Follow-up investigations in cerebrospinal fluid of patients with dementia with Lewy bodies and Alzheimer’s disease

Summary. Measuring proteins in cerebrospinal fluid (CSF) has gained wide acceptance for the differential diagnosis of dementia. Some groups have already extended these investigations in Alzheimers disease (AD) by asking how stable these markers are in follow-up analysis, if they depend on the stage of disease and whether they can be used to monitor the progression and biological effects of treatment. We evaluated 21 patients with dementia with Lewy bodies (DLB) and 19 patients with AD, on two occasions, with regard to levels of tau protein, tau protein phosphorylated at threonine 181 (p-tau), A42, A40 and S-100B protein, using a set of commercially available assays.Tau protein levels were lower in DLB in first and second LP compared to AD and decreased during course of both groups. P-tau levels were increased in AD and DLB and decreased during follow-up. A42 and A40 remained relatively stable during follow-up but we found a slight increase of the median A42 level in DLB, whereas in AD, A42 tends to decrease during follow-up. S-100B protein increased during follow-up in both diseases.The protein dynamics in DLB and AD are relatively similar. S-100B protein may be a useful marker for follow-up in neurodegenerative diseases but has to be analysed in longer follow-up periods. Tau protein may be used to differentiate between DLB and AD.Follow-up CSF analyses are of limited value for the differentiation of AD and DLB. We conclude that more specific markers have to be established for the differentiation and follow-up of these diseases.     

甲基苯丙胺通过L型钙通道致皮层神经元病理性蛋白APP及p⁃Tau过表达

目的：探讨甲基苯丙胺（methamphetamine,METH）暴露引起的阿尔兹海默病（Alzheimer’s disease,AD）样改变,阐述L型钙通道在该病理样改变中的作用。方法：借助原代培养的神经元,利用Western blot法,观察METH（0、30、100、300、1 000 μmol/L）暴露后引起AD样病理性蛋白淀粉样蛋白前体（amyloid precursor protein,APP）、磷酸化Tau蛋白（p?Tau）的表达,并观察钙通道抑制剂硝苯地平作用后APP、p?Tau表达的改变。结果：APP和p?Tau的表达随METH作用浓度和时间的增加而增高,具有剂量和时间依赖性。钙通道抑制剂硝苯地平（nifedipine,NIF）预先孵育后,METH引起的AD样改变明显改善。结论：METH暴露可引起AD病理性改变,L型钙通道抑制剂可部分逆转上述改变,因而L型钙通道可能作为对METH作用的干预靶点,具有潜在的干预价值。     

Prophylactic neuroprotective efficiency of co-administration of Ginkgo biloba and Trifolium pretense against sodium arsenite-induced neurotoxicity and dementia in different regions of brain and spinal cord of rats

The present study was carried out to evaluate the potential protective role of co-administration of Ginkgo biloba, Trifolium pretenseagainst sodium arsenite-induced neurotoxicity in different parts of brain (Cerebral cortex, Hippocampus, striatum and Hind brain) and in the spinal cord of rats. Sodium arsenite caused impairment in the acquisition and learning in all the behavioral tasks and caused significant increase in tumor necrosis factor-α,thiobarbituric acid-reactive substances andlipid profile, while caused significant decrease in glutathione, total thiol content, total antioxidant capacity, acetylcholinesterase, monoamine oxidase and ATPases activities. These results were confirmed by histopathological, fluorescence and scanning electron microscopy examination of different regions of brain. From these results sodium arsenite-induced neurodegenerative disorder in different regions of brain and spinal cord and this could be mediated through modifying the intracellular brain ions homeostasis, cholinergic dysfunction and oxidative damage. The presence of Ginkgo biloba and/orTrifolium pretense with sodium arsenite minimized its neurological damages. It was pronounced that using Ginkgo biloba and Trifolium pretense in combination was more effective as protective agents compared to use eachone of them alone.     

