脑脊液磷酸化tau蛋白的检测对阿尔茨海默病的诊断价值

目的通过对阿尔茨海默病(AD)患者脑脊液磷酸化tau蛋白检测的研究,探讨其对AD的诊断价值。方法采用ELISA法检测11例AD患者(AD组)、13例血管性痴呆患者(血管性痴呆组)及29例非神经系统疾病患者(正常对照组)的脑脊液磷酸化tau蛋白。结果与血管性痴呆组和正常对照组比较,AD组患者脑脊液中磷酸化tau蛋白含量明显增高(P<0.05)。血管性痴呆组患者脑脊液中磷酸化tau蛋白水平与正常对照组比较无明显差异(P>0.05)。结论检测脑脊液磷酸化tau蛋白含量可作为AD诊断的辅助指标。     

阿尔茨海默病和帕金森痴呆患者脑脊液中tau蛋白和β淀粉样蛋白水平的研究

目的探讨在阿尔茨海默病(AD)和帕金森痴呆(PDD)患者脑脊液(CSF)中tau蛋白和β淀粉样蛋白(Aβ1-42)的水平及临床意义。方法同时将符合美国国立神经病、语言障碍和脑卒中研究所-老年性痴呆及相关性疾病协会的“很可能AD”标准的22例AD组患者与20例PDD组患者和21例性别、年龄相匹配的无中枢神经系统疾患、无痴呆表现的心理疾病患者作为对照组(NC组)进行研究。结果3组CSF中tau蛋白平均浓度比较,AD组明显高于NC组(P<0.05);AD组与PDD组差异无显著性意义(P>0.05)。3组CSF中A1β-42平均浓度比较,AD组明显低于NC组(P<0.05),PDD组与NC组差异无显著性意义(P>0.05)。结论AD患者CSF中tau蛋白和Aβ1-42浓度变化是其重要的实验室表现,可以作为AD的辅助诊断指标和与PDD早期鉴别诊断的可能生物学指标。     

Neurofilament light chain in cerebrospinal fluid or blood as a biomarker for mild cognitive impairment: A systematic review and meta-analysis

Background:To allow early diagnosis and monitoring of disease progression, there is a need for biomarkers in mild cognitive impairment (MCI). Neurofilament light chain (NfL) is emerging protein biomarkers in neurodegenerative diseases and is of possible use in MCI. We aimed to assess the utility of NfL in blood and cerebrospinal fluid (CSF) as a biomarker in patients with MCI.Methods:A systematic search with comparison of NfL level between individuals with MCI and healthy controls were retrieved from PubMed, Embase, and Web of Science. The standard mean difference and 95% confidence interval were calculated using the random-effect model to analyze the differentiation of NfL between patients and controls.Results:A total of 7 studies were included. NfL was higher in 676 MCI than 504 healthy controls. Subgroup analysis according to sample type indicated that differentiation of NfL in CSF between patients with MCI and controls showed significant results but in blood. Moreover, the NfL increasing still existed when the NfL expression level was detected by enzyme-linked immunosorbent assay but single molecule array assay. However, no difference of NfL in MCI between Caucasian and Asian was found.Conclusions:NfL expression level in CSF was increased in MCI individuals, which indicated that NfL in CSF could be a potential biomarker of MCI.     

Long-term cognitive benefits of donepezil in Alzheimer's disease: A retrospective comparison between 1994–1999 and 2000–2004

Objective:   In order to address an issue of how long Alzheimer's disease (AD) patients should receive donepezil, we estimated long-term effect of donepezil on cognition as well as its influential factors. We also evaluated the additional effect of cerebrospinal fluid (CSF)-tau protein levels on diagnosis.
Methods:   We compared cognitive changes between current (2000–2004) AD patients (donepezil users) and previous AD patients, seen by us 1994–1999, without receiving donepezil (non-donepezil users) by a mixed effect model. Cognition was assessed by Mini-Mental State Examination (MMSE) at 6-month intervals up to 24 months. Sensitivity analysis was performed exclusively on patients with high CSF-tau protein levels (CSF-tau >330 pg/mL) to minimize inaccuracies of the diagnosis
Results:   From 495 AD patients reviewed, 192 patients (120 donepezil users and 72 controls) were eligible. Estimated annual decline of MMSE was 1.2 points (95% confidence interval (95%CI), 0.9–1.5) in the donepezil users, whereas it was 2.8 points (95%CI, 2.1–3.6) in the control group. The difference was statistically significant ( P  < 0.001). The sensitivity analysis demonstrated that these declines were 1.2 (95%CI, 0.8–1.6) and 3.1 (95%CI, 2.3–3.9) points in the donepezil users and control groups, respectively.
Conclusions:   Long-term donepezil use for at least 2 years appeared to be beneficial in maintaining cognition in AD patients. As the cholinergic central nervous system consistently degenerates over time, long-term use of donepezil may be an appropriate therapy. Discontinuation of donepezil may not be recommended as far as patients are in a stable condition.     

