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Abstract Sodium oligomannate (GV-971), an oligosaccharide drug approved in China for treating mild-to-moderate Alzheimer’s disease (AD), was previously found to recondition the gut microbiota and limit altered peripheral Th1 immunity in AD transgenic mice. As a follow-up study, we here made advances by pinpointing a Lactobacillus murinus (L.m.) strain that highly expressed a gene encoding a putative adhesin containing Rib repeats (Ribhigh-L.m.) particularly enriched in 5XFAD transgenic mice. Mechanistically, Ribhigh-L.m. adherence to the gut epithelia upregulated fecal metabolites, among which lactate ranked as the top candidate. Excess lactate stimulated the epithelial production of serum amyloid A (SAA) in the gut via the GPR81-NFκB axis, contributing to peripheral Th1 activation. Moreover, GV-971 disrupted the adherence of Ribhigh-L.m. to gut epithelia via direct binding to Rib, which corrected the excess lactate, reduced SAA, and alleviated Th1-skewed inflammation. Together, we gained further insights into the molecular link between gut bacteria and AD progression and the mechanism of GV-971 in treating AD.

Abstract Previous studies have suggested a potential association between the gut microbiota and arthritis. However, the causal links between the gut microbiota and various types of arthritis, as well as the potential mediating role of inflammatory proteins, remain unclear. Mendelian randomization was used to explore the causal relationships between gut microbiota, inflammatory proteins, and various forms of arthritis (osteoarthritis, rheumatoid and psoriatic arthritis, and ankylosing spondylitis [AS]). The inverse variance-weighted method was the primary analytical approach used. Furthermore, we examined the mediating role of inflammatory proteins in the pathway linking the gut microbiota to arthritis. Sensitivity analyses were performed to verify the robustness of the findings, and enrichment analyses were conducted to investigate the biological functions and pathways involved. We identified 11 positive and 14 negative causal effects linking the genetic liability of the gut microbiota to arthritis. Similarly, 9 positive and 8 negative causal effects between inflammatory proteins and arthritis were identified. Notably, an increased abundance of the order Bacillales (odds ratio [OR] = 1.199, 95% confidence interval [CI] = 1.030–1.394, P = 0.019) and higher interleukin-7 levels (OR = 1.322, 95% CI = 1.004–1.741, P = 0.046) significantly elevated the risk of AS. Furthermore, interleukin-7 mediated 13.8% of the effect caused by the order Bacillales, with a mediation effect size of β = 0.025 (95% CI = 0.001–0.064). Sensitivity and supplementary analyses revealed no significant evidence of horizontal pleiotropy or heterogeneity. Overall, our findings demonstrate causal links between the gut microbiota, inflammatory proteins, and four arthritis types, highlighting the gut microbiota as a potential therapeutic target. Crucially, interleukin-7 not only strongly correlated with AS but also partially mediated the effect exerted by the gut microbiota on AS, suggesting that managing the gut microbiota to modulate inflammatory proteins could serve as an effective therapeutic strategy for arthritis.

Abstract Introduction Constipation may be linked to cognitive decline and a higher risk of Alzheimer’s disease (AD). We aimed to investigate the association between constipation and positron emission tomography (PET) and blood-based AD biomarkers in older cognitively unimpaired (CU) adults with higher Aβ burden. Methods Constipation was diagnosed according to Rome IV criteria and the severity of constipation was evaluated by using a validated self-reported questionnaire. The participants underwent the examination of plasma AD biomarkers and 18F-florbetapir PET and 18F-MK6240 PET scans; the latter was only performed in the validation cohort. Correlation and multiple linear regression analyses were used to investigate the association between constipation and AD biomarkers. Results Two cohorts were included in our study. A total of 404 older participants with 126 of whom Aβ-PET positive were enrolled in the development cohort. Multiple linear regression analysis showed constipation was associated with plasma t-Tau, p-Tau-181, and neurofilament light chain (NfL) in participants with Aβ-PET (+). Meanwhile, no/mild constipation was associated with lower Aβ-PET standard uptake value ratio. The association between constipation and plasma biomarkers was different in the subgroups stratified by age, sex and APOE ε4 genotype. The above associations were further validated in the validation cohort containing 36 Aβ-PET (+) participants. Importantly, no/mild constipation was associated with less Tau burden evaluated by 18F-MK6240 PET Braak stages. Conclusion Our data indicate that no/mild constipation may be associated with lower plasma t-Tau, p-Tau-181, and NfL as well as less Aβ and Tau burden in older CU adults with Aβ deposition. Improving constipation and being away from defecation disorders may help reduce the risk of AD development.

IntroductionAlzheimer’s disease (AD) is a common neurological disorder. Based on clinical characteristics, it can be categorized into normal cognition (NC), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia (AD). Once the condition begins to progress, the process is usually irreversible. Therefore, early identification and intervention are crucial for patients. This study aims to explore the sensitivity of fNIRS in distinguishing between SCD and MCI.MethodsAn in-depth analysis of the Functional Connectivity (FC) and oxygenated hemoglobin (HbO) characteristics during resting state and different memory cognitive tasks is conducted on two patient groups to search for potential biomarkers. The 33 participants were divided into two groups: SCD and MCI.ResultsFunctional connectivity strength during the resting state and hemodynamic changes during the execution of Verbal Fluency Tasks (VFT) and MemTrax tasks were measured using fNIRS. The results showed that compared to individuals with MCI, patients with SCD exhibited higher average FC levels between different channels in the frontal lobe during resting state, with two channels’ FC demonstrating significant ability to distinguish between SCD and MCI. During the VFT task, the overall average HbO concentration in the frontal lobe of SCD patients was higher than that of MCI patients from 5 experimental paradigm. Receiver operating characteristic analysis indicated that the accuracy of the above features in distinguishing SCD from MCI was 78.8%, 72.7%, 75.8%, and 66.7%, respectively.DiscussionfNIRS could potentially serve as a non-invasive biomarker for the early detection of dementia.

