A derivative of trihydroxynaphthalenone and a pyrone metabolite from the endophytic fungus Talaromyces purpurpgenus.

A newly discovered trihydroxynaphthalenone derivative, epoxynaphthalenone (1) involving the condensation of ortho-hydroxyl groups into an epoxy structure, and a novel pyrone metabolite characterized as pyroneaceacid (2), were extracted from Talaromyces purpurpgenus, an endophytic fungus residing in Rhododendron molle. The structures of these compounds were elucidated through a comprehensive analysis of their NMR and HRESIMS data. The determination of absolute configurations was accomplished using electronic circular dichroism (ECD) calculations and CD spectra. Notably, these recently identified metabolites exhibited a moderate inhibitory activity against xanthine oxidase (XOD).

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.

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.

Two sydowic acid derivatives and a sulfonyl metabolite from the endophytic fungus Aspergillus sydowii.

Two new sydowic acid derivatives, a pair of enantiomers, involving (+)-sydowiccal (1a) and (-)-sydowiccal (1b), a new sulfonyl metabolite of 2-methoxy-5-methyl-3-(methylsulfonyl)phenol (2), as well as three known sydowic acid derivatives, were isolated from Aspergillus sydowii, an endophytic fungus of Rhododendron mole. The structures of these new compounds were elucidated by analyzing their NMR and HRESIMS data, and the absolute configurations of enantiomers were determined on the basis of the CD spectrum. Three new metabolites showed weak anti-inflammation on nitric oxide (NO) production in LPS-induced RAW 264.7 cells.

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.

The items in the Chinese version of the Montreal cognitive assessment basic discriminate among different severities of Alzheimer's disease.

BACKGROUND: To determine whether items of the Chinese version of the Montreal Cognitive Assessment Basic (MoCA-BC) could discriminate among cognitively normal controls (NC), and those with mild cognitive impairment (MCI), mild Alzheimer's disease (AD), and moderate-severe (AD), as well as their sensitivity and specificity. METHODS: MCI (n = 456), mild AD (n = 502) and moderate-severe AD (n = 102) patients were recruited from the memory clinic, Huashan Hospital, Shanghai, China. NC (n = 329) were recruited from health checkup outpatients. Five MoCA-BC item scores were collected in interviews. RESULTS: The MoCA-BC orientation test had high sensitivity and specificity for discrimination among MCI, mild AD and moderate-severe AD. The delayed recall memory test had high sensitivity and specificity for MCI screening. The verbal fluency test was efficient for detecting MCI and differentiating AD severity. CONCLUSIONS: Various items of the MoCA-BC can identify MCI patients early and identify the severity of dementia.

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.

Efficacy analysis of self-help position therapy after holmium laser lithotripsy via flexible ureteroscopy.

BACKGROUND: To observe the efficacy of self-help position therapy (SHPT) after holmium laser lithotripsy via flexible ureteroscopy (FURS). METHODS: From January 2010 to November 2015, 736 nephrolithiasis patients who had received FURS lithotripsy were analyzed retrospectively. In position group, 220 cases accepted SHPT after lithotripsies, and 428 cases as control, coming from another independent inpatient area in the same center. The stone-free status (SFS) between two groups were compared at the 2nd, 4th and 12th week ends by X-ray examinations. RESULTS: The preoperative incidence of hydronephrosis (25.9% vs. 18.0%, p = 0.018) or lower calyceal seeper (33.6% vs. 24.3%, p = 0.012) and the proportion of patients with > 2.0 cm stones (33.6% vs. 24.3%, p = 0.003) were all significantly higher in position group than in control group. There were no substantial difference between two groups in age, BMI, gender and medical histories. In postoperative followup, the incidence of hydronephrosis in position group was significantly lower than in control group (9.5% vs. 15.7%, p = 0.032) after removing double-J stents. In position group, the SFS of the 2nd week end (60.9% vs. 47.2%, p = 0.001), the 4th week end (74.1% vs. 62.8%, p = 0.004) and the 12th week end (86.9% vs. 79.4%, p = 0.021) were all significantly higher than those in control group. CONCLUSIONS: SHPT after holmium laser lithotripsy via FURS may increase postoperative SFS, accelerate stone fragment clearance, and decrease the incidence of hydronephrosis after removal of double-J stents. The therapy does not require professional assistance and is economical, simple, and effective.

The Etiology of Rapidly Progressive Dementia: A 3-Year Retrospective Study in a Tertiary Hospital in China.