Calcitonin gene-related peptide enhances CREB phosphorylation and attenuates tau protein phosphorylation in rat brain during focal cerebral ischemia/reperfusion

Calcitonin gene-related peptide (CGRP) is a potent vasodilator and immune cell modulator. Exogenous CGRP could increase the cerebral blood flow significantly and protect the ischemic neurons, but its mechanism is not entirely clear. The effect of CGRP on the expressions of CREB and tau in the ipsilateral parietal cortex were detected in focal cerebral ischemia/reperfusion model. The expression of CREB mRNA decreased in ischemia/reperfusion group (I/R group) compared with that of the sham operation group, and it got highest in CGRP group. CREB expression was lesser in I/R group than sham group, but it became more in CGRP group than I/R group. Phospho-CREB became more in I/R group, and it got most in CGRP group in the cortex. No significant difference was observed on Tau mRNA expression in all the groups. The level of tau hyperphosphorylation at Ser199/202 site and total tau in rat parietal cortex were significantly higher in I/R group than sham group. CGRP significantly inhibited tau hyperphosphorylation and the level of total tau also significantly reduced in CGRP group than that in I/R group. CGRP can upregulate the expression of CREB and phospho-CREB and attenuate the level of tau hyperphosphorylation in the ischemic neurons of the parietal cortex during focal cerebral ischemia/reperfusion. Phosphorylating CREB and inhibiting tau phosphorylation are probably involved in the mechanism of protective effect of CGRP to ischemic neurons.     

Biological Marker Candidates of Alzheimer's Disease in Blood, Plasma, and Serum

At the earliest clinical stages of Alzheimer's disease (AD), when first symptoms are mild, making a reliable and accurate diagnosis is difficult. AD related brain pathology and underlying molecular mechanisms precede symptoms. Biological markers can serve as supportive early screening and diagnostic tools as well as indicators of presymptomatic biochemical change. Moreover, biomarkers cover a variety of roles and functions such as disease prediction, indicating disease acuity and progression, and may ensure biological mapping of treatment outcome. Early screening, detection, and diagnosis of AD would permit earlier disease modifying intervention at potentially reversible stages. To date, most established biological markers from both cerebrospinal fluid neurochemistry and structural and functional neuroimaging have not reached widespread clinical application. Crucial remaining problems, such as easy acceptance and application of a test, cost-effectiveness, and noninvasiveness, need to be resolved. The development and validation of precise, reliable, and robust tests and biomarkers in blood, plasma, or serum has therefore been for a long time the ultimate focus of many research groups worldwide. Blood-based testing will most likely be the prerequisite to future sensitive screening of large populations at risk of AD and the baseline in a diagnostic flow approach to AD. The status and emerging perspectives on hypothesis and exploratory-based candidate biomarkers derived from blood, plasma, and serum are reviewed and discussed.     

Biomarkers for major depression and its delineation from neurodegenerative disorders

Major depressive disorders (MDD) are among the most debilitating diseases worldwide and occur with a high prevalence in elderly individuals. Neurodegenerative diseases (in particular Alzheimer's disease, AD) do also show a strong age-dependent increase in incidence and prevalence among the elderly population. A high number of geriatric patients with MDD show cognitive deficits and a very high proportion of AD patients present co-morbid MDD, which poses difficult diagnostic and prognostic questions. Especially in prodromal and in very early stages of AD, it is almost impossible to differentiate between pure MDD and MDD with underlying AD. Here, we give a comprehensive review of the literature on the current state of candidate biomarkers for MDD ("positive MDD markers") and briefly refer to established and validated diagnostic AD biomarkers in order to rule out underlying AD pathophysiology in elderly MDD subjects with cognitive impairments ("negative MDD biomarkers"). In summary, to date there is no evidence for positive diagnostic MDD biomarkers and the only way to delineate MDD from AD is to use "negative MDD" biomarkers. Because of this highly unsatisfactory current state of MDD biomarker research, we propose a research strategy targeting to detect and validate positive MDD biomarkers, which is based on a complex (genetic, molecular and neurophysiological) biological model that incorporates current state of the art knowledge on the pathobiology of MDD. This model delineates common pathways and the intersection between AD and MDD. Applying these concepts to MDD gives hope that positive MDD biomarkers can be successfully identified in the near future.     

甲基苯丙胺暴露对神经病理性蛋白APP及p-tau表达的影响

目的：观察甲基苯丙胺（methamphetamine,Meth）暴露后神经病理性蛋白β-淀粉样前体蛋白（amyloid precursor protein, APP）及p-tau表达的改变。方法：将30只C57BL/6J雄性小鼠随机分为对照组、生理盐水组,Meth组,Meth组腹腔注射给予10 mg/kg的剂量,1 d 2次,连续7 d。利用高尔基银染法观察Meth作用后大脑神经元数量及棘突的改变;采用Western blot法检测Meth暴露后神经病理性蛋白APP,p-tau表达的改变。结果：高尔基银染结果显示,Meth组与生理盐水组及对照组比较,神经元数量及棘突显著减少。通过Western blot发现Meth能剂量依赖及时间依赖性上调病理性蛋白β-APP及p-tau的表达,具有显著性差异（P<0.05）。此外,通过预孵L型钙通道的抑制剂硝苯地平,发现Meth引起的APP及p-tau上调显著被抑制。结论：Meth暴露可引起阿尔兹海默样病变,因而该研究可为Meth引起认知能力下降提供部分解释。     