Abstract Brain disease diagnosis using multiple imaging modalities has shown superior performance compared to using single modality, yet multi-modal data is not easily available in clinical routine due to cost or radiation risk. Here we propose a synthesis-empowered uncertainty-aware classification framework for brain disease diagnosis. To synthesize disease-relevant features effectively, a two-stage framework is proposed including multi-modal feature representation learning and representation transfer based on hierarchical similarity matching. Besides, the synthesized and acquired modality features are integrated based on evidential learning, which provides diagnosis decision and also diagnosis uncertainty. Our framework is extensively evaluated on five datasets containing 3758 subjects for three brain diseases including Alzheimer’s disease (AD), subcortical vascular mild cognitive impairment (MCI), and O[6]-methylguanine-DNA methyltransferase promoter methylation status for glioblastoma, achieving 0.950 and 0.806 in area under the ROC curve on ADNI dataset for discriminating AD patients from normal controls and progressive MCI from static MCI, respectively. Our framework not only achieves quasi-multimodal performance although using single-modal input, but also provides reliable diagnosis uncertainty.

Abstract The metabolic implications in Alzheimer’s disease (AD) remain poorly understood. Here, we conducted a metabolomics study on a moderately aging Chinese Han cohort (n = 1397; mean age 66 years). Conjugated bile acids, branch-chain amino acids (BCAAs), and glutamate-related features exhibited strong correlations with cognitive impairment, clinical stage, and brain amyloid-β deposition (n = 421). These features demonstrated synergistic performances across clinical stages and subpopulations and enhanced the differentiation of AD stages beyond demographics and Apolipoprotein E ε4 allele (APOE-ε4). We validated their performances in eight data sets (total n = 7685) obtained from Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and Memory and Aging Project (ROSMAP). Importantly, identified features are linked to blood ammonia homeostasis. We further confirmed the elevated ammonia level through AD development (n = 1060). Our findings highlight AD as a metabolic disease and emphasize the metabolite-mediated ammonia disturbance in AD and its potential as a signature and therapeutic target for AD.

Lithium-ion battery-based hybrid energy storage systems (ESSs) have been widely applied in various fields. Bidirectional DC/DC converters, crucial interfaces linking batteries and DC buses, serve as critical actuators for tasks such as DC bus regulation, on-line battery diagnosis, health-conscious energy management strategy, and fault tolerant control. Despite their importance, the control of bidirectional DC/DC converters in hybrid ESSs has rarely been independently discussed. Their control-related works are usually carried out by the unidirectional DC/DC converter modeling process with proportional–integral (PI)-type controllers. Therefore, recognizing the significance of pulsed power loads and the induced highly dynamic changes in battery voltage during real-world applications, this paper highlights the relevance of applying H∞-optimal controllers for bidirectional DC/DC converters based on its detailed control-oriented modeling process. To present a rigorous H∞-optimal controller synthesis process, this study includes a detailed experimental determination of the controller’s key parameters. Furthermore, extensive numerical tests across diverse battery operation scenarios have been conducted to demonstrate the advantages of applying H∞-optimal controllers for battery-based bidirectional DC/DC converters in hybrid ESSs.

IntroductionSome evidence suggests that fruit and alcohol consumption may be related to cognitive impairment.MethodsThis study conducted a cross-sectional study on the “correlation between eating habits and cognitive function of the middle-aged and elderly population in China.” The purpose of this study is to explore the relationship between fruit consumption, drinking habits and cognitive impairment in Chinese people over 50 years old.ResultsThe results show that the protective factors of cognitive impairment are the preference for berries and the daily intake of 100-200 grams grapes in Chinese middle-aged and elderly people with objective cognitive unimpaired. The habit of drinking red wine is a protective factor for cognitive impairment in Chinese middle-aged and elderly people with mild cognitive impairment (MCI). However, this study did not find the relationship between white wine, beer, yellow rice wine, liquor and cognitive impairment.DiscussionTherefore, we believe that berries, grapes and red wine consumption can protect the cognitive function of the middle-aged and elderly people in China, and the protective function is related to the basic cognitive state.

