discrimination, the areas under the curve (AUC) of some subfields were larger than the total hippocampus, but none observed significant difference. In addition, immediate recall scores were correlated to left CA1, CA2/3, CA4/DG, subiculum, and presubiculum (p < 0.05), and delayed recall scores were strongly related to bilateral CA2/3, CA4/DG, subiculum, and presubiculum (r = 0.38-0.52, p < 0.05). Conclusion Differential atrophy patterns in the bilateral hippocampal subfield volumes could serve the differential diagnosis in patients with different causes of mild dementia: left CA1 for tAD; left presubiculum for LSD; right CA4/DG, right presubiculum, and right subiculum for RSD; CA4/DG and right CA2/3 for DLB; right CA2/3 and right CA4/DG for PCA. Additionally, several hippocampal subfield volumes were significantly associated with memory scores, further highlighting the essential role of the hippocampus in memory decline.

The apolipoprotein E (APOE) e4 allele is a strong risk factor for Alzheimer’s disease (AD) in Caucasian and African American populations. It suggests that other genetic factors may modulate AD pathogenesis in Chinese populations, among which the frequency of this allele is reduced but the AD prevalence is maintained. The translocase of outer mitochondrial membrane 40 (TOMM40), which is located adjacent to APOE, may play an APOE-dependent role in modulating AD pathogenesis. This work aimed to investigate whether TOMM40 polymorphisms modulate AD risk independently of, or in conjunction with APOE polymorphisms in Chinese populations. We conducted a case–control study including 834 patients with AD recruited from the Memory Clinic and 643 cognitively normal participants recruited from the community. The Taqman SNP method was used for APOE genotyping, while TOMM40 polymorphism genotyping was conducted via a polymerase chain reaction-ligase detection reaction. The TOMM40 rs10119 and rs71352238 alleles were associated with AD independently of the patient APOE status. The rs10119 AA genotype and rs71352238 CC genotype were risk genotypes of AD. Individuals carrying a TOMM40 rs10119 GG/APOE e4+ (OR, 3.73; 95% CI 1.49-9.37; P = 0.005), TOMM40 rs10119 AG/APOE e4+ (OR, 4.16; 95% CI 3.30-5.24; P

Objects: Different variations of the Stroop Color-Word Test (SCWT) exist and the tests differ in the number of items on each test card. The optimal number of items per card of the SCWT is unclear. Methods: A comprehensive neuropsychological battery including the SCWT was administered to 237 cognitively normal controls (NC), 221 patients with mild cognitive impairment (MCI), and 160 patients with Alzheimer’s disease (AD). We compared the accuracy for different items of card C (SCWT-C10accuracy, SCWT-C24accuracy, and SCWT-C50accuracy) in distinguishing patients with MCI and AD from NC. Results: The correct responses for different items of card C were ranked in the order: NC > MCI > AD group and mild AD > moderate AD, except for SCWT-C24accuracy. The validity of SCWT-C24accuracy was similar to that of SCWT-C50accuracy for discriminating MCI and AD from NC, as well as different levels of AD. Conclusion: We concluded that the number of items on the accuracy of the response was unrelated to its sensitivity to deficits and we preferred the 24-item version in daily clinical use.

Background Patients who have sustained aneurysmal subarachnoid hemorrhage (aSAH) are thought to have cognitive impairment. However, little is known about the characteristics of functional imaging in patients with aSAH. In this study, we explored whole brain activity patterns in patients with aSAH using amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC). Methods Fifty patients with aSAH and 30 healthy controls were recruited and subjected to a resting-state functional magnetic resonance imaging scan and cognitive tasks. Abnormalities of ALFF and FC in patients with aSAH and the correlations with cognitive tasks were assessed. Results The aSAH group exhibited increased ALFF mainly in the left parahippocampal gyrus (PHG), left inferior temporal gyrus (ITG), and left thalamus (THAL). FC and regression analysis showed positive correlations between functional connectivity strength (FCS) and memory performance in several connections in the aSAH group. These included (1) decreased FC between the left PHG and left inferior parietal lobe; (2) decreased FC between the left ITG and bilateral inferior frontal gyrus orbital part (ORBinf), right middle frontal gyrus; and (3) increased FC between the left THAL and right inferior frontal gyrus orbital part (ORBinf), and right inferior frontal gyrus opercular part. Conclusions Our findings not only demonstrate the unique abnormal cerebral functional topology of patients with aSAH on both local and network levels, but also confirm the correlation between specific FCS and memory function in these patients. In addition, we have identified several potential imaging biomarkers for predicting cognitive outcomes in patients with aSAH.