安理申治疗阿尔茨海默病和轻度认知功能障碍的疗效观察

目的评估安理申治疗轻、中度阿尔茨海默病(Alzheimer's disease,AD)和轻度认知功能障碍(mildcognitive impairment,MCI)的疗效。方法采用配对双盲法进行。42例AD和32例MCI患者入组,其中37例用安理申片5mg,每晚1次;另37例用吡拉西坦片800mg,3次/d,疗程均为12周。结果安理申组总有效率70%,吡拉西坦组为40%,差异有统计学意义(P<0.01)。安理申组AD患者简易智能状态量表(MMSE)及日常生活功能水平量表(FAQ)分数较治疗前明显改善(P<0.05、P<0.01);安理申不良反应轻。结论安理申治疗AD和MCI安全有效。     

Antiaging medicine and mild cognitive impairment: practice and policy issues for geriatrics

The claim that aging itself is treatable or even preventable has repeatedly been made over the centuries. Antiaging medicine is the current leader of approaches that even claim that geriatrics as a discipline will become increasingly unnecessary. The concept of mild cognitive impairment (MCI) as a condition intermediate between normal cognitive aging and Alzheimer's disease highlights the conceptual and practical difficulty of differentiating aging from disease. What should geriatricians and their organizations make of scientifically mainstream attempts to decelerate, arrest, or compress aspects of the normal human aging, including the brain aging process? This article reviews the political, philosophical, practice‐related, and economical implications of antiaging medicine for geriatrics using MCI as a practical example. It concludes by suggesting actions that geriatricians should consider to strengthen their profession and to improve patient care in response to the challenges of longevity medicine.     

Current status of metals as therapeutic targets in Alzheimer's disease

There is accumulating evidence that interactions between beta-amyloid and copper, iron, and zinc are associated with the pathophysiology of Alzheimer's disease (AD). A significant dyshomeostasis of copper, iron, and zinc has been detected, and the mismanagement of these metals induces beta-amyloid precipitation and neurotoxicity. Chelating agents offer a potential therapeutic solution to the neurotoxicity induced by copper and iron dyshomeostasis. Currently, the copper and zinc chelating agent clioquinol represents a potential therapeutic route that may not only inhibit beta-amyloid neurotoxicity, but may also reverse the accumulation of neocortical beta-amyloid. A Phase II double-blind clinical trial of clioquinol with B12 supplementation will be published soon, and the results are promising. This article summarizes the role of transition metals in amyloidgenesis and reviews the potential promise of chelation therapy as a treatment for AD.     