Abstract Background Metabotropic glutamate receptor 5 (mGluR5) is involved in regulating integrative brain function and synaptic transmission. Aberrant mGluR5 signaling and relevant synaptic failure play a key role in the initial pathophysiological mechanism of Alzheimer’s disease (AD). The study aims to investigate the association between mGluR5 availability and AD’s biomarkers and cognitive function. Methods We examined 35 individuals with mGluR5 tracer [18F]PSS232 to assess mGluR5 availability, and with [18F]Florbetapir PET to assess global amyloid deposition, and [18F]FDG PET to assess glucose metabolism. The plasma neurofilament light (NfL) and p-tau181 levels in a subset of individuals were measured (n = 27). The difference in mGluR5 availability between the AD and normal control (NC) groups was explored. The associations of mGluR5 availability with amyloid deposition, glucose metabolism, gray matter volume (GMV), neuropsychological assessment scores, and plasma biomarkers were analyzed. Results The mGluR5 availability was significantly reduced in AD patients’ hippocampus and parahippocampal gyrus compared to NCs. Global amyloid deposition was positively associated with mGluR5 availability in the AD group and reversely associated in the NC group. The mGluR5 availability was positively correlated with regional glucose metabolism in the overall and stratified analyses. The availability of mGluR5 in the hippocampus and parahippocampal gyrus demonstrated a strong relationship with the GMV of the medial temporal lobe, plasma p-tau181 or NfL levels, and global cognitive performance. Conclusions [18F]PSS232 PET can quantify the changes of mGluR5 availability in the progression of AD. mGluR5 availability correlated not only with neuropathological biomarkers of AD but also with neurodegenerative biomarkers and cognitive performance. mGluR5 may be a novel neurodegenerative biomarker, and whether mGluR5 could be a potential therapeutic target for AD needs to be further studied.

Abstract Sex disparities in serum bile acid (BA) levels and Alzheimer's disease (AD) prevalence have been established. However, the precise link between changes in serum BAs and AD development remains elusive. Here, authors quantitatively determined 33 serum BAs and 58 BA features in 4 219 samples collected from 1 180 participants from the Alzheimer's Disease Neuroimaging Initiative. The findings revealed that these BA features exhibited significant correlations with clinical stages, encompassing cognitively normal (CN), early and late mild cognitive impairment, and AD, as well as cognitive performance. Importantly, these associations are more pronounced in men than women. Among participants with progressive disease stages (n = 660), BAs underwent early changes in men, occurring before AD. By incorporating BA features into diagnostic and predictive models, positive enhancements are achieved for all models. The area under the receiver operating characteristic curve improved from 0.78 to 0.91 for men and from 0.76 to 0.83 for women for the differentiation of CN and AD. Additionally, the key findings are validated in a subset of participants (n = 578) with cerebrospinal fluid amyloid‐beta and tau levels. These findings underscore the role of BAs in AD progression, offering potential improvements in the accuracy of AD prediction.

Alzheimer’s disease (AD) is a common cause of dementia, characterised by cerebral amyloid-β deposition, pathological tau and neurodegeneration. The prodromal stage of AD (pAD) refers to patients with mild cognitive impairment (MCI) and evidence of AD’s pathology. At this stage, disease-modifying interventions should be used to prevent the progression to dementia. Given the inherent heterogeneity of MCI, more specific biomarkers are needed to elucidate the underlying AD’s pathology. Although the uses of cerebrospinal fluid and positron emission tomography are widely accepted methods for detecting AD’s pathology, their clinical applications are limited by their high costs and invasiveness, particularly in low-income areas in China. Therefore, to improve the early detection of Alzheimer's disease (AD) pathology through cost-effective screening methods, a panel of 45 neurologists, psychiatrists and gerontologists was invited to establish a formal consensus on the screening of pAD in China. The supportive evidence and grades of recommendations are based on a systematic literature review and focus group discussion. National meetings were held to allow participants to review, vote and provide their expert opinions to reach a consensus. A majority (two-thirds) decision was used for questions for which consensus could not be reached. Recommended screening methods are presented in this publication, including neuropsychological assessment, peripheral biomarkers and brain imaging. In addition, a general workflow for screening pAD in China is established, which will help clinicians identify individuals at high risk and determine therapeutic targets.

Abstract Background Accurate prediction of cerebral amyloidosis with easily available indicators is urgently needed for diagnosis and treatment of Alzheimer’s disease (AD). Methods We examined plasma Aβ42, Aβ40, T-tau, P-tau181, and NfL, with APOE genotypes, cognitive test scores and key demographics in a large Chinese cohort (N = 609, aged 40 to 84 years) covering full AD spectrum. Data-driven integrated computational models were developed to predict brain β-amyloid (Aβ) pathology. Results Our computational models accurately predict brain Aβ positivity (area under the ROC curves (AUC) = 0.94). The results are validated in Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Particularly, the models have the highest prediction power (AUC = 0.97) in mild cognitive impairment (MCI) participants. Three levels of models are designed with different accuracies and complexities. The model which only consists of plasma biomarkers can predict Aβ positivity in amnestic MCI (aMCI) patients with AUC = 0.89. Generally the models perform better in participants without comorbidities or family histories. Conclusions The innovative integrated models provide opportunity to assess Aβ pathology in a non-invasive and cost-effective way, which might facilitate AD-drug development, early screening, clinical diagnosis and prognosis evaluation.

Zhou et al. utilise deep learning to improve polygenic risk analysis for Alzheimer’s disease. Their computational approach outperforms existing statistical methods and helps to identify potential biological mechanisms of Alzheimer’s disease risk.