Dementia with Lewy bodies (DLB) is the second most common degenerative dementia of the central nervous system. The technique 18F-fluorodeoxyglucose positron emission tomography (18F FDG PET) was used to investigate brain metabolism patterns in DLB patients. Conventional statistical methods did not consider intern metabolism transforming connections between various brain regions; therefore, most physicians do not understand the underlying neuropathology of DLB patients. In this study, 18F FDG-PET images and graph-theoretical methods were used to investigate alterations in whole-brain intrinsic functional connectivity in a Chinese DLB group and healthy control (HC) group. This experimental study was performed on 22 DLB patients and 22 HC subjects in Huashan Hospital, Shanghai, China. Experimental results indicate that compared with the HC group, the DLB group has severely impaired small-world network. Compared to those of the HC group, the clustering coefficients of the DLB group were higher and characteristic path lengths were longer, and in terms of global efficiencies, those of the DLB group was also lower. Moreover, four significantly altered regions were observed in the DLB group: Inferior frontal gyrus, opercular part (IFG.R), olfactory cortex (OLF.R), hippocampus (HIP.R), and fusiform gyrus (FFG.L). Amongst them, in the DLB group, betweenness centrality became strong in OLF.R, HIP.R, and FFG.L, whereas betweenness centrality became weaker in IFG.R. Finally, IFGoperc.R was selected as a seed and a voxel-wise correlation analysis was performed. Compared to the HC group, the DLB group showed several regions of strengthened connection with IFGoperc.R; these regions were located in the prefrontal cortex and regions of weakened connection were located in the occipital cortex. The results of this paper may help physicians to better understand and characterize DLB patients.

Background:Disclosing the diagnosis of Alzheimer's disease (AD) to a patient is controversial. There is significant stigma associated with a diagnosis of AD or dementia in China, but the attitude of the society toward disclosure of such a diagnosis had not been formally evaluated prior to our study. Therefore, we aimed to evaluate the attitude toward disclosing an AD diagnosis to patients in China with cognitive impairment from their caregivers, and the factors that may affect their attitude.Methods:We designed a 17-item questionnaire and administered this questionnaire to caregivers, who accompanied patients with cognitive impairment or dementia in three major hospitals in Shanghai, China. The caregiver's attitude toward disclosing the diagnosis of AD as evaluated by the questionnaire was compared to that of disclosing the diagnosis of terminal cancer.Results:A majority (95.7%) of the 175 interviewed participants (mean 14.2 years of education received) wished to know their own diagnosis if they were diagnosed with AD, and 97.6% preferred the doctor to tell their family members if they were diagnosed with AD. If a family member of the participants suffered from AD, 82.9% preferred to have the diagnosis disclosed to the patient. “Cognitive impairment” was the most accepted term by caregivers to disclose AD diagnosis in Chinese.Conclusion:This study suggests most of the well-educated individuals in a Chinese urban area favored disclosing the diagnosis when they or their family members were diagnosed with AD.

