Genome-wide meta-analysis identifies ancestry-specific loci for Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a devastating neurological disease with complex genetic etiology. Yet most known loci have only identified from the late-onset type AD in populations of European ancestry. METHODS: We performed a two-stage genome-wide association study (GWAS) of AD totaling 6878 Chinese and 63,926 European individuals. RESULTS: In addition to the apolipoprotein E (APOE) locus, our GWAS of two independent Chinese samples uncovered three novel AD susceptibility loci (KIAA2013, SLC52A3, and TCN2) and a novel ancestry-specific variant within EGFR (rs1815157). More replicated variants were observed in the Chinese (31%) than in the European samples (15%). In combining genome-wide associations and functional annotations, EGFR and TCN2 were prioritized as two of the most biologically significant genes. Phenome-wide Mendelian randomization suggests that high mean corpuscular hemoglobin concentration might protect against AD. DISCUSSION: The current study reveals novel AD susceptibility loci, emphasizes the importance of diverse populations in AD genetic research, and advances our understanding of disease etiology. HIGHLIGHTS: Loci KIAA2013, SLC52A3, and TCN2 were associated with Alzheimer's disease (AD) in Chinese populations. rs1815157 within the EGFR locus was associated with AD in Chinese populations. The genetic architecture of AD varied between Chinese and European populations. EGFR and TCN2 were prioritized as two of the most biologically significant genes. High mean corpuscular hemoglobin concentrations might have protective effects against AD.

Incremental value of amyloid PET in a tertiary memory clinic setting in China.

INTRODUCTION: The objective of this study is to investigate the incremental value of amyloid positron emission tomography (Aß-PET) in a tertiary memory clinic setting in China. METHODS: A total of 1073 patients were offered Aß-PET using 18F-florbetapir. The neurologists determined a suspected etiology (Alzheimer's disease [AD] or non-AD) with a percentage estimate of their confidence and medication prescription both before and after receiving the Aß-PET results. RESULTS: After disclosure of the Aß-PET results, etiological diagnoses changed in 19.3% of patients, and diagnostic confidence increased from 69.3% to 85.6%. Amyloid PET results led to a change of treatment plan in 36.5% of patients. Compared to the late-onset group, the early-onset group had a more frequent change in diagnoses and a higher increase in diagnostic confidence. DISCUSSION: Aß-PET has significant impacts on the changes of diagnoses and management in Chinese population. Early-onset cases are more likely to benefit from Aß-PET than late-onset cases. HIGHLIGHTS: Amyloid PET contributes to diagnostic changes and its confidence in Chinese patients. Amyloid PET leads to a change of treatment plans in Chinese patients. Early-onset cases are more likely to benefit from amyloid PET than late-onset cases.

Plasma Glial Fibrillary Acidic Protein in the Alzheimer Disease Continuum: Relationship to Other Biomarkers, Differential Diagnosis, and Prediction of Clinical Progression.

BACKGROUND: Plasma glial fibrillary acidic protein (GFAP) has emerged as a promising biomarker in neurological disorders, but further evidence is required in relation to its usefulness for diagnosis and prediction of Alzheimer disease (AD). METHODS: Plasma GFAP was measured in participants with AD, non-AD neurodegenerative disorders, and controls. Its diagnostic and predictive value were analyzed alone or combined with other indicators. RESULTS: A total of 818 participants were recruited (210 followed). Plasma GFAP was significantly higher in AD than in non-AD dementia and non-demented individuals. It increased in a stepwise pattern from preclinical AD, through prodromal AD to AD dementia. It effectively distinguished AD from controls [area under the curve (AUC) > 0.97] and non-AD dementia (AUC > 0.80) and distinguished preclinical (AUC > 0.89) and prodromal AD (AUC > 0.85) from Aß-normal controls. Adjusted or combined with other indicators, higher levels of plasma GFAP displayed predictive value for risk of AD progression (adjusted hazard radio= 4.49, 95%CI, 1.18-16.97, P = 0.027 based on the comparison of those above vs below average at baseline) and cognitive decline (standard-ß=0.34, P = 0.002). Additionally, it strongly correlated with AD-related cerebrospinal fluid (CSF)/neuroimaging markers. CONCLUSIONS: Plasma GFAP effectively distinguished AD dementia from multiple neurodegenerative diseases, gradually increased across the AD continuum, predicted the individual risk of AD progression, and strongly correlated with AD CSF/neuroimaging biomarkers. Plasma GFAP could serve as both a diagnostic and predictive biomarker for AD.