Abstract Visual interpretation is considered the gold standard for amyloid scans in clinical practice. However, dichotomous classification of amyloid deposition by visual reading always results in bias due to rater experience. Therefore, there is a need for a more lenient and flexible amyloid‐equivocal classification in clinical practice. A total of 461 participants were included in this study. Amyloid and glucose positron‐emission tomography was performed, and neuropsychological tests were evaluated. A disease‐specific deep‐learning method was used to identify amyloid equivocality. Amyloid deposition, glucose metabolism, and cognitive performance were analyzed and compared among amyloid‐positive, amyloid‐negative, and amyloid‐equivocal groups. Clinically diagnosed Alzheimer's disease individuals and subjects with normal cognition were used to create amyloid biomarker cut points to support the definition of equivocal amyloid deposition. A total of 139 amyloid‐equivocal individuals were identified by deep learning methods. They displayed intermediate amyloid deposition between that of amyloid‐positive (standardized uptake value ratio [SUVr]: 1.25 ± 0.10 vs. 1.47 ± 0.20, p < 0.001) and amyloid‐negative (SUVr: 1.25 ± 0.10 vs. 1.18 ± 0.07, p < 0.001) individuals. No difference in glucose metabolism or cognitive performance was observed between amyloid negativity and equivocality. Furthermore, the SUVr for the whole cortex, the precuneus, and the frontal lobe served as auxiliary criteria supporting the diagnosis of equivocal amyloid deposition. We also established a guide to assist in the interpretation of amyloid equivocality by visual reading with auxiliary criteria including two cut points and deep learning methods.

Highlights There are significant sex differences in Chinese population with cognitive impairment in Lewy body disease. Women were more common in dementia with Lewy bodies and mild cognitive impairment with Lewy bodies cases, had more frequent and severe neuropsychiatric symptoms, and poorer cognition than men. Men predominant in Parkinson’s disease with mild cognitive impairment and Parkinson’s disease with dementia cases, and performed more frequent RBD and parkinsonism than women. Dementia with Lewy bodies vs. Parkinson’s disease with dementia, and mild cognitive impairment with Lewy bodies vs. Parkinson’s disease with mild cognitive impairment are distinct disease forms and should not be confused.

Abstract Background Alzheimer’s disease (AD), a progressive neurodegenerative disease, is the most common cause of dementia worldwide. Accumulating data support the contributions of the peripheral immune system in AD pathogenesis. However, there is a lack of comprehensive understanding about the molecular characteristics of peripheral immune cells in AD. Methods To explore the alterations of cellular composition and the alterations of intrinsic expression of individual cell types in peripheral blood, we performed cellular deconvolution in a large-scale bulk blood expression cohort and identified cell-intrinsic differentially expressed genes in individual cell types with adjusting for cellular proportion. Results We detected a significant increase and decrease in the proportion of neutrophils and B lymphocytes in AD blood, respectively, which had a robust replicability across other three AD cohorts, as well as using alternative algorithms. The differentially expressed genes in AD neutrophils were enriched for some AD-associated pathways, such as ATP metabolic process and mitochondrion organization. We also found a significant enrichment of protein-protein interaction network modules of leukocyte cell-cell activation, mitochondrion organization, and cytokine-mediated signaling pathway in neutrophils for AD risk genes including CD33 and IL1B. Both changes in cellular composition and expression levels of specific genes were significantly associated with the clinical and pathological alterations. A similar pattern of perturbations on the cellular proportion and gene expression levels of neutrophils could be also observed in mild cognitive impairment (MCI). Moreover, we noticed an elevation of neutrophil abundance in the AD brains. Conclusions We revealed the landscape of molecular perturbations at the cellular level for AD. These alterations highlight the putative roles of neutrophils in AD pathobiology.

Reactive oxygen species (ROS) has great influence in many physiological or pathological processes in organisms. In the site of bone defects, the overproduced ROS significantly affects the dynamic balance process of bone regeneration. Many antioxidative organic and inorganic antioxidants showed good osteogenic ability, which has been widely used for bone repair. It is of great significance to summarize the antioxidative bone repair materials (ABRMs) to provide guidance for the future design and preparation of osteogenic materials with antioxidative function. Here, this review introduced the major research direction of ABRM at present in nanoscale, 2-dimensional coating, and 3-dimensional scaffolds. Moreover, the referring main active substances and antioxidative properties were classified, and the positive roles of antioxidative materials for bone repair have also been clearly summarized in signaling pathways, antioxidant enzymes, cellular responses and animal levels.

Abstract Background Although previous studies have demonstrated that the hippocampus plays a role in verbal memory, the role of hippocampal subfields in visual memory is uncertain, especially in those with preclinical Alzheimer's disease (AD). This study aimed to examine relationships between hippocampal subfield volumes and visual memory in SCD (subjective cognitive decline) and aMCI (amnestic mild cognitive impairment). Methods The study sample included 47 SCD patients, 62 aMCI patients, and 51 normal controls (NCs) and was recruited from Shanghai Jiao Tong University Affiliated Sixth People's Hospital. Visual memory was measured by the subtests of BVMT-R (Brief Visuospatial Memory Test-Revised), PLT (Pictorial Learning Test), DMS (Delayed Matching to Sample), and PAL (Paired Associates Learning). Hippocampal subfield volumes were estimated using FreeSurfer software (version 6.0). We modeled the association between visual memory and relative hippocampal subfield volumes (dividing by estimated total intracranial volume) using Pearson's correlation and linear regression. Results Compared with the NC group, patients with SCD did not find any relative hippocampal subregion atrophy, and the aMCI group found atrophy in CA1, molecular layer, subiculum, GC-ML-DG, CA4, and CA3. After adjusting for covariates (age, sex, and APOE ε4 status) and FDR (false discovery rate) correction of p (q values)