Background: Rapidly progressive dementia (RPD), characterized by a rapid cognitive decline leading to dementia, comprises a diverse range of disorders. Despite advancements in diagnosis and treatment, research on RPD primarily focuses on Western populations. Objective: This study aims to explore the etiology and demographics of RPD in Chinese patients. Methods: We retrospectively analyzed 323 RPD inpatients at Huashan Hospital from May 2019 to March 2023. Data on sociodemographic factors, epidemiology, clinical presentation, and etiology were collected and analyzed. Results: The median onset age of RPD patients was 60.7 years. Two-thirds received a diagnosis within 6 months of symptom onset. Memory impairment was the most common initial symptom, followed by behavioral changes. Neurodegenerative diseases accounted for 47.4% of cases, with central nervous system inflammatory diseases at 30.96%. Autoimmune encephalitis was the leading cause (16.7%), followed by Alzheimer's disease (16.1%), neurosyphilis (11.8%), and Creutzfeldt-Jakob disease (9.0%). Alzheimer's disease, Creutzfeldt-Jakob disease, and frontotemporal dementia were the primary neurodegenerative causes, while autoimmune encephalitis, neurosyphilis, and vascular cognitive impairment were the main non-neurodegenerative causes. Conclusions: The etiology of RPD in Chinese patients is complex, with neurodegenerative and non-neurodegenerative diseases equally prevalent. Recognizing treatable conditions like autoimmune encephalitis and neurosyphilis requires careful consideration and differentiation.

Muyocoxanthones O-S: Undescribed xanthones with antioxidative damage bioactivity to cardiomyocytes from the endophytic fungus Muyocopron laterale.

The metabolites from the endophytic fungus Muyocopron laterale hosted in the medicinal plant Tylophora ovata were investigated, and five undescribed xanthones, muyocoxanthones O-S, along with seven known compounds were isolated. Their structures were elucidated by HR-ESI-MS, NMR, and ECD calculations. Compounds were evaluated for their anti-cardiomyocyte oxidative damage activity using a model of oxidative damage induced by cell hypoxia incubation. Muyocoxanthones O-Q and blennolide L exhibited moderate activity against oxidative damage to cardiomyocytes with relative viabilities of 62.4, 54.8, 60.3 and 54.9%, respectively.

Genome-wide association study of brain tau deposition as measured by 18F-flortaucipir positron emission tomography imaging.

The related genetic variants of tau deposition, a seminal pathological hallmark of Alzheimer's disease, remain poorly understood. We sought to perform a genome-wide association study of brain tau load as measured by AV1451 positron emission tomography (PET). Among 543 non-demented European individuals, novel associations with higher tau were identified for rs56298435 (p = 8.35 × 10-10, ß=0.31) within ZBTB20, and for rs150532 (p = 1.90 × 10-8, ß=0.26) in the protein phosphorylation regulatory gene EYA4. The APOE association additionally reached genome-wide significant when APOE ε4 was not adjusted. Minor allele carriers of rs56298435 or rs150532 showed higher levels of tau PET load. As expected, phosphorylated-tau analyses in both plasma and cerebrospinal fluid also revealed the same direction of effect. Functionally, the effects of novel loci on cognitive decline could be mediated by tau pathology. In addition, we observed that the expression of VNN2 as regulated by rs150532, together with EYA4, displayed significant correlations with the tau-related gene MAPT in numerous brain regions. Our novel finding lends additional credence to heritable underpinnings of tau deposition.

Undescribed meleagrin alkaloids from the endophytic fungus Penicillium commune.

Six undescribed meleagrin analogues, isomeleagrin, meleagrin F, meleagrin G, methylmeleagrin G, isomethylmeleagrin G and meleagrin H, were isolated from the endophytic fungus Penicillium commune, which was obtained from the fresh leaves of a toxic medicinal plant, Tylophora ovata. The structures of these analogues were elucidated through extensive spectroscopic data analysis, and their absolute configurations were characterized by calculated electronic circular dichroism (ECD). Structurally, meleagrin F features an undescribed skeleton with an aniline moiety, which is linked to meleagrin through a C-C bond at C8-C26. Connecting N19-C3' through the C-N bond in meleagrin G, methylmeleagrin G, isomethylmeleagrin G and meleagrin H was rare for amino acid condensation. The cytotoxicity activity of these undescribed compounds was evaluated, and isomeleagrin exhibited a selective cytotoxicity activity against HGC27 cells with an IC50 value of 2.01 µM.