18 F-Florzolotau Positron Emission Tomography Imaging of Tau Pathology in the Living Brains of Patients with Corticobasal Syndrome.

BACKGROUND: Recent development in tau-sensitive tracers has sparkled significant interest in tracking tauopathies using positron emission tomography (PET) biomarkers. However, the ability of 18 F-florzolotau PET imaging to topographically characterize tau pathology in corticobasal syndrome (CBS) remains unclear. Further, the question as to whether disease-level differences exist with other neurodegenerative tauopathies is still unanswered. OBJECTIVE: To analyze the topographical patterns of tau pathology in the living brains of patients with CBS using 18 F-florzolotau PET imaging and to examine whether differences with other tauopathies exist. METHODS: 18 F-florzolotau PET imaging was performed in 20 consecutive patients with CBS, 20 cognitively healthy controls (HCs), 20 patients with Alzheimer's disease (AD), and 16 patients with progressive supranuclear palsy-Richardson's syndrome (PSP-RS). Cerebrospinal fluid (CSF) levels of ß-amyloid biomarkers were quantified in all patients with CBS. 18 F-florzolotau uptake was quantitatively assessed using standardized uptake value ratios. RESULTS: Of the 20 patients with CBS, 19 (95%) were negative for CSF biomarkers of amyloid pathology; of them, three had negative 18 F-florzolotau PET findings. Compared with HCs, patients with CBS showed increased 18 F-florzolotau signals in both cortical and subcortical regions. In addition, patients with CBS were characterized by higher tracer retentions in subcortical regions compared with those with AD and showed a trend toward higher signals in cortical areas compared with PSP-RS. An asymmetric pattern of 18 F-florzolotau uptake was associated with an asymmetry of motor severity in patients with CBS. CONCLUSIONS: In vivo 18 F-florzolotau PET imaging holds promise for distinguishing CBS in the spectrum of neurodegenerative tauopathies. © 2023 International Parkinson and Movement Disorder Society.

Pharmacological treatment of neuropsychiatric symptoms of dementia: a network meta-analysis.

BACKGROUND: Pharmacological treatments are very common to be used for alleviating neuropsychiatric symptoms (NPS) in dementia. However, decision on drug selection is still a matter of controversy. AIMS: To summarise the comparative efficacy and acceptability of currently available monotherapy drug regimens for reducing NPS in dementia. METHOD: We searched PubMed, MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials between inception and 26 December 2022 without language restrictions; and reference lists scanned from selected studies and systematic reviews. Double-blind randomised controlled trials were identified from electronic databases for reporting NPS outcomes in people with dementia. Primary outcomes were efficacy and acceptability. Confidence in the evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). RESULTS: We included 59 trials (15,781 participants; mean age, 76.6 years) and 15 different drugs in quantitative syntheses. Risperidone (standardised mean difference [SMD] -0.20, 95% credible interval [CrI] -0.40 to -0.10) and galantamine (-0.20, -0.39 to -0.02) were more effective than placebo in short-term treatment (median duration: 12 weeks). Galantamine (odds ratio [OR] 1.95, 95% CrI 1.38-2.94) and rivastigmine (1.87, 1.24-2.99) were associated with more dropouts than placebo, and some active drugs. Most of the results were rated as low or very low according to CINeMA. CONCLUSIONS: Despite the scarcity of high-quality evidence, risperidone is probably the best pharmacological option to consider for alleviating NPS in people with dementia in short-term treatment when considering the risk-benefit profile of drugs.

A comparative study on the validations of three cognitive screening tests in identifying subtle cognitive decline.