IntroductionThe accumulation of endogenous formaldehyde is considered a pathogenic factor in Alzheimer’s disease (AD). The purpose of this study was to investigate the relationship between urinary formic acid and plasma biomarkers in AD.Materials and methodsFive hundred and seventy-four participants were divided into five groups according to their diagnosis: 71 with normal cognitive (NC), 101 with subjective cognitive decline (SCD), 131 with cognitive impairment without mild cognitive impairment (CINM), 158 with mild cognitive impairment (MCI), and 113 with AD.ResultsWith the progression of the disease, urinary formic acid levels showed an overall upward trend. Urinary formic acid was significantly correlated with Mini-Mental State Examination (MMSE) scores, the Chinese version of Addenbrooke’s Cognitive Examination III (ACE-III) scores, and Montreal Cognitive Assessment-Basic (MoCA-B) time. The areas under the receiver operating characteristic curves (AUC) of urinary formic acid in distinguishing NC from AD was 0.797, which was similar to that of plasma neurofilament light chain (NfL; AUC = 0.768) and better than other plasma biomarkers (Aβ40, Aβ42, Aβ42/Aβ40, T-tau, P-tau181, and P-tau181/T-tau). We also found that using urinary formic acid and formaldehyde levels could improve the accuracy of using plasma biomarkers to determine AD disease stage.DiscussionOur study revealed the possibility of urinary formic acid as a potential novel biomarker for the early diagnosis of AD.

Abstract Purpose Recent 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 methods A 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. Results Based 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 (all P

Abstract Background This 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. Methods A 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. Results The 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 (both P

IntroductionNeurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease, are heavy burdens to global health and economic development worldwide. Mounting evidence suggests that exercise, a type of non-invasive intervention, has a positive impact on the life quality of elderly with neurodegenerative diseases. X-omics are powerful tools for mapping global biochemical changes in disease and treatment.MethodThree major databases were searched related to current studies in exercise intervention on neurodegenerative diseases using omics tools, including metabolomics, metagenomics, genomics, transcriptomics, and proteomics.ResultWe summarized the omics features and potential mechanisms associated with exercise and neurodegenerative diseases in the current studies. Three main mechanisms by which exercise affects neurodegenerative diseases were summed up, including adult neurogenesis, brain-derived neurotrophic factor (BDNF) signaling, and short-chain fatty acids (SCFAs) metabolism.ConclusionOverall, there is compelling evidence that exercise intervention is a feasible way of preventing the onset and alleviating the severity of neurodegenerative diseases. These studies highlight the importance of exercise as a complementary approach to the treatment and intervention of neurodegenerative diseases in addition to traditional treatments. More mechanisms on exercise interventions for neurodegenerative diseases, the specification of exercise prescriptions, and differentiated exercise programs should be explored so that they can actually be applied to the clinic.

Subjective cognitive decline (SCD) as an indicator of preclinical Alzheimer’s disease (AD) may precede mild cognitive impairment (MCI) over several decades. Self-reported cognitive decline as a typical clinical manifestation is critical in preclinical AD. Metacognition represents a person’s ability to accurately assess cognition. Our study aimed to examine (1) the alternations of metamemory in a cohort across the Alzheimer’s continuum, (2) the association between metamemory and cognition, and (3) the relationship of cortical thickness in four regions of interest (ROI) with metamemory scores. Six hundred ninety-seven participants were classified as 79 AD dementia, 161 aMCI, 261 SCD, and 196 cognitively unimpaired (CU) individuals, in which 418 participants aged above 65, 131 participants with Aβ+ after receiving positron emission tomography, and 602 participants received sMRI. The degree of confidence (DOC) was measured by calculating discrepancies between judgments and memory performance. We assessed the relationships between DOC tertiles and cognition and analyzed the screening power, then investigated the partial correlation between DOC and ROIs, controlled by age, sex, and cognition. In the Aβ+ subgroup, SCD showed significantly higher DOC scores than the CU group. There was an increasing trend of overconfidence with the decline of cognition across the AD spectrum (P for trend < 0.001). After adjusting for age, sex, and education, the lower degree of confidence-long-term delay recall (DOC-LD) tertiles were associated with lower odds ratio in SCD, aMCI, and AD in the Aβ+ subgroup (all P for trend < 0.05). The area under the curves of DOC scores for screening SCD from CU in the Aβ+ subgroup was better than that in all participants and the age ≥65 subgroup. Partial correlation showed that in the Aβ+ subgroup, DOC-SD (degree of confidence-short-term delay recall) was negatively correlated with the anterior cingulate cortex; DOC-LD was negatively correlated with the cortices of parahippocampal, anterior cingulate, posterior cingulate, and medial orbitofrontal. In individuals with Aβ+, SCD exhibited a detectable metamemory alternation before objective cognitive impairment could be tested, indicated by the overestimation in the memory performance. The pattern of an increasing trend of overconfidence across SCD, aMCI, and AD dementia supports the view of a continuum in Alzheimer’s disease.

Summary: Background: 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. Methods: 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. Findings: 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). Interpretation: 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. Funding: This work was partly supported by National Key R&D 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.

Abstract 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.

Abstract 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, p

Abstract 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

Semantic dementia patients present with a core semantic impairment and variations of language, behavioural and face recognition abilities. Here, the authors build a unified multidimensional model to capture all these graded symptoms and map them to the variations in the patients’ frontotemporal atrophy.