Investigating Causal Relations Between Circulating Metabolites and Alzheimer's Disease: A Mendelian Randomization Study.

BACKGROUND: Metabolomics is a promising approach that can be used to understand pathophysiological pathways of Alzheimer's disease (AD). However, the causal relationships between metabolism and AD are poorly understood. OBJECTIVE: We aimed to investigate the causal association between circulating metabolites and risk of AD through two-sample Mendelian randomization (MR) approach. METHODS: Genetic associations with 123 circulating metabolic traits were utilized as exposures. Summary statistics data from International Genomics of Alzheimer's Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was performed using family history of AD data from UK Biobank (27,696 cases of maternal AD, 14,338 cases of paternal AD, and 272,244 controls). We utilized inverse-variance weighted method as primary method. RESULTS: We found significantly increased risks of developing AD per standard deviation increase in the levels of circulating ApoB (odd ratio[OR] = 3.18; 95% confidence interval[CI]: 1.52-6.66, p = 0.0022), glycoprotein acetyls (OR = 1.21; 95% CI: 1.05-1.39, p = 0.0093), total cholesterol (OR = 2.73; 95% CI: 1.41-5.30, p = 0.0030), and low-density lipoprotein (LDL) cholesterol (OR = 2.34; 95% CI: 1.53-3.57, p = 0.0001). Whereas glutamine (OR = 0.81; 95% CI: 0.71-0.92, p = 0.0011) were significantly associated with lower risk of AD. We also detected causal effects of several different composition of LDL fractions on increased AD risk, which has been verified in validation. However, we found no association between circulating high-density lipoprotein cholesterol and AD. CONCLUSION: Our findings suggest causal effects of circulating glycoprotein acetyls, ApoB, LDL cholesterol, and serum total cholesterol on higher risk of AD, whereas glutamine showed the protective effect.

Very Early-Onset Alzheimer's Disease in the Third Decade of Life with de novo PSEN1 Mutations.

Mutations in Presenilin-1 (PSEN1) have been found to be associated with very early onset Alzheimer's disease (VEOAD). Here, we reported two patients with VEOAD caused by de novo PSEN1 mutations. A 33-year-old man with a de novo p.F177S mutation in PSEN1 presented with progressive decline in memory and daily function. A 37-year-old woman with a de novo PSEN1 p.L381V mutation presented with onset memory impairment, developed cerebellar syndrome, rigidity, and spastic paraparesis. The Amyloid/Tau/Neurodegeneration (ATN) biomarker profiles of both patients were A + T + (N)+. Our finding increases the genetic knowledge of VEOAD and extends the ethnic distribution of PSEN1 mutations.

Testing a Family Supportive End of Life Care Intervention in a Chinese Neonatal Intensive Care Unit: A Quasi-experimental Study With a Non-randomized Controlled Trial Design.

Background: Neonatal death often occurs in tertiary Neonatal Intensive Care Units (NICUs). In China, end-of-life-care (EOLC) does not always involve parents. Aim: The aim of this study is to evaluate a parent support intervention to integrate parents at the end of life of their infant in the NICU. Methods: A quasi-experimental study using a non-randomized clinical trial design was conducted between May 2020 and September 2021. Participants were infants in an EOLC pathway in the NICU and their parents. Parents were allocated into a family supportive EOLC intervention group or a standard EOLC group based on their wishes. The primary outcomes depression (Edinburgh Postnatal Depression Scale for mothers; Hamilton Depression rating scale for fathers) and Satisfaction with Care were measured 1 week after infants' death. Student t-test for continuous variables and the Chi-square test categorical variables were used in the statistical analysis. Results: In the study period, 62 infants died and 45 infants and 90 parents were enrolled; intervention group 20 infants, standard EOLC group 25 infants. The most common causes of death in both groups were congenital abnormalities (n = 20, 44%). Mean gestational age of infants between the family supportive EOLC group and standard EOLC group was 31.45 vs. 33.8 weeks (p = 0.234). Parents between both groups did not differ in terms of age, delivery of infant, and economic status. In the family support group, higher education levels were observed among mother (p = 0.026) and fathers (p = 0.020). Both mothers and fathers in the family supportive EOLC group had less depression compared to the standard EOLC groups; mothers (mean 6.90 vs. 7.56; p = 0.017) and fathers (mean 20.7 vs. 23.1; p < 0.001). Parents reported higher satisfaction in the family supportive EOLC group (mean 88.9 vs. 86.6; p < 0.001). Conclusions: Supporting parents in EOLC in Chinese NICUs might decreased their depression and increase satisfaction after the death of their infant. Future research needs to focus on long-term effects and expand on larger populations with different cultural backgrounds. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT05270915.