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 < 0.01). However, MCI showed significant decline in all cognitive performances (P < 0.01). The scores of MMSE, MoCA-CV and MES all showed a progressive downward trend within the groups of NC, SCD and MCI (P < 0.001). In ROC Analyses for discriminating individuals with SCD from NC, the most appropriate MES cutoff was 84, with a sensitivity of 74.3%, a specificity of 60.8% and 0.738 for AUC (95%CI, 0.675-0.801). By contrast, MMSE and MOCA-CV had poor sensitivity (67.4 and 70.8%, respectively) and specificity (51.0 and 52.9%, respectively), and smaller AUCs (0.643 and 0.644, respectively) than the MES. CONCLUSION: As a screening test, MES is more efficacious in identifying SCD from normal controls than MMSE and MoCA-CV.

Mortality of Alzheimer's Disease Patients: A 10-Year Follow-up Pilot Study in Shanghai.

BACKGROUND: Identifying risk factors and mortality of individuals with Alzheimer's disease (AD) could have important implications for the clinical management of AD. OBJECTIVE: This pilot study aimed to examine the overall mortality of AD patients over a 10-year surveillance period in Shanghai, China. This study is an extension of our previous investigation on mortality of neurodegenerative diseases. METHODS: One hundred and thirty-two AD patients recruited from the memory clinics of two hospitals in Shanghai in 2007 were followed up until December 31, 2017 or death, representing a follow-up period of up to 10 years. Overall standardized mortality ratios (SMRs) were calculated, and predictors for survival at recruitment were estimated. RESULTS: Sixty-seven patients had died by December 31, 2017, and the SMR at 10 years of follow-up was 1.225 (95% confidence interval 0.944-1.563). Employing Cox's proportional hazard modeling, lower Mini-Mental State Examination score, and comorbid diabetes predicted poor survival in this cohort. CONCLUSION: This pilot study suggests a similar survival trend of patients with AD compared to the general population in Shanghai urban region. Poor cognitive status and comorbid diabetes had a negative impact on the survival of AD patients.

Pilot testing the caregiver self-management intervention for caregivers of relatives with dementia.

This study was designed to examine the feasibility of a caregiving self-management support program developed for caregivers of relatives with dementia in Shanghai. A total of 41 caregivers were recruited for a quasi-experimental study. The experimental group of 26 participants attended six bi-weekly social support group sessions. The control group of 15 participants received three monthly telephone instructions. All of participants received an illustrated caregiver educational booklet and three educational presentations during a six-month follow-up period. The results demonstrated a stronger sense of self-efficacy regarding the gathering of information about dementia care in both study groups compared to the baseline data. Caregivers participating in the group sessions reported better health-related quality of life, improved responses to behavioral disturbances, and efficacy in the management of stress than those who received telephone instructions. This study provided some preliminary information regarding ways to improve self-management for the target population in mainland China.

An abbreviated version of Silhouettes test: a brief validated mild cognitive impairment screening tool.

OBJECTIVES: To revise an abbreviated version of the Silhouettes subtest of the Visual Object and Space Perception (VOSP) battery in order to recognize mild cognitive impairment (MCI) and determine the optimal cutoffs to differentiate among cognitively normal controls (NC), MCI, and Alzheimer's Disease (AD) in the Chinese elderly. DESIGN: A cross-sectional validation study. SETTING: Huashan Hospital, Shanghai, China. SUBJECTS: A total of 591 participants: Individuals with MCI (n = 211), AD (n = 139) and NC (n = 241) were recruited from the Memory Clinic, Huashan Hospital, Shanghai, China. METHODS: Baseline neuropsychological battery (including VOSP) scores were collected from firsthand data. An abbreviated version of silhouettes test (Silhouettes-A) was revised from the original English version more suitable for the elderly, including eight silhouettes of animals and seven silhouettes of inanimate objects, with a score ranging from 0 to 15. RESULTS: Silhouettes-A was an effective test to screen MCI in the Chinese elderly with good sensitivity and specificity, similar to the Montreal cognitive assessment and superior to other single tests reflecting language, spatial, or executive function. However, it had no advantage in distinguishing MCI from AD. The corresponding optimal cutoff scores of Silhouettes-A were 10 for screening MCI and 8 for AD. CONCLUSION: Silhouettes-A is a quick, simple, sensitive, and dependable cognitive test to distinguish among NC, MCI, and AD patients.