Whether and how the apolipoprotein E (APOE) ε4 genotype specifically modulates brain network connectivity in patients with amnestic mild cognitive impairment (aMCI) remain largely unknown. Here, we employed resting-state (‘task-free’) functional MRI and network centrality approaches to investigate local (degree centrality, DC) and global (eigenvector centrality, EC) functional integrity in the whole-brain connectome in 156 older adults, including 66 aMCI patients (27 ε4-carriers and 39 non-carriers) and 90 healthy controls (45 ε4-carriers and 45 non-carriers). We observed diagnosis-by-genotype interactions on DC in the left superior/middle frontal gyrus, right middle temporal gyrus and cerebellum, with higher values in the ε4-carriers than non-carriers in the aMCI group. We further observed diagnosis-by-genotype interactions on EC, with higher values in the right middle temporal gyrus but lower values in the medial parts of default-mode network in the ε4-carriers than non-carriers in the aMCI group. Notably, these genotype differences in DC or EC were absent in the control group. Finally, the network connectivity DC values were negatively correlated with cognitive performance in the aMCI ε4-carriers. Our findings suggest that the APOE genotype selectively modulates the functional integration of brain networks in patients with aMCI, thus providing important insight into the gene-connectome interaction in this disease.

Background There is significant evidence that physical activity has profound effects on the neurochemistry and plasticity of the brain and may prevent cognitive decline. Objective This study aimed to determine the association between physical activity and incident dementia among older Chinese adults. Methods In the prospective phase of the Shanghai Aging Study, 1,648 community-dwellers aged 60 years or older were followed for an average of 5 years. Their physical activity was assessed based on questionnaires. The physical activities were further transformed into metabolic equivalent values. A consensus diagnosis of incident dementia was ascertained based on medical, neurological, and neuropsychological data and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Results We identified 166 incident dementia cases; the incidence rate was 19.4 per 1000 person-years. A multivariate Cox regression model indicated that compared to low levels of physical activity, medium-to-high levels of physical activity were associated with a reduced risk of dementia (hazard ratio, 95% confidence interval = 0.62, 0.44-0.89) after adjusting for age, sex, years of education, apolipoprotein E ɛ4, and other confounders. Conclusion Our findings demonstrate that medium-to-high level of physical activity is protective against dementia in older adults.

Background Subtle cognitive decline (SCD) may represent a very early stage of objective cognitive impairment before mild cognitive impairment (MCI), with less neuronal damage and more functional reservation. Detecting individuals with SCD is imperative for dementia prevention and treatment. In this study, we aimed to compare the validations of three cognitive screening tests, Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment-Chinese Version (MoCA-CV), and Memory and Executive Screening (MES), in identifying subtle cognitive decline. Methods A total of 407 individuals were recruited, including 147 cognitively normal controls (NC), 102 individuals with subtle cognitive decline (SCD) and 158 individuals with mild cognitive impairment (MCI) according to the operational neuropsychological criteria proposed by Jak and Bondi’s. All participants underwent standardized comprehensive neuropsychological tests and the three cognitive screening tests. Chi-square analysis was used to compare the cognitive performance among the groups of NC, SCD and MCI. Receiver operating characteristic (ROC) curves were used to evaluate the abilities of MMSE, MoCA-CV and MES in discriminating NC, SCD and MCI. Results Compared with NC, SCD showed a significant decline only in the tests of memory, such as Auditory Verbal Learning Test (AVLT), Rey-Osterrieth Complex Figure Test (CFT) and Prospective Memory Test (PrM) (P P P Conclusion As a screening test, MES is more efficacious in identifying SCD from normal controls than MMSE and MoCA-CV.

We used pulsed arterial spin labeling (PASL) to investigate differences in cerebral blood flow (CBF) between 26 patients with amnestic mild cognitive impairment (aMCI) and 27 controls with normal cognition (NC). Hypoperfusion was observed in the right temporal pole of the middle temporal gyrus and the right inferior temporal gyrus in the aMCI compared with NC group. Interestingly, hyperperfusion was observed in the left temporal pole of the middle temporal gyrus, left superior temporal gyrus, bilateral precuneus, postcentral gyrus, right inferior parietal lobule, and right angular gyrus in the aMCI group, which likely resulted from a compensatory mechanism to maintain advanced neural activities. We found that mean CBF in the right inferior temporal gyrus, precuneus, and postcentral gyrus was positively correlated with cognitive ability in the aMCI but not NC group. Collectively, our data indicate that PASL is a useful noninvasive technique for monitoring changes in CBF and predicting cognitive decline in aMCI.