MRI and CSF studies in the early diagnosis of Alzheimer's disease

The main goal of our studies has been to use MRI, FDG-PET, and CSF biomarkers to identify in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI), the earliest clinically detectable evidence for brain changes due to Alzheimer's disease (AD). A second goal has been to describe the cross-sectional and longitudinal interrelationships amongst anatomical, CSF and cognition measures in these patient groups. It is now well known that MRI-determined hippocampal atrophy predicts the conversion from MCI to AD. In our summarized studies, we show that the conversion of NL subjects to MCI can also be predicted by reduced entorhinal cortex (EC) glucose metabolism, and by the rate of medial temporal lobe atrophy as determined by a semi-automated regional boundary shift analysis (BSA-R). However, whilst atrophy rates are predictive under research conditions, they are not specific for AD and cannot be used as primary evidence for AD. Consequently, we will also review our effort to improve the diagnostic specificity by evaluating the use of CSF biomarkers and to evaluate their performance in combination with neuroimaging. Neuropathology studies of normal ageing and MCI identify the hippocampal formation as an early locus of neuronal damage, tau protein pathology, elevated isoprostane levels, and deposition of amyloid beta 1-42 (Abeta42). Many CSF studies of MCI and AD report elevated T-tau levels (a marker of neuronal damage) and reduced Abeta42 levels (possibly due to increased plaque sequestration). However, CSF T-tau and Abeta42 level elevations may not be specific to AD. Elevated isoprostane levels are also reported in AD and MCI but these too are not specific for AD. Importantly, it has been recently observed that CSF levels of P-tau, tau hyperphosphorylated at threonine 231 (P-tau231) are uniquely elevated in AD and elevations found in MCI are useful in predicting the conversion to AD. In our current MCI studies, we are examining the hypothesis that elevations in P-tau231 are accurate and specific indicators of AD-related changes in brain and cognition. In cross-section and longitudinally, our results show that evaluations of the P-tau231 level are highly correlated with reductions in the MRI hippocampal volume and by using CSF and MRI measures together one improves the separation of NL and MCI. The data suggests that by combining MRI and CSF measures, an early (sensitive) and more specific diagnosis of AD is at hand. Numerous studies show that neither T-tau nor P-tauX (X refers to all hyper-phosphorylation site assays) levels are sensitive to the longitudinal progression of AD. The explanation for the failure to observe longitudinal changes is not known. One possibility is that brain-derived proteins are diluted in the CSF compartment. We recently used MRI to estimate ventricular CSF volume and demonstrated that an MRI-based adjustment for CSF volume dilution enables detection of a diagnostically useful longitudinal P-tau231 elevation. Curiously, our most recent data show that the CSF isoprostane level does show significant longitudinal elevations in MCI in the absence of dilution correction. In summary, we conclude that the combined use of MRI and CSF incrementally contributes to the early diagnosis of AD and to monitor the course of AD. The interim results also suggest that a panel of CSF biomarkers can provide measures both sensitive to longitudinal change as well as measures that lend specificity to the AD diagnosis.     

Long-term effects of melatonin or 17 beta-estradiol on improving spatial memory performance in cognitively impaired, ovariectomized adult rats

Melatonin is an endogenously generated potent antioxidant. Our previous studies indicate that melatonin improved learning and memory deficits in APP695 transgenic mouse of Alzheimer's disease. An ovariectomized (OVX) rat model which is characterized by progressive memory deficits, central cholinergic nerve system degeneration and differentiation/apoptosis imbalance is the ideal in vivo model in which to test the neuroprotective effects of melatonin. OVX Sprague-Dawley rats received daily injections of melatonin (5, 10 and 20 mg/kg) or 17 beta-estradiol (E2, 80 microg/kg) or sesame oil for 16 wk. Morris water maze results showed that ovarian steroid deprivation resulted in spatial memory impairment, while melatonin and E2 significantly ameliorated spatial memory deficits in OVX rats. The latency to find the hidden platform and the distance to reach the platform become shorter in both melatonin and E2-treated rats compared with those that were only OVX. Four months after OVX, the choline acetyltransferase activity in the frontal cortex and hippocampus were greatly decreased in comparison with the controls. Melatonin and E2 antagonized the effects induced by OVX. Interestingly, the activity of the acetylcholinesterase was not altered in any group of rats. DNA fragmentation was presented in the front cortex of the OVX rats. Melatonin and E2 reduced the number of apoptotic neurons. These findings demonstrate the important effects of melatonin and E2 on cholinergic neurons and support the potential application of melatonin in the treatment of dementia in postmenopausal women. Our results indicate that neuroprotection by melatonin partly correlated to modulation of apoptosis and protection of the cholinergic system. Early long-term melatonin application is a promising strategy which could potentially be applied in a clinic setting.     

蒙特利尔认知评估量表用于轻度认知功能障碍患者评估的初步研究

目的探讨中文版蒙特利尔认知评估量表(Montreal cognitive assessment scale,MoCA)用于轻度认知功能障碍(mild cognitive impairment,MCI)评估的可行性。方法选择MCI患者128例(MCI组),另选同期健康体检者101例(对照组)。分别给予MoCA和简易智能状态检查量表(MMSE)评估,并分析评估结果。结果对照组和MCI组MoCA总分与MMSE总分呈正相关(r=0.352,P<0.05;r=0.765,P<0.01);MoCA评分明显低于MMSE评分(P<0.01)。与对照组比较,MCI组MoCA总分及各亚项得分明显降低(P<0.01)。MoCA筛查MCI敏感性为97.66%,特异性为95.05%,MMSE筛查MCI敏感性为32.03%,特异性为100%。结论 MCI患者及健康体检人群MoCA总分与MMSE总分相关;MoCA用于MCI筛查时敏感性优于MMSE。     