Caregivers' attitude toward disclosure of Alzheimer's disease diagnosis in Urban China.

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.

Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A, for the treatment of Alzheimer's disease.

AIM: Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects. METHODS: This was a double-blinded, placebo-controlled, randomized, single- and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including Cmax, AUC0-72 h and AUC0-∞ were calculated. Tolerance assessments were conducted throughout the study. RESULTS: ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (<0.05 ng/mL). After single-dose administration of ZT-1, the mean tmax of huperzine A was 0.76-0.82 h; the AUC0-72 h and Cmax of huperzine A showed approximately dose-proportional increase over the dose range of 0.5-1 mg. After the multiple-dose administration of ZT-1, a steady-state level of huperzine A was achieved within 2 d. No serious adverse events were observed. CONCLUSION: ZT-1 is a pro-drug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers.

Genetic and Neuroimaging Analysis of SIGMAR1 for Frontotemporal Dementia.

BACKGROUND: Recently, Sigma nonopioid intracellular receptor 1 (SIGMAR1) variants have been shown harboring C9orf72 pathogenic repeat expansions in some frontotemporal dementia (FTD) cases. However, no SIGMAR1 genotype analysis has been reported in a cohort absent of C9orf72 pathogenic repeat expansions to date. OBJECTIVE: The present study investigated the contribution of SIGMAR1 independent of C9orf72 gene status to FTD spectrum syndromes. METHODS: We directly sequencing the entire coding region and a minimum of 50 bp from each of the flanking introns of SIGMAR1 gene in 82 sporadic FTD patients (female: male = 42 : 40) and 417 controls. For the patient carrying SIGMAR1 variant, a follow-up 3T MR imaging was performed in the study. RESULTS: Gene sequencing of SIGMAR1 revealed a rare 3'UTR nucleotide variation rs192856872 in a male patient with semantic dementia independent of C9orf72 gene status. The MR imaging showed asymmetrical atrophy in the anterior temporal lobes and the degeneration extends caudally into the posterior temporal lobes as the disease progresses. ESEFinder analysis showed new SRSF1 and SRSF1-IgM-BRCA1 binding sites with significant scores, which is predicted to affect normal splicing. CONCLUSION: We found a novel SIGMAR1 variant independent of C9orf72 gene status associated with semantic dementia phenotype.

Memory and Executive Screening (MES): a brief cognitive test for detecting mild cognitive impairment.

BACKGROUND: Mild cognitive impairment (MCI), defined as a transitional zone between normal cognition and dementia, requires a battery of formal neuropsychological tests administered by a trained rater for its diagnosis. The objective of this study was to develop a screening tool for MCI. METHODS: One hundred ninety seven cognitively normal controls (NC), one hundred sixteen patients with amnestic MCI -single domain (aMCI-sd), one hundred ninety five patients with amnestic MCI-multiple domain (aMCI-md), and two hundred twenty eight patients with mild Alzheimer's disease (AD) were evaluated by comprehensive neuropsychological tests and by the Memory and Executive Screening (MES). RESULTS: Correlation analysis showed that the three indicators of the MES were significantly negatively related with age (P<0.05), yet not related with education (P>0.05). There was no ceiling or floor effect. Test completion averaged seven minutes (421.14±168.31 seconds). The receiver operating characteristics (ROC) analyses performed on the aMCI-sd group yielded 0.89 for the area under the curve (AUC) (95% CI, 0.85-0.92) for the MES-total score, with sensitivity of 0.795 and specificity of 0.828. There was 81% correct classification rate when the cut-off was set at less than 75. Meanwhile, the aMCI-md group yielded 0.95 for the AUC (95% CI, 0.93-0.97) for the MES-total score, with sensitivity of 0.87 and specificity of 0.91, and 90% correct classification rate when the cut-off was set at less than 72. CONCLUSION: The MES, minimally time-consuming, may be a valid and easily administered cognitive screening tool with high sensitivity and specificity for aMCI, with single or multiple domain impairment.