新生大鼠HIBD后海马p-Tau蛋白与脑神经元凋亡表达变化

目的:观察微管相关蛋白磷酸Tau( p-tau)在缺氧缺血性脑损伤( HIBD)新生大鼠脑组织中的表达变化. 方法:将80只7日龄SD清洁级大鼠随机分为假手术组40 只和HIBD组(均按处死时间点分为3、6、12、24、48 小时5 个亚组)40只. 参照Rice法建立HIBD动物模型,假手术组仅暴露左颈总动脉,不作缺氧处理,2 组均于HIBD手术结束后3、6、12、24、48小时5个时间点断头取脑. 并分别取其脑组织切片,采用免疫组化S-P法检测其脑室周围白质区 p-tau 的表达,末端脱氧核苷酸转移酶缺口标志 ( TUNEL) 法检测其神经细胞凋亡. 结果:假手术组海马区有部分 p-tau蛋白表达及少量凋亡细胞, 各时间点无明显变化. HIBD组 p-tau的表达在3 小时后开始增加,12 小时达表达高峰后即开始呈下降趋势,与假手术组比较差异均有统计学意义 (F=95.67,p=0.000 <0.05) ;细胞凋亡在处理后3 小时即开始增加,至24小时小时达表达高峰,与假手术组比较差异均有统计学意义(F=18.829,p=0.001 <0.05). 结论:HIBD可造成新生大鼠海马区p-tau蛋白及神经元凋亡表达增加.     

Alzheimer's disease progression model based on integrated biomarkers and clinical measures

Aim:

Biomarkers and image markers of Alzheimer''s disease (AD), such as cerebrospinal fluid Aβ₄₂ and p-tau, are effective predictors of cognitive decline or dementia. The aim of this study was to integrate these markers with a disease progression model and to identify their abnormal ranges.

Methods:

The data of 395 participants, including 86 normal subjects, 108 early mild cognitive impairment (EMCI) subjects, 120 late mild cognitive impairment (LMCI) subjects, and 81 AD subjects were obtained from the Alzheimer''s Disease Neuroimaging Initiative (ADNI) database. For the participants, baseline and long-term data on cerebrospinal fluid Aβ₄₂ and p-tau, hippocampal volume, and ADAS-cog were available. Various linear and nonlinear models were tested to determine the associations among the ratio of Aβ₄₂ to p-tau (the Ratio), hippocampal volume and ADAS-cog.

Results:

The most likely models for the Ratio, hippocampal volume, and ADAS-cog (logistic, E_max, and linear models, respectively) were used to construct the final model. Baseline disease state had an impact on all the 3 endpoints (the Ratio, hippocampal volume, and ADAS-cog), while APOEε4 genotype and age only influence the Ratio and hippocampal volume.

Conclusion:

The Ratio can be used to identify the disease stage for an individual, and clinical measures integrated with the Ratio improve the accuracy of mild cognitive impairment (MCI) to AD conversion forecasting.     

电针调控p38MAPK通路降低AD大鼠海马磷酸化tau蛋白表达的研究

目的 通过测定海马内磷酸化p38MAPK和tau蛋白的表达,探讨针灸治疗阿尔茨海默病模型大鼠的作用机理。方法 实验动物采用海马内注射Aβ_1-40复制AD动物造模,分为正常组、假手术组、模型组和电针组。电针组取百会穴和双侧肾俞进行电针治疗。Morris水迷宫检测各组大鼠记忆能力,免疫组化、Western blot检测大鼠海马内p-p38MAPK和p-tau Thr181蛋白表达情况。结果 电针组大鼠学习记忆能力显著提高,有统计学意义（P<0.05）;模型组大鼠海马内p-p38MAPK和p-tau Thr181蛋白表达明显高于正常组,经电针治疗后表达显著减少,均有统计学意义（P<0.05）。结论 针灸治疗可调控p38MAPK通路,降低AD大鼠海马p-tau蛋白表达,改善学习记忆能力。