Background: Genome-wide association studies have identified many Alzheimer’s disease (AD) genetic-risk single nucleotide polymorphisms (SNPs) and indicated the important role of the cholesterol/lipid metabolism pathway in AD pathogenesis. This study aims to investigate the effects of cholesterol and genetic risk factors on progression of mild cognitive impairment (MCI) to AD.Methods: We prospectively followed 316 MCI participants aged ≥50 years with a baseline cholesterol profile and SNP genotyping data for 4.5 years on average in a sub-cohort of the Shanghai Aging Study. Total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol in serum were measured at baseline. SNP genotyping was performed using a MassARRAY system. At follow-up, consensus diagnosis of incident dementia and AD were established based on medical, neurological, and neuropsychological examinations. Cox regression models were used to assess the association of cholesterol and SNP with incident AD.Results: The AG/AA genotypes of PVRL2 rs6859 were significantly associated with increased incident AD in MCI participants, compared with GG genotype (adjusted hazard ratio [HR] 2.75, 95% confidence interval [CI] 1.32–5.76, p = .007, false discovery rate–adjusted p = .030). In PVRL2 rs6859 AG/AA carriers, each-1 mmol/L higher level of LDL-C was significantly associated with a 48% decreased risk of AD (adjusted HR 0.52, 95%CI 0.33–0.84, p = .007). Consistent results were obtained when using LDL-C as the categorical variable (P for trend = 0.016).Conclusion: The relationship between LDL-C and progression of MCI may be influenced by genetic variants.

Urine-based formaldehyde has been reported to be a potential biomarker for Alzheimer’s disease (AD). However, there is a lack of research about the correlation between urine formaldehyde and cognitive abilities in the clinical spectrum of AD, especially the preclinical period. The relationship of urine formaldehyde with APOE genotype, brain Aβ status and plasma pathological markers in AD are also not clear. This study intends to explore the correlation between urine formaldehyde and cognitive abilities throughout the AD continuum, to evaluate the role of APOE genotype and Aβ accumulation on urine formaldehyde, and further to clarify the relationship between urine formaldehyde level and AD plasma pathological markers. We recruited 72 cognitively normal controls (NC), 110 subjective cognitive decline (SCD), 140 objectively defined subtle cognitive decline (Obj-SCD), 171 mild cognitive impairment (MCI) and 136 AD dementia participants. Next, we collected the data of clinical materials, neuropsychological examination, APOE genotyping, urine formaldehyde concentration, 18F-florbetapir PET imaging and plasma biomarkers. Compared with NC, Obj-SCD and MCI groups, the level of urine formaldehyde was found to be significantly upregulated in SCD group. In addition, the level of urine formaldehyde was significantly higher in AD group compared to both NC and MCI groups. Further subgroup analysis showed that, the level of urine formaldehyde was higher in APOE ε4+ subgroup compared to APOE ε4– subgroup in both NC and AD groups. There was no difference in urine formaldehyde level between the brain Aβ+ subgroup and Aβ– subgroup in each group. In addition, regression analysis showed urine formaldehyde level was correlated with gender, plasma Aβ42 and p-Tau181/T-tau. The dynamic change of urine formaldehyde in the AD continuum could be used as a potential biomarker, and combined with comprehensive cognitive evaluation could become a useful method to distinguish SCD from NC and Obj-SCD, and to distinguish MCI from AD.

Background: Sarcopenia is a geriatric syndrome characterized by progressive loss of muscle mass, function and quality and associated with a range of adverse health outcomes including disability. Despite a negative correlation between muscle mass and follicle-stimulating hormone (FSH) levels in postmenopausal women, it is unclear if FSH is associated with sarcopenia and its poor outcomes, especially in older men.Methods: We used cross-sectional data from 360 men aged over 80 who participated in health check-ups to investigate correlations between serum FSH and sarcopenia, individual sarcopenia components, low physical performance (gait speed ≤ 0.8 m/s) and instrumental activities of daily living (IADL) disability. Sarcopenia and severe sarcopenia were diagnosed according to the revised definition of the European Working Group on Sarcopenia in Old People (EWGSOP2).Results: The prevalence of sarcopenia was 17.8% in this population. In binary logistic regression analysis, compared with higher FSH group, lower FSH group showed a significant reduction in the risk of low calf circumference (a surrogate for muscle mass; OR 0.308, 95% CI 0.109–0.868, P = 0.026) after adjusting potential confounders including age, waist circumference, education, exercise, associated biochemical parameters, other sex hormones and high-sensitivity C-reactive protein. The correlation between FSH and low handgrip strength was marginally significant (OR 0.390, 95% CI 0.151–1.005, P = 0.051). No associations were observed between FSH and sarcopenia, severe sarcopenia, and disability in adjusted models.Conclusion: In older men, circulating FSH was not associated with sarcopenia, sarcopenia severity, the majority of its components and adverse health outcome (IADL disability), with the exception of low calf circumference. Further work is needed to better elucidate the association of FSH and low muscle quantity by adopting more accurate measurement method of appendicular skeletal muscle mass such as DXA, CT or MRI.