The ‘hub-and-spoke’ theory of semantic representation proposes that semantic knowledge is processed in a network comprising modality-specific regions connected to an amodal semantic hub. By studying semantic dementia, Chen et al. identify the semantic hub and its general and modality-specific white matter connections., The hub-and-spoke semantic representation theory posits that semantic knowledge is processed in a neural network, which contains an amodal hub, the sensorimotor modality-specific regions, and the connections between them. The exact neural basis of the hub, regions and connectivity remains unclear. Semantic dementia could be an ideal lesion model to construct the semantic network as this disease presents both amodal and modality-specific semantic processing (e.g. colour) deficits. The goal of the present study was to identify, using an unbiased data-driven approach, the semantic hub and its general and modality-specific semantic white matter connections by investigating the relationship between the lesion degree of the network and the severity of semantic deficits in 33 patients with semantic dementia. Data of diffusion-weighted imaging and behavioural performance in processing knowledge of general semantic and six sensorimotor modalities (i.e. object form, colour, motion, sound, manipulation and function) were collected from each subject. Specifically, to identify the semantic hub, we mapped the white matter nodal degree value (a graph theoretical index) of the 90 regions in the automated anatomical labelling atlas with the general semantic abilities of the patients. Of the regions, only the left fusiform gyrus was identified as the hub because its structural connectivity strength (i.e. nodal degree value) could significantly predict the general semantic processing of the patients. To identify the general and modality-specific semantic connections of the semantic hub, we separately correlated the white matter integrity values of each tract connected with the left fusiform gyrus, with the performance for general semantic processing and each of six semantic modality processing. The results showed that the hub region worked in concert with nine other regions in the semantic memory network for general semantic processing. Moreover, the connection between the hub and the left calcarine was associated with colour-specific semantic processing. The observed effects could not be accounted for by potential confounding variables (e.g. total grey matter volume, regional grey matter volume and performance on non-semantic control tasks). Our findings refine the neuroanatomical structure of the semantic network and underline the critical role of the left fusiform gyrus and its connectivity in the network.

Background The Mild Behavioral Impairment Checklist (MBI-C), a screening scale for neuropsychiatric symptom evaluation, facilitates Alzheimer's disease (AD) screening. However, its validity and reliability for use as an AD screening tool have not been determined. Objective To develop an AD screening scale suitable for the Chinese population. Methods The MBI-C was translated into Chinese and back-translated with the original author's consent. Forty-six AD patients, attending the Xuanwu hospital memory clinic, and 50 sex- and education-matched controls from the community underwent a full neuropsychological evaluation, including MBI-C assessment. Among them, 15 AD patients were evaluated repeatedly, and eight were evaluated simultaneously by two different clinicians, to assess MBI-C reliability. Results The MBI-C demonstrated good internal consistency reliability, test-retest reliability, and inter-rater reliability. Its optimal cutoff point was 6/7 for identifying AD dementia, with a sensitivity of 86.96% and specificity of 86.00%, and its detection rate for moderate-severe AD dementia was higher than that of the Neuropsychiatric Inventory Questionnaire (NPI-Q). Pearson's correlation coefficients ranged from 0.702 to 0.831, indicating content validity. Seven factors were extracted during principal component analysis, with a cumulative contribution of 70.55%. Moreover, the Pearson's correlation coefficient was 0.758, indicating its criterion validity. The MBI-C could also distinguish AD dementia severity. MBI-C scores were significantly negatively correlated with MMSE and MoCA scores, and positively correlated with ADL scores. Conclusion This study showed that the Chinese version of MBI-C has high reliability and validity, and could replace the NPI-Q for AD dementia screening in the Chinese population.