老年人轻度认知损害危险因素的调查分析

目的 调查北京老年人轻度认知损害(MCD)与年龄、性别、体质指数等的关系.方法 应用简易精神状态检查,对北京东直门社区招募的129例老年人进行认知功能评估.结果 检出记忆型轻度认知损害(aMCI)37例(28.7%),阿尔茨海默病(AD)36例(27.9%),认知正常者56例(43.4%).aMCI和AD患者年龄高于认知正常者,分别为(67.6±7.5)岁、(66.6±8.2)岁和(62.5±7.9)岁,两两比较差异均有统计学意义(t值分别为2.847、-1.747和-2.429,P>0.05、P<0.01和P<0.01);aMCI和AD患者受教育年限低(P<0.05);aMCI和AD患者的血压较认知正常者高(P<0.05);aMCI体质指数高于其他两组(P<0.05),不同性别老年人aMCI和AD患病率差异无统计学意义(P>0.05);不同月份出生aMCI和AD患病率差异无统计学意义(P>0.05).结论 aMCI患病率与年龄、教育程度、高血压和体质指数等因素有关,与性别、出生月份无关.     

Methods to improve the detection of mild cognitive impairment

We examined whether the performance of the National Institute of Aging's Consortium to Establish a Registry for Alzheimer's Disease's 10-word list (CWL), part of the consortium's neuropsychological battery, can be improved for detecting Alzheimer's disease and related disorders early. We focused on mild cognitive impairment (MCI) and mild dementia because these stages often go undetected, and their detection is important for treatment. Using standardized diagnostic criteria combined with history, physical examination, and cognitive, laboratory, and neuroimaging studies, we staged 471 community-dwelling subjects for dementia severity by using the Clinical Dementia Rating Scale. We then used correspondence analysis (CA) to derive a weighted score for each subject from their item responses over the three immediate- and one delayed-recall trials of the CWL. These CA-weighted scores were used with logistic regression to predict each subject's probability of impairment, and receiver operating characteristic analysis was used to measure accuracy. For MCI vs. normal, accuracy was 97% [confidence interval (C.I.) 97-98%], sensitivity was 94% (C.I. 93-95%), and specificity was 89% (C.I. 88-91%). For MCI/mild dementia vs. normal, accuracy was 98% (C.I. 98-99%), sensitivity was 96% (C.I. 95-97%), and specificity was 91% (C.I. 89-93%). MCI sensitivity was 12% higher (without lowering specificity) than that obtained with the delayed-recall total score (the standard method for CWL interpretation). Optimal positive and negative predictive values were 100% and at least 96.6%. These results show that CA-weighted scores can significantly improve early detection of Alzheimer's disease and related disorders.     

早发和晚发遗忘型轻度认知损害与阿尔茨海默病的神经心理学比较研究

目的:比较早发性与晚发性阿尔茨海默病(AD)、早发性和晚发性遗忘型轻度认知损害(aMCI)的神经心理学表现。方法:记忆障碍门诊患者根据首诊年龄分组,70岁为晚发组。接受简明精神状态量表(MMSE)、听觉词语学习测验(AVMT)、逻辑记忆测验(LM)、斯特鲁普(Stroop)色词测验(CWT)、Rey-Osterrich复杂图形测验(CFT)、言语流畅性测验(VFT)、连线测验(TMT)、画钟测验(CDT)等。结果:共257例患者,分为4组,分别为早发AD34例,晚发AD78例,早发aMCI58例,晚发aMCI87例;早发、晚发AD间大部分神经心理学表现相似;早发aMCI患者在大部分测验上的表现优于晚发患者,听觉词语延迟回忆、言语流畅性、TMTB耗时等项目的差异最为显著(P<0.01)。晚发aMCI患者逻辑记忆即刻、延迟回忆更佳。结论:早发与晚发AD认知损害较为相似,晚发aMCI患者的认知损害较早发aMCI患者更为弥漫。     

Melatonin alleviates behavioral deficits associated with apoptosis and cholinergic system dysfunction in the APP 695 transgenic mouse model of Alzheimer's disease