Background: Different from diabetic hyperglycemia, stress-induced hyperglycemia (SIH) can better reflect elevated blood glucose owing to intracerebral hemorrhage (ICH). However, studies about the outcome of ICH patients with SIH are still very limited. Aims: This study aimed to investigate whether SIH measured by stress-induced hyperglycemia ratio (SHR) was associated with hematoma expansion and poor outcomes in patients with ICH. Methods: A consecutive series of patients with spontaneous ICH from two clinical centers admitted within 24 h after symptom onset were enrolled for prospective analysis. SHR was defined as admission fasting blood glucose divided by estimated average glucose [1.59 × Hemoglobin A1c (%) − 2.59]. This study investigated the association between SHR and hematoma expansion, and short-term and long-term poor outcomes using univariate and multivariate logistic regression analyses. Results: A total of 313 ICH patients were enrolled in the study. SHR was markedly higher in patients with hematoma expansion and poor outcomes ( p

Backgrounds: Subjective cognitive decline (SCD), one of the important clinical indicators for preclinical Alzheimer's disease (AD), is primarily defined as self-perceived cognitive decline without objective evidence for cognitive impairment. However, the accuracy of their self-evaluation of cognition is unclear. This study sought to investigate the capacity for self-evaluation of own cognitive performance in SCD by applying an objective metamemory paradigm. Methods: 147 individuals with SCD were classified into four subgroups by their subjective feeling of worse performance than peers or not (P+/-) and whether they have objectively slight cognitive impairment compared to normative data (S+/-). Metamemory scores, the amplitude of the low-frequency fluctuation (ALFF), fractional low-frequency fluctuation amplitude (fALFF), and cortical thickness were compared among four subgroups. Partial correlations between neuropsychological scores and neuroimaging measures were examined, controlling for age, sex, and education years. Results: SCD S+P- showed the worst performance in short-term delayed recall and the worst metamemory performance, indicated by the highest value in the degree of confidence of short-term delayed recall (DOC-N4) and long-term cued recall (DOC-N6) and the worst value in relative accuracy of judgments of short-term delayed recall (ROJ-N4). ALFF values in the bilateral superior medial frontal and olfactory cortices and the left superior orbitofrontal gyrus cortex were significantly higher in SCD P- compared with SCD P+ groups (all P

Several studies show that APOE-ε4 coding variants are associated with Alzheimer’s disease (AD) risk. Here, Zhou et al. perform fine-mapping of the APOE region and find AD risk haplotypes with non-coding variants in the PVRL2 and APOC1 regions that are associated with relevant endophenotypes.

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.

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.

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.

ObjectivesTo 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.MethodsOne 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.ResultsThe 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).ConclusionDifferential 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.

(1) Background: The SKT (Syndrom Kurztest) is a short cognitive performance test that consists of nine subtests and assesses deficits of memory and attention. This study was aimed at exploring the SKT target population in China and evaluating the reliability and validity of the Chinese version of the SKT; (2) Methods: A total of 1624 patients aged over 60 years old were recruited in the Sixth People’s Hospital in Shanghai. The SKT raw scores were recorded. Cronbach’s alpha coefficient was determined to assess the internal consistency reliability of the SKT. Principal factor analysis was performed to evaluate the factor structure of the SKT subtests. Correlation analyses were carried out to confirm the relationship between the modified SKT and standardized neuropsychological tests. The influence of age and educational years on SKT raw scores were detected using multiple regression analyses. Validations of the SKT subtests for detecting Mild Cognitive Impairment (MCI) from Negative Control(NC)(were determined by Receiver operating characteristic (ROC) curves; (3) Results: The internal consistency among the subtests’ scores was high: Cronbach’s α = 0.827. The SKT memory test provided a high predictive validity in detecting aMCI with a sensitivity of 90.1% and specificity of 79.3%. (4) Conclusions: Based on our experience with 1624 elderly patients in Shanghai, the Chinese version of SKT has good stability and may be a reliable and valid screening tool for detecting MCI.

Introduction: Previous literature has revealed that the anterior temporal lobe (ATL) is the semantic hub of left-sided or mixed semantic dementia (SD), whilst the semantic hub of right-sided SD has not been examined. Methods: Seventeen patients with right-sided SD, 18 patients with left-sided SD and 20 normal controls (NC) underwent neuropsychological assessments and magnetic resonance imaging scans. We investigated the relationship between the degree of cerebral atrophy in the whole brain and the severity of semantic deficits in left and right-sided SD samples, respectively. Results: We found the semantic deficits of right-sided SD patients were related to bilateral fusiform gyri and left temporal pole, whilst the left fusiform gyrus correlated with the semantic performance of left-sided SD patients. Moreover, all the findings couldn't be accounted for by total gray matter volume (GMV) or general cognitive degradation of patients. Discussion: These results provide novel evidence for the current semantic theory, that the important regions for semantic processing include both anterior and posterior temporal lobes. Keywords: Semantic dementia, Lesion-behavior mapping, Laterality of brain atrophy, Semantic deficits

Abstract 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: The relationship between cholesterol and cognitive function is unclear from the previous studies. This study was conducted to explore this association in older Chinese adults.Methods: Data were from the Shanghai Aging Study, comprising 3,836 residents aged 50 years or over in an urban community. Diagnoses of dementia and mild cognitive impairment were established according to the fourth edition of diagnostic and statistical manual of mental disorders (DSM-IV) and Petersen criteria. Multivariate logistic regression models, non-matched and propensity score (PS) matched, were used to examine the association between cholesterol levels and cognitive function.Results: There was a significantly higher proportion of participants with low levels of total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) in the dementia group than in groups without dementia (P < 0.05). High LDL-C level was inversely associated with dementia, with a negative trend in the PS matched model. TC and high density lipoprotein cholesterol (HDL-C) were not significantly related to dementia in either non-matched models or PS matched models.Conclusion: Our result indicates that high level of LDL-C is inversely associated with dementia. High level of LDL-C may be considered as a potential protective factor against cognition decline.