Whole-Exome Sequencing Identified a Novel Mutation in RNF216 in a Family with Gordon Holmes Syndrome.

Gordon Holmes syndrome (GHS) is a rare disease characterized by hypogonadotropic hypogonadism (HH), progressive cognitive decline and variable movement disorders. Mutations in RNF216 have been found to be associated with GHS. Here, we identify a novel homozygous RNF216 p.E650X mutation causing GHS. The proband presented with onset dysarthria and developed cerebellar ataxia and cognitive impairment, with a history of azoospermia at the age of 28 years. Cerebellar atrophy and white matter lesions were found in the cerebral hemispheres and brainstem. Low gonadotropin serum levels were also observed. Whole-exome sequencing (WES) revealed a novel homozygous nonsense variant in RNF216, c.1948G>T; p.E650X. Our finding furthers the genetic knowledge of GHS and extends the ethnic distribution of RNF216 mutations.

Serum Uric Acid Levels in Neurodegenerative Disorders: A Cross-Sectional Study.

BACKGROUND: Excessive oxidative stress may contribute to neurodegeneration by leading to protein aggregation and mitochondrial dysfunction. Uric acid (UA) is an important endogenous antioxidant that protects against oxidative stress, yet its exact role in neurodegeneration remains unclear. OBJECTIVE: To explore the performance of serum UA in neurodegenerative disorders. METHODS: A total of 839 controls and 840 patients, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), motor neuron disease (MND), Creutzfeldt-Jakob disease (CJD), and mixed dementia (MixD) were enrolled. Fasting serum UA levels were measured in all participants and compared between patients and controls. Linear regression models were utilized to explore possible relationships of serum UA with cognition, disease duration, age, and age of onset. RESULTS: Compared to controls (355.48 ±â€Š85.38 µmol/L), serum UA was significantly lower in AD (291.29 ±â€Š83.49 µmol/L, p < 0.001), PD (286.95 ±â€Š81.78 µmol/L, p < 0.001), PSP (313.32 ±â€Š88.19 µmol/L, p < 0.001), FTD (313.89 ±â€Š71.18 µmol/L, p = 0.001), and DLB (279.23 ±â€Š65.51 µmol/L, p < 0.001), adjusting for confounding factors including age, gender, education, etc. In addition, serum UA was positively correlated with cognitive levels in all patients (Mini-Mental State Examination: r = 0.136, p = 0.001; and Montreal Cognitive Assessment Scale: r = 0.108, p = 0.009). CONCLUSION: Decreased levels of serum UA were correlated with AD, PD, PSP, FTD, and DLB, offering significant potential as a promisingly relevant, less-invasive marker of multiple neurodegenerative disorders.

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.

Mild behavioral impairment correlates of cognitive impairments in older adults without dementia: mediation by amyloid pathology.

The relationship between mild behavioral impairment (MBI) and Alzheimer's disease (AD) is intricate and still not well investigated. The purpose of the study is to examine the roles of the AD imaging pathologies in modulating the associations of MBI with cognitive impairments. We analyzed 1129 participants (563 [49.86%] female), who had measures of Neuropsychiatric Inventory Questionnaire (NPI-Q), cognition, and amyloid PET AD biomarkers from the Alzheimer's disease Neuroimaging Initiative (ADNI). We assess the longitudinal neuropathological and clinical correlates of baseline MBI via linear mixed effects and Cox proportional hazard models. The mediation analyses were used to test the mediation effects of AD pathologies on cognition. We found that MBI was associated with worse global cognition as represented by Mini-Mental State Examination (MMSE) (p < 0.001), and higher ß-amyloid burden (p < 0.001). ß-amyloid partially mediated the effects of MBI on cognition with the mediation percentage varied from 14.67 to 40.86% for general cognition, memory, executive, and language functions for non-dementia individuals. However, no significant associations were discovered between MBI and tau burden or neurodegeneration. Furthermore, longitudinal analyses revealed that individuals with MBI had a faster increase in brain amyloid burden (p < 0.001) and a higher risk of clinical conversion (HR = 2.42, 95% CI = 1.45 to 4.01 p < 0.001). In conclusion, MBI could be an imperative prediction indicator of clinical and pathological progression. In addition, amyloid pathologies might partially mediate the influences of MBI on cognitive impairments and AD risk.