[Survey of comorbidities for hospitalized patients with cognitive disorders].

OBJECTIVE: To provide rationales for the prevention and treatment of elderly patients with cognitive disorders through comparing the comorbidities according to different etiologies and severities. METHODS: Six groups of different cognitive status were selected. There were 438 normal cognitive subjects (NC) from Jing'an community of Shanghai. Five other groups were from the Memory Clinic at our hospital from June 2006 to June 2010. There were subjective memory complaints (n = 443, SMC), mild cognitive impairment (n = 540, MCI), vascular cognitive impairment-non dementia (n = 119, VCI-ND), Alzheimer's disease (n = 337, AD) and vascular dementia (n = 54, VaD). All participants finished a battery of neuropsychological tests and completed the survey of such comorbidities as stroke, conscious disturbance, hypertension, diabetes, head injuries and excessive drinking. RESULTS: The comorbidity rates of diabetes were 11.4%, 9.9%, 16.1%, 14.2%, 12.4% and 18.5% in 6 groups (NC, SMC, MCI, VCI-ND, AD, VaD) respectively. There were no differences for overall or pairwise chi square tests. The rates of stroke, hypertension and excessive drinking in patients of VCI-ND and VaD were higher than those of SMC, MCI and AD. The comorbidity rates in the VCI-ND and VaD group were 54.6% vs 62.9% for stroke; 61.3% vs 79.6% for hypertension; 22.6% vs 37.0% for excessive drinking. Whereas in the SMC, MCI and AD groups, the rates were 9.4%, 10.9% and 3.0% for stroke; 44.9%, 47.2% and 42.1% for hypertension; 18.0%, 18.3% and 15.1% for excessive drinking. No distinct differences existed for the comorbidity rates among SMC, MCI and AD groups or among different degrees of AD. CONCLUSION: Etiologies rather than severities determine the different rates of comorbidities in the elders with cognitive impairment.

Genetic profiles of familial late-onset Alzheimer's disease in China: The Shanghai FLOAD study.

Compared with early-onset familial AD (FAD), the heritability of most familial late-onset Alzheimer's disease (FLOAD) cases still remains unclear. However, there are few reported genetic profiles of FLOAD to date. In the present study, targeted sequencing of selected candidate genes was conducted for each of 90 probands with FLOAD and 101 unrelated matched normal controls among Chinese Han population. Results show a significantly lower rate of mutation in APP and PSENs, and APOE ε4 genetic risk is higher for FLOAD. Among the Chinese FLOAD population, the most frequent variant was CR1 rs116806486 [5.6%, 95% CI (1.8%, 12.5%)], followed by coding variants of TREM2 (4.4%, 95%CI (1.2%, 10.9%)) and novel mutations of ACE [3.3%, 95%CI (0.7%, 9.4%)]. Next, we found that novel pathogenic mutations in ACE including frame-shift and nonsense mutations were in association with FLOAD regardless of APOE ε4 status. Evidence from the Alzheimer's disease Neuroimaging Initiative (ADNI) database also supported this finding in different ethnicities. Results of in vitro analysis suggest that frame-shift and nonsense mutations in ACE may be involved in LOAD through decreased ACE protein levels without affecting direct processing of APP.

Pharmacological treatments for psychotic symptoms in dementia: A systematic review with pairwise and network meta-analysis.