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.

The presence of both apolipoprotein E (APOE) ε4 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 ε4 affects intrinsic functional brain networks, both in healthy populations and in AD patients. However, it remains largely unclear whether and how ε4 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 ε4 carriers and 38 aMCI ε3ε3 carriers. In the present study, we first observe that ε4-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 ε3ε3 carriers, the ε4 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 ε4 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 ε4 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 ε4 carriers to AD.

Abstract Introduction The Shanghai Aging Study is a community‐based study aiming to investigate the incidence and progression of cognitive decline in Chinese elderly, with the operational procedures and diagnostic criteria similar to cohort studies in developed countries. Methods We prospectively evaluated 362 individuals with mild cognitive impairment (MCI) diagnosed at baseline through a clinical and neuropsychological interview. Diagnoses of dementia and MCI were made using standard criteria via consensus diagnosis. Results The conversion rate to dementia was 6.0 per 100 person‐years, while the reversion rate to cognitive normal was 7.8 per 100 person‐years. Amnestic MCI multiple domains was the most risky type for dementia (conversion rate: 14.2 per 100 person‐years). Older age (hazard ratio [HR] = 1.09), apolipoprotein E (APOE ε4) (HR = 2.15), and low MMSE score (HR = 1.18) were predictors for dementia. Discussion Approximately 6% of elderly with MCI progress to dementia annually. Prospective studies are needed to further examine risk and protective predictors and to seek proper interventions for cognitive decline.

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.

Individuals with semantic dementia (SD) typically suffer from selective semantic deficits due to degenerative brain atrophy. Although some brain regions have been found to be correlated with the semantic impairments of SD patients, it is unclear if the damage is actually responsible for SD patients’ semantic disorders because these findings were primarily obtained by examining the roles of local individual regions themselves without considering the influence of other regions that are functionally or structurally connected to the local individual regions. To resolve this problem, we investigated, from the brain network perspective, the relationship between the brain-network measures of regions and connections with semantic performance in 17 SD patients. We found that the severity of semantic deficits of SD patients was significantly correlated with the degree centrality values of the left anterior hippocampus (aHIP). Moreover, the semantic performance of the patients was also significantly correlated with the strength of gray matter functional connectivity of this region and two other regions: the left temporal pole/insula (TP/INS) and the left middle temporal gyrus. We further observed that the strength of the white matter structural connectivity of the left aHIP-left TP/INS tract could effectively predict the semantic performance of SD patients. When we controlled for a wide range of potential confounding factors (e.g., total gray matter volume), the above effects still held well. These findings revealed the critical brain network with the left aHIP as the center that could be contributing to the semantic impairments of SD.

Oral health has been found to be associated with cognitive function in basic research and epidemiology studies. Most of these studies had no comprehensive clinical diagnosis on cognitive function. This study firstly reported the association between tooth loss and cognitive function among Chinese older population.The study included 3,063 community dwelling older adults aged 60 or above from the Shanghai Aging Study. Number of teeth missing was obtained from self-reporting questionnaire and confirmed by trained interviewers. Participants were diagnosed as "dementia", "mild cognitive impairment (MCI)", or "cognitive normal" by neurologists using DSM-IV and Petersen criteria. Multivariate logistic regression model was applied to examine the association between number of teeth missing and cognitive function.The study participants had an average of 10.2 teeth lost. Individuals with dementia lost 18.7 teeth on average, much higher than those with MCI (11.8) and cognitive normal (9.3) (p16 were significantly associated with dementia with an OR of 1.56 (95%CI 1.12-2.18).Having over 16 missing teeth was associated with severe cognitive impairment among Chinese older adults. Poor oral health might be considered as a related factor of neurodegenerative symptom among older Chinese population.

BACKGROUND: Many scoring systems exist for clock drawing task variants. However, none of them are reliable in evaluating longitudinal changes of cognitive function. The purpose of this study is to create a simple yet optimal scoring procedure to evaluate cognitive decline using a clinic-based sample. METHODS: Clock-drawings from 121 participants (76 individuals with no dementia and later did not develop dementia after a mean 41.2-month follow-up, 45 individuals with no dementia became demented after a mean 42.3-month follow-up) were analyzed using t-test to determine a new and simplified CDT scoring system. The new scoring method was then compared with other commonly used systems. RESULTS: In the converters, there were only 7 items that are significantly different between the initial visits and the second visits. We propose a new scoring system that includes the seven critical items: numbers are equally spaced (12-3-6-9) (p = 0.031), the other eight numbers are marked (p = 0.022), numbers are clockwise (p = 0.002), all numbers are correct (p = 0.030), distance between numbers is constant (p = 0.016), clock has two hands (p = 0.000), arrows are drawn (p = 0.003). Compared with other traditionally used scoring methods, this based change clock drawing test (BCCDT) has one of the most balanced sensitivities/specificities with a clinic-based sample. CONCLUSIONS: The new CDT scoring system provides further evidence in support of a simple and reliable clock-drawing scoring system in follow-up studies to evaluate cognitive decline, which can be used in assessing the efficacy of medicine.