Erythrocyte sphingolipid species as biomarkers of Alzheimer's disease

Diagnosing Alzheimer’s disease(AD)in the early stage is challenging.Informative biomarkers can be of great value for population-based screening.Metabolomics studies have been used to find potential biomarkers,but commonly used tissue sources can be difficult to obtain.The objective of this study was to determine the potential utility of erythrocyte metabolite profiles in screening for AD.Unlike some commonly-used sources such as cerebrospinal fluid and brain tissue,erythrocytes are plentiful and easily accessed.Moreover,erythrocytes are metabolically active,a feature that distinguishes this sample source from other bodily fluids like plasma and urine.In this preliminary pilot study,the erythrocyte metabolomes of 10 histopathologically confirmed AD patients and 10 patients without AD(control(CTRL))were compared.Whole blood was collected post-mortem and erythrocytes were analyzed using ultraperformance liquid chromatography tandem mass spectrometry.Over 750 metabolites were identified in AD and CTRL erythrocytes.Seven were increased in AD while 24 were decreased(P<0.05).The majority of the metabolites increased in AD were associated with amino acid metabolism and all of the decreased metabolites were associated with lipid metabolism.Prominent among the potential biomarkers were 10 sphingolipid or sphingolipid-related species that were consistently decreased in AD patients.Sphingolipids have been previously implicated in AD and other neurological conditions.Furthermore,previous studies have shown that erythrocyte sphingolipid concentrations vary widely in normal,healthy adults.Together,these observations suggest that certain erythrocyte lipid phenotypes could be markers of risk for development of AD.

多奈哌齐治疗重度阿尔茨海默病患者:双盲、平行分组、安慰剂对照研究

Background: The cholinesterase inhibitor donepezil is used to treat mild-to-moderate Alzheimer’s disease. Its efficacy in severe dementia has not been assessed and is controversial. Our aim was to ascertain the effectiveness of donepezil in patients with severe Alzheimer’s disease, by focusing primarily on cognition and activities of daily living. Methods: We did a 6-month, double-blind, parallel-group, placebo-controlled study in 248 patients with severe Alzheimer‘s disease (mini mental state examination score 1-10) who were living in assisted care nursing homes ran by trained staff in Sweden. We assigned patients oral donepezil (5 mg per day for 30 days then up to 10 mg per day thereafter, n=128) or matched placebo (n=120). Our primary endpoints were change from baseline to month 6 in the severe impairment battery (SIB) and modified Alzheimer’s Disease Cooperative Study activities of daily living inventory for severe Alzheimer’s disease (ADCS-ADL-severe). We analysed outcomes for patients with data at baseline and at one or more other timepoints (modified intent-to-treat population) with last observation carried forward used to replace missing data. Findings: 95 patients assigned donepezil and 99 patients assigned placebo completed the study. Patients treated with donepezil improved more in SIB scores and declined less in ADCS-ADL-severe scores at 6 months after initiation of treatment compared with baseline than did controls (least squares [LS] mean difference, 5.7, 95%CI 1.5-9.8; p=0.008, and 1.7, 0.2-3.2; p=0.03, respectively). The incidence of adverse events was comparable between groups (donepezil 82%[n=105] vs placebo 76%[n=91]), with most being transient and mild or moderate in severity. More patients discontinued treatment because of adverse events in the donepezil group (n=20) than in the placebo group (n=8). Interpretation: Donepezil improves cognition and preserves function in individuals with severe Alzheimer’s disease who live in nursing homes.

阿尔茨海默病和痴呆的临床前期预测指标:一项临床病理学研究

Background: To understand the earliest signs of cognitive decline caused by Alzheimer disease (AD) and other illnesses causing dementia, information is needed from well-characterized individuals without dementia studied longitudinally until autopsy. Objective: To determine clinical and cognitive features associated with the development of AD or other dementias in older adults. Design: Longitudinal study of memory and aging. Setting: Alzheimer’s Disease Research Center, St Louis, Mo. Main Outcome Measures: Clinical Dementia Rating, its sum of boxes, and neuropathologic diagnosis of dementia. Participants: Eighty control participants who eventually came to autopsy. Results: Individuals who did not develop dementia showed stable cognitive performance. Entry predictors of dementia were age, deficits in problem solving as well as memory, slowed psychomotor performance, and depressive features. Minimal cognitive decline occurred prior to dementia diagnosis, after which sharp decline was noted. Even individuals who were minimally cognitively impaired (Clinical Dementia Rating=0.5) typically had neuropathologic AD at autopsy. Histopathologic AD also was present in 34%of individuals who did not have dementia at death; these individuals without dementia showed an absence of practice effects on cognitive testing. Conclusions: Increased age, depressive features, and even minimal cognitive impairment, as determined clinically by Clinical Dementia Rating sum of boxes and by slowed psychomotor performance, identify older individuals with out dementia who develop dementia. Older adults who do not develop dementia ha ve stable cognitive performance. The absence of practice effects may denote the subset of older adults without dementia with histopathologic AD, which may refle ct a preclinical stage of the illness.