Psychotic symptoms of dementia are highly prevalent and lead to poor medical outcomes and substantial dysfunction. To date, which drug to use remains controversial without a summary of all direct or indirect comparisons of pharmacotherapy. Therefore, we conducted a systematic review with pairwise and network meta-analysis to examine efficacy and tolerability outcomes of pharmacological treatments in dementia patients. MEDLINE, Cochrane Library, EMBASE, and PubMed were searched systematically up to August 31, 2020. We included trials of cholinesterase inhibitors (ChEIs), memantine, antipsychotics, antidepressants, and mood stabilizers, with final approval from the U.S. Food and Drug Administration. We ranked the comparative effects of all drugs against placebo with surface under the cumulative ranking (SUCRA) probabilities. This analysis is based on 34 trials, which included 10,415 patients randomly assigned to 15 commonly used drug regimens. Donepezil (standardized mean difference [SMD] -0.30, 95% credible interval [CrI] -0.50 to -0.12; SUCRA, 0.85), memantine (SMD -0.20, 95%CrI -0.34 to -0.07; SUCRA, 0.68) and aripiprazole (SMD -0.17, 95% CrI -0.32 to -0.02; SUCRA, 0.62) showed greater benefit than placebo, and with relatively good tolerability in network meta-analyses. Risperidone was also found to be more efficacious than placebo (SMD -0.16, 95% CrI -0.28 to -0.05; SUCRA, 0.60), but with poor tolerability (odds ratios [OR] 1.50, 95% CrI 1.06-2.26). Donepezil, memantine, haloperidol, aripiprazole and risperidone were more efficacious than quetiapine (SMDs ranged from -0.36 to -0.22). Besides, donepezil, memantine and mirtazapine were more efficacious than sertraline (SMDs ranged from -0.47 to -0.36). Most of the results were rated as "low" to "very low". Several effective treatment choices for psychotic symptoms are available across drug classes. Donepezil, memantine and aripiprazole are probably the appropriate options to consider when a pharmacological treatment is indicated. Given the limitations of the meta-analytic approach and the low methodological quality of the majority of studies, our results should be cautiously interpreted.

Modifiable risk factors for incident dementia and cognitive impairment: An umbrella review of evidence.

BACKGROUND: Dementia and cognitive impairment can be attributed to genetic and modifiable factors. Considerable evidence emerged in modifiable factors and urgently requires standardized evaluation. We conducted an umbrella review to evaluate the strength and validity of the existing evidence. METHODS: We searched PubMed, Embase, CINAHL and Cochrane Database of Systematic Reviews to identify relevant systematic reviews and meta-analyses of prospective studies regarding the associations of dementia and cognitive impairment with modifiable factors. For each association, we analyzed the summary effect size, 95 % confidence interval, 95 % prediction interval, heterogeneity, small study effect and excess significance bias. Mendelian randomization studies were descriptively reviewed further exploring the causality of the associations. RESULTS: In total, 12,015 articles were identified, of which 118 eligible studies yielded 243 unique associations. Convincing evidence was found for associations of dementia and cognitive impairment with early-life education, midlife to late-life plasma glucose, BMI, atrial fibrillation, benzodiazepine use, and gait speed. Suggestive to highly suggestive evidence was found for that of midlife to late-life blood pressure, homocysteine, cerebrovascular diseases, hearing impairment, respiratory illness, anemia, smoking, alcohol consumption, diet, sleep, physical activity and social engagement. Among convincing evidence, Mendelian randomization studies verified causal relationships of education and plasma glucose with Alzheimer's disease. LIMITATIONS: Low quality of the studies included. CONCLUSIONS: Modifiable risk factors identified in this study, especially those with high-level evidence, should be considered in dementia prevention. Our results support a valuable rationale for future experimental designs to establish further evidence for the associations in larger populations.

Comparative study of two Chinese versions of Montreal Cognitive Assessment for Screening of Mild Cognitive Impairment.