Background: Approximately 40 independent Single Nucleotide Polymorphisms (SNPs) have been associated with Alzheimer’s Disease (AD) or cognitive decline in genome-wide association studies. Methods: We aimed to evaluate the joint effect of genetic polymorphisms and environmental factors on the progression from Mild Cognitive Impairment (MCI) to AD (MCI-AD progression) in a Chinese community cohort. Conclusion: Demographic, DNA and incident AD diagnosis data were derived from the follow-up of 316 participants with MCI at baseline of the Shanghai Aging Study. The associations of 40 SNPs and environmental predictors with MCI-AD progression were assessed using the Kaplan-Meier method with the log-rank test and Cox regression model. Results: Rs4147929 at ATP-binding cassette family A member 7 (ABCA7) (AG/AA vs. GG, hazard ratio [HR] = 2.43, 95% confidence interval [CI] 1.24-4.76) and body mass index (BMI) (overweight vs. non-overweight, HR = 0.41, 95% CI 0.22-0.78) were independent predictors of MCI-AD progression. In the combined analyses, MCI participants with the copresence of non-overweight BMI and the ABCA7 rs4147929 (AG/AA) risk genotype had an approximately 6-fold higher risk of MCI-AD progression than those with an overweight BMI and a non-risk genotype (HR = 6.77, 95% CI 2.60-17.63). However, a nonsignificant result was found when participants carried only one of these two risk factors (nonoverweight BMI and AG/AA of ABCA7 rs4147929). Conclusion: ABCA7 rs4147929 and BMI jointly affect MCI-AD progression. MCI participants with the rs4147929 risk genotype may benefit from maintaining an overweight BMI level with regard to their risk for incident AD.

Supplemental Digital Content is available in the text., Objective To explore the effect of APOE polymorphisms on patients with cognitive impairments in The Chinese Han population. Materials and methods A total of 1027 cases with Alzheimer’s disease (AD), 40 cases with vascular dementia (VaD), 28 cases with behavioral variant frontotemporal dementia (bvFTD), 54 cases with semantic dementia (SD), 44 cases with dementia with Lewy bodies (DLB), 583 cases with mild cognitive impairment (MCI), and 32 cases with vascular cognitive impairment no dementia (VCIND) were recruited consecutively from memory disorders clinics in Huashan Hospital between January 2010 and December 2014. The 1149 cognitively normal controls were recruited from the community epidemiologic investigations. The APOE genotypes were determined using the TaqMan assay. Results The distribution of genotype and allele frequencies of APOE differed significantly between control and AD or MCI, with ε4 increasing the risk of AD and MCI in a dose-dependent pattern and ε2 decreasing the risk of AD, but not the risk of MCI. As for VaD, significant differences in the APOE genotype distribution were found compared with the controls. E4/4 increased the risk of VaD and ε4 increased the risk of VCIND in women. The allele distribution differed between bvFTD and controls, but genotype and allele frequencies of APOE did not affect the risk of bvFTD, SD, and DLB. Conclusion In The Chinese Han population, APOE ε4 increased the risk of AD and MCI in a dose-dependent manner and ε2 decreased the risk of AD as reported previously. APOE ε4 might increase risk in VaD and female patients with VCIND, but no effects of APOE on bvFTD, DLB, and SD were found.