Melatonin is an endogenous antioxidant and free radical scavenger. A transgenic (Tg) mouse model for Alzheimer's disease mimics the accumulation of senile plaques, neuronal apoptosis and memory impairment. Previous studies indicated that melatonin reduced beta-amyloid (Abeta)-induced neurotoxicity. In this study, after giving melatonin at 10 mg/kg to APP 695 transgenic (APP 695 Tg) mice for 4 months, we evaluated the long-term influence of melatonin on behavior, biochemical and neuropathologic changes in APP 695 Tg mice. Step-down and step-through passive avoidance tests suggested that 8-month-old APP 695 Tg mice showed decreases in step-down latency and step-through latency and increases in count of error throughout the entire learning trial and memory session, which suggested learning and memory impairment. However, melatonin alleviated learning and memory deficits. Additionally, choline acetyltransferase (ChAT) activity also decreased in the frontal cortex and hippocampus of APP 695 Tg mice compared with non-Tg littermates. Melatonin supplementation increased ChAT activity in the frontal cortex and hippocampus. DNA fragmentation was present in the frontal cortex of the APP 695 Tg mice; melatonin reduced the number of apoptotic neurons. Congo Red staining and Bielschowsky silver impregnation both showed the apparent extracellular Abeta deposition in frontal cortex of APP 695 Tg mice. However, melatonin decreased the Abeta deposits. Our results indicate that neuroprotection by melatonin is partly related to modulation of apoptosis and protection of the cholinergic system. Early rational melatonin interventions may be one of the most promising strategies in the development of approaches to retard or prevent Abeta-mediated disease progression.     

Possible therapeutic value of melatonin in mild cognitive impairment: a retrospective study

Mild cognitive impairment (MCI) is an etiologically heterogeneous syndrome characterized by cognitive impairment preceding dementia. Approximately 12% of MCI patients convert to Alzheimer's disease (AD) or other dementia disorders every year. In the present report we retrospectively examined the initial and final neuropsychological assessment of 50 MCI outpatients, 25 of whom had received daily 3-9 mg of a fast-release melatonin preparation p.o. at bedtime for 9-18 months. Melatonin was given in addition to the standard medication prescribed by the attending psychiatrist. Patients treated with melatonin showed significantly better performance in Mini Mental State Examination and the cognitive subscale of the Alzheimer's Disease Assessment Scale. After application of a battery of neuropsychological tests including Mattis' test, Digit-symbol test, Trail A and B tasks and the Rey's verbal test, better performance was found in melatonin-treated patients, except for the Digit-symbol test score which remained unchanged. Abnormally high Beck Depression Inventory scores decreased in melatonin-treated patients, concomitantly with an improvement in wakefulness and sleep quality. The results suggest that melatonin can be a useful add-on drug for treating MCI in a clinical setting.     

QT dispersion and heart rate variability abnormalities in Alzheimer's disease and in mild cognitive impairment

OBJECTIVES: To investigate the effect of cardiovascular changes (i.e., QT interval, QT dispersion (QTD), heart rate variability (HRV), and other cardiovascular measures) in subjects with Alzheimer's disease (AD) and mild cognitive impairment (MCI). DESIGN: Each subject underwent clinical and cognitive examination, a structural brain imaging study, echocardioDoppler, electrocardiogram (ECG), HRV analysis using 24-hour ECG monitoring, and 24-hour blood pressure monitoring. SETTING: Community population-based sample of patients admitted to an AD center for investigation of cognitive disturbances. PARTICIPANTS: Thirty-three subjects with AD, 39 subjects with MCI, and 29 cognitive healthy subjects (controls) matched for demographic characteristics, hypertensive condition, smoking habits, and laboratory parameters were enrolled consecutively. MEASUREMENTS: Clinical and cognitive examination, structural brain imaging study, echocardioDoppler, ECG, HRV analysis using 24-hour ECG monitoring, and 24-hour blood pressure monitoring. RESULTS: QTD and QT corrected dispersion mean values were significantly higher in patients with AD than in patients with MCI and controls and higher in patients with MCI than in controls. HRV time and domain parameters were lower in patients with AD than in patients with MCI and controls. No difference in other cardiovascular measures was found. QTD and HRV were found to be significantly correlated with the degree of cognitive impairment. CONCLUSION: These findings support the presence of a peculiar neuroanatomic dysfunction in patients with AD and MCI that parallels the disease progression. These noninvasive parameters might prove to be powerful predictive tools in the worsening of cognitive function and mortality risk.     

从阿尔茨海默病新诊断指南看轻度认知功能损害概念的变化

阿尔茨海默病（AD）是以认知功能损害为突出表现的神经系统退变性疾病。轻度认知功能障碍（MCI）是认知功能低于同龄及文化背景的正常人但未达到痴呆程度的认知功能损害状态,被认为是痴呆、特别是AD的危险因素。临床及流行病学的研究表明MCI存在着异质性,有关MCI的概念及转归一直存在争论。随着对AD痴呆前阶段的关注,有必要了解MCI的含义及其变化。本文复习了MCI概念的提出、定义及其内容上发生的变化,并介绍了新的NIA—AD工作组AD诊断指南。