Our aim was to compare the utility and accuracy of the Chinese Version of Montreal Cognitive Assessment Basic (MoCA-BC) and the Montreal Cognitive Assessment-Beijing Version (MoCA-BJ) in the identification of mild cognitive impairment (MCI) under different education levels. A sample of individuals with MCI (n = 295), Alzheimer's disease (AD; n = 254), and normal controls (NC; n = 259) at 2 Memory Clinics and communities was administered the MoCA-BC, MoCA-BJ, Mini-Mental State Examination (MMSE), and other neuropsychological tests. The discriminant validity of the MoCA-BC and MoCA-BJ as diagnostic instruments was ascertained. The overall discriminant validity for detection of MCI from NC (receiver operating characteristic area under the curve [95% confidence interval]) was that the MoCA-BC (0.95 [0.93, 0.97]) had better sensitivity and accuracy than MoCA-BJ (0.87 [0.84, 0.90]). In addition, we provide an easy to use table that enables the conversion of MoCA-BC to the MoCA-BJ scores or to MMSE scores. The MoCA-BC and MoCA-BJ provided good diagnostic accuracy when compared to MMSE. The MoCA-BC, which was proved to be an appropriate tool when screening for MCI among elderly subjects, can now be compared directly with the MoCA-BJ.

Retinal biomarkers in Alzheimer's disease and mild cognitive impairment: A systematic review and meta-analysis.

BACKGROUND: Retinal changes may reflect the pathophysiological processes in the central nervous system and can be assessed by imaging modalities non-invasively. We aim to localize candidate retinal biomarkers in Alzheimer's disease (AD), mild cognitive impairment (MCI), and preclinical AD. METHODS: We systematically searched PubMed, EMBASE, Scopus, and Web of Science from inception to January 2021 for observational studies that investigated retinal imaging and electrophysiological markers in AD, MCI, and preclinical AD. Between-groups standardized mean differences (SMDs) with 95 % confidence intervals were computed using random-effects models. RESULTS: Of 19,727 citations identified, 126 articles were eligible for inclusion. Compared with healthy controls, the thickness of peripapillary retinal nerve fiber layer (pRNFL; SMD = -0.723, p < 0.001), total macular (SMD = -0.612, p < 0.001), and subfoveal choroid (SMD = -0.888, p < 0.001) were significantly reduced in patients with AD. Compared with healthy controls, patients with MCI also had lower thickness of pRNFL (SMD = -0.324, p < 0.001), total macular (SMD = -0.302, p < 0.001), and subfoveal choroid (SMD = -0.462, p = 0.020). Other candidate biomarkers included the optic nerve head morphology, retinal amyloid deposition, microvascular morphology and densities, blood flow, and electrophysiological markers. CONCLUSIONS: Retinal structural, vascular, and electrophysiological biomarkers hold great potential for the diagnosis, prognosis and risk assessment of AD and MCI. These biomarkers warrant further development in the future, especially in diagnostic test accuracy and longitudinal studies.

[Comparative study of depression status in patients with subjective memory complaints and mild cognitive impairment].

OBJECTIVE: To understand the nature of subjective memory complaints through comparative study of depression status of patients with subjective memory complaints and mild cognitive impairment. METHODS: A total of 214 patients were assessed with the Center for Epidemiologic Studies Depression (CES-D) scale, the Geriatric Depression Scale and some neuropsychological tests. Among them, 76 were of subjective memory complaints (SMC), 74 amnestic mild cognitive impairment-single domain (aMCI-s) and 64 amnestic mild cognitive impairment-multiple domain (aMCI-m). RESULTS: According to CESD, 31% of the patients had symptoms of depression. The ratios were 30%, 24% and 39% in SMC, aMCI-s and aMCI-m groups respectively. GDS study showed that 43% of the patients had symptoms of depression. The ratios were 47%, 30% and 53% in SMC, aMCI-s and aMCI-m groups respectively. The ratio in SMC group fell between the other two groups. The total score of CESD (12 +/- 10) or GDS (11 +/- 6) of the SMC group, reflecting the severity of depression, fell between aMCI-s (CESD: 11 +/- 8, GDS: 9 +/- 5) and (CESD: 15 +/- 11, GDS: 12 +/- 7) groups. There was no significant difference between them in comparison with either aMCI-s or aMCI-m group (P > 0.05). But the total score of CESD or GDS was significantly different between aMCI-m and aMCI-s groups (P < 0.05). The depression status was worse in aMCI-m group than that in aMCI-s group. CONCLUSION: There is no significant discrepancy in the incidence and severity of depression between SMC and aMCI groups. It indicates that depressive mood is not the specific cause of SMC.