The clinical manifestation of Lewy body dementia (DLB) is distinct from Alzheimer's disease (AD), but overlap with Parkinson's disease dementia (PDD). However, little is known about different topology properties of abnormal brain networks associated with these neurodegenerative diseases. In order to study the difference of brain networks in various dementia subtypes, we used $^{\mathbf {18}}\text{F}$-Fluorodeoxyglucose positron emission tomography ($^{\mathbf {18}}\text{F}$-FDG PET) images and graph theory methods to investigate altered whole-brain intrinsic glucose metabolic functional networks in three Chinese dementia groups compared to healthy control (HC) group, including 22 AD patients, 18 PDD patients, 22 DLB patients and 22 HC subjects from Huashan Hospital, Shanghai, China. The experimental results disclosed that in the three dementia groups, compared to HC group, the small-world characteristics were lost. Additionally, compared with HC group, the clustering coefficients of three dementia groups were higher; the characteristic path lengths were longer. In terms of local efficiency and global efficiency, it was at the lowest level in DLB group. We also found differences about distributions of hub regions amongst the four groups. This finding could further help physicians to understand pathological mechanisms of different dementia.

Background: In addition to the increasing evidence for a molecular mechanism of rho kinase 1 ( ROCK1 ) in Alzheimer’s disease (AD), there are several published studies regarding the relationship between ROCK1 gene polymorphisms and neurological diseases. However, it is unknown whether there is an association between the polymorphisms of ROCK1 and AD. We sought to identify the potential association between ROCK1 gene polymorphisms and AD in the Chinese Han population. Methods: A total of 295 patients with AD and 206 healthy controls from multiple centers were enrolled in this study. Three single-nucleotide polymorphisms (SNPs) (rs35996865, rs11873284, and rs2127958) in ROCK1 gene were analyzed using Sanger sequencing. Results: We did not find any significant differences between AD and control groups with regards to the frequency of these three ROCK1 polymorphisms. Further, the three SNP genotype frequencies and allele frequencies did not show significant differences between patients of AD and controls in APOE4 -stratified subjects (P>0.01). Additionally, the three SNPs did not show significant differences even when adopting a four-inheritance model by logistic regression. Conclusions: This is the first multicenter pilot study to evaluate the contribution of ROCK1 genetic variance to AD risk. Our data demonstrated that the ROCK1 gene may not influence the risk of AD by interacting with APOE among Chinese Han people.

Background: To explore the association between blood pressure and cognition in older participants in the Shanghai Aging Study.Methods: Data were drawn from 3,327 participants at the baseline of Shanghai Aging Study. History of hypertension was inquired and confirmed from participants' medical records. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by research nurses in the early morning. Participants were diagnosed with “cognitive normal,” “mild cognitive impairment (MCI),” or “dementia” by neurologists using DSM-IV and Petersen criteria. Multivariate logistic regression was used to evaluate the association between history of hypertension, duration of hypertension, SBP, DBP, or classification of blood pressure and cognitive function. Generalized linear model was used to assess the relation between duration of hypertension, SBP, or DBP and Mini Mental State Examination (MMSE).Results: A significantly higher proportion of hypertension [78 (76.5%)] was found in participants with dementia than in those with MCI [347 (59.3%)] and cognitive normal [1,350 (51.1%)] (P < 0.0001). Participants with dementia had significantly higher SBP [157.6 (26.1) mmHg] than those with MCI [149.0 (23.7) mmHg] and cognitive normal [143.7 (22.6) mmHg] (P < 0.0001). After adjusting for sex, age, education, living alone, body mass index, anxiety, depression, heart disease, diabetes, and stroke, the likelihood of having dementia was positively associated with history of hypertension (OR = 2.10; 95% CI: 1.22, 3.61), duration of hypertension (OR = 1.02 per increment year; 95% CI: 1.01, 1.04), higher SBP (OR = 1.14 per increment of 10 mmHg; 95% CI: 1.04, 1.25), higher DBP (OR = 1.22 per increment of 10 mmHg; 95% CI: 1.02, 1.45), moderate hypertension (OR = 2.09; 95% CI: 1.10, 3.99), or severe hypertension (OR = 2.45; 95% CI: 1.20, 4.99). The MMSE score was inversely correlated to duration of hypertension (β = −0.0088 per increment year; 95% CI: −0.0158, −0.0018, P = 0.0132), SBP (β = −0.0655 per increment of 10 mmHg; 95% CI: −0.1022, −0.0288, P = 0.0005), and DBP (β = −0.1230 per increment of 10 mmHg; 95% CI: −0.1915, −0.0545, P = 0.0004).Conclusion: Our results suggest that hypertension and high blood pressure may be potential risk factors for dementia. Blood pressure management for the elderly may be important for maintaining cognitive vitality.

Variants in triggering receptor expressed on myeloid cells 2 (TREM2) are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer's disease. TREM2 homozygous mutations cause Nasu-Hakola disease, an early-onset recessive form of dementia preceded by bone cysts and fractures. The same type of mutations has been shown to cause frontotemporal dementia without the presence of any bone phenotype. Herein, we report a Chinese Han consanguineous family carrying a novel TREM2 mutation, presenting with early-onset dementia similar to behavioral variant frontotemporal dementia with mild radiological bone involvement. Minigene reporter assay showed the variant disturbed splicing by preservation of intron 2 in transcription. In our investigation, the clinical and genetic spectra of Chinese early-onset dementia patients were expanded; TREM2 mutations should be screened in familial and Chinese early-onset dementia patients.

The presence of both apolipoprotein E (APOE) e4 allele and amnestic mild cognitive impairment (aMCI) are considered to be risk factors for Alzheimer’s disease (AD). Numerous neuroimaging studies have suggested that the modulation of APOE ɛ4 affects intrinsic functional brain networks, both in healthy populations and in AD patients. However, it remains largely unclear whether and how e4 allele modulates the brain’s functional network architecture in subjects with aMCI. Using resting-state functional magnetic resonance imaging (fMRI) and graph-theory approaches-functional connectivity strength (FCS), we investigate the topological organization of the whole-brain functional network in 28 aMCI e4 carriers and 38 aMCI e3e3 carriers. In the present study, we first observe that e4-related FCS increases in the right hippocampus/parahippocampal gyrus (HIP/PHG). Subsequent seed-based resting-state functional connectivity (RSFC) analysis revealed that, compared with the e3e3 carriers, the e4 carriers had lower or higher RSFCs between the right HIP/PHG seed and the bilateral medial prefrontal cortex (MPFC) or the occipital cortex, respectively. Further correlation analyses have revealed that the FCS values in the right HIP/PHG and lower HIP/PHG-RSFCs with the bilateral MPFC were significantly correlated with the impairment of episodic memory and executive function in the aMCI e4 carriers. Importantly, the logistic regression analysis showed that the HIP/PHG-RSFC with the bilateral MPFC predicted aMCI-conversion to AD. These findings suggest that the APOE e4 allele may modulate the large-scale brain network in aMCI subjects, facilitating our understanding of how the entire assembly of the brain network reorganizes in response to APOE variants in aMCI. Further longitudinal studies need to be conducted, in order to examine whether these network measures could serve as primary predictors of conversion from aMCI e4 carriers to AD.

Lin Huang,1 Ke-Liang Chen,1 Bi-Ying Lin,1 Le Tang,1 Qian-Hua Zhao,1 Ying-Ru Lv,2,* Qi-Hao Guo1,* 1Department of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; 2Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China *These authors contributed equally to this work Objectives: To find out whether the Chinese version of Montreal Cognitive Assessment Basic (MoCA-BC) and its subtests could be applied in discrimination among cognitively normal controls (NC), mild cognitive impairment (MCI), mild and moderate Alzheimer’s Disease (AD), and furthermore, to determine the optimal cutoffs most sensitive to distinguish between them.Design: A cross-sectional validation study.Setting: Huashan Hospital, Shanghai, China.Participants: There was a total of 1,969 participants: individuals with MCI (n=663), mild (n=345), moderate (n=441) AD, and cognitively NC (n=520) were recruited from the Memory Clinic, Huashan Hospital, Shanghai, China.Measurements: Baseline MoCA-BC scores were collected from firsthand data. Two subtests were calculated from MoCA-BC: the Memory Index Score of MoCA-BC (MoCA-BC-MIS) and the Non-memory Index Score of MoCA-BC (MoCA-BC-NM).Results: MoCA-BC was an effective cognitive tool to discriminate among NC, MCI, mild and moderate AD in the Chinese elderly across all education groups, implying that it was efficient not only for detecting MCI, but for different severities of AD as well. For MCI screening, the total score of MoCA-BC (MoCA-BC-T) and MoCA-BC-MIS had similar high sensitivity and specificity. For discrimination among MCI, mild and moderate AD, the MoCA-BC-T and MoCA-BC-NM had similar performance.Conclusion: MoCA-BC is an effective cognitive test to distinguish between NC, MCI, mild and moderate AD among the Chinese elderly with various levels of education. Keywords: mild cognitive impairment, Montreal Cognitive Assessment, Alzheimer’s disease, cutoff study

Dementia has become a serious disease in elderly population. Graph theory based brain network analysis method is considered as a popular and universal technique in the field of the neurosciences. It can help neuroscientists to investigate the neuropathology of dementia, especially to understand dementia subtypes. However, brain network analysis for various dementia subtypes at the same time is still limited. The aim at this study is to investigate the similarities and differences in brain network modular parameters of three dementia subtypes: Alzheimer's disease (AD), Parkinson's disease dementia (PDD), Lewy body dementia (DLB). Health control has also been compared. All subjects of health control(HC), AD, PDD and DLB groups were from Huashan Hospital. Using topological analysis algorithms, we found that HC brain was divided into 4 modules; AD brain was divided into 4 modules; PDD brain was divided into 6 modules; and DLB brain was divided into 10 modules, which demonstrated differences in these dementia subtypes. We also found that right thalamus area was scattered in all dementia subtypes. After using the seed point correlation analysis, it can be seen that the connections between right thalamus and subcortical, frontal gyrus were enhanced and the connections with the occipital gyrus was attenuated in dementia subtypes. As a result, findings in this paper are expected to be useful for neuroscientists to further understand the pathology of AD, PDD and DLB.

The temporal lobe is a central core of neurodegeneration in Alzheimer's disease and semantic dementia. The severe semantic memory impairments in semantic dementia have been attributed to their pronounced anterior temporal lobe atrophy and functional disruption. In contrast, medial and posterior temporal lobe damage predominantly found in patients with Alzheimer's disease has been associated with episodic memory disturbance. Despite these seemingly distinct neuropathological signatures that correspond well to the syndrome-typical symptomatology, hippocampal deterioration common in Alzheimer's disease and semantic dementia appears paradoxical. In attempting to gain more insight into mutual and divergent functional alterations of Alzheimer's disease and semantic dementia, we assessed intrinsic functional connectivity between temporal lobe regions in patients with Alzheimer's disease (n = 16), semantic dementia (n = 23), and healthy controls (n = 17). Other than the majority of studies that conducted comparable analyses, we were particularly interested in connectivity alterations between functional rather than anatomical regions, and therefore used a functional parcellation of the temporal cortex. Unexpectedly, the Alzheimer's disease group showed only a single connection with reduced functional connectivity as compared to the controls. It was comprised of the right orbitofrontal cortex and the right anterior temporal lobe. In contrast, functional connectivity was decreased in the semantic dementia group in six connections, mainly involving hippocampus, lingual gyrus, temporal pole, and orbitofrontal cortex. In our view, the relatively intact functional connectivity in the Alzheimer's disease sample was owed to their relative mild state of the disease. Nevertheless, we identified a common pathway with semantic dementia, since functional connectivity between right anterior temporal lobe and right orbitofrontal cortex was reduced in both dementia types. This might be related to impairments in social behavior frequently observed in patients. Moreover, besides the expected functional connectivity disruptions in brain regions associated with language processing and semantic memory, our results point to the importance of an intact anterior temporal lobe for a sound semantic and social functioning.